hazylavender/biorxiv-abstract · Datasets at Hugging Face

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10.1101/719013	Cell cycle variants during Drosophila accessory gland development	Box, A. M.; Ramesh, N. A.; Nandakumar, S.; Church, S. J.; Prasad, D.; Afrakhteh, A.; Taichman, R. S.; Buttitta, L.	Laura Buttitta	University of Michigan	2024-02-01T00:00:00	4	new results	cc_by_nc_nd	developmental biology	https://www.biorxiv.org/content/early/2024/02/01/719013.source.xml	The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate containing two secretory epithelial cell types, termed main and secondary cells. This tissue is responsible for making and secreting seminal fluid proteins and other molecules that contribute to successful reproduction. The cells of this tissue are bi-nucleate and polyploid, due to variant cell cycles that include endomitosis and endocycling during metamorphosis. Here we provide evidence of additional cell cycle variants in this tissue. We show that main cells of the gland are connected by ring canals that form after the penultimate mitosis and we describe an additional post-eclosion endocycle required for gland maturation that is dependent on juvenile hormone signaling. We present evidence that the main cells of the Drosophila melanogaster accessory gland undergo a unique cell cycle reprogramming throughout organ development that results in step-wise cell cycle truncations culminating in cells containing two octoploid nuclei with under-replicated heterochromatin in the mature gland. We propose this tissue as a model to study developmental and hormonal temporal control of cell cycle variants in terminally differentiating tissues.	NA	biorxiv
10.1101/721696	Myelin-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner.	Fazazi, M. R.; Doss, P. M. I. A.; Pereira, R.; Fudge, N.; Regmi, A.; Joly-Beauparlant, C.; Akbar, I.; Yeola, A. P.; Mailhot, B.; Baillargeon, J.; Grenier, P.; Bertrand, N.; Lacroix, S.; Droit, A.; Moore, C. S.; Rojas, O. L.; Rangachari, M.	Manu Rangachari	Laval University	2023-09-06T00:00:00	5	new results	cc_by	immunology	https://www.biorxiv.org/content/early/2023/09/06/721696.source.xml	Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered a T cell-mediated disease. However, accumulating evidence points to a crucial role for B cells in disease processes. IgH[MOG] mice possess a transgenic immunoglobulin heavy chain derived from a monoclonal antibody specific to myelin oligodendrocyte glycoprotein (MOG), a key target for autoimmune responses. Here, using the experimental autoimmune encephalomyelitis (EAE) model of MS, we investigated the susceptibility of IgH[MOG] mice to CD4+ T cell-driven disease that was induced by active immunization with MOG[35-55] autoantigen. We found that immunized IgH[MOG] mice rapidly developed severe EAE, characterized by the aggregation of T and B cells in the CNS meninges. We observed an increased presence of class-switched and inflammatory cytokine-positive B cells in the IgH[MOG] CNS, as well as a greater frequency of IL-17- and GM-CSF-producing CD4+ T cells. Production of the Th17 maintenance factor IL-23 was increased from IgH[MOG] CNS-infiltrating B cells, and in vivo blockade of IL-23p19 strongly attenuated disease severity in IgH[MOG] mice. Strikingly, we observed an increased frequency of PD-1+CXCR5- T peripheral helper (Tph)-like cells in the CNS parenchyma and dura mater of IgH[MOG] mice. Both Tph accumulation in the CNS, as well as meningeal inflammation, were again sharply reduced upon IL-23p19 blockade in vivo. Notably, CNS-infiltrating B and Tph cells from IgH[MOG] mice showed an upregulation of genes related to neurodegeneration and oxidative phosphorylation, and IL-23 blockade reduced ROS production from these cells in vivo. Altogether, these data show that MOG-specific B cells contribute to severe CD4+ T cell-driven EAE by promoting CNS accumulation of Th17 and Tph cells, as well as tertiary lymphoid organs in the CNS meninges, in an IL-23 dependent manner.	10.1038/s41467-024-49259-0	biorxiv
10.1101/722397	A new QRS detector stress test combining temporal jitter and accuracy (JA) reveals significant performance differences amongst popular detectors	Porr, B.; Macfarlane, P. W.	Bernd Porr	University of Glasgow	2023-07-27T00:00:00	5	contradictory results	cc_by_nc_nd	bioengineering	https://www.biorxiv.org/content/early/2023/07/27/722397.source.xml	QRS detection within an electrocardiogram (ECG) is the basis of virtually any further processing and any error caused by this detection will propagate to further processing stages. However, standard benchmarking procedures of QRS detectors are seriously flawed because they report almost always close to 100% accuracy for any QRS detection algorithm. This is due to the use of large temporal error margins and noise-free ECG databases which grossly overestimate their performance. The use of a large fixed error margin masks temporal jitter between detection and ground truth measurements. Here, we present a new performance measure (JF) which combines temporal jitter with the F-score, and also an ECG database with decreasing levels of signal to noise ratios based on noise generated from different tasks. Our new performance measure JF fully encompasses all the types of errors that can occur, equally weights them and provides a percentage value which allows direct comparison between QRS detection algorithms. In combination with the new noisy ECG database, the JF performance measure now varies between 50% and 100% for different detectors and signal to noise conditions thereby making it possible to find the best detector for an application.	NA	biorxiv
10.1101/722397	A new QRS detector stress test combining temporal jitter and F-score (JF) reveals significant performance differences amongst popular detectors	Porr, B.; Macfarlane, P. W.	Bernd Porr	University of Glasgow	2024-03-30T00:00:00	6	contradictory results	cc_by_nc_nd	bioengineering	https://www.biorxiv.org/content/early/2024/03/30/722397.source.xml	QRS detection within an electrocardiogram (ECG) is the basis of virtually any further processing and any error caused by this detection will propagate to further processing stages. However, standard benchmarking procedures of QRS detectors are seriously flawed because they report almost always close to 100% accuracy for any QRS detection algorithm. This is due to the use of large temporal error margins and noise-free ECG databases which grossly overestimate their performance. The use of a large fixed error margin masks temporal jitter between detection and ground truth measurements. Here, we present a new performance measure (JF) which combines temporal jitter with the F-score, and also an ECG database with decreasing levels of signal to noise ratios based on noise generated from different tasks. Our new performance measure JF fully encompasses all the types of errors that can occur, equally weights them and provides a percentage value which allows direct comparison between QRS detection algorithms. In combination with the new noisy ECG database, the JF performance measure now varies between 50% and 100% for different detectors and signal to noise conditions thereby making it possible to find the best detector for an application.	NA	biorxiv
10.1101/721001	Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models	Uechi, H.; Sridharan, S.; Nijssen, J.; Bilstein, J.; Iglesias-Artola, J. M.; Kishigami, S.; Casablancas-Antras, V.; Poser, I.; Martinez, E. J.; Boczek, E.; Wagner, M.; Tomschke, N.; de Jesus Domingues, A. M.; Pal, A.; Doeleman, T.; Kour, S.; Anderson, E. N.; Stein, F.; Lee, H. O.; Zhang, X.; Fritsch, A. W.; Jahnel, M.; Fursch, J.; Murthy, A. C.; Alberti, S.; Bickle, M.; Fawzi, N. L.; Nadler, A.; David, D. C.; Pandey, U. B.; Hermann, A.; Stengel, F.; Davis, B. G.; Baldwin, A. J.; Savitski, M. M.; Hyman, A. A.; Wheeler, R. J.	Anthony A Hyman	Max Planck Institute of Molecular Cell Biology and Genetics	2024-01-05T00:00:00	3	new results	cc_by	cell biology	https://www.biorxiv.org/content/early/2024/01/05/721001.source.xml	Neurodegenerave diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutaons in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separaon which, when aberrant, can lead to altered condensaon behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic condensaon of stress granule proteins. Thermal proteome profiling showed that lipoamide preferentially stabilises intrinsically disordered domain-containing proteins. These include SRSF1 and SFPQ, stress granule proteins necessary for lipoamide activity. The redox state of SFPQ correlates with its condensate-dissolving behaviour, in concordance with the importance of the dithiolane ring for lipoamide activity. In animals, lipoamide ameliorates aging-associated aggregaon of a stress granule reporter, improves neuronal morphology, and recovers motor defects caused by expression of ALS-associated FUS and TDP-43 mutants. In conclusion, lipoamide is a well-tolerated small molecule modulator of stress granule condensaon and dissection of its molecular mechanism identified a cellular pathway for redox regulaon of stress granule formaon.	NA	biorxiv
10.1101/743435	Association of Ddx5/p68 protein with the upstream erythroid enhancer element (EHS1) of the Klf1 gene	Chen, X.; Pillay, S.; Lohmann, F.; Bieker, J. J.	James J Bieker	Mount Sinai School of Medicine, New York, NY	2023-04-03T00:00:00	2	new results	cc_by_nc_nd	molecular biology	https://www.biorxiv.org/content/early/2023/04/03/743435.source.xml	EKLF/KLF1 is an essential transcription factor that plays a global role in erythroid transcriptional activation. Its own regulation is of interest, as it displays a highly restricted expression pattern, limited to erythroid cells and its progenitors. Here we use biochemical affinity purification to identify the Ddx5/p68 protein as an activator of KLF1 by virtue of its interaction with the erythroid-specific DNAse hypersensitive site upstream enhancer element (EHS1). We postulate that its range of interactions with other proteins known to interact with this element render it part of the enhanseosome complex critical for optimal expression of KLF1. These individual interactions provide quantitative contributions that, in sum, establish high level activity of the KLF1 promoter and suggest they can be selectively manipulated for clinical benefit.	NA	biorxiv
10.1101/743120	Shielding working memory from distraction is more effortful than flexible updating	Papadopetraki, D.; Froboese, M. I.; Westbrook, A. J.; Zandbelt, B. B.; Cools, R.	Danae Papadopetraki	Donders Institute for Congnitive Neuroimaging; Radboud University Nijmegen; Radboud university Medical Center, Department of Psychiatry, Nijmegen	2024-05-24T00:00:00	2	new results	cc_by_nd	neuroscience	https://www.biorxiv.org/content/early/2024/05/24/743120.source.xml	Exerting cognitive control is known to carry a subjective effort cost and people are generally biased to avoid it. Recent theorizing suggests that the cost of cognitive effort serves as a motivational signal to bias people away from excessive focusing and towards more cognitive flexibility. We asked whether the effort cost of stable distractor resistance is higher than that of flexible updating of working memory representations. We tested this prediction by using (i) a delayed response paradigm in which we manipulate demands for distractor resistance and flexible updating, as well as (ii) a subsequent cognitive effort discounting paradigm that allows us to quantify subjective effort costs. We demonstrate, in two different samples (28 and 62 participants) that participants discount tasks both high in distractor resistance and flexible updating when comparing with taking a break. As predicted, when directly contrasting distractor resistance and flexible updating the subjective cost of performing a task requiring distractor resistance is higher than that requiring flexible updating.	NA	biorxiv
10.1101/759506	Cardiac competence of the paraxial head mesoderm fades concomitant with a shift towards the head skeletal muscle programme	Alzamrooni, A. M. A. M.; Mendes Vieira, P. J.; Murciano, N.; Wolton, M.; Schubert, F. R.; Robson, S. C.; Dietrich, S.	Susanne Dietrich	University of Portsmouth	2023-05-14T00:00:00	3	new results	cc_by_nc_nd	developmental biology	https://www.biorxiv.org/content/early/2023/05/14/759506.source.xml	The vertebrate head mesoderm provides the heart, the great vessels, some smooth and most head skeletal muscle, in addition to parts of the skull. It has been speculated that the ability to generate cardiac and smooth muscle is the evolutionary ground-state of the tissue. However, whether indeed the entire head mesoderm has generic cardiac competence, how long this may last, and what happens as cardiac competence fades, is not clear. Bone morphogenetic proteins (Bmps) are known to promote cardiogenesis. Using 41 different marker genes in the chicken embryo, we show that the paraxial head mesoderm that normally does not engage in cardiogenesis has the ability to respond to Bmp for a long time. However, Bmp signals are interpreted differently at different time points. Up to early head fold stages, the paraxial head mesoderm is able to read Bmps as signal to engage in the cardiac programme; the ability to upregulate smooth muscle markers is retained slightly longer. Notably, as cardiac competence fades, Bmp promotes the head skeletal muscle programme instead. The switch from cardiac to skeletal muscle competence is Wnt-independent as Wnt caudalises the head mesoderm and also suppresses Msc-inducing Bmp provided by the prechordal plate, thus suppressing both the cardiac and the head skeletal muscle programmes. Our study for the first time suggests a specific transition state in the embryo when cardiac competence is replaced by skeletal muscle competence. It sets the stage to unravel the cardiac-skeletal muscle antagonism that is known to partially collapse in heart failure. Summary statementThe head mesoderm has generic cardiac competence until early head fold stages. Thereafter, cardiac competence fades in the paraxial region, and Bmp promotes head skeletal muscle programmes instead of cardiac programmes.	10.1016/j.ydbio.2023.06.005	biorxiv
10.1101/761346	A dual function of the IDA peptide in regulating cell separation and modulating plant immunity at the molecular level	Lalun, V. O.; Breiden, M.; Galindo-Trigo, S.; Smakowska-Luzan, E.; Simon, R.; Butenko, M. A.	Melinka Alonso Butenko	University of Oslo	2024-02-15T00:00:00	3	new results	cc_by_nc_nd	plant biology	https://www.biorxiv.org/content/early/2024/02/15/761346.source.xml	The abscission of floral organs and emergence of lateral roots in Arabidopsis is regulated by the peptide ligand INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) and the receptor protein kinases HAESA (HAE) and HAESA-LIKE 2 (HSL2). During these cell separation processes, the plant induces defense-associated genes to protect against pathogen invasion. However, the molecular coordination between abscission and immunity has not been thoroughly explored. Here we show that IDA induces a release of cytosolic calcium ions (Ca2+) and apoplastic production of reactive oxygen species, which are signatures of early defense responses. In addition, we find that IDA promotes late defense responses by the transcriptional upregulation of genes known to be involved in immunity. When comparing the IDA induced early immune responses to known immune responses, such as those elicited by flagellin22 treatment, we observe both similarities and differences. We propose a molecular mechanism by which IDA promotes signatures of an immune response in cells destined for separation to guard them from pathogen attack.	10.7554/eLife.87912	biorxiv
10.1101/761346	A dual function of the IDA peptide in regulating cell separation and modulating plant immunity at the molecular level	Lalun, V. O.; Breiden, M.; Galindo-Trigo, S.; Smakowska-Luzan, E.; Simon, R.; Butenko, M. A.	Melinka Alonso Butenko	University of Oslo	2024-03-26T00:00:00	4	new results	cc_by_nc_nd	plant biology	https://www.biorxiv.org/content/early/2024/03/26/761346.source.xml	The abscission of floral organs and emergence of lateral roots in Arabidopsis is regulated by the peptide ligand INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) and the receptor protein kinases HAESA (HAE) and HAESA-LIKE 2 (HSL2). During these cell separation processes, the plant induces defense-associated genes to protect against pathogen invasion. However, the molecular coordination between abscission and immunity has not been thoroughly explored. Here we show that IDA induces a release of cytosolic calcium ions (Ca2+) and apoplastic production of reactive oxygen species, which are signatures of early defense responses. In addition, we find that IDA promotes late defense responses by the transcriptional upregulation of genes known to be involved in immunity. When comparing the IDA induced early immune responses to known immune responses, such as those elicited by flagellin22 treatment, we observe both similarities and differences. We propose a molecular mechanism by which IDA promotes signatures of an immune response in cells destined for separation to guard them from pathogen attack.	10.7554/eLife.87912	biorxiv
10.1101/751222	A nonlinear relationship between prediction errors and learning rates in human reinforcement learning	Ikwunne, B.; Parham, J.; Pulcu, E.	Erdem Pulcu	University of Oxford	2024-07-31T00:00:00	4	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2024/07/31/751222.source.xml	Reinforcement-learning (RL) models have been pivotal to our understanding of how agents perform learning-based adaptions in dynamically changing environments. However, the exact nature of the relationship (e.g. linear, logarithmic etc.) between key components of RL models such as prediction errors (PEs; the difference between the agents expectation and the actual outcome) and learning rates (LRs; a coefficient used by agents to update their beliefs about the environment) has not been studied in detail. Here, across (i) simulations, (ii) reanalyses of readily available datasets and (iii) a novel experiment, we demonstrate that the relationship between PEs and LRs is (i) nonlinear over the PE/LR space, and (ii) it can be better accounted for by an exponential-logarithmic function that can transform the magnitude of PEs instantaneously to LRs. In line with the temporal predictions of this model, we show that physiological correlates of LRs accumulate while learners observe the outcome of their choices and update their beliefs about the environment.	NA	biorxiv
10.1101/773507	Gravity-based microfiltration reveals unexpected prevalence of circulating tumor cell clusters in ovarian and colorectal cancer	Meunier, A.; Hernandez-Castro, J. A.; Chahley, N.; Communal, L.; Kheireddine, S.; Koushki, N.; Davoudvandi, N.; Al Habyan, S.; Peant, B.; Lazaris, A.; Ng, A.; Veres, T.; McCaffrey, L.; Provencher, D.; Metrakos, P.; Mes-Masson, A.-M.; Juncker, D.	David Juncker	McGill University	2023-12-05T00:00:00	2	new results	cc_by_nc_nd	bioengineering	https://www.biorxiv.org/content/early/2023/12/05/773507.source.xml	Circulating tumor cells (CTCs) are rare (few cells per milliliter of blood) and mostly isolated as single cell CTCs (scCTCs). CTC clusters (cCTCs), even rarer, are of growing interest, notably because of their higher metastatic potential, but very difficult to isolate. Here, we introduce gravity-based microfiltration (G{micro}F) for facile isolation of cCTCs while minimizing unwanted cluster disaggregation, with [~]85% capture efficiency. G{micro}F from orthotopic ovarian cancer mouse models, from 17 epithelial ovarian cancer (EOC) with either localized or metastatic disease, and from 13 metastatic colorectal cancer liver metastasis (CRCLM) patients uncovered cCTCs in every case, with between 2-100+ cells. cCTCs represented between 5-30% of all CTC capture events, and 10-80% of CTCs were clustered; remarkably, in 10 patients, most CTCs were circulating not as scCTCs, but as cCTCs. G{micro}F uncovered the unexpected prevalence and frequency of cCTCs including sometimes very large ones in EOC patients, and motivates additional studies to uncover their properties and role in disease progression.	NA	biorxiv
10.1101/784678	ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication	Espada, C. E.; da Rocha, E. L.; Ricciardi-Jorge, T.; dos Santos, A. A.; Soares, Z. G.; Malaquias, G.; Patricio, D. d. O.; Kozlova, E. G.; dos Santos, P. F.; Bordignon, J.; Sanford, T. J.; Fajardo, T.; Sweeney, T.; Bafica, A.; Mansur, D. S.	Daniel Santos Mansur	Universidade Federal de Santa Catarina	2023-07-15T00:00:00	4	new results	cc_by_nc_nd	immunology	https://www.biorxiv.org/content/early/2023/07/15/784678.source.xml	The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.	10.3389/fimmu.2024.1331731	biorxiv
10.1101/784678	ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication	Espada, C. E.; da Rocha, E. L.; Ricciardi-Jorge, T.; dos Santos, A. A.; Soares, Z. G.; Malaquias, G.; Patricio, D. d. O.; Kozlova, E. G.; dos Santos, P. F.; Bordignon, J.; Sanford, T. J.; Fajardo, T.; Sweeney, T.; Bafica, A.; Mansur, D. S.	Daniel Santos Mansur	Universidade Federal de Santa Catarina	2023-10-19T00:00:00	5	new results	cc_by_nc_nd	immunology	https://www.biorxiv.org/content/early/2023/10/19/784678.source.xml	The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.	10.3389/fimmu.2024.1331731	biorxiv
10.1101/784678	ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication	Espada, C. E.; da Rocha, E. L.; Ricciardi-Jorge, T.; dos Santos, A. A.; Soares, Z. G.; Malaquias, G.; Patricio, D. d. O.; Kozlova, E. G.; dos Santos, P. F.; Bordignon, J.; Sanford, T. J.; Fajardo, T.; Sweeney, T.; Bafica, A.; Mansur, D. S.	Daniel Santos Mansur	Universidade Federal de Santa Catarina	2023-11-01T00:00:00	6	new results	cc_by_nc_nd	immunology	https://www.biorxiv.org/content/early/2023/11/01/784678.source.xml	The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.	10.3389/fimmu.2024.1331731	biorxiv
10.1101/784157	Technical artifact drives apparent deviation from Hardy-Weinberg equilibrium at CCR5-Δ32 and other variants in gnomAD	Karczewski, K. J.; Gauthier, L. D.; Daly, M. J.	Konrad J Karczewski	Broad Institute	2023-07-29T00:00:00	2	contradictory results	cc_by	genomics	https://www.biorxiv.org/content/early/2023/07/29/784157.source.xml	Following an earlier report suggesting increased mortality due to homozygosity at the CCR5-{Delta}32 allele1, Wei and Nielsen recently suggested a deviation from Hardy-Weinberg Equilibrium (HWE) observed in public variant databases as additional supporting evidence for this hypothesis2. Here, we present a re-analysis of the primary data underlying this variant database and identify a pervasive genotyping artifact, especially present at long insertion and deletion polymorphisms. Specifically, very low levels of contamination can affect the variant calling likelihood models, leading to the misidentification of homozygous individuals as heterozygous, and thereby creating an apparent depletion of homozygous calls, which is especially prominent at large insertions and deletions. The deviation from HWE observed at CCR5-{Delta}32 is a consequence of this specific genotyping error mode rather than a signature of selective pressure at this locus.	NA	biorxiv
10.1101/790378	Enhancing autophagy by redox regulation extends lifespan in Drosophila	Lennicke, C.; Bjedov, I.; Grönke, S.; Menger, K. E.; James, A. M.; Castillo-Quan, J. I.; van Leeuwen, L. A. G.; Foley, A.; Buricova, M.; Adcott, J.; Montoya, A.; Kramer, H. B.; Shliaha, P. V.; Logan, A.; Cabreiro, F.; Murphy, M. P.; Partridge, L.; Cocheme, H. M.	Helena M Cochemé	MRC London Institute of Medical Sciences, UK	2024-05-10T00:00:00	2	new results	cc_by	molecular biology	https://www.biorxiv.org/content/early/2024/05/10/790378.source.xml	Dysregulation of redox homeostasis has been implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in flies. As anticipated, these flies were strongly resistant to a range of oxidative stress challenges, but interestingly were sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan upon catalase up-regulation, as the survival benefits were completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.	NA	biorxiv
10.1101/793943	Energy landscape steering mediates dynamic coupling in ATP-driven protein translocation by the bacterial Sec machinery	Crossley, J. A.; Allen, W. J.; Watkins, D. W.; Sabir, T.; Radford, S. E.; Tuma, R.; Collinson, I.; Fessl, T.	Roman Tuma	University of Leeds, United Kingdom and University of South Bohemia, Czech Republic	2023-06-06T00:00:00	4	new results	cc_by_nc_nd	biophysics	https://www.biorxiv.org/content/early/2023/06/06/793943.source.xml	The Sec translocon is a highly conserved membrane complex for transport of polypeptides across, or into, lipid bilayers. In bacteria, the core protein-channel SecYEG resides in the inner-membrane, through which secretion is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the dynamic state of SecYEG throughout the hydrolytic cycle of SecA. We show that the SecYEG channel fluctuates between open and closed states faster ([~]20-fold during transport) than ATP turnover; while the nucleotide status of SecA modulates the rates of opening and closure. Interestingly, a SecY variant (PrlA4), exhibiting faster protein transport, but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore; thereby improving the efficiency of translocation. Thus, contrary to prevailing structure-based models, SecYEG plays an integral part in the translocation mechanism through dynamic allosteric coupling in which SecA steers the energy landscape of the protein-channel.	NA	biorxiv
10.1101/795930	Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8	Tzioras, M.; Daniels, M. J.; Davies, C.; Baxter, P.; King, D.; McKay, S.; Varga, B. V.; Popovic, K.; Hernandez, M.; Stevenson, A. J.; Barrington, J.; Drinkwater, E.; Borella, J. A.; Holloway, R. K.; Tulloch, J.; Latta, C.; Kandasamy, J.; Sokol, D.; Smith, C.; Miron, V.; Karadottir, R. T.; Hardingham, G.; Henstridge, C. M.; Brennan, P.; McColl, B. W.; Spires-Jones, T. L.	Tara L Spires-Jones	The University of Edinburgh	2023-04-05T00:00:00	2	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2023/04/05/795930.source.xml	Synapse loss correlates with cognitive decline in Alzheimers disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared to non-disease controls, and that proximity to amyloid-{beta} plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting MFG-E8 function rescued the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation. One-Sentence SummaryGlial cells ingest synapses in Alzheimers disease and antibody treatment reduces this ingestion in cultured human cells.	10.1016/j.xcrm.2023.101175	biorxiv
10.1101/801563	Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses	Frederiksen, S. D.; Wicki-Stordeur, L. E.; Swayne, L. A.	Leigh A. Swayne	University of Victoria	2023-04-27T00:00:00	2	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2023/04/27/801563.source.xml	Many neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signalling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 PANX1-interacting proteins identified from mouse Neuro2a cells). To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinsons disease, and Alzheimers disease. Next, to further probe PANX1 signalling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signalling pathways and protein-protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological conditions connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation.	10.1080/19336950.2023.2253102	biorxiv
10.1101/801563	Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses	Frederiksen, S. D.; Wicki-Stordeur, L. E.; Swayne, L. A.	Leigh A. Swayne	University of Victoria	2023-05-10T00:00:00	3	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2023/05/10/801563.source.xml	Many neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signalling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 PANX1-interacting proteins identified from mouse Neuro2a cells). To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinsons disease, and Alzheimers disease. Next, to further probe PANX1 signalling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signalling pathways and protein-protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological conditions connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation.	10.1080/19336950.2023.2253102	biorxiv
10.1101/803205	Caliban: Accurate cell tracking and lineage construction in live-cell imaging experiments with deep learning	Schwartz, M.; Moen, E.; Miller, G.; Dougherty, T.; Borba, E.; Ding, R.; Graf, W.; Pao, E.; Van Valen, D. A.	David Ashley Van Valen	California Institute of Technology	2023-09-06T00:00:00	3	new results	cc_by	bioinformatics	https://www.biorxiv.org/content/early/2023/09/06/803205.source.xml	While live-cell imaging is a powerful approach to studying the dynamics of cellular systems, converting these imaging data into quantitative, single-cell records of cellular behavior has been a longstanding challenge. Deep learning methods have proven capable of performing cell segmentation--a critical task for analyzing live-cell imaging data--but their performance in cell tracking has been limited by a lack of dynamic datasets with temporally consistent single-cell labels. We bridge this gap through the integrated development of labeling and deep learning methodology. We present a new framework for scalable, human-in-the-loop labeling of live-cell imaging movies, which we use to label a large collection of movies of fluorescently labeled cell nuclei. We use these data to create a new deep-learning-based cell-tracking method that achieves state-of-the-art performance in cell tracking. We have made all of the data, code, and software publicly available with permissive open-source licensing through the DeepCell projects web portal https://deepcell.org.	NA	biorxiv
10.1101/803205	Caliban: Accurate cell tracking and lineage construction in live-cell imaging experiments with deep learning	Schwartz, M.; Moen, E.; Miller, G.; Dougherty, T.; Borba, E.; Ding, R.; Graf, W.; Pao, E.; Van Valen, D. A.	David Ashley Van Valen	California Institute of Technology	2023-09-12T00:00:00	4	new results	cc_by	bioinformatics	https://www.biorxiv.org/content/early/2023/09/12/803205.source.xml	While live-cell imaging is a powerful approach to studying the dynamics of cellular systems, converting these imaging data into quantitative, single-cell records of cellular behavior has been a longstanding challenge. Deep learning methods have proven capable of performing cell segmentation--a critical task for analyzing live-cell imaging data--but their performance in cell tracking has been limited by a lack of dynamic datasets with temporally consistent single-cell labels. We bridge this gap through the integrated development of labeling and deep learning methodology. We present a new framework for scalable, human-in-the-loop labeling of live-cell imaging movies, which we use to label a large collection of movies of fluorescently labeled cell nuclei. We use these data to create a new deep-learning-based cell-tracking method that achieves state-of-the-art performance in cell tracking. We have made all of the data, code, and software publicly available with permissive open-source licensing through the DeepCell projects web portal https://deepcell.org.	NA	biorxiv
10.1101/803205	Caliban: Accurate cell tracking and lineage construction in live-cell imaging experiments with deep learning	Schwartz, M.; Moen, E.; Miller, G.; Dougherty, T.; Borba, E.; Ding, R.; Graf, W.; Pao, E.; Van Valen, D. A.	David Ashley Van Valen	California Institute of Technology	2024-08-07T00:00:00	5	new results	cc_by	bioinformatics	https://www.biorxiv.org/content/early/2024/08/07/803205.source.xml	While live-cell imaging is a powerful approach to studying the dynamics of cellular systems, converting these imaging data into quantitative, single-cell records of cellular behavior has been a longstanding challenge. Deep learning methods have proven capable of performing cell segmentation--a critical task for analyzing live-cell imaging data--but their performance in cell tracking has been limited by a lack of dynamic datasets with temporally consistent single-cell labels. We bridge this gap through the integrated development of labeling and deep learning methodology. We present a new framework for scalable, human-in-the-loop labeling of live-cell imaging movies, which we use to label a large collection of movies of fluorescently labeled cell nuclei. We use these data to create a new deep-learning-based cell-tracking method that achieves state-of-the-art performance in cell tracking. We have made all of the data, code, and software publicly available with permissive open-source licensing through the DeepCell projects web portal https://deepcell.org.	NA	biorxiv
10.1101/805614	An Improved Chromosome-scale Genome Assembly and Population Genetics resource for Populus tremula.	Robinson, K. M.; Schiffthaler, B.; Liu, H.; Westman, S. M.; Rendon-Anaya, M.; Ahlgren Kalman, T.; Kumar, V.; Canovi, C.; Bernhardsson, C.; Delhomme, N.; Jenkins, J.; Wang, J.; Mähler, N.; Richau, K. H.; Stokes, V.; A'Hara, S.; Cottrell, J.; Coeck, K.; Diels, T.; Vandepoele, K.; Mannapperuma, C.; Park, E.-J.; Plaisance, S.; Jansson, S.; Ingvarsson, P. K.; Street, N. R.	Bastian Schiffthaler	Umea Plant Science Center	2024-04-08T00:00:00	2	new results	cc_by_nc_nd	genomics	https://www.biorxiv.org/content/early/2024/04/08/805614.source.xml	Aspen (Populus tremula L.) is a widely distributed keystone species and a model system for forest tree genomics, with extensive resources developed for population genetics and genomics. Here we present an updated resource comprising a chromosome-scale assembly of P. tremula and population genetics and genomics data integrated into the PlantGenIE.org web resource. We demonstrate use of the diverse data types included to explore the genetic basis of natural variation in leaf size and shape as examples of traits with complex genetic architecture. We present a chromosome-scale genome assembly generated using long-read sequencing, optical and high-density genetic maps containing 39,894 annotated genes with functional annotations for 73,765 transcripts from 37,184 gene loci. We conducted whole-genome resequencing of the Ume[a] Aspen (UmAsp) collection comprising 227 aspen individuals. We utilised the assembly, the UmAsp re-sequencing data and existing whole genome re-sequencing data from the Swedish Aspen (SwAsp) and Scottish Aspen (ScotAsp) collections to perform genome-wide association analyses (GWAS) using Single Nucleotide Polymorphisms (SNPs) for leaf physiognomy phenotypes. We conducted Assay of Transposase Accessible Chromatin sequencing (ATAC-Seq) and identified genomic regions of accessible chromatin and subset SNPs to these regions, which improved the GWAS detection rate. We identified candidate long non-coding RNAs in leaf samples and quantified their expression in an updated co-expression network (AspLeaf, available in PlantGenIE.org), which we further used to explore the functions of candidate genes identified from the GWAS. We examined synteny to the reference P. trichocarpa assembly and identified P. tremula-specific regions. Analysis of whole-genome duplication indicated differential substitution rates for the two Populus species, indicating more rapid evolution in P. tremula. A GWAS of 26 leaf physiognomy traits and all SNPs in each of the three aspen collections found significant associations for only two traits in ScotAsp collection and one in UmAsp, whereas subsetting SNPs to those in open chromatin regions revealed associations for a further four traits among all three aspen collections. The significant SNPs were associated with genes annotated for developmental and growth functions, which represent candidates for further study. Of particular interest was a 177-kbp region of chromosome 9 harbouring SNPs associated with multiple leaf phenotypes in ScotAsp, with the set of SNPs in linkage disequilibrium explaining 24 to 30 % of the phenotypic variation in leaf indent depth variation. We have incorporated the assembly, population genetics, genomics and leaf physiognomy GWAS data into the PlantGenIE.org web resource, including updating existing genomics data to the new genome version. This enables easy exploration and visualisation of the genomics data and exploration of GWAS results. We provide all raw and processed data used for the presented analyses to facilitate reuse in future studies.	NA	biorxiv
10.1101/810259	Plasmid carriage and the unorthodox use of Fisher's theorem in evolutionary biology	Reding, C.	Carlos Reding	University of Exeter	2023-05-04T00:00:00	11	new results	cc_by_nc_nd	evolutionary biology	https://www.biorxiv.org/content/early/2023/05/04/810259.source.xml	The link between fitness and reproduction rate is a central tenet in microbiology, and indeed evolutionary biology: Mutants reproducing faster than the dominant wild-type are favoured by selection, but otherwise the mutation is lost. This link was given by Ronald Fisher in 1930 under the assumption that fitness can only change through mutations that boost or hinder growth rate, whence the use of logarithms on growth data by experimentalists. Here I show that logarithms are highly sensitive to sampling times, resulting in fitness estimates that are not constant over the growth of bacterial cultures. This variability invalidates typical selection measurements, and unfit mutants can be co-maintained if they reach their equilibrium. And this is what I observed in competition assays between two Escherichia coli constructs, one of which harbours a nontransmissible plasmid that protects against tetracycline (pGW155B), without using antibiotic. Despite growing 40% slower than its drug-sensitive counterpart, the construct harbouring the plasmid persisted throughout the competition. And, perhaps more importantly, maintained the plasmid. My study suggests that reliance on growth rate masks that selection on plasmid carriage may be stronger than previously thought--explaining the seemingly-paradoxical abundance of plasmids in nature.	NA	biorxiv
10.1101/810259	Plasmid carriage and the unorthodox use of fitness in microbial genetics	Reding, C.	Carlos Reding	University of Exeter	2023-08-28T00:00:00	12	new results	cc_by_nc_nd	evolutionary biology	https://www.biorxiv.org/content/early/2023/08/28/810259.source.xml	The link between fitness and reproduction rate is a central tenet in microbiology, and indeed evolutionary biology: Mutants reproducing faster than the dominant wild-type are favoured by selection, but otherwise the mutation is lost. This link was given by Ronald Fisher in 1930 under the assumption that fitness can only change through mutations that boost or hinder growth rate, whence the use of logarithms on growth data by experimentalists. Here I show that logarithms are highly sensitive to sampling times, resulting in fitness estimates that are not constant over the growth of bacterial cultures. This variability invalidates typical selection measurements, and unfit mutants can be co-maintained if they reach their equilibrium. And this is what I observed in competition assays between two Escherichia coli constructs, one of which harbours a nontransmissible plasmid that protects against tetracycline (pGW155B), without using antibiotic. Despite growing 40% slower than its drug-sensitive counterpart, the construct harbouring the plasmid persisted throughout the competition. And, perhaps more importantly, maintained the plasmid. My study suggests that reliance on growth rate masks that selection on plasmid carriage may be stronger than previously thought--explaining the seemingly-paradoxical abundance of plasmids in nature.	NA	biorxiv
10.1101/810259	Plasmid carriage and the unorthodox use of fitness in microbial genetics	Reding, C.	Carlos Reding	University of Exeter	2023-11-20T00:00:00	13	new results	cc_by_nc_nd	evolutionary biology	https://www.biorxiv.org/content/early/2023/11/20/810259.source.xml	The link between fitness and reproduction rate is a central tenet in microbiology, and indeed evolutionary biology: Mutants reproducing faster than the dominant wild-type are favoured by selection, but otherwise the mutation is lost. This link was given by Ronald Fisher in 1930 under the assumption that fitness can only change through mutations that boost or hinder growth rate, whence the use of logarithms on growth data by experimentalists. Here I show that logarithms are highly sensitive to sampling times, resulting in fitness estimates that are not constant over the growth of bacterial cultures. This variability invalidates typical selection measurements, and unfit mutants can be co-maintained if they reach their equilibrium. And this is what I observed in competition assays between two Escherichia coli constructs, one of which harbours a nontransmissible plasmid that protects against tetracycline (pGW155B), without using antibiotic. Despite growing 40% slower than its drug-sensitive counterpart, the construct harbouring the plasmid persisted throughout the competition. And, perhaps more importantly, maintained the plasmid. My study suggests that reliance on growth rate masks that selection on plasmid carriage may be stronger than previously thought--explaining the seemingly-paradoxical abundance of plasmids in nature.	NA	biorxiv
10.1101/812198	Effective mechanical potential of cell-cell interaction explains three-dimensional morphologies during early embryogenesis	Koyama, H.; Okumura, H.; Ito, A. M.; Nakamura, K.; Otani, T.; Kato, K.; Fujimori, T.	Hiroshi Koyama	National Institute for Basic Biology	2023-06-26T00:00:00	6	new results	cc_by_nc_nd	biophysics	https://www.biorxiv.org/content/early/2023/06/26/812198.source.xml	Mechanical forces are critical for the emergence of diverse three-dimensional morphologies of multicellular systems. However, it remains unclear what kind of mechanical parameters at cellular level substantially contribute to tissue morphologies. This is largely due to technical limitations of live measurements of cellular forces. Here we developed a framework for inferring and modeling mechanical forces of cell-cell interactions. First, by analogy to coarse-grained models in molecular and colloidal sciences, we approximated cells as particles, where mean forces (i.e. effective forces) of pairwise cell-cell interactions are considered. Then, the forces were statistically inferred by fitting the mathematical model to cell tracking data. This method was validated by using synthetic cell tracking data resembling various in vivo situations. Application of our method to the cells in the early embryos of mice and the nematode Caenorhabditis elegans revealed that cell-cell interaction forces can be written as a pairwise potential energy in a manner dependent on cell-cell distances. Importantly, the profiles of the pairwise potentials were quantitatively different among species and embryonic stages, and the quantitative differences correctly described the differences of their morphological features such as spherical vs. distorted cell aggregates, and tightly vs. non-tightly assembled aggregates. We conclude that the effective pairwise potential of cell-cell interactions is a live measurable parameter whose quantitative differences can be a parameter describing three-dimensional tissue morphologies. Author summaryEmergence of diverse three-dimensional morphologies of multicellular organisms is one of the most intriguing phenomena in nature. Due to the complex situations in living systems (e.g. a lot of genes are involved in morphogenesis.), a model for describing the emergent properties of multicellular systems has not been established. To approach this issue, approximation of the complex situations to limited numbers of parameters is required. Here, we searched for mechanical parameters for describing morphologies. We developed a statistical method for inferring mechanical potential energy of cell-cell interactions in three-dimensional tissues; the mechanical potential is an approximation of various mechanical components such as cell-cell adhesive forces, cell surface tensions, etc. Then, we showed that the quantitative differences in the potential is sufficient to reproduce basic three-dimensional morphologies observed during the mouse and C. elegans early embryogenesis, revealing a direct link between cellular level mechanical parameters and three-dimensional morphologies. Our framework provides a noninvasive tool for measuring spatiotemporal cellular forces, which would be useful for studying morphogenesis of larger tissues including organs and their regenerative therapy.	10.1371/journal.pcbi.1011306	biorxiv
10.1101/839811	The astrocyte-enriched gene CG11000 plays a crucial role in the development, locomotion and lifespan of D. melanogaster	Najafi, H.; Wong, K.; Salkini, A. H.; Miao, H.; Kim, W. J.	Woo Jae Kim	University of Ottawa	2023-09-12T00:00:00	4	new results	cc_by_nc_nd	genetics	https://www.biorxiv.org/content/early/2023/09/12/839811.source.xml	The brain of Drosophila melanogaster is a complex organ with various cell types, orchestrating the physiology and behaviors of the fly. While each cell type in the Drosophila brain is known to express a unique set of genes, their complete genetic profile is still unknown. Advances in the RNA-sequencing techniques at single cell resolution facilitate identifying novel cell type-specific markers and/or examining the specificity of the available markers. In this study, exploiting a single cell RNA sequencing data of Drosophila optic lobe (which comprises two thirds of the brain with extensive cell type diversity), we first categorized cell types based on their known molecular markers, then the genes with enriched expression in astrocytes were identified. Consistent with previous findings, the known glial markers CG34335, Inx2 and nrv2 as well as the astrocytic genes CG9394, Eaat1, Gat, Gs2 and CG1552 exhibited enriched expression in the identified astrocyte cluster. Moreover, we identified CG11000 as a gene with positive expression correlation with the astrocytic marker Eaat1. The positive expression correlation between CG11000 and Eaat1 genes was also observed in the single-cell RNA-sequencing data of Drosophila mid-brain as well as in the bulk RNA-sequencing data of Drosophila whole brain during development. Immunostaining of the brains dissected from adult flies showed overlapping fluorescence signals of CG11000 and Eaat1 expression, supporting co-expression of these genes in a set of single cells in Drosophila optic lobe. At the physiological level, RNAi-mediated suppression of CG11000 impeded th normal development of male flies without any effects on females. In adult flies, CG11000 suppression affected the locomotion activity and lifespan of D. melanogaster in an astrocyte-specific manner, suggesting pivotal role of CG11000 gene in astrocytes.	NA	biorxiv
10.1101/852129	Sympathetic innervation directs Ankyrin G, voltage-gated Nav and KCNQ1 channels to the neuro-cardiac junctions	Shcherbakova, O. G.	Olga G Shcherbakova	Petersburg Nuclear Physics Institute named by B.P. Konstantinov of NRC Kurchatov Institute	2023-06-09T00:00:00	3	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2023/06/09/852129.source.xml	The sympathetic nervous system plays a central role in the cardiovascular response to acute stress by increasing heart rate and contractility. Despite the importance of functional connections between sympathetic nerves and cardiac myocytes, very little is known about the structural and functional organization of the neuro-cardiac synapses. Earlier, we demonstrated that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons2. In the present study, we addressed the question if sympathetic innervation may affect localization of the cardiac ion channels. We have found that ankyrin G, scaffold protein involved in targeting ion channels and transporters, is localized at the postsynaptic sites in the cardiac myocytes innervated by sympathetic neurons. Consistent with the roles of ankyrin G in targeting Nav channels to specific domains in neurons and cardiac myocytes, we have observed an increased density of Nav channels at the neuro-cardiac junctions in co-cultures of cardiac myocytes and sympathetic neurons. We have also found that KCNQ1 channels are enriched at that sites. The increased density of Nav and KCNQ1 channels at the sites of sympathetic innervation is likely to play a role in regulation of the cardiac excitability by sympathetic nervous system.	NA	biorxiv
10.1101/859942	Prioritized neural processing of social threats during perceptual decision-making	El Zein, M.; Mennella, R.; Sequestro, M.; Meaux, E.; Wyart, V.; Grezes, J.	Emilie Meaux	INSERM U960, LNC2, Ecole Normale Superieure de Paris, PSL University	2024-01-02T00:00:00	4	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2024/01/02/859942.source.xml	Emotional signals, notably those signaling threat, benefit from prioritized processing in the human brain. Yet, it remains unclear whether perceptual decisions about the emotional, threat-related aspects of stimuli involve specific or similar neural computations compared to decisions about their non-threatening/non-emotional components. We developed a novel behavioral paradigm in which participants performed two different detection tasks (emotion vs. color) on the same, two-dimensional visual stimuli. Electroencephalographic (EEG) activity in a cluster of central electrodes reflected the amount of perceptual evidence around 100ms following stimulus onset, when the decision concerned emotion, not color. Second, participants choice could be predicted earlier for emotion (240ms) than for color (380ms) by the mu (10Hz) rhythm, which reflects motor preparation. Taken together, these findings indicate that perceptual decisions about threat-signaling dimensions of facial displays are associated with prioritized neural coding in action-related brain regions, supporting the motivational value of socially relevant signals.	10.1016/j.isci.2024.109951	biorxiv
10.1101/871020	Quantitative Real-Time PCR assays for species-specific detection and quantification of Baltic Sea spring bloom dinoflagellates	Brink, A. M.; Kremp, A.; Gorokhova, E.	Annica M. Brink	Stockholm University	2024-03-09T00:00:00	2	new results	cc_by_nc_nd	molecular biology	https://www.biorxiv.org/content/early/2024/03/09/871020.source.xml	In the Baltic Sea, the dinoflagellates Apocalathium malmogiense, Biecheleria baltica, and Gymnodinium corollarium are important contributors to the spring bloom. However, their relative contribution to the bloom community cannot be unambiguously determined by conventional light microscopy due to lack of resolution of distinctive morphological features of the three species. Here, we describe a molecular approach based on a quantitative real-time polymerase chain reaction (qPCR) primer and probe system, targeting the ITS1 and ITS2 regions of the rRNA gene for all three species and enabling their quantification. The specificity of the method was demonstrated using monocultures of A. malmogiense, B. baltica, G. corollarium as well as three other dinoflagellate species co-occurring in the Baltic Sea during spring and validated using field-collected phytoplankton samples.	NA	biorxiv
10.1101/2019.12.13.875526	An Alignment-free Method for Phylogeny Estimation using Maximum Likelihood	Zahin, T.; Abrar, M. H.; Rahman, M.; Tasnim, T.; Bayzid, M. S.; Rahman, A.	Atif Rahman	Bangladesh University of Engineering and Technology	2024-07-29T00:00:00	2	new results	cc_by_nd	bioinformatics	https://www.biorxiv.org/content/early/2024/07/29/2019.12.13.875526.source.xml	While alignment has traditionally been the primary approach for establishing homology prior to phylogenetic inference, alignment-free methods offer a simplified alternative, particularly beneficial when handling genome-wide data involving long sequences and complex events such as rearrangements. Moreover, alignment-free methods become crucial for data types like genome skims, where assembly is impractical. However, despite these benefits, alignment-free techniques have not gained widespread acceptance since they lack the accuracy of alignment-based techniques, primarily due to their reliance on simplified models of pairwise distance calculation. Here, we present a likelihood based alignment-free technique for phylogenetic tree construction. We encode the presence or absence of k-mers in genome sequences in a binary matrix, and estimate phylogenetic trees using a maximum likelihood approach. We analyze the performance of our method on seven real datasets and compare the results with the state of the art alignment-free methods. Results suggest that our method is competitive with existing alignment-free tools. This indicates that maximum likelihood based alignment-free methods may in the future be refined to outperform alignment-free methods relying on distance calculation as has been the case in the alignment-based setting. A likelihood based alignment-free method for phylogeny estimation is implemented for the first time in a software named PO_SCPLOWEAFOWLC_SCPLOW, which is available at: https://github.com/hasin-abrar/Peafowlrepo.	NA	biorxiv
10.1101/2019.12.12.868489	Is N-Hacking Ever OK? A Simulation-based study	Reinagel, P.	Pamela Reinagel	UCSD	2023-08-24T00:00:00	4	new results	cc_by_nc_nd	scientific communication and education	https://www.biorxiv.org/content/early/2023/08/24/2019.12.12.868489.source.xml	After an experiment has been completed, a trend may be observed that is "not quite significant". Sometimes in this situation, researchers collect more data in an effort to achieve statistical significance. Such "N-hacking" is condemned because it can lead to an excess of false positive results. I use simulations to demonstrate how N-hacking causes false positives. However, in a parameter regime relevant for many experiments, the increase in false positives is quite modest. Moreover, results obtained this way have higher Positive Predictive Value than non-incremented experiments of the same sample size and statistical power. In other words, adding a few more observations to shore up a nearly-significant result can increase the reproducibility of results, counter to some current rhetoric. Many experiments are non-confirmatory, and unplanned sample augmentation with reasonable decision rules would not cause rampant irreproducibility in that context.	10.1371/journal.pbio.3002345	biorxiv
10.1101/2019.12.12.868489	Is N-Hacking Ever OK? A Simulation-based study	Reinagel, P.	Pamela Reinagel	UCSD	2023-08-24T00:00:00	4	new results	cc_by_nc_nd	scientific communication and education	https://www.biorxiv.org/content/early/2023/08/24/2019.12.12.868489.source.xml	After an experiment has been completed, a trend may be observed that is "not quite significant". Sometimes in this situation, researchers collect more data in an effort to achieve statistical significance. Such "N-hacking" is condemned because it can lead to an excess of false positive results. I use simulations to demonstrate how N-hacking causes false positives. However, in a parameter regime relevant for many experiments, the increase in false positives is quite modest. Moreover, results obtained this way have higher Positive Predictive Value than non-incremented experiments of the same sample size and statistical power. In other words, adding a few more observations to shore up a nearly-significant result can increase the reproducibility of results, counter to some current rhetoric. Many experiments are non-confirmatory, and unplanned sample augmentation with reasonable decision rules would not cause rampant irreproducibility in that context.	10.1371/journal.pbio.3002345	biorxiv
10.1101/2019.12.20.884734	Genetic erosion reduces biomass temporal stability in wild fish populations.	Prunier, J. G.; Chevalier, M.; Raffard, A.; Loot, G.; Poulet, N.; Blanchet, S.	Jerome G. Prunier	CNRS	2023-04-05T00:00:00	3	new results	cc_by_nc	ecology	https://www.biorxiv.org/content/early/2023/04/05/2019.12.20.884734.source.xml	Genetic diversity sustains species adaptation. However, it may also support key ecosystems functions and services that can be altered by the worldwide loss of genetic diversity. Here, using long-term wild fish data, we demonstrate that populations with high genetic diversity do not reach higher biomasses than populations with low genetic diversity. Nonetheless, populations with high genetic diversity have much more stable biomasses over recent decades than populations having suffered from genetic erosion, which has implications for the provision of ecosystem services and the risk of population extinction. Our results strengthen the importance of adopting prominent environmental policies to conserve this important biodiversity facet.	10.1038/s41467-023-40104-4	biorxiv
10.1101/2019.12.20.884262	Cognitive control of behavior and hippocampal information processing without medial prefrontal cortex	Park, E.; Reilly, K. O.; Grubbs, G.; Taborga, D.; Nicholas, K.; Ahmeda, A. S.; Ruiz, N.; Kim, N.; Segura-Carrillo, S.; Fenton, A. A.	Kally O'Reilly	Columbia University	2024-04-11T00:00:00	3	new results	cc_by_nd	neuroscience	https://www.biorxiv.org/content/early/2024/04/11/2019.12.20.884262.source.xml	Cognitive control tasks require using one class of information and ignoring competing classes of information. A central role for the medial prefrontal cortex (mPFC) in cognitive control is well established because mPFC damage impairs tasks that may require cognitive control, as inferred, typically from the task design. We tested the "central-computation" hypothesis that rat mPFC is essential for cognitive control. Ibotenic acid lesion of the mPFC was effective and altered the coordination of metabolic activity in remaining structures. The lesion did not impair an active place avoidance task that requires cognitive control, nor did it impair concurrent alternation between task-relevant and task-irrelevant hippocampal CA1 representations of space. Conflict avoidance learning that tests cognitive flexibility was impaired, but not initial learning or long-term memory. These findings support an alternative "local-computation" hypothesis: the computations required for cognitive control can occur locally in brain networks independently of the mPFC, as demonstrated.	NA	biorxiv
10.1101/2020.01.03.893776	A long tail of truth and beauty: A zigzag pattern of feather formation explains the symmetry, complexity, and beauty of the peacock's tail	Singh, R. S.; Jagadeeshan, S.	Rama Shankar Singh	McMaster University	2023-08-17T00:00:00	3	new results	cc_by_nc_nd	evolutionary biology	https://www.biorxiv.org/content/early/2023/08/17/2020.01.03.893776.source.xml	One hundred and fifty years after the publication of Darwins sexual selection theory, the problem of the peacocks train remains unsolved. Darwin assumed that the peacocks long train was maladaptive and was the indirect effect of selection by female mate choice based on the trains beauty. While a relationship between the feathers elaborate features and mating success has been shown, the concept of eyespots as the basis of female choice remains controversial. We examined the anatomical plan underlying feather development using museum specimens and observed a zigzag pattern of feather follicles that determined both the number and the hexagonal arrangement of eyespots on the train as well as, strikingly, the individual eyespots color rings. While the zigzag pattern explains the symmetry, complexity, and structural beauty of the peacocks train, it also precludes individual eyespot variation. The only available variation in eyespot number is expected to be due to annual addition of new rows of 10/11 feathers as a function of age, giving rise to an inherently determined eyespot number. New insights show that eyespot number and feather length are developmentally correlated and an asymptotic function of a males age, that their effects on female choice would be confounded and inseparable, and that male vigor would be a crucial factor affecting male fitness. Females may not always choose males with the largest number of eyespots, as older males may lack vigor. We propose a multimodal model of female choice based on male size, vigor, and beauty where females see eyespot and train size not as separate traits but as one complex trait combining both. The new model may be able to explain conflicting results and why eyespot number alone may not be sufficient to explain female choice. Beauty is truth, truth beauty. Keats	NA	biorxiv
10.1101/2020.01.04.894907	Genome-wide Functional Characterization of Escherichia coli Promoters and Sequence Elements Encoding Their Regulation	Urtecho, G.; Insigne, K.; Tripp, A. D.; Brinck, M.; Lubock, N. B.; Acree, C.; Kim, H.; Chan, T.; Kosuri, S.	Sriram Kosuri	UCLA	2023-10-12T00:00:00	2	new results	cc_by_nc	microbiology	https://www.biorxiv.org/content/early/2023/10/12/2020.01.04.894907.source.xml	Despite decades of intense genetic, biochemical, and evolutionary characterizations of bacterial promoters, we lack the ability to identify or predict transcriptional activities of promoters using primary sequence. Even in simple, well-characterized organisms such as E. coli there is little agreement on the number, location, and strength of promoters. We use a genomically-encoded massively parallel reporter assay to perform the first full characterization of autonomous promoter activity across the E. coli genome. We measure promoter activity of >300,000 sequences spanning the entire genome and map 2,228 promoters active in rich media. Surprisingly, 944 of these promoters were found within intragenic sequences and are associated with conciliatory sequence adaptations by both the protein-coding regions and overlapping RNAP binding sites. Furthermore, we perform a scanning mutagenesis of 2,057 promoters to uncover sequence elements regulating promoter activity, revealing 3,317 novel regulatory elements. Finally, we show that despite these large datasets and modern machine learning algorithms, predicting endogenous promoter activity from primary sequence is still challenging.	NA	biorxiv
10.1101/2020.01.09.900514	Defective Function of α-Ketoglutarate Dehydrogenase Exacerbates Mitochondrial ATP Deficits during Complex I Deficiency	Piroli, G. G.; Manuel, A. M.; McCain, R. S.; Smith, H. H.; Ozohanics, O.; Mellid, S.; Cotham, W. E.; Walla, M. D.; Cascon, A.; Ambrus, A.; Frizzell, N.	Norma Frizzell	University of South Carolina	2023-08-10T00:00:00	3	new results	cc_by_nc_nd	biochemistry	https://www.biorxiv.org/content/early/2023/08/10/2020.01.09.900514.source.xml	The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration, suggesting a mechanistic role in neurodegenerative decline. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the -ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the OXPHOS ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.	10.1016/j.redox.2023.102932	biorxiv
10.1101/2020.01.11.899559	Macromolecular and cytological changes in fission yeast G0 nuclei	Tan, Z. Y.; Cai, S.; Paithankar, S. A.; Nie, X.; Shi, J.; Gan, L.	Lu Gan	National University of Singapore	2024-04-10T00:00:00	2	new results	cc_by_nc_nd	cell biology	https://www.biorxiv.org/content/early/2024/04/10/2020.01.11.899559.source.xml	When starved of nitrogen, fission yeast Schizosaccharomyces pombe cells enter a quiescent "G0" state with smaller nuclei and transcriptional repression. The genomics of S. pombe G0 cells has been well studied, but much of its nuclear cell biology remains unknown. Here we use confocal microscopy, immunoblots, and electron cryotomography to investigate the cytological, biochemical, and ultrastructural differences between S. pombe proliferating, G1-arrested, and G0 cell nuclei, with an emphasis on the histone acetylation, RNA polymerase II fates, and macromolecular complex packing. Compared to proliferating cells, G0 cells have lower levels of histone acetylation, nuclear RNA polymerase II, and active transcription. The G0 nucleus has similar macromolecular crowding yet fewer chromatin-associated multi-megadalton globular complexes. Induced histone hyperacetylation in G0 results in cells that have larger nuclei and therefore less compact chromatin. However, these histone-hyperacetylated G0 cells remain transcriptionally repressed with similar nuclear crowding. Canonical nucleosomes - those that resemble the crystal structure - are rare in proliferating, G1-arrested, and G0 cells. Our study therefore shows that extreme changes in nucleus physiology are possible without extreme reorganisation at the macromolecular level. SummaryWe use multiple cell-biological techniques to compare proliferating and quiescent G0 fission yeast cell nucleus transcription, histone acetylation, macromolecular packing.	NA	biorxiv
10.1101/2020.01.12.903393	Calcium-independent lipid release from astrocytes modulates neuronal excitability	Wang, F.; Bradshaw, H. B.; Jablonska, B.; Pena, S. E.; Xavier, J.; Gong, S.; Li, B.; Chandler-Militello, D.; Bekar, L. K.; Smith, N. A.	Nathan A Smith	Children's National Research Institute	2024-05-19T00:00:00	6	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2024/05/19/2020.01.12.903393.source.xml	An accumulating amount of data suggests that Ca2+-dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE2). Surprisingly, the buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca2+-independent pathway regulates the release of PGE2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCEUntil now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.	NA	biorxiv
10.1101/2020.01.12.903393	Calcium-independent lipid release from astrocytes modulates neuronal excitability	Wang, F.; Bradshaw, H. B.; Jablonska, B.; Pena, S. E.; Chittaranjan, S.; Xavier, J.; Gong, S.; Li, B.; Chandler-Militello, D.; Bekar, L. K.; Smith, N. A.	Nathan A Smith	Children's National Research Institute	2024-07-30T00:00:00	7	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2024/07/30/2020.01.12.903393.source.xml	An accumulating amount of data suggests that Ca2+-dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE2). Surprisingly, the buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca2+-independent pathway regulates the release of PGE2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCEUntil now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.	NA	biorxiv
10.1101/2020.01.29.926022	CopyMix: Mixture Model Based Single-Cell Clustering and Copy Number Profiling using Variational Inference	Safinianaini, N.; P. E. de Souza, C.; Roth, A.; Koptagel, H.; Toosi, H.; Lagergren, J.	Negar Safinianaini	School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, Stockholm, Sweden	2023-10-17T00:00:00	6	new results	cc_by	bioinformatics	https://www.biorxiv.org/content/early/2023/10/17/2020.01.29.926022.source.xml	Investigating tumor heterogeneity using single-cell sequencing technologies is imperative to understand how tumors evolve since each cell subpopulation harbors a unique set of genomic features that yields a unique phenotype, which is bound to have clinical relevance. Clustering of cells based on copy number data obtained from single-cell DNA sequencing provides an opportunity to identify different tumor cell subpopulations. Accordingly, computational methods have emerged for single-cell copy number profiling and clustering; however, these two tasks have been handled sequentially by applying various ad-hoc pre- and post-processing steps; hence, a procedure vulnerable to introducing clustering artifacts. Moreover, clonal copy number profiling has been missing except for one method, CONET, which unfortunately computes it by a post-processing tool. Finally, a common copy number profiling tool, HMMcopy, requires parameter tuning. We avoid the clustering artifact issues and provide clonal copy number profiles without the labor of parameter tuning in our method, CopyMix, a Variational Inference for a novel mixture model, by jointly inferring cell clusters and their underlying copy number profile. We evaluate CopyMix using simulated data and published biological data from ovarian cancer. The results reveal high clustering performance and low errors in copy number profiling. These favorable results indicate a considerable potential to obtain clinical impact by using CopyMix in studies of cancer tumor heterogeneity.	NA	biorxiv
10.1101/2020.01.30.926790	Alu insertion-mediated dsRNA structure formation with pre-existing Alu elements as a novel disease-causing mechanism	Masson, E.; Maestri, S.; Bordeau, V.; Cooper, D. N.; Ferec, C.; Chen, J.-M.	Jian-Min Chen	Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200 Brest, France	2024-04-03T00:00:00	2	new results	cc_by_nc_nd	genetics	https://www.biorxiv.org/content/early/2024/04/03/2020.01.30.926790.source.xml	We previously identified a homozygous Alu insertion variant (Alu_Ins) in the 3-UTR of the SPINK1 gene as the cause of a novel pediatric disease. Although we established that Alu_Ins leads to the complete loss of SPINK1 mRNA expression, the precise mechanisms remained elusive. Here we aimed to elucidate these mechanisms through a hypothesis-driven approach. Initially, we speculated that Alu_Ins could independently disrupt mRNA 3 end formation and/or affect other post-transcriptional processes such as nuclear export and translation, due to its particular location. However, the presence of Alu_Ins in the 3-UTR resulted in only an ~50% reduction in luciferase reporter activity compared to the wild-type, suggesting the involvement of additional mechanisms. Using RepeatMasker, we identified two Alu elements within SPINK1s third intron, both of which resided in an orientation opposite to that of Alu_Ins. Through RNAfold predictions and full-length gene expression assays designed to examine orientation-dependent interactions between Alu repeats, we present evidence linking the detrimental effect of Alu_Ins to extensive double-stranded RNA structures formed between Alu_Ins and pre-existing intronic Alu sequences. Our results reveal a novel pathogenetic mechanism involving an Alu insertion, highlighting the importance of considering interactions between new and pre-existing Alu elements in inverted orientations within disease-associated genes.	NA	biorxiv
10.1101/2020.02.03.926295	The hidden cost of receiving favors: A theory of indebtedness	Gao, X.; Jolly, E.; Yu, H.; Liu, H.; Zhou, X.; Chang, L. J.	Luke J Chang	Peking University	2023-05-26T00:00:00	4	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2023/05/26/2020.02.03.926295.source.xml	Receiving help or a favor from another person can sometimes have a hidden cost for the beneficiary. In this study, we explore these hidden costs by developing and validating a conceptual model of indebtedness across three studies that combine a large scale online questionnaire, an interpersonal game, computational modeling, and neuroimaging. Our model captures how individuals perceive the altruistic and strategic intentions of the benefactor. These inferences produce distinct feelings of guilt and obligation that together comprise indebtedness and motivate reciprocity. Perceived altruistic intentions convey care and concern and are associated with activity in insula, ventromedial prefrontal cortex and dorsolateral prefrontal cortex, while inferred strategic intentions convey expectations of future reciprocity and are associated with activation in temporal parietal junction and dorsomedial prefrontal cortex. We further develop a neural utility model of indebtedness using multivariate patterns of brain activity that captures the tradeoff between these feelings and reliably predicts reciprocity behavior.	NA	biorxiv
10.1101/2020.02.09.940494	Pathogen community composition and co-infection patterns in a wild community of rodents	Abbate, J. L.; Galan, M.; Razzauti, M.; Sironen, T.; Voutilainen, L.; Henttonen, H.; Gasqui, P.; Cosson, J.-F.; Charbonnel, N.	Nathalie Charbonnel	CBGP, INRAE, CIRAD, IRD, Montpellier SupAgro, Univ Montpellier, Montpellier, France	2023-07-21T00:00:00	3	new results	cc_by_nc_nd	ecology	https://www.biorxiv.org/content/early/2023/07/21/2020.02.09.940494.source.xml	Rodents are major reservoirs of pathogens that can cause disease in humans and livestock. It is therefore important to know what pathogens naturally circulate in rodent populations, and to understand the factors that may influence their distribution in the wild. Here, we describe the occurrence and distribution patterns of a range of endemic and zoonotic pathogens circulating among rodent communities in northern France. The community sample consisted of 713 rodents, including 11 host species from diverse habitats. Rodents were screened for virus exposure (hantaviruses, cowpox virus, Lymphocytic choriomeningitis virus, Tick-borne encephalitis virus) using antibody assays. Bacterial communities were characterized using 16S rRNA amplicon sequencing of splenic samples. Multiple correspondence (MCA), multiple regression and association screening (SCN) analyses were used to determine the degree to which extrinsic factors (study year and site; host habitat, species, sex and age class) contributed to pathogen community structure, and to identify patterns of associations between pathogens within hosts. We found a rich diversity of bacterial genera, with 36 known or suspected to be pathogenic. We revealed that host species is the most important determinant of pathogen community composition, and that hosts that share habitats can have very different pathogen communities. Pathogen diversity and co-infection rates also vary among host species. Aggregation of pathogens responsible for zoonotic diseases suggests that some rodent species may be more important for transmission risk than others. Moreover, we detected positive associations between several pathogens, including Bartonella, Mycoplasma species, Cowpox virus (CPXV) and hantaviruses, and these patterns were generally specific to particular host species. Altogether, our results suggest that host and pathogen specificity is the most important driver of pathogen community structure, and that interspecific pathogen-pathogen associations also depend on host species.	10.24072/pcjournal.370	biorxiv
10.1101/2020.02.09.940494	Pathogen community composition and co-infection patterns in a wild community of rodents	Abbate, J. L.; Galan, M.; Razzauti, M.; Sironen, T.; Voutilainen, L.; Henttonen, H.; Gasqui, P.; Cosson, J.-F.; Charbonnel, N.	Nathalie Charbonnel	CBGP, INRAE, CIRAD, IRD, Montpellier SupAgro, Univ Montpellier, Montpellier, France	2023-11-14T00:00:00	4	new results	cc_by_nc_nd	ecology	https://www.biorxiv.org/content/early/2023/11/14/2020.02.09.940494.source.xml	Rodents are major reservoirs of pathogens that can cause disease in humans and livestock. It is therefore important to know what pathogens naturally circulate in rodent populations, and to understand the factors that may influence their distribution in the wild. Here, we describe the occurrence and distribution patterns of a range of endemic and zoonotic pathogens circulating among rodent communities in northern France. The community sample consisted of 713 rodents, including 11 host species from diverse habitats. Rodents were screened for virus exposure (hantaviruses, cowpox virus, Lymphocytic choriomeningitis virus, Tick-borne encephalitis virus) using antibody assays. Bacterial communities were characterized using 16S rRNA amplicon sequencing of splenic samples. Multiple correspondence (MCA), multiple regression and association screening (SCN) analyses were used to determine the degree to which extrinsic factors (study year and site; host habitat, species, sex and age class) contributed to pathogen community structure, and to identify patterns of associations between pathogens within hosts. We found a rich diversity of bacterial genera, with 36 known or suspected to be pathogenic. We revealed that host species is the most important determinant of pathogen community composition, and that hosts that share habitats can have very different pathogen communities. Pathogen diversity and co-infection rates also vary among host species. Aggregation of pathogens responsible for zoonotic diseases suggests that some rodent species may be more important for transmission risk than others. Moreover, we detected positive associations between several pathogens, including Bartonella, Mycoplasma species, Cowpox virus (CPXV) and hantaviruses, and these patterns were generally specific to particular host species. Altogether, our results suggest that host and pathogen specificity is the most important driver of pathogen community structure, and that interspecific pathogen-pathogen associations also depend on host species.	10.24072/pcjournal.370	biorxiv
10.1101/2020.02.13.946517	Protein interaction mapping reveals widespread targeting of development-related host transcription factors by phytoplasma effectors	Correa Marrero, M.; Capdevielle, S.; Huang, W.; Al-Subhi, A. M.; Busscher, M.; Busscher-Lange, J.; van der Wal, F.; de Ridder, D.; van Dijk, A. D. J.; Hogenhout, S. A.; Immink, R. G. H.	Richard G.H. Immink	Wageningen University & Research	2023-07-23T00:00:00	2	new results	cc_by_nc_nd	plant biology	https://www.biorxiv.org/content/early/2023/07/23/2020.02.13.946517.source.xml	Phytoplasmas are pathogenic bacteria that reprogram plant host development for their own benefit. Previous studies have characterized a few different phytoplasma effector proteins that destabilize specific plant transcription factors. However, these are only a small fraction of the potential effectors used by phytoplasmas; therefore, the molecular mechanisms through which phytoplasmas modulate their hosts require further investigation. To obtain further insights into the phytoplasma infection mechanisms, we generated a protein-protein interaction network between a broad set of phytoplasma effectors and a large, unbiased collection of Arabidopsis thaliana transcription factors and transcriptional regulators. We found widespread, but specific, interactions between phytoplasma effectors and host transcription factors, especially those related to host developmental processes. In particular, many unrelated effectors target specific sets of TCP transcription factors, which regulate plant development and immunity. Comparison with other host-pathogen protein interaction networks shows that phytoplasma effectors have unusual targets, indicating that phytoplasmas have evolved a unique and unusual infection strategy. This study contributes a rich and solid data source that guides further investigations of the functions of individual effectors, as demonstrated for some herein. Moreover, the dataset provides insights into the underlying molecular mechanisms of phytoplasma infection.	10.1111/tpj.16546	biorxiv
10.1101/2020.02.13.948539	Slow oscillation-spindle coupling predicts sequence-based language learning	Cross, Z. R.; Helfrich, R. F.; Corcoran, A. W.; Kohler, M. J.; Coussens, S.; Zou-Williams, L.; Schlesewsky, M.; Gaskell, M. G.; Knight, R. T.; Bornkessel-Schlesewsky, I.	Zachariah R Cross	Cognitive and Systems Neuroscience Research Hub, University of South Australia	2023-11-27T00:00:00	3	new results	cc_by_nd	neuroscience	https://www.biorxiv.org/content/early/2023/11/27/2020.02.13.948539.source.xml	Sentence comprehension involves the rapid decoding of semantic and grammatical information, a process fundamental to communication. As with other cognitive processes, language comprehension relies partly on long-term memory. However, the electrophysiological mechanisms underpinning the initial encoding and generalisation of higher-order linguistic knowledge remains elusive, particularly from a sleep-based consolidation perspective. One candidate mechanism that may subserve the consolidation of language is the temporal coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement sleep (NREM). To examine this hypothesis, we analysed electroencephalographic (EEG) data recorded from 35 participants (Mage = 25.4, SD = 7.10; 16 males) during an artificial language learning task, contrasting performance between individuals who were given an 8hr nocturnal sleep period or an equivelant period of wake. We found that sleep relative to wake was associated with superior performance for rules that followed a sequence-based word order. Post-sleep sequence-based word order processing was associated with an increase in task-related theta power, an electrophysiological signature of successful memory consolidation. Frontal NREM SO-spindle coupling was also positively associated with behavioural sensitivity to sequence-based word order rules, as well as with task-related theta power. As such, theta activity during retrieval of previously learned information correlates with SO-spindle coupling, thus linking neural activity in the sleeping and waking brain. Taken together, this study presents converging behavioural and neurophysiological evidence for a role of NREM SO-spindle coupling and task-related theta activity as signatures of successful memory consolidation and retrieval in the context of higher-order language learning. SIGNIFICANCE STATEMENTThe endogenous temporal coordination of neural oscillations supports information processing during both wake and sleep states. Here we demonstrate that slow oscillation-spindle coupling during non-rapid eye movement sleep predicts the consolidation of complex grammatical rules and modulates task-related oscillatory dynamics previously implicated in sentence processing. We show that increases in theta power predict enhanced sensitivity to grammatical violations after a period of sleep and strong slow oscillation-spindle coupling modulates subsequent task-related theta activity to influence behaviour. Our findings reveal a complex interaction between both wake- and sleep-related oscillatory dynamics during the early stages of language learning beyond the single word level.	NA	biorxiv
10.1101/2020.02.19.955351	Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knock-out, and LacZ knock-in mice.	Kwak, H.; Cho, E.-H.; Cho, E. B.; Lee, Y.-N.; Shahapal, A.; Yong, H. J.; Reyes-Alcaraz, A.; Jeong, Y.; Lee, Y.; Lee, M.; Ha, N.; Oh, S.; Lee, J. K.; Lee, W. S.; Kim, W. K.; Hwang, J.-I.; Seong, J. Y.	Jae Young Seong	Graduate School of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea	2024-07-26T00:00:00	2	contradictory results	cc_by_nd	genetics	https://www.biorxiv.org/content/early/2024/07/26/2020.02.19.955351.source.xml	FAM19A5 is a novel secretory protein primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function through sphingosine-1-phosphate receptor 2 (S1PR2). In our study, we investigated FAM19A5 transcript and protein levels in peripheral tissues, including adipose tissues, from wild-type, FAM19A5 knockout, and FAM19A5 LacZ knockin mice. We found that FAM19A5 transcript levels in the central nervous system were much greater than those in any of the peripheral tissues, including adipose tissues. Furthermore, the FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for Western blot analysis. Additionally, we found that the FAM19A5 protein did not interact with S1PR2 in terms of G protein-mediated signal transduction, {beta}-arrestin recruitment, or ligand-mediated internalization. Taken together, our findings revealed basal levels of FAM19A5 transcripts and proteins in peripheral tissues, confirming its primary expression in the central nervous system and lack of significant interaction with S1PR2.	NA	biorxiv
10.1101/2020.02.20.957548	A New World begomovirus infecting Cotton in Argentina	Delfosse, V.; Debat, H.; Zavallo, D.; Moyano, S.; Luna, F.; Bonacic Kresic, I.; Asurmendi, S.; Gomez-Talquenca, S.; Distefano, A. J.	Humberto Debat	IPAVE-CIAP-INTA	2023-08-08T00:00:00	2	new results	cc_by_nc_nd	microbiology	https://www.biorxiv.org/content/early/2023/08/08/2020.02.20.957548.source.xml	Cotton (Gossypium spp.) is a globally significant cash crop cultivated for its versatile fiber, widely used in the textile industry. Cotton, as other crops, is vulnerable to infectious pathogens. Several of them, including viruses, are a major threat to cotton production. Geminiviruses (family Geminiviridae) are insect transmitted, small non-enveloped viruses, with circular single-stranded DNA genomes, which are encapsidated in quasi-icosahedral geminated virions. Here we present evidence of a novel begomovirus (genus Begomovirus) infecting cotton from Argentina. Two circular ssDNA virus sequences were assembled from high-throughput sequencing data from Gossyipium hirsutum cotton samples showing mosaic symptoms from Argentina. Structural and functional annotation indicated that the virus sequences corresponded to complete DNA components A and B of a novel New World bipartite begomovirus. Genetic distance and evolutionary analyses support that the detected sequences correspond to a new virus, a tentative prototype member of a novel species which we propose the name "Cotton mosaic virus" (CoMV).	NA	biorxiv
10.1101/2020.02.25.965376	A rapid, accurate approach to inferring pedigrees in endogamous populations	Williams, C. M.; Scelza, B.; Slack, S. D.; Mathias, R. A.; Watson, H.; Barnes, K. C.; Lange, E.; Johnson, R. K.; Gignoux, C. R.; Ramachandran, S.; Henn, B. M.	Brenna M Henn	Dept. of Anthropology and UC Davis Genome Center, University of California, Davis	2024-07-16T00:00:00	3	new results	cc_by_nc_nd	bioinformatics	https://www.biorxiv.org/content/early/2024/07/16/2020.02.25.965376.source.xml	Accurate reconstruction of pedigrees from genetic data remains a challenging problem. Pedigree inference algorithms are often trained only on European-descent families in urban locations. Many relationship categories can be difficult to distinguish (e.g. half-sibships versus avuncular) without external information. Furthermore, existing methods perform poorly in endogamous populations for which there may be reticulations within the pedigrees and elevated haplotype sharing. We present a simple, rapid algorithm which initially uses only high-confidence first-degree relationships to seed a machine learning step based on summary statistics of identity-by-descent (IBD) sharing. One of these statistics, our "haplotype score", is novel and can be used to: (1) distinguish half-sibling pairs from avuncular or grandparent-grandchildren pairs; and (2) assign individuals to ancestor versus descendant generation. We test our approach in a sample of 700 individuals from northern Namibia, sampled from an endogamous population called the Himba. Due to a culture of concurrent relationships in the Himba, there is a high proportion of half-sibships. We accurately identify first through fourth-degree relationships and distinguish between various second-degree relationships: half-sibships, avuncular pairs, and grandparent-grandchildren. We further validate our approach in a second diverse African-descent dataset, the Barbados Asthma Genetics Study (BAGS). Accurate reconstruction of pedigrees holds promise for tracing allele frequency trajectories, improved phasing and other population genomic questions.	NA	biorxiv
10.1101/2020.02.27.968339	Spiking attractor model of motor cortex explains modulation of neural and behavioral variability by prior target information	Rostami, V.; Rost, T.; Schmitt, F. J.; van Albada, S. J.; Riehle, A.; P. Nawrot, M.	Vahid Rostami	Computational Systems Neuroscience, Institute of Zoology, University of Cologne, Cologne, Germany	2024-03-05T00:00:00	4	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2024/03/05/2020.02.27.968339.source.xml	When preparing a movement, we often rely on partial or incomplete information, which can decrement task performance. In behaving monkeys we show that the degree of cued target information is reflected in both, neural variability in motor cortex and behavioral reaction times. We study the underlying mechanisms in a spiking motor-cortical attractor model. By introducing a novel and biologically realistic network topology where excitatory neuron clusters are locally balanced with inhibitory neuron clusters we robustly achieve metastable network activity across a wide range of network parameters. In application to the monkey task, the model performs target-specific action selection and accurately reproduces the task-epoch dependent reduction of trial-to-trial variability in vivo where the degree of reduction directly reflects the amount of processed target information, while spiking irregularity remained constant throughout the task. In the context of incomplete cue information, the increased target selection time of the model can explain increased behavioral reaction times . We conclude that context-dependent neural and behavioral variability is a signum of attractor computation in the motor cortex.	10.1038/s41467-024-49889-4	biorxiv
10.1101/2020.02.29.971424	Trypanosoma brucei ultra-structure cell modifications caused by knockdown of the ribonuclease Rrp44/Dis3	Cesaro, G.; Hiraiwa, P. M.; Carneiro, F. R. G.; Rouam, V.; Legrand, P.; Conesa, J. J.; Refregiers, M.; Pereiro, E.; Guimaraes, B. G.; Jamme, F.; Zanchin, N. I. T.	Nilson I. T. Zanchin	Carlos Chagas Institute, Oswaldo Cruz Foundation, FIOCRUZ-PR, Curitiba-PR, Brazil	2024-01-31T00:00:00	2	new results	cc_by_nc_nd	cell biology	https://www.biorxiv.org/content/early/2024/01/31/2020.02.29.971424.source.xml	Rrp44/Dis3 is an essential protein conserved in all eukaryotes that functions in the maturation of many different RNA precursors and RNA surveillance. The Trypanosoma brucei Rrp44/Dis3 homologue (TbRRP44) is required for maturation of pre-rRNA, spliced leader, and U3 snoRNA precursors. Its depletion leads to inhibition of cell proliferation and eventually to cell death. In this work, we showed that TbRRP44 depletion causes a massive expansion of acidic and lysosome-derived vacuoles, enlargement of cell and nuclei sizes without changes in DNA content, mitochondrial inactivation, and autophagy induction. Consistently, 3D reconstructions using cryo-soft X-ray tomography revealed extreme vacuolation of the cytoplasm and numerous cellular alterations, including an increase in size and number of calcium-containing vesicles and lipid droplets. These multiple defects indicate that a combination of alterations converge to induce lysosome expansion. With time, the cytoplasm is taken up by lysosome-derived vacuoles, which may be a final stage leading to the cell death triggered by TbRRP44 depletion. These studies provide the first evidence on the ultra-structure cell modifications caused by deficiency of this essential ribonuclease in T. brucei.	NA	biorxiv
10.1101/2020.03.05.979468	Neurons in the ventral striatopallidal complex modulate lateral hypothalamic orexin/hypocretin neuron activity: Implications for reward-seeking	Mitchell, C. S.; Mohammadkhani, A.; Manning, E. E.; Campbell, E. J.; Fisher, S. D.; Yeoh, J. W.; Pearl, A. J.; Iredale, J. A.; Burton, N. J.; Qiao, M.; Bains, J. S.; McNally, G. P.; Andrews, Z. A.; Graham, B. A.; Scammel, T. E.; Lowell, B. B.; Kong, D.; Borgland, S. L.; Dayas, C. V.	Christopher V Dayas	School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia.	2024-03-03T00:00:00	2	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2024/03/03/2020.03.05.979468.source.xml	Reward-seeking involves the engagement and computation of multiple physiological and motivational parameters. The lateral hypothalamus (LH) is a necessary node in the circuits that control food-seeking and motivation. One group of cells that plays an important yet incompletely understood role in these processes are the orexin/hypocretin (OX/HT) neurons. OX/HT cells are located exclusively within the LH and are implicated in feeding, arousal, and reward-seeking behavior. Importantly, the role of OX/HT neurons in consummatory versus reward-seeking actions is not fully defined, nor are the circuits that control the activity of these neurons under different behavioral states. Here we show that OX/HT neurons respond in real time to food presentation and that this response is modulated by differences in metabolic state. We observed increased OX/HT neuron activity on approach to food, but this activity trended towards pre-approach levels by the start of the consummatory phase. Next, we studied ventrostriatopallidal (VSP) inputs to the OX/HT neurons. Using optogenetics and cell type-specific electrophysiology, we found that ventral pallidum inputs onto OX/HT neurons exert strong inhibitory (and weak excitatory) effects whereas the lateral nucleus accumbens shell provides weaker direct inhibitory connections with OX/HT neurons. These findings reveal that the activity of OX/HT neurons is strongly modulated by metabolic and hedonic state. Further, OX/HT neurons is primarily associated with food approach and that the effect of VSP-terminal output is to suppress OX/HT activity.	NA	biorxiv
10.1101/2020.03.11.988238	Immune Digital Twin Blueprint: A Comprehensive Simulatable Model of the Human Immune System	Moore, R.; Amin, R.; Aghamiri, S.; Mohammed, A.; La Fleur, A.; Puniya, B. L.; Helikar, T.	Tomas Helikar	University of Nebraska - Lincoln	2023-05-16T00:00:00	2	new results	cc_by_nd	systems biology	https://www.biorxiv.org/content/early/2023/05/16/2020.03.11.988238.source.xml	The immune system is a complex and dynamic network, crucial for combating infections and maintaining health. Developing a comprehensive digital twin of the immune system requires incorporating essential cellular components and their interactions. This study presents the first blueprint for an immune system digital twin, consisting of a comprehensive and simulatable mechanistic model. It integrates 51 innate and adaptive immune cells, 37 secretory factors, and 11 disease conditions, providing the foundation for developing a multi-scale model. The cellular-level model demonstrates its potential in characterizing immune responses to various single and combinatorial disease conditions. By making the model available in easy-to-use formats directly in the Cell Collective platform, the community can easily and further expand it. This blueprint represents a significant step towards developing general-purpose immune digital twins, with far-reaching implications for the future of digital twin technology in life sciences and healthcare, advancing patient care, and accelerating precision medicine.	NA	biorxiv
10.1101/2020.03.11.988238	Immune Digital Twin Blueprint: A Comprehensive Mechanistic Model of the Human Immune System	Amin, R.; Aghamiri, S.; Puniya, B. L.; Mayo, L.; Startsev, D.; Poore, K.; Helikar, R. M.; Helikar, T.	Tomas Helikar	University of Nebraska - Lincoln	2024-07-31T00:00:00	3	new results	cc_by_nd	systems biology	https://www.biorxiv.org/content/early/2024/07/31/2020.03.11.988238.source.xml	The immune system is a complex and dynamic network, crucial for combating infections and maintaining health. Developing a comprehensive digital twin of the immune system requires incorporating essential cellular components and their interactions. This study presents the first blueprint for an immune system digital twin, consisting of a comprehensive and simulatable mechanistic model. It integrates 51 innate and adaptive immune cells, 37 secretory factors, and 11 disease conditions, providing the foundation for developing a multi-scale model. The cellular-level model demonstrates its potential in characterizing immune responses to various single and combinatorial disease conditions. By making the model available in easy-to-use formats directly in the Cell Collective platform, the community can easily and further expand it. This blueprint represents a significant step towards developing general-purpose immune digital twins, with far-reaching implications for the future of digital twin technology in life sciences and healthcare, advancing patient care, and accelerating precision medicine.	NA	biorxiv
10.1101/2020.03.17.995431	pyComBat, a Python tool for batch effects correction in high-throughput molecular data using empirical Bayes methods	Behdenna, A.; Colange, M.; Haziza, J.; Gema, A. P.; Appe, G.; Azencott, C.-A.; Nordor, A.	Akpéli Nordor	Epigene Labs, Paris, France	2023-08-29T00:00:00	3	confirmatory results	cc_by_nc_nd	bioinformatics	https://www.biorxiv.org/content/early/2023/08/29/2020.03.17.995431.source.xml	BackgroundVariability in datasets is not only the product of biological processes: they are also the product of technical biases. ComBat and ComBat-Seq are among the most widely used tools for correcting those technical biases, called batch effects, in, respectively, microarray and RNA-Seq expression data. ResultsIn this technical note, we present a new Python implementation of ComBat and ComBat-Seq. While the mathematical framework is strictly the same, we show here that our implementations: (i) have similar results in terms of batch effects correction; (ii) are as fast or faster than the original implementations in R and; (iii) offer new tools for the bioinformatics community to participate in its development. pyComBat is implemented in the Python language and is distributed under GPL-3.0 (https://www.gnu.org/licenses/gpl-3.0.en.html) license as a module of the inmoose package. Source code is available at https://github.com/epigenelabs/inmoose and Python package at https://pypi.org/project/inmoose. ConclusionsWe present a new Python implementation of state-of-the-art tools ComBat and ComBat-Seq for the correction of batch effects in microarray and RNA-Seq data. This new implementation, based on the same mathematical frameworks as ComBat and ComBat-Seq, offers similar power for batch effect correction, at reduced computational cost. Contactakpeli@epigenelabs.com	10.1186/s12859-023-05578-5	biorxiv
10.1101/2020.03.22.002618	Solving the where problem in neuroanatomy: a generative framework with learned mappings to register multimodal, incomplete data into a reference brain	Tward, D. J.; Gray, B. D. P.; Li, X.; Huo, B.; Banerjee, S.; Savoia, S.; Mezias, C.; Das, S.; Miller, M.; Mitra, P. P.	Daniel Jacob Tward	Johns Hopkins University	2024-02-28T00:00:00	2	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2024/02/28/2020.03.22.002618.source.xml	A current focus of research in neuroscience is to enumerate, map and annotate neuronal cell types in whole vertebrate brains using different modalities of data acquisition. Mapping these molecular and anatomical datasets into a common reference space remains a key challenge. While several brain-to-atlas mapping workflows exist, they do not adequately address challenges of modern high throughput neuroimaging, including multimodal and multiscale signals, missing data or non reference signals, and geometric quantification of individual variation. Our solution is to implement a generative statistical model that describes the likelihood of imaging data given a sequence of transforms of an atlas image, and a framework for maximum a posteriori estimation of unknown parameters capturing the issues listed above. The key idea in our approach is to minimize the difference between synthetic image volumes and real data over these parameter. Rather than merely using mappings as a "normalization" step, we implement tools for using their local metric changes as an opportunity for geometric quantification of technical and biological sources of variation in an unprecedented manner. While the framework is used to compute pairwise mappings, our approach particularly allows for easy compositions across chains of multimodality datasets. We apply these methods across a broad range of datasets including various combinations of in-vivo and ex-vivo MRI, 3D STP and fMOST data sets, 2D serial histology sections, and brains processed for snRNAseq with tissue partially removed. We show biological utility by quantifying cell density and diffeomorphic characterization of brain shape fluctuations across biological covariates. We note that the magnitude of individual variation is often greater than differences between different sample preparation techniques. To facilitate community accessibility, we implement our algorithm as open source, include a web based framework, and implement input and output dataset standards. Our work establishes a quantitative, scalable and streamlined workflow for unifying a broad spectrum of multi-modal whole-brain light microscopic data volumes into a coordinate-based atlas framework. This work enables large scale integration of whole brain data sets that are essential in modern neuroscience.	NA	biorxiv
10.1101/2020.03.23.003962	Flagellar dynamics reveal fluctuations and kinetic limit in the Escherichia coli chemotaxis network	Bano, R.; Mears, P.; Golding, I.; Chemla, Y. R.	Yann R Chemla	University of Illinois at Urbana-Champaign	2023-12-03T00:00:00	3	new results	cc_by_nc_nd	biophysics	https://www.biorxiv.org/content/early/2023/12/03/2020.03.23.003962.source.xml	The Escherichia coli chemotaxis network, by which bacteria modulate their random run/tumble swimming pattern to navigate their environment, must cope with unavoidable number fluctuations ("noise") in its molecular constituents like other signaling networks. The probability of clockwise (CW) flagellar rotation, or CW bias, is a measure of the chemotaxis networks output, and its temporal fluctuations provide a proxy for network noise. Here we quantify fluctuations in the chemotaxis signaling network from the switching statistics of flagella, observed using time-resolved fluorescence microscopy of individual optically trapped E. coli cells. This approach allows noise to be quantified across the dynamic range of the network. Large CW bias fluctuations are revealed at steady state, which may play a critical role in driving flagellar switching and cell tumbling. When the network is stimulated chemically to higher activity, fluctuations dramatically decrease. A stochastic theoretical model, inspired by work on gene expression noise, points to CheY activation occurring in bursts, driving CW bias fluctuations. This model also shows that an intrinsic kinetic ceiling on network activity places an upper limit on activated CheY and CW bias, which when encountered suppresses network fluctuations. This limit may also prevent cells from tumbling unproductively in steep gradients.	NA	biorxiv
10.1101/2020.03.23.003061	Modality-independent effect of gravity in shaping the internal representation of 3D space	Theo, M.; Gabriela, H. A.; Leonardo, A.; Gilles, C.; Mathieu, B.; Joseph, M.; Michele, T.	Michele Tagliabue	Université de Paris, Integrative Neuroscience and Cognition Center, CNRS UMR 8002, F-75270 Paris, France.	2023-06-11T00:00:00	2	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2023/06/11/2020.03.23.003061.source.xml	Human 3D perception of visual objects is flawed by distortions, which are influenced by non-visual factors, such as gravitational vestibular signals. Whether gravity acts specifically on the visual system or at a higher, modality-independent, level of information processing remains unknown. To test these modality-specific vs modality-independent hypotheses, we performed experiments comparing visual versus haptic 3D shape perception in normo-gravity and microgravity. The results obtained for upright and supine posture in 1g show that visual and haptic perceptual anisotropies are systematically in opposing ego-centered, but not gravity-centered, directions suggesting they share a common origin. On the other hand, microgravity significantly modulates both visual and haptic perceptual distortion in the same direction. Overall, our results show a clear link between the visual and haptic perceptual distortions and demonstrate a role of gravity-related signals on a modality-independent internal representation of 3D space used to interpret incoming sensory inputs.	10.1523/JNEUROSCI.2457-20.2023	biorxiv
10.1101/2020.03.26.009795	Fifty shades of The Virtual Brain: Converging optimal working points yield biologically plausibleelectrophysiological and imaging features	Triebkorn, P.; Meier, J.; Zimmermann, J.; Stefanovski, L.; Roy, D.; Solodkin, A.; Jirsa, V.; Deco, G.; Breakspear, M.; Schirner, M.; McIntosh, A. R.; Ritter, P.	Paul Triebkorn	Charite Universitatsmedizin Berlin	2024-05-15T00:00:00	2	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2024/05/15/2020.03.26.009795.source.xml	Brain network modeling studies are often limited with respect to the number of data features fitted, although capturing multiple empirical features is important to validate the models overall biological plausibility. Here we construct personalized models from multimodal data of 50 healthy individuals (18-80 years) with The Virtual Brain and demonstrate that an individuals brain has its own converging optimal working point in the parameter space that predicts multiple empirical features in functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). We further show that bimodality in the alpha band power - as an explored novel feature - arises as a function of global coupling and exhibits inter-regional differences depending on the degree. Reliable inter-individual differences with respect to these optimal working points were found that seem to be driven by the individual structural rather than by the functional connectivity. Our results provide the groundwork for future multimodal brain modeling studies.	NA	biorxiv
10.1101/2020.04.06.028092	Post-transcriptional splicing can occur in a slow-moving zone around the gene	Cote, A. J.; O'Farrell, A.; Dardani, I.; Dunagin, M.; Cote, C. J.; Wan, Y.; Bayatpour, S.; Drexler, H. L.; Alexander, K. A.; Chen, F.; Wassie, A. T.; Patel, R.; Pham, K.; Boyden, E. S.; Berger, S.; Phillips-Cremins, J.; Churchman, L. S.; Raj, A.	Arjun Raj	University of Pennsylvania	2023-06-13T00:00:00	3	new results	cc_by	cell biology	https://www.biorxiv.org/content/early/2023/06/13/2020.04.06.028092.source.xml	Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription site proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.	10.7554/eLife.91357	biorxiv
10.1101/2020.04.06.028092	Post-transcriptional splicing can occur in a slow-moving zone around the gene	Cote, A. J.; O'Farrell, A.; Dardani, I.; Dunagin, M.; Cote, C. J.; Wan, Y.; Bayatpour, S.; Drexler, H. L.; Alexander, K. A.; Chen, F.; Wassie, A. T.; Patel, R.; Pham, K.; Boyden, E. S.; Berger, S.; Phillips-Cremins, J.; Churchman, L. S.; Raj, A.	Arjun Raj	University of Pennsylvania	2023-11-13T00:00:00	4	new results	cc_by	cell biology	https://www.biorxiv.org/content/early/2023/11/13/2020.04.06.028092.source.xml	Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription site proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.	10.7554/eLife.91357	biorxiv
10.1101/2020.04.07.029009	Disseminating cells in human tumours acquire an EMT cancer stem cell state that is predictive of metastasis	Youssef, G.; Gammon, L.; Ambler, L.; Lunetto, S.; Scemama, A.; Cottom, H.; Piper, K.; Mackenzie, I. C.; Philpott, M. P.; Biddle, A.	Adrian Biddle	Queen Mary University of London	2023-05-03T00:00:00	2	new results	cc_by	cancer biology	https://www.biorxiv.org/content/early/2023/05/03/2020.04.07.029009.source.xml	Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as markers of EMT CSCs with enhanced plasticity. This afforded the opportunity to investigate whether retention of EpCAM and CD24 alongside upregulation of the EMT marker Vimentin can identify disseminating EMT CSCs in human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 84 human oral cancer specimens, we see a significant enrichment of single EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.	10.7554/eLife.90298	biorxiv
10.1101/2020.04.20.049866	The accelerated infectious disease risk in the Anthropocene: more outbreaks and wider global spread	Morand, S.; Walther, B. A.	Bruno Andreas Walther	National Sun Yat-sen University	2023-08-24T00:00:00	2	confirmatory results	cc_by_nc_nd	ecology	https://www.biorxiv.org/content/early/2023/08/24/2020.04.20.049866.source.xml	The greatly accelerated economic growth during the Anthropocene has resulted in astonishing improvements in many aspects of human well-being, but has also caused the acceleration of risks, such as the interlinked biodiversity and climate crisis. Here, we report on another risk: the accelerated infectious disease risk associated with the number and geographic spread of human infectious disease outbreaks. Using the most complete, reliable, and up-to-date database on human infectious disease outbreaks (GIDEON), we show that the number of disease outbreaks, the number of diseases involved in these outbreaks, and the number of countries affected have increased during the entire Anthropocene. Furthermore, the spatial distribution of these outbreaks is becoming more globalized in the sense that the overall modularity of the disease networks across the globe has decreased, meaning disease outbreaks have become increasingly pandemic in their nature. This decrease in modularity is associated with tremendous increases in mobility, especially in air traffic. We also show that those countries and regions which are most central within these disease networks tend to be countries and global regions with higher GDPs. Therefore, one cost of greater economic growth and the associated increased global mobility is the increased risk of disease outbreaks and their wider spread. Finally, the recent global outbreaks of Covid-19 and monkeypox allowed us to demonstrate that the time of first occurrence in each country was correlated with each countrys centrality value in the disease network. We briefly discuss three different scenarios of how mobility may develop in the future which decision-makers might discuss in light of our results.	NA	biorxiv
10.1101/2020.04.22.043422	Phenotypic innovation in one tooth induced concerted developmental evolution in another	Semon, M.; Gueguen, L.; Steklikova, K.; Mouginot, M.; Peltier, M.; Veber, P.; Pantalacci, S.	Marie Semon	LBMC / ENS Lyon	2023-05-02T00:00:00	3	new results	cc_by_nc_nd	evolutionary biology	https://www.biorxiv.org/content/early/2023/05/02/2020.04.22.043422.source.xml	Serial appendages are similar organs found at different places in the body, such as fore/hindlimbs or different teeth. They are bound to develop with the same pleiotropic genes, apart from identity genes. These identity genes have logically been implicated in cases where a single appendage evolved a drastically new shape while the other retained an ancestral shape, by enabling developmental changes specifically in one organ. Here, we showed that independent evolution involved developmental changes happening in both organs, in two well characterized model systems. Mouse upper molars evolved a new dental plan with two more cusps on the lingual side, while the lower molar kept a much more ancestral morphology, as did the molars of hamster, our control species. We obtained quantitative timelines of cusp formation and corresponding transcriptomic timeseries in the 4 molars. We found that a molecular and morphogenetic identity of lower and upper molars predated the mouse and hamster divergence and likely facilitated the independent evolution of molars lingual side in the mouse lineage. We found 3 morphogenetic changes which could combine to cause the supplementary cusps in the upper molar and a candidate gene, Bmper. Unexpectedly given its milder morphological divergence, we observed extensive changes in mouse lower molar development. Its transcriptomic profiles diverged as much as, and co-evolved extensively with, those of the upper molar. Consistent with the transcriptomic quantifications, two out of the three morphogenetic changes also impacted lower molar development. Moving to limbs, we show the drastic evolution of the bat wing also involved gene expression co-evolution and a combination of specific and pleiotropic changes. Independent morphological innovation in one organ therefore involves concerted developmental evolution of the other organ. This is facilitated by evolutionary flexibility of its development, a phenomenon known as Developmental System Drift. AUTHOR SUMMARYSerial organs, such as the different wings of an insect or the different limbs or teeth of a vertebrate, can develop into drastically different shapes due to the position-specific expression of so-called "identity" genes. Often during evolution, one organ evolves a new shape while another retains a conserved shape. It was thought that identity genes were responsible for these cases of independent evolution, by enabling developmental changes specifically in one organ. Here, we showed that developmental changes evolved in both organs to enable the independent evolution of the upper molar in mice and the wing in bats. In the organ with the new shape, several developmental changes combine. In the organ with the conserved shape, part of these developmental changes are seen as well. This modifies the development but is not sufficient to drastically change the phenotype, a phenomenon known as "Developmental System Drift", DSD. Thus, the independent evolution of one organ relies on concerted molecular changes, which will contribute to adaptation in one organ and be no more than DSD in another organ. This concerted evolution could apply more generally to very different body parts and explain previous observations on gene expression evolution.	NA	biorxiv
10.1101/2020.04.24.014852	HiTaC: a Hierarchical Taxonomic Classifier for Fungal ITS Sequences	Miranda, F. M.; Azevedo, V. A. C.; Ramos, R. T. J.; Renard, B. Y.; C. Piro, V.	Vitor C. Piro	Hasso Plattner Institut	2023-06-04T00:00:00	4	new results	cc_by	bioinformatics	https://www.biorxiv.org/content/early/2023/06/04/2020.04.24.014852.source.xml	BackgroundFungi play a key role in several important ecological functions, ranging from organic matter decomposition to symbiotic associations with plants. Moreover, fungi naturally inhabit the human body and can be beneficial when administered as probiotics. In mycology, the internal transcribed spacer (ITS) region was adopted as the universal marker for classifying fungi. Hence, an accurate and robust method for ITS classification is not only desired for the purpose of better diversity estimation, but it can also help us gain a deeper insight into the dynamics of environmental communities and ultimately comprehend whether the abundance of certain species correlate with health and disease. Although many methods have been proposed for taxonomic classification, to the best of our knowledge, none of them fully explore the taxonomic tree hierarchy when building their models. This in turn, leads to lower generalization power and higher risk of committing classification errors. ResultsHere we introduce HiTaC, a robust hierarchical machine learning model for accurate ITS classification, which requires a small amount of data for training and can handle imbalanced datasets. HiTaC was thoroughly evaluated with the established TAXXI benchmark and could correctly classify fungal ITS sequences of varying lengths and a range of identity differences between the training and test data. HiTaC outperforms state-of-the-art methods when trained over noisy data, consistently achieving higher F1-score and sensitivity across different taxonomic ranks, improving sensitivity by 6.9 percentage points over top methods in the most noisy dataset available on TAXXI. ConclusionsHiTaC is publicly available at the Python package index, BIO-CONDA and Docker Hub. It is released under the new BSD license, allowing free use in academia and industry. Source code and documentation, which includes installation and usage instructions, are available at https://gitlab.com/dacs-hpi/hitac.	10.1186/s12859-024-05839-x	biorxiv
10.1101/2020.04.24.014852	HiTaC: a hierarchical taxonomic classifier for fungal ITS sequences compatible with QIIME2	Miranda, F. M.; Azevedo, V. A. C.; Ramos, R. T. J.; Renard, B. Y.; C. Piro, V.	Vitor C. Piro	Hasso Plattner Institut	2024-03-15T00:00:00	5	new results	cc_by	bioinformatics	https://www.biorxiv.org/content/early/2024/03/15/2020.04.24.014852.source.xml	BackgroundFungi play a key role in several important ecological functions, ranging from organic matter decomposition to symbiotic associations with plants. Moreover, fungi naturally inhabit the human body and can be beneficial when administered as probiotics. In mycology, the internal transcribed spacer (ITS) region was adopted as the universal marker for classifying fungi. Hence, an accurate and robust method for ITS classification is not only desired for the purpose of better diversity estimation, but it can also help us gain a deeper insight into the dynamics of environmental communities and ultimately comprehend whether the abundance of certain species correlate with health and disease. Although many methods have been proposed for taxonomic classification, to the best of our knowledge, none of them fully explore the taxonomic tree hierarchy when building their models. This in turn, leads to lower generalization power and higher risk of committing classification errors. ResultsHere we introduce HiTaC, a robust hierarchical machine learning model for accurate ITS classification, which requires a small amount of data for training and can handle imbalanced datasets. HiTaC was thoroughly evaluated with the established TAXXI benchmark and could correctly classify fungal ITS sequences of varying lengths and a range of identity differences between the training and test data. HiTaC outperforms state-of-the-art methods when trained over noisy data, consistently achieving higher F1-score and sensitivity across different taxonomic ranks, improving sensitivity by 6.9 percentage points over top methods in the most noisy dataset available on TAXXI. ConclusionsHiTaC is publicly available at the Python package index, BIO-CONDA and Docker Hub. It is released under the new BSD license, allowing free use in academia and industry. Source code and documentation, which includes installation and usage instructions, are available at https://gitlab.com/dacs-hpi/hitac.	10.1186/s12859-024-05839-x	biorxiv
10.1101/2020.04.24.059097	Characterising a stable five-species microbial community for use in experimental evolution and ecology.	Castledine, M.; Pennycook, J.; Newbury, A.; Lear, L.; Erdos, Z.; Lewis, R.; Kay, S.; Sanders, D.; Sunderhauf, D.; Buckling, A.; Hesse, E.; Padfield, D.	Daniel Padfield	University of Exeter	2024-04-11T00:00:00	2	new results	cc_by_nd	ecology	https://www.biorxiv.org/content/early/2024/04/11/2020.04.24.059097.source.xml	Model microbial communities are regularly used to test ecological and evolutionary theory as they are easy to manipulate and have fast generation times, allowing for large-scale, high throughput experiments. A key assumption for most model microbial communities is that they stably coexist, but this is rarely tested experimentally. Here we report the (dis)assembly of a five-species microbial community from a metacommunity of soil microbes that can be used for future experiments. Using reciprocal invasion from rare experiments we show that all species can coexist and we demonstrate that the community is stable for a long time ([~]600 generations). Crucially for future work, we show that each species can be identified by their plate morphologies, even after >1 year in co-culture. We characterise pairwise species interactions and produce high-quality reference genomes for each species. This stable five-species community can be used to test key questions in microbial ecology and evolution.	NA	biorxiv
10.1101/2020.04.25.061531	WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder	Singh, A. K.; Praharaj, M.; Lombardo, K. A.; Yoshida, T.; Matoso, A.; Baras, A. S.; Zhao, L.; Prasad, P.; Powell, J. D.; Kates, M.; McConkey, D.; Pardoll, D. M.; Bishai, W. R.; Bivalacqua, T. J.	Trinity J. Bivalacqua	Johns Hopkins School of Medicine	2023-12-20T00:00:00	4	withdrawn	cc_by	cancer biology	https://www.biorxiv.org/content/early/2023/12/20/2020.04.25.061531.source.xml	Withdrawal StatementThe authors have withdrawn their manuscript owing to irregularities in the Source Data supporting some figures. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding authors.	10.1038/s41467-022-28509-z	biorxiv
10.1101/2020.04.27.063628	Toxoplasma FER1 is a versatile and dynamic mediator of differential microneme trafficking and microneme exocytosis	Tagoe, D. N.; Ribeiro E Silva, A.; Drozda, A. A.; Coppens, I.; Coleman, B. I.; Gubbels, M.-J.	Marc-Jan Gubbels	Boston College	2024-06-11T00:00:00	2	new results	cc_by_nc_nd	cell biology	https://www.biorxiv.org/content/early/2024/06/11/2020.04.27.063628.source.xml	Toxoplasma gondii is a polarized cell concentrating several secretory organelles at the apical pole. The secretory micronemes come in two sub-populations differentiated by dependence on the Rab5A/C in their biogenesis. Calcium-dependent exocytosis of micronemes occurs at the very apical tip and is critical for parasite egress from its host cell, adhesion and invasion of the next cell. Ferlins represent a protein family with roles in exocytosis containing multiple Ca2+-sensing C2 domains. We determined that T. gondiis ferlin 1 (FER1) localized dynamically to the parasites secretory pathway. FER1 function was dissected by dominant negative overexpression strategies. We demonstrated that FER1 traffics microneme organelles along the following trajectories:1. From the trans-Golgi-endosomes network to the subpellicular cortex; 2. Along the cortex to the apical end; 3. To the apical tip for fusion with the plasma membrane; 4. Retrograde transport allowing microneme recycling from mother to daughter; 5. Differential microneme sub-population traffic. Finally, FER1 overexpression triggers a microneme exocytosis burst, supporting the notion that the radially organized micronemes at the apical tip comprise a readily-releasable microneme pool. In summary, FER1 is pivotal for dynamic microneme trafficking, acts differently on the two microneme subpopulations, and acts on the plasma membrane fusion step during microneme exocytosis.	NA	biorxiv
10.1101/2020.04.28.065755	Single-cell copy number calling and event history reconstruction	Kuipers, J.; Tuncel, M. A.; Ferreira, P. F.; Jahn, K.; Beerenwinkel, N.	Niko Beerenwinkel	D-BSSE, ETH Zurich	2024-06-03T00:00:00	2	new results	cc_by_nc_nd	cancer biology	https://www.biorxiv.org/content/early/2024/06/03/2020.04.28.065755.source.xml	Copy number alterations are driving forces of tumour development and the emergence of intra-tumour heterogeneity. A comprehensive picture of these genomic aberrations is therefore essential for the development of personalised and precise cancer diagnostics and therapies. Single-cell sequencing offers the highest resolution for copy number profiling down to the level of individual cells. Recent high-throughput protocols allow for the processing of hundreds of cells through shallow whole-genome DNA sequencing. The resulting low read-depth data poses substantial statistical and computational challenges to the identification of copy number alterations. We developed SCICoNE, a statistical model and MCMC algorithm tailored to single-cell copy number profiling from shallow whole-genome DNA sequencing data. SCICoNE reconstructs the history of copy number events in the tumour and uses these evolutionary relationships to identify the copy number profiles of the individual cells. We show the accuracy of this approach in evaluations on simulated data and demonstrate its practicability in applications to two breast cancer samples from different sequencing protocols.	NA	biorxiv
10.1101/2020.04.29.069138	Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity	Ceddia, R. P.; Zurawski, Z.; Thompson Gray, A.; Adegboye, F.; McDonald-Boyer, A.; Shi, F.; Liu, D.; Maldonado, J.; Feng, J.; Li, Y.; Alford, S.; Ayala, J. E.; McGuinness, O. P.; Collins, S.; Hamm, H. E.	Heidi E Hamm	Vanderbilt University	2023-06-06T00:00:00	4	new results	cc_by_nc_nd	physiology	https://www.biorxiv.org/content/early/2023/06/06/2020.04.29.069138.source.xml	Negative regulation of exocytosis from secretory cells throughout the body is accomplished through inhibitory signals from Gi/o G protein-coupled receptors by G{beta}{gamma} subunit inhibition of two common mechanisms: (i) decreased calcium entry and (ii) direct interaction of G{beta}{gamma} with the Soluble N-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. We have previously shown that disabling the second mechanism with a truncation of SNAP25 (SNAP25{Delta}3/{Delta}3) decreases the affinity of G{beta}{gamma} for the SNARE complex, leaving exocytotic fusion as well as modulation of calcium entry intact but disabling GPCR inhibition of exocytosis. Here we report significant beneficial metabolic remodeling in mice carrying this mutation. Chow-fed SNAP25{Delta}3/{Delta}3 mice exhibit enhanced insulin sensitivity and increased beiging of white fat. In response to a high fat diet, the metabolic protection was amplified in SNAP25{Delta}3/{Delta}3 mice. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. This metabolic protection in SNAP25{Delta}3/{Delta}3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting basal autonomic activity is required. Direct electrode stimulation of sympathetic neurons exocytosis from SNAP25{Delta}3/{Delta}3 inguinal adipose depot resulted in enhanced and prolonged norepinephrine release. Thus, the G{beta}{gamma}-SNARE interaction represents a cellular mechanism that deserves further exploration as a new avenue for combatting metabolic disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/069138v4_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@2c1fa0org.highwire.dtl.DTLVardef@d076ceorg.highwire.dtl.DTLVardef@27e351org.highwire.dtl.DTLVardef@bce219_HPS_FORMAT_FIGEXP M_FIG C_FIG	NA	biorxiv
10.1101/2020.05.04.075119	Single-cell RNA sequencing reveals subset-specific functional reprogramming of CD4+ T-cells from PLHIV upon ex vivo HDAC inhibition and biomarkers of cells harbouring non-silent proviruses	Kazmierski, J.; Postmus, D.; Wyler, E.; Fadejeva, J.; Steijaert, T.; Fischer, C.; Jansen, J.; Koppe, U.; Gunsenheimer-Bartmeyer, B.; Meixenberger, K.; Vitcetz, S.; Sohn, M.; Loyal, L.; Thiel, A.; Sauer, S.; Bannert, N.; Landthaler, M.; GOFFINET, C.	Christine GOFFINET	Charite - Universitaetsmedizin Berlin	2023-06-04T00:00:00	2	new results	cc_by_nc	microbiology	https://www.biorxiv.org/content/early/2023/06/04/2020.05.04.075119.source.xml	Shock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcription in vitro, ex vivo and in vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+ T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+ T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+ T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivation per se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-{beta} and -14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies.	NA	biorxiv
10.1101/2020.05.04.075119	Type I interferons sensitise HIV-1-reactivating T-cells for NK cell-mediated elimination despite HDACi-imposed dysregulation of innate immunity	Prigann, J.; Postmus, D.; Pietrobon, A. J.; Wyler, E.; Jansen, J.; Moeller, L.; Fadejeva, J.; Steijaert, T.; Fischer, C.; Koppe, U.; Gunsenheimer-Bartmeyer, B.; Meixenberger, K.; Vitcetz, S.; Sohn, M.; Loyal, L.; Thiel, A.; Sauer, S.; Sutter, K.; Dittmer, U.; Laue, M.; Bannert, N.; Landthaler, M.; GOFFINET, C.	Christine GOFFINET	Charite - Universitaetsmedizin Berlin	2023-11-19T00:00:00	3	new results	cc_by_nc	microbiology	https://www.biorxiv.org/content/early/2023/11/19/2020.05.04.075119.source.xml	Shock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcription in vitro, ex vivo and in vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+ T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+ T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+ T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivation per se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-{beta} and -14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies.	NA	biorxiv
10.1101/2020.05.08.080929	The evolution of sex allocation in metapopulations	Roux, C.; Mullon, C. D. L.; Pannell, J.	John Pannell	Univ. of Lausanne	2024-04-08T00:00:00	2	new results	cc_by_nc_nd	evolutionary biology	https://www.biorxiv.org/content/early/2024/04/08/2020.05.08.080929.source.xml	Selection in inbred populations is expected to favor female-biased sex ratios in dioecious populations as a result of local mate competition, a prediction that finds strong support in situations where females have control of the sex ratio. Local mate competition due to inbreeding should also promote female-biased sex allocation in hermaphrodites, with reduced emphasis on the production and dispersal of sperm or pollen relative to that of eggs, ovules or seeds. While inbreeding can be the direct result of the mating system in local populations, it can also be brought about by population turnover in metapopulations with frequent local extinction and recolonization. This effect of population turnover has previously been considered for species with separate sexes. Here, we use both formal analysis and individual-based simulations to explore the effect of population turnover on sex allocation in partially self-fertilizing hermaphroditic metapopulations. Using simulations, we also assess the extent to which different genetic measures of inbreeding and population differentiation predict the equilibrium sex allocation. We find that population turnover can select for strongly female-biased sex allocation in hermaphroditic metapopulations, particularly if amongdeme dispersal is low, even where local demes are fully outcrossing. In such situations, FST is a good predictor of the equilibrium sex allocation, and much better than the alternative differentiation measures GST and Josts D. Our study extends predictions for sex allocation in subdivided populations to hermaphroditic species, and draws attention in general to the power of Wrights hierarchical inbreeding statistics to predict the sex allocation in metapopulations at equilibrium.	NA	biorxiv
10.1101/2020.05.08.084848	Generating Synthetic Signaling Networks for in Silico Modeling Studies	Xu, J.; Wiley, H. S.; Sauro, H. M.	Herbert M. Sauro	University of Washington	2023-05-15T00:00:00	2	new results	cc_by_nc_nd	systems biology	https://www.biorxiv.org/content/early/2023/05/15/2020.05.08.084848.source.xml	Predictive models of signaling pathways have proven to be difficult to develop. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. To meet this need, we developed a method for generating artificial signaling networks that were reasonably realistic and thus could be treated as ground truth models. These synthetic models could then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. We defined the reaction degree and reaction distance to measure the topology of reaction networks, especially to consider enzymes. To determine whether our generated signaling networks displayed meaningful behavior, we compared them with signaling networks from the BioModels Database. This comparison indicated that our generated signaling networks had high topological similarities with BioModels signaling networks with respect to the reaction degree and distance distributions. In addition, our synthetic signaling networks had similar behavioral dynamics with respect to both steady states and oscillations, suggesting that our method generated synthetic signaling networks comparable with BioModels and thus could be useful for building network evaluation tools. HighlightsO_LIWe provided a Julia script to generate synthetic signaling networks. C_LIO_LIWe defined reaction degree and distance to measure the reaction network topology. C_LIO_LIWe provided the Python scripts to calculate the reaction network topology. C_LIO_LIThe synthetic signaling networks had topological similarities with the BioModels. C_LIO_LIThe synthetic signaling networks had dynamic similarities with the BioModels. C_LI	NA	biorxiv
10.1101/2020.05.08.084848	Generating synthetic signaling networks for in silico modeling studies	Xu, J.; Wiley, S.; Sauro, H. M.	Herbert M. Sauro	University of Washington	2024-02-01T00:00:00	3	new results	cc_by_nc_nd	systems biology	https://www.biorxiv.org/content/early/2024/02/01/2020.05.08.084848.source.xml	Predictive models of signaling pathways have proven to be difficult to develop. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. To meet this need, we developed a method for generating artificial signaling networks that were reasonably realistic and thus could be treated as ground truth models. These synthetic models could then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. We defined the reaction degree and reaction distance to measure the topology of reaction networks, especially to consider enzymes. To determine whether our generated signaling networks displayed meaningful behavior, we compared them with signaling networks from the BioModels Database. This comparison indicated that our generated signaling networks had high topological similarities with BioModels signaling networks with respect to the reaction degree and distance distributions. In addition, our synthetic signaling networks had similar behavioral dynamics with respect to both steady states and oscillations, suggesting that our method generated synthetic signaling networks comparable with BioModels and thus could be useful for building network evaluation tools. HighlightsO_LIWe provided a Julia script to generate synthetic signaling networks. C_LIO_LIWe defined reaction degree and distance to measure the reaction network topology. C_LIO_LIWe provided the Python scripts to calculate the reaction network topology. C_LIO_LIThe synthetic signaling networks had topological similarities with the BioModels. C_LIO_LIThe synthetic signaling networks had dynamic similarities with the BioModels. C_LI	NA	biorxiv
10.1101/2020.05.08.084848	Generating synthetic signaling networks for in silico modeling studies	Xu, J.; Wiley, S.; Sauro, H. M.	Herbert M. Sauro	University of Washington	2024-06-07T00:00:00	4	new results	cc_by_nc_nd	systems biology	https://www.biorxiv.org/content/early/2024/06/07/2020.05.08.084848.source.xml	Predictive models of signaling pathways have proven to be difficult to develop. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. To meet this need, we developed a method for generating artificial signaling networks that were reasonably realistic and thus could be treated as ground truth models. These synthetic models could then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. We defined the reaction degree and reaction distance to measure the topology of reaction networks, especially to consider enzymes. To determine whether our generated signaling networks displayed meaningful behavior, we compared them with signaling networks from the BioModels Database. This comparison indicated that our generated signaling networks had high topological similarities with BioModels signaling networks with respect to the reaction degree and distance distributions. In addition, our synthetic signaling networks had similar behavioral dynamics with respect to both steady states and oscillations, suggesting that our method generated synthetic signaling networks comparable with BioModels and thus could be useful for building network evaluation tools. HighlightsO_LIWe provided a Julia script to generate synthetic signaling networks. C_LIO_LIWe defined reaction degree and distance to measure the reaction network topology. C_LIO_LIWe provided the Python scripts to calculate the reaction network topology. C_LIO_LIThe synthetic signaling networks had topological similarities with the BioModels. C_LIO_LIThe synthetic signaling networks had dynamic similarities with the BioModels. C_LI	NA	biorxiv
10.1101/2020.05.12.079863	Haplotype-based analysis distinguishes maternal-fetal genetic contribution to pregnancy-related outcomes	Srivastava, A. K.; Juodakis, J.; Sole-Navais, P.; Chen, J.; Bacelis, J.; Teramo, K.; Hallman, M.; Njolstad, P. R.; Evans, D. M.; Jacobsson, B.; Muglia, L. J.; Zhang, G.	Ge Zhang	Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, USA	2023-06-30T00:00:00	2	new results	cc_by_nc_nd	genetics	https://www.biorxiv.org/content/early/2023/06/30/2020.05.12.079863.source.xml	AbstractGenotype-based approaches for the estimation of SNP-based narrow-sense heritability [Formula] have limited utility in pregnancy-related outcomes due to confounding by the shared alleles between mother and child. Here, we propose a haplotype-based approach to estimate the genetic variance attributable to three haplotypes - maternal transmitted [Formula], maternal non-transmitted [Formula] and paternal transmitted [Formula] in mother-child pairs. We show through extensive simulations that our haplotype-based approach outperforms the conventional and contemporary approaches for resolving the contribution of maternal and fetal effects, particularly when m1 and p1 have different effects in the offspring. We apply this approach to estimate the explicit and relative maternal-fetal genetic contribution to the phenotypic variance of gestational duration and gestational duration adjusted fetal size measurements at birth in 10,375 mother-child pairs. The results reveal that variance of gestational duration is mainly attributable to m1 and m2 ([Formula]= 17.3%, S. E. = 5.2%; [Formula] = 12.2%, S. E. = 5.2%; [Formula] = 0.0%, S. E. = 5.0%). In contrast, variance of fetal size measurements at birth are mainly attributable to m1 and p1 ([Formula] = 18.6 - 36.4%, [Formula] = 0.0 - 5.2% and [Formula] = 4.4 - 13.6%). Our results suggest that gestational duration and fetal size measurements are primarily genetically determined by the maternal and fetal genomes, respectively. In addition, a greater contribution of m1 as compared to m2 and p1 [Formula] to birth length and head circumference suggests a substantial influence of correlated maternal-fetal genetic effects on these traits. Our newly developed approach provides a direct and robust alternative for resolving explicit maternal and fetal genetic contributions to the phenotypic variance of pregnancy-related outcomes.	NA	biorxiv
10.1101/2020.05.14.096032	Mycobacteria inhibit neutrophil recruitment to avoid neutrophil-assisted killing by macrophages	Candel, S.; Ramakrishnan, L.	Lalita Ramakrishnan	University of Cambridge	2023-07-26T00:00:00	4	withdrawn	cc_by	molecular biology	https://www.biorxiv.org/content/early/2023/07/26/2020.05.14.096032.source.xml	This article was withdrawn on 29 July 2020 after inaccuracies were identified in the experiments reported in the manuscript. The corresponding author, Professor Lalita Ramakishnan, reported concerns regarding data in the manuscript to the University of Cambridge. An investigation by the University of Cambridge concluded that data related to Alox5 -/-; mpx-/- double knockout zebrafish included in the manuscript had been fabricated. If you have any questions, please contact the corresponding author (Lalita Ramakrishnan, lr404@cam.ac.uk).	NA	biorxiv
10.1101/2020.05.14.096230	scRNA-seq analysis of colon and esophageal tumors uncovers abundant microbial reads in myeloid cells undergoing proinflammatory transcriptional alterations	Robinson, W.; Stone, J. K.; Schischlik, F.; Gasmi, B.; Kelly, M. C.; Seibert, C.; Dadkhah, K.; Gertz, E. M.; Lee, J. S.; Zhu, K.; Ma, L.; Wang, X. W.; Sahinalp, C.; Patro, R.; Leiserson, M. D.; Harris, C. C.; Schäffer, A. A.; Ruppin, E.	Eytan Ruppin	Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute	2023-04-28T00:00:00	3	new results	cc0	cancer biology	https://www.biorxiv.org/content/early/2023/04/28/2020.05.14.096230.source.xml	The study of the tumor microbiome has been garnering increased attention. We developed a computational pipeline (CSI-Microbes) for identifying microbial reads from single-cell RNA sequencing (scRNA-seq) data. Using a series of controlled experiments and analyses, we performed the first systematic evaluation of the efficacy of recovering microbial UMIs by multiple scRNA-seq technologies, which identified the newer 10x chemistries (3 v3 and 5) as the best suited approach. Based on these findings, we analyzed patient esophageal and colorectal carcinomas and found that reads from distinct genera tend to co-occur in the same host cells, testifying to possible intracellular polymicrobial interactions. Microbial reads are disproportionately abundant within myeloid cells that upregulate proinflammatory cytokines like IL1B and CXCL8 and downregulate antigen processing and presentation (APP) pathways. The latter, however, are markedly upregulated in infected tumor cells. These results testify that intracellular bacteria predominately reside within co-opted myeloid cells, which inflame the tumor microenvironment and may influence immunotherapy response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/096230v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@16399a5org.highwire.dtl.DTLVardef@1fc464dorg.highwire.dtl.DTLVardef@16ba6c5org.highwire.dtl.DTLVardef@91fa4c_HPS_FORMAT_FIGEXP M_FIG C_FIG	NA	biorxiv
10.1101/2020.05.15.097907	HerpesDRG: a comprehensive resource for human herpesvirus antiviral drug resistance genotyping	Charles, O. J.; Venturini, C.; Goldstein, R. A.; Breuer, J.	Judith Breuer	University College London	2023-10-24T00:00:00	2	new results	cc_by_nc_nd	bioinformatics	https://www.biorxiv.org/content/early/2023/10/24/2020.05.15.097907.source.xml	The prevention and treatment of many herpesvirus associated diseases is based on the utilization of antiviral therapies, however therapeutic success is limited by the development of drug resistance. A comprehensive point of truth of resistance conferring mutations has been missing but would be important to aid the development of antiviral drugs and in management of infections. We therefore developed HerpesDRG, a drug resistance mutation database for all the known important genes and current treatment options, built from a systematic review of available genotype to phenotype literature. The database is released along with an R package to provide a low barrier of entry to variant resistance annotation and clinical implication analysis from common sanger and NGS sequence data. This represents the first openly available and community maintainable knowledgebase of drug resistance mutations for the human herpes viruses (HHV), developed for the community of researchers and clinicians tackling HHV drug resistance. AvailabilityThe HerpesDRG database is available at github.com/ojcharles/herpesdrg-db. The R package for resistance genotyping data is available at github.com/ojcharles/herpesdrg. A user-friendly webserver is available at cmv-resistance.ucl.ac.uk/herpesdrg	NA	biorxiv
10.1101/2020.05.20.106930	WITHDRAWN: Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific	Salter, E. W.; Lei, G.; Choi, S.-L.; Ralph, L. T.; Zhang, L.; Jin, F.; Kadia, A.; Wang, J.; Georgiou, J.; Collingridge, G. L.	Graham L Collingridge	Lunenfeld-Tanenbaum Research Institute/University of Toronto/University of Bristol/TANZ Centre for Research in Neurodegenerative Diseases	2023-09-26T00:00:00	2	withdrawn	cc_by	neuroscience	https://www.biorxiv.org/content/early/2023/09/26/2020.05.20.106930.source.xml	Withdrawal statementThe authors have withdrawn their manuscript owing to the results of this pre-print being based on experiments performed prior to COVID-19 shutdowns, which required a near complete culling of the mouse colony. Upon re-initiating the colony, the phenotype outlined in the pre-print could no longer be observed and as such we have decided to withdraw the pre-print. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.	NA	biorxiv
10.1101/2020.05.25.114959	Improvements in task performance after practice are associated with scale-free dynamics of brain activity	Kardan, O.; Stier, A. J.; Layden, E. A.; Choe, K. W.; Lyu, M.; Zhang, X.; Beilock, S. L.; Rosenberg, M. D.; Berman, M. G.	Omid Kardan	University of Chicago	2023-04-04T00:00:00	2	new results	cc_by_nc_nd	neuroscience	https://www.biorxiv.org/content/early/2023/04/04/2020.05.25.114959.source.xml	Although practicing a task generally benefits later performance on that same task, there are individual differences in practice effects. One avenue to model such differences comes from research showing that brain networks extract functional advantages from operating in the vicinity of criticality, a state in which brain network activity is more scale-free. We hypothesized that higher scale-free signal from fMRI data, measured with the Hurst exponent (H), indicates closer proximity to critical states. We tested whether individuals with higher H during repeated task performance would show greater practice effects. In Study 1, participants performed a dual-n-back task (DNB) twice during MRI (n = 56). In Study 2, we used two runs of n-back task (NBK) data from the Human Connectome Project sample (n = 599). In Study 3, participants performed a word completion task (CAST) across 6 runs (n = 44). In all three studies, multivariate analysis was used to test whether higher H was related to greater practice-related performance improvement. Supporting our hypothesis, we found patterns of higher H that reliably correlated with greater performance improvement across participants in all three studies. However, the predictive brain regions were distinct, suggesting that the specific spatial H{uparrow} patterns are not task-general.	10.1162/netn_a_00319	biorxiv
10.1101/2020.05.26.104687	Pictorial balance is a bottom-up aesthetic property mediated by eye movements. A model of a primitive visual operating system explains balance and visual properties of pictures	Corwin, D. M.	David M Corwin	David Corwin MD	2023-08-22T00:00:00	18	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2023/08/22/2020.05.26.104687.source.xml	Pictorial balance has been used to explain why some paintings evoke feelings of unity and harmony. This study shows how it is calculated and proposes an evolutionary reason for its existence. The concept of pictorial balance as a center of mass effect, i.e. the feeling that somehow a person on the left seems to be balanced by a tree on the right, originated at the beginning of the 20th century. It had never been mentioned in art commentary of the previous 500 years, and yet has become a widely assumed but unsubstantiated explanation of why some paintings evoke feelings of unity and harmony. Despite the lack of historical documentation, the perception of pictorial balance exists. This study shows how the low-level visual system calculates balance, how it evokes feelings of unity and harmony, and its evolutionary importance in visualizing the world of moving organisms. It is done by means of a study of an elusive pictorial effect known to painters, in which these feelings are evoked. In such pictures the image seems to be perceived as a whole without the need to fixate on individual depicted objects. The effect was first described by a 17th century critic Roger de Piles and subsequently by a few renowned artists. The author hypothesized that this response was due to the painting being in a state of perfect balance. Computer modeling found that such a picture must have bilateral luminance symmetry with a lighter lower half by [~]1.07. A study was conducted in which the identical picture seen sequentially in slightly different frames could seem different to observers because of the change in balance created by the frames. The results indicate that the extent to which the pairs were seen as different correlated with two methods of calculating balance. One of them could be understood as a possible primitive visual operating system for identifying other moving organisms as ever-changing vectors of balance. The more balanced the painting, the more it will be seen as a whole object by emphasizing peripheral vision and decreasing the tendency to fixate on what is in the picture, causing the painting to be perceived as unified and harmonious. It is proposed that in the evolution of vision there is a luminance pathway that was later superseded by other pathways using color vision. This explains the percept of balance and other visual phenomena.	NA	biorxiv
10.1101/2020.05.26.104687	Pictorial balance is a bottom-up aesthetic property mediated by eye movements. A model of a primitive visual operating system explains balance and visual properties of pictures	Corwin, D. M.	David M Corwin	David Corwin MD	2024-04-18T00:00:00	19	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2024/04/18/2020.05.26.104687.source.xml	Pictorial balance has been used to explain why some paintings evoke feelings of unity and harmony. This study shows how it is calculated and proposes an evolutionary reason for its existence. The concept of pictorial balance as a center of mass effect, i.e. the feeling that somehow a person on the left seems to be balanced by a tree on the right, originated at the beginning of the 20th century. It had never been mentioned in art commentary of the previous 500 years, and yet has become a widely assumed but unsubstantiated explanation of why some paintings evoke feelings of unity and harmony. Despite the lack of historical documentation, the perception of pictorial balance exists. This study shows how the low-level visual system calculates balance, how it evokes feelings of unity and harmony, and its evolutionary importance in visualizing the world of moving organisms. It is done by means of a study of an elusive pictorial effect known to painters, in which these feelings are evoked. In such pictures the image seems to be perceived as a whole without the need to fixate on individual depicted objects. The effect was first described by a 17th century critic Roger de Piles and subsequently by a few renowned artists. The author hypothesized that this response was due to the painting being in a state of perfect balance. Computer modeling found that such a picture must have bilateral luminance symmetry with a lighter lower half by [~]1.07. A study was conducted in which the identical picture seen sequentially in slightly different frames could seem different to observers because of the change in balance created by the frames. The results indicate that the extent to which the pairs were seen as different correlated with two methods of calculating balance. One of them could be understood as a possible primitive visual operating system for identifying other moving organisms as ever-changing vectors of balance. The more balanced the painting, the more it will be seen as a whole object by emphasizing peripheral vision and decreasing the tendency to fixate on what is in the picture, causing the painting to be perceived as unified and harmonious. It is proposed that in the evolution of vision there is a luminance pathway that was later superseded by other pathways using color vision. This explains the percept of balance and other visual phenomena.	NA	biorxiv
10.1101/2020.05.26.104687	Pictorial balance is a bottom-up neuro-aesthetic property mediating attention and eye movements. A model of a primitive visual operating system explains the property of balance and some visual properties of pictures	Corwin, D. M.	David M Corwin	David Corwin MD	2024-08-26T00:00:00	20	new results	cc_by	neuroscience	https://www.biorxiv.org/content/early/2024/08/26/2020.05.26.104687.source.xml	Pictorial balance has been used to explain why some paintings evoke feelings of unity and harmony. This study shows how it is calculated and proposes an evolutionary reason for its existence. The concept of pictorial balance as a center of mass effect, i.e. the feeling that somehow a person on the left seems to be balanced by a tree on the right, originated at the beginning of the 20th century. It had never been mentioned in art commentary of the previous 500 years, and yet has become a widely assumed but unsubstantiated explanation of why some paintings evoke feelings of unity and harmony. Despite the lack of historical documentation, the perception of pictorial balance exists. This study shows how the low-level visual system calculates balance, how it evokes feelings of unity and harmony, and its evolutionary importance in visualizing the world of moving organisms. It is done by means of a study of an elusive pictorial effect known to painters, in which these feelings are evoked. In such pictures the image seems to be perceived as a whole without the need to fixate on individual depicted objects. The effect was first described by a 17th century critic Roger de Piles and subsequently by a few renowned artists. The author hypothesized that this response was due to the painting being in a state of perfect balance. Computer modeling found that such a picture must have bilateral luminance symmetry with a lighter lower half by [~]1.07. A study was conducted in which the identical picture seen sequentially in slightly different frames could seem different to observers because of the change in balance created by the frames. The results indicate that the extent to which the pairs were seen as different correlated with two methods of calculating balance. One of them could be understood as a possible primitive visual operating system for identifying other moving organisms as ever-changing vectors of balance. The more balanced the painting, the more it will be seen as a whole object by emphasizing peripheral vision and decreasing the tendency to fixate on what is in the picture, causing the painting to be perceived as unified and harmonious. It is proposed that in the evolution of vision there is a luminance pathway that was later superseded by other pathways using color vision. This explains the percept of balance and other visual phenomena.	NA	biorxiv

10.1101/719013

Cell cycle variants during Drosophila accessory gland development

Box, A. M.; Ramesh, N. A.; Nandakumar, S.; Church, S. J.; Prasad, D.; Afrakhteh, A.; Taichman, R. S.; Buttitta, L.

Laura Buttitta

University of Michigan

2024-02-01T00:00:00

4

new results

cc_by_nc_nd

developmental biology

https://www.biorxiv.org/content/early/2024/02/01/719013.source.xml

The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate containing two secretory epithelial cell types, termed main and secondary cells. This tissue is responsible for making and secreting seminal fluid proteins and other molecules that contribute to successful reproduction. The cells of this tissue are bi-nucleate and polyploid, due to variant cell cycles that include endomitosis and endocycling during metamorphosis. Here we provide evidence of additional cell cycle variants in this tissue. We show that main cells of the gland are connected by ring canals that form after the penultimate mitosis and we describe an additional post-eclosion endocycle required for gland maturation that is dependent on juvenile hormone signaling. We present evidence that the main cells of the Drosophila melanogaster accessory gland undergo a unique cell cycle reprogramming throughout organ development that results in step-wise cell cycle truncations culminating in cells containing two octoploid nuclei with under-replicated heterochromatin in the mature gland. We propose this tissue as a model to study developmental and hormonal temporal control of cell cycle variants in terminally differentiating tissues.

NA

biorxiv

10.1101/721696

Myelin-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner.

Fazazi, M. R.; Doss, P. M. I. A.; Pereira, R.; Fudge, N.; Regmi, A.; Joly-Beauparlant, C.; Akbar, I.; Yeola, A. P.; Mailhot, B.; Baillargeon, J.; Grenier, P.; Bertrand, N.; Lacroix, S.; Droit, A.; Moore, C. S.; Rojas, O. L.; Rangachari, M.

Manu Rangachari

Laval University

2023-09-06T00:00:00

5

new results

cc_by

immunology

https://www.biorxiv.org/content/early/2023/09/06/721696.source.xml

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered a T cell-mediated disease. However, accumulating evidence points to a crucial role for B cells in disease processes. IgH[MOG] mice possess a transgenic immunoglobulin heavy chain derived from a monoclonal antibody specific to myelin oligodendrocyte glycoprotein (MOG), a key target for autoimmune responses. Here, using the experimental autoimmune encephalomyelitis (EAE) model of MS, we investigated the susceptibility of IgH[MOG] mice to CD4+ T cell-driven disease that was induced by active immunization with MOG[35-55] autoantigen. We found that immunized IgH[MOG] mice rapidly developed severe EAE, characterized by the aggregation of T and B cells in the CNS meninges. We observed an increased presence of class-switched and inflammatory cytokine-positive B cells in the IgH[MOG] CNS, as well as a greater frequency of IL-17- and GM-CSF-producing CD4+ T cells. Production of the Th17 maintenance factor IL-23 was increased from IgH[MOG] CNS-infiltrating B cells, and in vivo blockade of IL-23p19 strongly attenuated disease severity in IgH[MOG] mice. Strikingly, we observed an increased frequency of PD-1+CXCR5- T peripheral helper (Tph)-like cells in the CNS parenchyma and dura mater of IgH[MOG] mice. Both Tph accumulation in the CNS, as well as meningeal inflammation, were again sharply reduced upon IL-23p19 blockade in vivo. Notably, CNS-infiltrating B and Tph cells from IgH[MOG] mice showed an upregulation of genes related to neurodegeneration and oxidative phosphorylation, and IL-23 blockade reduced ROS production from these cells in vivo. Altogether, these data show that MOG-specific B cells contribute to severe CD4+ T cell-driven EAE by promoting CNS accumulation of Th17 and Tph cells, as well as tertiary lymphoid organs in the CNS meninges, in an IL-23 dependent manner.

10.1038/s41467-024-49259-0

biorxiv

10.1101/722397

A new QRS detector stress test combining temporal jitter and accuracy (JA) reveals significant performance differences amongst popular detectors

Porr, B.; Macfarlane, P. W.

Bernd Porr

University of Glasgow

2023-07-27T00:00:00

5

contradictory results

cc_by_nc_nd

bioengineering

https://www.biorxiv.org/content/early/2023/07/27/722397.source.xml

QRS detection within an electrocardiogram (ECG) is the basis of virtually any further processing and any error caused by this detection will propagate to further processing stages. However, standard benchmarking procedures of QRS detectors are seriously flawed because they report almost always close to 100% accuracy for any QRS detection algorithm. This is due to the use of large temporal error margins and noise-free ECG databases which grossly overestimate their performance. The use of a large fixed error margin masks temporal jitter between detection and ground truth measurements. Here, we present a new performance measure (JF) which combines temporal jitter with the F-score, and also an ECG database with decreasing levels of signal to noise ratios based on noise generated from different tasks. Our new performance measure JF fully encompasses all the types of errors that can occur, equally weights them and provides a percentage value which allows direct comparison between QRS detection algorithms. In combination with the new noisy ECG database, the JF performance measure now varies between 50% and 100% for different detectors and signal to noise conditions thereby making it possible to find the best detector for an application.

NA

biorxiv

10.1101/722397

A new QRS detector stress test combining temporal jitter and F-score (JF) reveals significant performance differences amongst popular detectors

Porr, B.; Macfarlane, P. W.

Bernd Porr

University of Glasgow

2024-03-30T00:00:00

6

contradictory results

cc_by_nc_nd

bioengineering

https://www.biorxiv.org/content/early/2024/03/30/722397.source.xml

QRS detection within an electrocardiogram (ECG) is the basis of virtually any further processing and any error caused by this detection will propagate to further processing stages. However, standard benchmarking procedures of QRS detectors are seriously flawed because they report almost always close to 100% accuracy for any QRS detection algorithm. This is due to the use of large temporal error margins and noise-free ECG databases which grossly overestimate their performance. The use of a large fixed error margin masks temporal jitter between detection and ground truth measurements. Here, we present a new performance measure (JF) which combines temporal jitter with the F-score, and also an ECG database with decreasing levels of signal to noise ratios based on noise generated from different tasks. Our new performance measure JF fully encompasses all the types of errors that can occur, equally weights them and provides a percentage value which allows direct comparison between QRS detection algorithms. In combination with the new noisy ECG database, the JF performance measure now varies between 50% and 100% for different detectors and signal to noise conditions thereby making it possible to find the best detector for an application.

NA

biorxiv

10.1101/721001

Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models

Uechi, H.; Sridharan, S.; Nijssen, J.; Bilstein, J.; Iglesias-Artola, J. M.; Kishigami, S.; Casablancas-Antras, V.; Poser, I.; Martinez, E. J.; Boczek, E.; Wagner, M.; Tomschke, N.; de Jesus Domingues, A. M.; Pal, A.; Doeleman, T.; Kour, S.; Anderson, E. N.; Stein, F.; Lee, H. O.; Zhang, X.; Fritsch, A. W.; Jahnel, M.; Fursch, J.; Murthy, A. C.; Alberti, S.; Bickle, M.; Fawzi, N. L.; Nadler, A.; David, D. C.; Pandey, U. B.; Hermann, A.; Stengel, F.; Davis, B. G.; Baldwin, A. J.; Savitski, M. M.; Hyman, A. A.; Wheeler, R. J.

Anthony A Hyman

Max Planck Institute of Molecular Cell Biology and Genetics

2024-01-05T00:00:00

3

new results

cc_by

cell biology

https://www.biorxiv.org/content/early/2024/01/05/721001.source.xml

Neurodegenerave diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutaons in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separaon which, when aberrant, can lead to altered condensaon behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic condensaon of stress granule proteins. Thermal proteome profiling showed that lipoamide preferentially stabilises intrinsically disordered domain-containing proteins. These include SRSF1 and SFPQ, stress granule proteins necessary for lipoamide activity. The redox state of SFPQ correlates with its condensate-dissolving behaviour, in concordance with the importance of the dithiolane ring for lipoamide activity. In animals, lipoamide ameliorates aging-associated aggregaon of a stress granule reporter, improves neuronal morphology, and recovers motor defects caused by expression of ALS-associated FUS and TDP-43 mutants. In conclusion, lipoamide is a well-tolerated small molecule modulator of stress granule condensaon and dissection of its molecular mechanism identified a cellular pathway for redox regulaon of stress granule formaon.

NA

biorxiv

10.1101/743435

Association of Ddx5/p68 protein with the upstream erythroid enhancer element (EHS1) of the Klf1 gene

Chen, X.; Pillay, S.; Lohmann, F.; Bieker, J. J.

James J Bieker

Mount Sinai School of Medicine, New York, NY

2023-04-03T00:00:00

2

new results

cc_by_nc_nd

molecular biology

https://www.biorxiv.org/content/early/2023/04/03/743435.source.xml

EKLF/KLF1 is an essential transcription factor that plays a global role in erythroid transcriptional activation. Its own regulation is of interest, as it displays a highly restricted expression pattern, limited to erythroid cells and its progenitors. Here we use biochemical affinity purification to identify the Ddx5/p68 protein as an activator of KLF1 by virtue of its interaction with the erythroid-specific DNAse hypersensitive site upstream enhancer element (EHS1). We postulate that its range of interactions with other proteins known to interact with this element render it part of the enhanseosome complex critical for optimal expression of KLF1. These individual interactions provide quantitative contributions that, in sum, establish high level activity of the KLF1 promoter and suggest they can be selectively manipulated for clinical benefit.

NA

biorxiv

10.1101/743120

Shielding working memory from distraction is more effortful than flexible updating

Papadopetraki, D.; Froboese, M. I.; Westbrook, A. J.; Zandbelt, B. B.; Cools, R.

Danae Papadopetraki

Donders Institute for Congnitive Neuroimaging; Radboud University Nijmegen; Radboud university Medical Center, Department of Psychiatry, Nijmegen

2024-05-24T00:00:00

2

new results

cc_by_nd

neuroscience

https://www.biorxiv.org/content/early/2024/05/24/743120.source.xml

Exerting cognitive control is known to carry a subjective effort cost and people are generally biased to avoid it. Recent theorizing suggests that the cost of cognitive effort serves as a motivational signal to bias people away from excessive focusing and towards more cognitive flexibility. We asked whether the effort cost of stable distractor resistance is higher than that of flexible updating of working memory representations. We tested this prediction by using (i) a delayed response paradigm in which we manipulate demands for distractor resistance and flexible updating, as well as (ii) a subsequent cognitive effort discounting paradigm that allows us to quantify subjective effort costs. We demonstrate, in two different samples (28 and 62 participants) that participants discount tasks both high in distractor resistance and flexible updating when comparing with taking a break. As predicted, when directly contrasting distractor resistance and flexible updating the subjective cost of performing a task requiring distractor resistance is higher than that requiring flexible updating.

NA

biorxiv

10.1101/759506

Cardiac competence of the paraxial head mesoderm fades concomitant with a shift towards the head skeletal muscle programme

Alzamrooni, A. M. A. M.; Mendes Vieira, P. J.; Murciano, N.; Wolton, M.; Schubert, F. R.; Robson, S. C.; Dietrich, S.

Susanne Dietrich

University of Portsmouth

2023-05-14T00:00:00

3

new results

cc_by_nc_nd

developmental biology

https://www.biorxiv.org/content/early/2023/05/14/759506.source.xml

The vertebrate head mesoderm provides the heart, the great vessels, some smooth and most head skeletal muscle, in addition to parts of the skull. It has been speculated that the ability to generate cardiac and smooth muscle is the evolutionary ground-state of the tissue. However, whether indeed the entire head mesoderm has generic cardiac competence, how long this may last, and what happens as cardiac competence fades, is not clear. Bone morphogenetic proteins (Bmps) are known to promote cardiogenesis. Using 41 different marker genes in the chicken embryo, we show that the paraxial head mesoderm that normally does not engage in cardiogenesis has the ability to respond to Bmp for a long time. However, Bmp signals are interpreted differently at different time points. Up to early head fold stages, the paraxial head mesoderm is able to read Bmps as signal to engage in the cardiac programme; the ability to upregulate smooth muscle markers is retained slightly longer. Notably, as cardiac competence fades, Bmp promotes the head skeletal muscle programme instead. The switch from cardiac to skeletal muscle competence is Wnt-independent as Wnt caudalises the head mesoderm and also suppresses Msc-inducing Bmp provided by the prechordal plate, thus suppressing both the cardiac and the head skeletal muscle programmes. Our study for the first time suggests a specific transition state in the embryo when cardiac competence is replaced by skeletal muscle competence. It sets the stage to unravel the cardiac-skeletal muscle antagonism that is known to partially collapse in heart failure. Summary statementThe head mesoderm has generic cardiac competence until early head fold stages. Thereafter, cardiac competence fades in the paraxial region, and Bmp promotes head skeletal muscle programmes instead of cardiac programmes.

10.1016/j.ydbio.2023.06.005

biorxiv

10.1101/761346

A dual function of the IDA peptide in regulating cell separation and modulating plant immunity at the molecular level

Lalun, V. O.; Breiden, M.; Galindo-Trigo, S.; Smakowska-Luzan, E.; Simon, R.; Butenko, M. A.

Melinka Alonso Butenko

University of Oslo

2024-02-15T00:00:00

3

new results

cc_by_nc_nd

plant biology

https://www.biorxiv.org/content/early/2024/02/15/761346.source.xml

The abscission of floral organs and emergence of lateral roots in Arabidopsis is regulated by the peptide ligand INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) and the receptor protein kinases HAESA (HAE) and HAESA-LIKE 2 (HSL2). During these cell separation processes, the plant induces defense-associated genes to protect against pathogen invasion. However, the molecular coordination between abscission and immunity has not been thoroughly explored. Here we show that IDA induces a release of cytosolic calcium ions (Ca2+) and apoplastic production of reactive oxygen species, which are signatures of early defense responses. In addition, we find that IDA promotes late defense responses by the transcriptional upregulation of genes known to be involved in immunity. When comparing the IDA induced early immune responses to known immune responses, such as those elicited by flagellin22 treatment, we observe both similarities and differences. We propose a molecular mechanism by which IDA promotes signatures of an immune response in cells destined for separation to guard them from pathogen attack.

10.7554/eLife.87912

biorxiv

10.1101/761346

A dual function of the IDA peptide in regulating cell separation and modulating plant immunity at the molecular level

Lalun, V. O.; Breiden, M.; Galindo-Trigo, S.; Smakowska-Luzan, E.; Simon, R.; Butenko, M. A.

Melinka Alonso Butenko

University of Oslo

2024-03-26T00:00:00

4

new results

cc_by_nc_nd

plant biology

https://www.biorxiv.org/content/early/2024/03/26/761346.source.xml

The abscission of floral organs and emergence of lateral roots in Arabidopsis is regulated by the peptide ligand INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) and the receptor protein kinases HAESA (HAE) and HAESA-LIKE 2 (HSL2). During these cell separation processes, the plant induces defense-associated genes to protect against pathogen invasion. However, the molecular coordination between abscission and immunity has not been thoroughly explored. Here we show that IDA induces a release of cytosolic calcium ions (Ca2+) and apoplastic production of reactive oxygen species, which are signatures of early defense responses. In addition, we find that IDA promotes late defense responses by the transcriptional upregulation of genes known to be involved in immunity. When comparing the IDA induced early immune responses to known immune responses, such as those elicited by flagellin22 treatment, we observe both similarities and differences. We propose a molecular mechanism by which IDA promotes signatures of an immune response in cells destined for separation to guard them from pathogen attack.

10.7554/eLife.87912

biorxiv

10.1101/751222

A nonlinear relationship between prediction errors and learning rates in human reinforcement learning

Ikwunne, B.; Parham, J.; Pulcu, E.

Erdem Pulcu

University of Oxford

2024-07-31T00:00:00

4

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2024/07/31/751222.source.xml

Reinforcement-learning (RL) models have been pivotal to our understanding of how agents perform learning-based adaptions in dynamically changing environments. However, the exact nature of the relationship (e.g. linear, logarithmic etc.) between key components of RL models such as prediction errors (PEs; the difference between the agents expectation and the actual outcome) and learning rates (LRs; a coefficient used by agents to update their beliefs about the environment) has not been studied in detail. Here, across (i) simulations, (ii) reanalyses of readily available datasets and (iii) a novel experiment, we demonstrate that the relationship between PEs and LRs is (i) nonlinear over the PE/LR space, and (ii) it can be better accounted for by an exponential-logarithmic function that can transform the magnitude of PEs instantaneously to LRs. In line with the temporal predictions of this model, we show that physiological correlates of LRs accumulate while learners observe the outcome of their choices and update their beliefs about the environment.

NA

biorxiv

10.1101/773507

Gravity-based microfiltration reveals unexpected prevalence of circulating tumor cell clusters in ovarian and colorectal cancer

Meunier, A.; Hernandez-Castro, J. A.; Chahley, N.; Communal, L.; Kheireddine, S.; Koushki, N.; Davoudvandi, N.; Al Habyan, S.; Peant, B.; Lazaris, A.; Ng, A.; Veres, T.; McCaffrey, L.; Provencher, D.; Metrakos, P.; Mes-Masson, A.-M.; Juncker, D.

David Juncker

McGill University

2023-12-05T00:00:00

2

new results

cc_by_nc_nd

bioengineering

https://www.biorxiv.org/content/early/2023/12/05/773507.source.xml

Circulating tumor cells (CTCs) are rare (few cells per milliliter of blood) and mostly isolated as single cell CTCs (scCTCs). CTC clusters (cCTCs), even rarer, are of growing interest, notably because of their higher metastatic potential, but very difficult to isolate. Here, we introduce gravity-based microfiltration (G{micro}F) for facile isolation of cCTCs while minimizing unwanted cluster disaggregation, with [~]85% capture efficiency. G{micro}F from orthotopic ovarian cancer mouse models, from 17 epithelial ovarian cancer (EOC) with either localized or metastatic disease, and from 13 metastatic colorectal cancer liver metastasis (CRCLM) patients uncovered cCTCs in every case, with between 2-100+ cells. cCTCs represented between 5-30% of all CTC capture events, and 10-80% of CTCs were clustered; remarkably, in 10 patients, most CTCs were circulating not as scCTCs, but as cCTCs. G{micro}F uncovered the unexpected prevalence and frequency of cCTCs including sometimes very large ones in EOC patients, and motivates additional studies to uncover their properties and role in disease progression.

NA

biorxiv

10.1101/784678

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

Espada, C. E.; da Rocha, E. L.; Ricciardi-Jorge, T.; dos Santos, A. A.; Soares, Z. G.; Malaquias, G.; Patricio, D. d. O.; Kozlova, E. G.; dos Santos, P. F.; Bordignon, J.; Sanford, T. J.; Fajardo, T.; Sweeney, T.; Bafica, A.; Mansur, D. S.

Daniel Santos Mansur

Universidade Federal de Santa Catarina

2023-07-15T00:00:00

4

new results

cc_by_nc_nd

immunology

https://www.biorxiv.org/content/early/2023/07/15/784678.source.xml

The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.

10.3389/fimmu.2024.1331731

biorxiv

10.1101/784678

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

Espada, C. E.; da Rocha, E. L.; Ricciardi-Jorge, T.; dos Santos, A. A.; Soares, Z. G.; Malaquias, G.; Patricio, D. d. O.; Kozlova, E. G.; dos Santos, P. F.; Bordignon, J.; Sanford, T. J.; Fajardo, T.; Sweeney, T.; Bafica, A.; Mansur, D. S.

Daniel Santos Mansur

Universidade Federal de Santa Catarina

2023-10-19T00:00:00

5

new results

cc_by_nc_nd

immunology

https://www.biorxiv.org/content/early/2023/10/19/784678.source.xml

The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.

10.3389/fimmu.2024.1331731

biorxiv

10.1101/784678

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

Espada, C. E.; da Rocha, E. L.; Ricciardi-Jorge, T.; dos Santos, A. A.; Soares, Z. G.; Malaquias, G.; Patricio, D. d. O.; Kozlova, E. G.; dos Santos, P. F.; Bordignon, J.; Sanford, T. J.; Fajardo, T.; Sweeney, T.; Bafica, A.; Mansur, D. S.

Daniel Santos Mansur

Universidade Federal de Santa Catarina

2023-11-01T00:00:00

6

new results

cc_by_nc_nd

immunology

https://www.biorxiv.org/content/early/2023/11/01/784678.source.xml

The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.

10.3389/fimmu.2024.1331731

biorxiv

10.1101/784157

Technical artifact drives apparent deviation from Hardy-Weinberg equilibrium at CCR5-Δ32 and other variants in gnomAD

Karczewski, K. J.; Gauthier, L. D.; Daly, M. J.

Konrad J Karczewski

Broad Institute

2023-07-29T00:00:00

2

contradictory results

cc_by

genomics

https://www.biorxiv.org/content/early/2023/07/29/784157.source.xml

Following an earlier report suggesting increased mortality due to homozygosity at the CCR5-{Delta}32 allele1, Wei and Nielsen recently suggested a deviation from Hardy-Weinberg Equilibrium (HWE) observed in public variant databases as additional supporting evidence for this hypothesis2. Here, we present a re-analysis of the primary data underlying this variant database and identify a pervasive genotyping artifact, especially present at long insertion and deletion polymorphisms. Specifically, very low levels of contamination can affect the variant calling likelihood models, leading to the misidentification of homozygous individuals as heterozygous, and thereby creating an apparent depletion of homozygous calls, which is especially prominent at large insertions and deletions. The deviation from HWE observed at CCR5-{Delta}32 is a consequence of this specific genotyping error mode rather than a signature of selective pressure at this locus.

NA

biorxiv

10.1101/790378

Enhancing autophagy by redox regulation extends lifespan in Drosophila

Lennicke, C.; Bjedov, I.; Grönke, S.; Menger, K. E.; James, A. M.; Castillo-Quan, J. I.; van Leeuwen, L. A. G.; Foley, A.; Buricova, M.; Adcott, J.; Montoya, A.; Kramer, H. B.; Shliaha, P. V.; Logan, A.; Cabreiro, F.; Murphy, M. P.; Partridge, L.; Cocheme, H. M.

Helena M Cochemé

MRC London Institute of Medical Sciences, UK

2024-05-10T00:00:00

2

new results

cc_by

molecular biology

https://www.biorxiv.org/content/early/2024/05/10/790378.source.xml

Dysregulation of redox homeostasis has been implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in flies. As anticipated, these flies were strongly resistant to a range of oxidative stress challenges, but interestingly were sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan upon catalase up-regulation, as the survival benefits were completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.

NA

biorxiv

10.1101/793943

Energy landscape steering mediates dynamic coupling in ATP-driven protein translocation by the bacterial Sec machinery

Crossley, J. A.; Allen, W. J.; Watkins, D. W.; Sabir, T.; Radford, S. E.; Tuma, R.; Collinson, I.; Fessl, T.

Roman Tuma

University of Leeds, United Kingdom and University of South Bohemia, Czech Republic

2023-06-06T00:00:00

4

new results

cc_by_nc_nd

biophysics

https://www.biorxiv.org/content/early/2023/06/06/793943.source.xml

The Sec translocon is a highly conserved membrane complex for transport of polypeptides across, or into, lipid bilayers. In bacteria, the core protein-channel SecYEG resides in the inner-membrane, through which secretion is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the dynamic state of SecYEG throughout the hydrolytic cycle of SecA. We show that the SecYEG channel fluctuates between open and closed states faster ([~]20-fold during transport) than ATP turnover; while the nucleotide status of SecA modulates the rates of opening and closure. Interestingly, a SecY variant (PrlA4), exhibiting faster protein transport, but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore; thereby improving the efficiency of translocation. Thus, contrary to prevailing structure-based models, SecYEG plays an integral part in the translocation mechanism through dynamic allosteric coupling in which SecA steers the energy landscape of the protein-channel.

NA

biorxiv

10.1101/795930

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8

Tzioras, M.; Daniels, M. J.; Davies, C.; Baxter, P.; King, D.; McKay, S.; Varga, B. V.; Popovic, K.; Hernandez, M.; Stevenson, A. J.; Barrington, J.; Drinkwater, E.; Borella, J. A.; Holloway, R. K.; Tulloch, J.; Latta, C.; Kandasamy, J.; Sokol, D.; Smith, C.; Miron, V.; Karadottir, R. T.; Hardingham, G.; Henstridge, C. M.; Brennan, P.; McColl, B. W.; Spires-Jones, T. L.

Tara L Spires-Jones

The University of Edinburgh

2023-04-05T00:00:00

2

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2023/04/05/795930.source.xml

Synapse loss correlates with cognitive decline in Alzheimers disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared to non-disease controls, and that proximity to amyloid-{beta} plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting MFG-E8 function rescued the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation. One-Sentence SummaryGlial cells ingest synapses in Alzheimers disease and antibody treatment reduces this ingestion in cultured human cells.

10.1016/j.xcrm.2023.101175

biorxiv

10.1101/801563

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

Frederiksen, S. D.; Wicki-Stordeur, L. E.; Swayne, L. A.

Leigh A. Swayne

University of Victoria

2023-04-27T00:00:00

2

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2023/04/27/801563.source.xml

Many neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signalling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 PANX1-interacting proteins identified from mouse Neuro2a cells). To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinsons disease, and Alzheimers disease. Next, to further probe PANX1 signalling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signalling pathways and protein-protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological conditions connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation.

10.1080/19336950.2023.2253102

biorxiv

10.1101/801563

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

Frederiksen, S. D.; Wicki-Stordeur, L. E.; Swayne, L. A.

Leigh A. Swayne

University of Victoria

2023-05-10T00:00:00

3

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2023/05/10/801563.source.xml

Many neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signalling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 PANX1-interacting proteins identified from mouse Neuro2a cells). To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinsons disease, and Alzheimers disease. Next, to further probe PANX1 signalling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signalling pathways and protein-protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological conditions connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation.

10.1080/19336950.2023.2253102

biorxiv

10.1101/803205

Caliban: Accurate cell tracking and lineage construction in live-cell imaging experiments with deep learning

Schwartz, M.; Moen, E.; Miller, G.; Dougherty, T.; Borba, E.; Ding, R.; Graf, W.; Pao, E.; Van Valen, D. A.

David Ashley Van Valen

California Institute of Technology

2023-09-06T00:00:00

3

new results

cc_by

bioinformatics

https://www.biorxiv.org/content/early/2023/09/06/803205.source.xml

While live-cell imaging is a powerful approach to studying the dynamics of cellular systems, converting these imaging data into quantitative, single-cell records of cellular behavior has been a longstanding challenge. Deep learning methods have proven capable of performing cell segmentation--a critical task for analyzing live-cell imaging data--but their performance in cell tracking has been limited by a lack of dynamic datasets with temporally consistent single-cell labels. We bridge this gap through the integrated development of labeling and deep learning methodology. We present a new framework for scalable, human-in-the-loop labeling of live-cell imaging movies, which we use to label a large collection of movies of fluorescently labeled cell nuclei. We use these data to create a new deep-learning-based cell-tracking method that achieves state-of-the-art performance in cell tracking. We have made all of the data, code, and software publicly available with permissive open-source licensing through the DeepCell projects web portal https://deepcell.org.

NA

biorxiv

10.1101/803205

Caliban: Accurate cell tracking and lineage construction in live-cell imaging experiments with deep learning

Schwartz, M.; Moen, E.; Miller, G.; Dougherty, T.; Borba, E.; Ding, R.; Graf, W.; Pao, E.; Van Valen, D. A.

David Ashley Van Valen

California Institute of Technology

2023-09-12T00:00:00

4

new results

cc_by

bioinformatics

https://www.biorxiv.org/content/early/2023/09/12/803205.source.xml

While live-cell imaging is a powerful approach to studying the dynamics of cellular systems, converting these imaging data into quantitative, single-cell records of cellular behavior has been a longstanding challenge. Deep learning methods have proven capable of performing cell segmentation--a critical task for analyzing live-cell imaging data--but their performance in cell tracking has been limited by a lack of dynamic datasets with temporally consistent single-cell labels. We bridge this gap through the integrated development of labeling and deep learning methodology. We present a new framework for scalable, human-in-the-loop labeling of live-cell imaging movies, which we use to label a large collection of movies of fluorescently labeled cell nuclei. We use these data to create a new deep-learning-based cell-tracking method that achieves state-of-the-art performance in cell tracking. We have made all of the data, code, and software publicly available with permissive open-source licensing through the DeepCell projects web portal https://deepcell.org.

NA

biorxiv

10.1101/803205

Caliban: Accurate cell tracking and lineage construction in live-cell imaging experiments with deep learning

Schwartz, M.; Moen, E.; Miller, G.; Dougherty, T.; Borba, E.; Ding, R.; Graf, W.; Pao, E.; Van Valen, D. A.

David Ashley Van Valen

California Institute of Technology

2024-08-07T00:00:00

5

new results

cc_by

bioinformatics

https://www.biorxiv.org/content/early/2024/08/07/803205.source.xml

While live-cell imaging is a powerful approach to studying the dynamics of cellular systems, converting these imaging data into quantitative, single-cell records of cellular behavior has been a longstanding challenge. Deep learning methods have proven capable of performing cell segmentation--a critical task for analyzing live-cell imaging data--but their performance in cell tracking has been limited by a lack of dynamic datasets with temporally consistent single-cell labels. We bridge this gap through the integrated development of labeling and deep learning methodology. We present a new framework for scalable, human-in-the-loop labeling of live-cell imaging movies, which we use to label a large collection of movies of fluorescently labeled cell nuclei. We use these data to create a new deep-learning-based cell-tracking method that achieves state-of-the-art performance in cell tracking. We have made all of the data, code, and software publicly available with permissive open-source licensing through the DeepCell projects web portal https://deepcell.org.

NA

biorxiv

10.1101/805614

An Improved Chromosome-scale Genome Assembly and Population Genetics resource for Populus tremula.

Robinson, K. M.; Schiffthaler, B.; Liu, H.; Westman, S. M.; Rendon-Anaya, M.; Ahlgren Kalman, T.; Kumar, V.; Canovi, C.; Bernhardsson, C.; Delhomme, N.; Jenkins, J.; Wang, J.; Mähler, N.; Richau, K. H.; Stokes, V.; A'Hara, S.; Cottrell, J.; Coeck, K.; Diels, T.; Vandepoele, K.; Mannapperuma, C.; Park, E.-J.; Plaisance, S.; Jansson, S.; Ingvarsson, P. K.; Street, N. R.

Bastian Schiffthaler

Umea Plant Science Center

2024-04-08T00:00:00

2

new results

cc_by_nc_nd

genomics

https://www.biorxiv.org/content/early/2024/04/08/805614.source.xml

Aspen (Populus tremula L.) is a widely distributed keystone species and a model system for forest tree genomics, with extensive resources developed for population genetics and genomics. Here we present an updated resource comprising a chromosome-scale assembly of P. tremula and population genetics and genomics data integrated into the PlantGenIE.org web resource. We demonstrate use of the diverse data types included to explore the genetic basis of natural variation in leaf size and shape as examples of traits with complex genetic architecture. We present a chromosome-scale genome assembly generated using long-read sequencing, optical and high-density genetic maps containing 39,894 annotated genes with functional annotations for 73,765 transcripts from 37,184 gene loci. We conducted whole-genome resequencing of the Ume[a] Aspen (UmAsp) collection comprising 227 aspen individuals. We utilised the assembly, the UmAsp re-sequencing data and existing whole genome re-sequencing data from the Swedish Aspen (SwAsp) and Scottish Aspen (ScotAsp) collections to perform genome-wide association analyses (GWAS) using Single Nucleotide Polymorphisms (SNPs) for leaf physiognomy phenotypes. We conducted Assay of Transposase Accessible Chromatin sequencing (ATAC-Seq) and identified genomic regions of accessible chromatin and subset SNPs to these regions, which improved the GWAS detection rate. We identified candidate long non-coding RNAs in leaf samples and quantified their expression in an updated co-expression network (AspLeaf, available in PlantGenIE.org), which we further used to explore the functions of candidate genes identified from the GWAS. We examined synteny to the reference P. trichocarpa assembly and identified P. tremula-specific regions. Analysis of whole-genome duplication indicated differential substitution rates for the two Populus species, indicating more rapid evolution in P. tremula. A GWAS of 26 leaf physiognomy traits and all SNPs in each of the three aspen collections found significant associations for only two traits in ScotAsp collection and one in UmAsp, whereas subsetting SNPs to those in open chromatin regions revealed associations for a further four traits among all three aspen collections. The significant SNPs were associated with genes annotated for developmental and growth functions, which represent candidates for further study. Of particular interest was a 177-kbp region of chromosome 9 harbouring SNPs associated with multiple leaf phenotypes in ScotAsp, with the set of SNPs in linkage disequilibrium explaining 24 to 30 % of the phenotypic variation in leaf indent depth variation. We have incorporated the assembly, population genetics, genomics and leaf physiognomy GWAS data into the PlantGenIE.org web resource, including updating existing genomics data to the new genome version. This enables easy exploration and visualisation of the genomics data and exploration of GWAS results. We provide all raw and processed data used for the presented analyses to facilitate reuse in future studies.

NA

biorxiv

10.1101/810259

Plasmid carriage and the unorthodox use of Fisher's theorem in evolutionary biology

Reding, C.

Carlos Reding

University of Exeter

2023-05-04T00:00:00

11

new results

cc_by_nc_nd

evolutionary biology

https://www.biorxiv.org/content/early/2023/05/04/810259.source.xml

The link between fitness and reproduction rate is a central tenet in microbiology, and indeed evolutionary biology: Mutants reproducing faster than the dominant wild-type are favoured by selection, but otherwise the mutation is lost. This link was given by Ronald Fisher in 1930 under the assumption that fitness can only change through mutations that boost or hinder growth rate, whence the use of logarithms on growth data by experimentalists. Here I show that logarithms are highly sensitive to sampling times, resulting in fitness estimates that are not constant over the growth of bacterial cultures. This variability invalidates typical selection measurements, and unfit mutants can be co-maintained if they reach their equilibrium. And this is what I observed in competition assays between two Escherichia coli constructs, one of which harbours a nontransmissible plasmid that protects against tetracycline (pGW155B), without using antibiotic. Despite growing 40% slower than its drug-sensitive counterpart, the construct harbouring the plasmid persisted throughout the competition. And, perhaps more importantly, maintained the plasmid. My study suggests that reliance on growth rate masks that selection on plasmid carriage may be stronger than previously thought--explaining the seemingly-paradoxical abundance of plasmids in nature.

NA

biorxiv

10.1101/810259

Plasmid carriage and the unorthodox use of fitness in microbial genetics

Reding, C.

Carlos Reding

University of Exeter

2023-08-28T00:00:00

12

new results

cc_by_nc_nd

evolutionary biology

https://www.biorxiv.org/content/early/2023/08/28/810259.source.xml

The link between fitness and reproduction rate is a central tenet in microbiology, and indeed evolutionary biology: Mutants reproducing faster than the dominant wild-type are favoured by selection, but otherwise the mutation is lost. This link was given by Ronald Fisher in 1930 under the assumption that fitness can only change through mutations that boost or hinder growth rate, whence the use of logarithms on growth data by experimentalists. Here I show that logarithms are highly sensitive to sampling times, resulting in fitness estimates that are not constant over the growth of bacterial cultures. This variability invalidates typical selection measurements, and unfit mutants can be co-maintained if they reach their equilibrium. And this is what I observed in competition assays between two Escherichia coli constructs, one of which harbours a nontransmissible plasmid that protects against tetracycline (pGW155B), without using antibiotic. Despite growing 40% slower than its drug-sensitive counterpart, the construct harbouring the plasmid persisted throughout the competition. And, perhaps more importantly, maintained the plasmid. My study suggests that reliance on growth rate masks that selection on plasmid carriage may be stronger than previously thought--explaining the seemingly-paradoxical abundance of plasmids in nature.

NA

biorxiv

10.1101/810259

Plasmid carriage and the unorthodox use of fitness in microbial genetics

Reding, C.

Carlos Reding

University of Exeter

2023-11-20T00:00:00

13

new results

cc_by_nc_nd

evolutionary biology

https://www.biorxiv.org/content/early/2023/11/20/810259.source.xml

The link between fitness and reproduction rate is a central tenet in microbiology, and indeed evolutionary biology: Mutants reproducing faster than the dominant wild-type are favoured by selection, but otherwise the mutation is lost. This link was given by Ronald Fisher in 1930 under the assumption that fitness can only change through mutations that boost or hinder growth rate, whence the use of logarithms on growth data by experimentalists. Here I show that logarithms are highly sensitive to sampling times, resulting in fitness estimates that are not constant over the growth of bacterial cultures. This variability invalidates typical selection measurements, and unfit mutants can be co-maintained if they reach their equilibrium. And this is what I observed in competition assays between two Escherichia coli constructs, one of which harbours a nontransmissible plasmid that protects against tetracycline (pGW155B), without using antibiotic. Despite growing 40% slower than its drug-sensitive counterpart, the construct harbouring the plasmid persisted throughout the competition. And, perhaps more importantly, maintained the plasmid. My study suggests that reliance on growth rate masks that selection on plasmid carriage may be stronger than previously thought--explaining the seemingly-paradoxical abundance of plasmids in nature.

NA

biorxiv

10.1101/812198

Effective mechanical potential of cell-cell interaction explains three-dimensional morphologies during early embryogenesis

Koyama, H.; Okumura, H.; Ito, A. M.; Nakamura, K.; Otani, T.; Kato, K.; Fujimori, T.

Hiroshi Koyama

National Institute for Basic Biology

2023-06-26T00:00:00

6

new results

cc_by_nc_nd

biophysics

https://www.biorxiv.org/content/early/2023/06/26/812198.source.xml

Mechanical forces are critical for the emergence of diverse three-dimensional morphologies of multicellular systems. However, it remains unclear what kind of mechanical parameters at cellular level substantially contribute to tissue morphologies. This is largely due to technical limitations of live measurements of cellular forces. Here we developed a framework for inferring and modeling mechanical forces of cell-cell interactions. First, by analogy to coarse-grained models in molecular and colloidal sciences, we approximated cells as particles, where mean forces (i.e. effective forces) of pairwise cell-cell interactions are considered. Then, the forces were statistically inferred by fitting the mathematical model to cell tracking data. This method was validated by using synthetic cell tracking data resembling various in vivo situations. Application of our method to the cells in the early embryos of mice and the nematode Caenorhabditis elegans revealed that cell-cell interaction forces can be written as a pairwise potential energy in a manner dependent on cell-cell distances. Importantly, the profiles of the pairwise potentials were quantitatively different among species and embryonic stages, and the quantitative differences correctly described the differences of their morphological features such as spherical vs. distorted cell aggregates, and tightly vs. non-tightly assembled aggregates. We conclude that the effective pairwise potential of cell-cell interactions is a live measurable parameter whose quantitative differences can be a parameter describing three-dimensional tissue morphologies. Author summaryEmergence of diverse three-dimensional morphologies of multicellular organisms is one of the most intriguing phenomena in nature. Due to the complex situations in living systems (e.g. a lot of genes are involved in morphogenesis.), a model for describing the emergent properties of multicellular systems has not been established. To approach this issue, approximation of the complex situations to limited numbers of parameters is required. Here, we searched for mechanical parameters for describing morphologies. We developed a statistical method for inferring mechanical potential energy of cell-cell interactions in three-dimensional tissues; the mechanical potential is an approximation of various mechanical components such as cell-cell adhesive forces, cell surface tensions, etc. Then, we showed that the quantitative differences in the potential is sufficient to reproduce basic three-dimensional morphologies observed during the mouse and C. elegans early embryogenesis, revealing a direct link between cellular level mechanical parameters and three-dimensional morphologies. Our framework provides a noninvasive tool for measuring spatiotemporal cellular forces, which would be useful for studying morphogenesis of larger tissues including organs and their regenerative therapy.

10.1371/journal.pcbi.1011306

biorxiv

10.1101/839811

The astrocyte-enriched gene CG11000 plays a crucial role in the development, locomotion and lifespan of D. melanogaster

Najafi, H.; Wong, K.; Salkini, A. H.; Miao, H.; Kim, W. J.

Woo Jae Kim

University of Ottawa

2023-09-12T00:00:00

4

new results

cc_by_nc_nd

genetics

https://www.biorxiv.org/content/early/2023/09/12/839811.source.xml

The brain of Drosophila melanogaster is a complex organ with various cell types, orchestrating the physiology and behaviors of the fly. While each cell type in the Drosophila brain is known to express a unique set of genes, their complete genetic profile is still unknown. Advances in the RNA-sequencing techniques at single cell resolution facilitate identifying novel cell type-specific markers and/or examining the specificity of the available markers. In this study, exploiting a single cell RNA sequencing data of Drosophila optic lobe (which comprises two thirds of the brain with extensive cell type diversity), we first categorized cell types based on their known molecular markers, then the genes with enriched expression in astrocytes were identified. Consistent with previous findings, the known glial markers CG34335, Inx2 and nrv2 as well as the astrocytic genes CG9394, Eaat1, Gat, Gs2 and CG1552 exhibited enriched expression in the identified astrocyte cluster. Moreover, we identified CG11000 as a gene with positive expression correlation with the astrocytic marker Eaat1. The positive expression correlation between CG11000 and Eaat1 genes was also observed in the single-cell RNA-sequencing data of Drosophila mid-brain as well as in the bulk RNA-sequencing data of Drosophila whole brain during development. Immunostaining of the brains dissected from adult flies showed overlapping fluorescence signals of CG11000 and Eaat1 expression, supporting co-expression of these genes in a set of single cells in Drosophila optic lobe. At the physiological level, RNAi-mediated suppression of CG11000 impeded th normal development of male flies without any effects on females. In adult flies, CG11000 suppression affected the locomotion activity and lifespan of D. melanogaster in an astrocyte-specific manner, suggesting pivotal role of CG11000 gene in astrocytes.

NA

biorxiv

10.1101/852129

Sympathetic innervation directs Ankyrin G, voltage-gated Nav and KCNQ1 channels to the neuro-cardiac junctions

Shcherbakova, O. G.

Olga G Shcherbakova

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of NRC Kurchatov Institute

2023-06-09T00:00:00

3

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2023/06/09/852129.source.xml

The sympathetic nervous system plays a central role in the cardiovascular response to acute stress by increasing heart rate and contractility. Despite the importance of functional connections between sympathetic nerves and cardiac myocytes, very little is known about the structural and functional organization of the neuro-cardiac synapses. Earlier, we demonstrated that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons2. In the present study, we addressed the question if sympathetic innervation may affect localization of the cardiac ion channels. We have found that ankyrin G, scaffold protein involved in targeting ion channels and transporters, is localized at the postsynaptic sites in the cardiac myocytes innervated by sympathetic neurons. Consistent with the roles of ankyrin G in targeting Nav channels to specific domains in neurons and cardiac myocytes, we have observed an increased density of Nav channels at the neuro-cardiac junctions in co-cultures of cardiac myocytes and sympathetic neurons. We have also found that KCNQ1 channels are enriched at that sites. The increased density of Nav and KCNQ1 channels at the sites of sympathetic innervation is likely to play a role in regulation of the cardiac excitability by sympathetic nervous system.

NA

biorxiv

10.1101/859942

Prioritized neural processing of social threats during perceptual decision-making

El Zein, M.; Mennella, R.; Sequestro, M.; Meaux, E.; Wyart, V.; Grezes, J.

Emilie Meaux

INSERM U960, LNC2, Ecole Normale Superieure de Paris, PSL University

2024-01-02T00:00:00

4

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2024/01/02/859942.source.xml

Emotional signals, notably those signaling threat, benefit from prioritized processing in the human brain. Yet, it remains unclear whether perceptual decisions about the emotional, threat-related aspects of stimuli involve specific or similar neural computations compared to decisions about their non-threatening/non-emotional components. We developed a novel behavioral paradigm in which participants performed two different detection tasks (emotion vs. color) on the same, two-dimensional visual stimuli. Electroencephalographic (EEG) activity in a cluster of central electrodes reflected the amount of perceptual evidence around 100ms following stimulus onset, when the decision concerned emotion, not color. Second, participants choice could be predicted earlier for emotion (240ms) than for color (380ms) by the mu (10Hz) rhythm, which reflects motor preparation. Taken together, these findings indicate that perceptual decisions about threat-signaling dimensions of facial displays are associated with prioritized neural coding in action-related brain regions, supporting the motivational value of socially relevant signals.

10.1016/j.isci.2024.109951

biorxiv

10.1101/871020

Quantitative Real-Time PCR assays for species-specific detection and quantification of Baltic Sea spring bloom dinoflagellates

Brink, A. M.; Kremp, A.; Gorokhova, E.

Annica M. Brink

Stockholm University

2024-03-09T00:00:00

2

new results

cc_by_nc_nd

molecular biology

https://www.biorxiv.org/content/early/2024/03/09/871020.source.xml

In the Baltic Sea, the dinoflagellates Apocalathium malmogiense, Biecheleria baltica, and Gymnodinium corollarium are important contributors to the spring bloom. However, their relative contribution to the bloom community cannot be unambiguously determined by conventional light microscopy due to lack of resolution of distinctive morphological features of the three species. Here, we describe a molecular approach based on a quantitative real-time polymerase chain reaction (qPCR) primer and probe system, targeting the ITS1 and ITS2 regions of the rRNA gene for all three species and enabling their quantification. The specificity of the method was demonstrated using monocultures of A. malmogiense, B. baltica, G. corollarium as well as three other dinoflagellate species co-occurring in the Baltic Sea during spring and validated using field-collected phytoplankton samples.

NA

biorxiv

10.1101/2019.12.13.875526

An Alignment-free Method for Phylogeny Estimation using Maximum Likelihood

Zahin, T.; Abrar, M. H.; Rahman, M.; Tasnim, T.; Bayzid, M. S.; Rahman, A.

Atif Rahman

Bangladesh University of Engineering and Technology

2024-07-29T00:00:00

2

new results

cc_by_nd

bioinformatics

https://www.biorxiv.org/content/early/2024/07/29/2019.12.13.875526.source.xml

While alignment has traditionally been the primary approach for establishing homology prior to phylogenetic inference, alignment-free methods offer a simplified alternative, particularly beneficial when handling genome-wide data involving long sequences and complex events such as rearrangements. Moreover, alignment-free methods become crucial for data types like genome skims, where assembly is impractical. However, despite these benefits, alignment-free techniques have not gained widespread acceptance since they lack the accuracy of alignment-based techniques, primarily due to their reliance on simplified models of pairwise distance calculation. Here, we present a likelihood based alignment-free technique for phylogenetic tree construction. We encode the presence or absence of k-mers in genome sequences in a binary matrix, and estimate phylogenetic trees using a maximum likelihood approach. We analyze the performance of our method on seven real datasets and compare the results with the state of the art alignment-free methods. Results suggest that our method is competitive with existing alignment-free tools. This indicates that maximum likelihood based alignment-free methods may in the future be refined to outperform alignment-free methods relying on distance calculation as has been the case in the alignment-based setting. A likelihood based alignment-free method for phylogeny estimation is implemented for the first time in a software named PO_SCPLOWEAFOWLC_SCPLOW, which is available at: https://github.com/hasin-abrar/Peafowlrepo.

NA

biorxiv

10.1101/2019.12.12.868489

Is N-Hacking Ever OK? A Simulation-based study

Reinagel, P.

Pamela Reinagel

UCSD

2023-08-24T00:00:00

4

new results

cc_by_nc_nd

scientific communication and education

https://www.biorxiv.org/content/early/2023/08/24/2019.12.12.868489.source.xml

After an experiment has been completed, a trend may be observed that is "not quite significant". Sometimes in this situation, researchers collect more data in an effort to achieve statistical significance. Such "N-hacking" is condemned because it can lead to an excess of false positive results. I use simulations to demonstrate how N-hacking causes false positives. However, in a parameter regime relevant for many experiments, the increase in false positives is quite modest. Moreover, results obtained this way have higher Positive Predictive Value than non-incremented experiments of the same sample size and statistical power. In other words, adding a few more observations to shore up a nearly-significant result can increase the reproducibility of results, counter to some current rhetoric. Many experiments are non-confirmatory, and unplanned sample augmentation with reasonable decision rules would not cause rampant irreproducibility in that context.

10.1371/journal.pbio.3002345

biorxiv

10.1101/2019.12.12.868489

Is N-Hacking Ever OK? A Simulation-based study

Reinagel, P.

Pamela Reinagel

UCSD

2023-08-24T00:00:00

4

new results

cc_by_nc_nd

scientific communication and education

https://www.biorxiv.org/content/early/2023/08/24/2019.12.12.868489.source.xml

After an experiment has been completed, a trend may be observed that is "not quite significant". Sometimes in this situation, researchers collect more data in an effort to achieve statistical significance. Such "N-hacking" is condemned because it can lead to an excess of false positive results. I use simulations to demonstrate how N-hacking causes false positives. However, in a parameter regime relevant for many experiments, the increase in false positives is quite modest. Moreover, results obtained this way have higher Positive Predictive Value than non-incremented experiments of the same sample size and statistical power. In other words, adding a few more observations to shore up a nearly-significant result can increase the reproducibility of results, counter to some current rhetoric. Many experiments are non-confirmatory, and unplanned sample augmentation with reasonable decision rules would not cause rampant irreproducibility in that context.

10.1371/journal.pbio.3002345

biorxiv

10.1101/2019.12.20.884734

Genetic erosion reduces biomass temporal stability in wild fish populations.

Prunier, J. G.; Chevalier, M.; Raffard, A.; Loot, G.; Poulet, N.; Blanchet, S.

Jerome G. Prunier

CNRS

2023-04-05T00:00:00

3

new results

cc_by_nc

ecology

https://www.biorxiv.org/content/early/2023/04/05/2019.12.20.884734.source.xml

Genetic diversity sustains species adaptation. However, it may also support key ecosystems functions and services that can be altered by the worldwide loss of genetic diversity. Here, using long-term wild fish data, we demonstrate that populations with high genetic diversity do not reach higher biomasses than populations with low genetic diversity. Nonetheless, populations with high genetic diversity have much more stable biomasses over recent decades than populations having suffered from genetic erosion, which has implications for the provision of ecosystem services and the risk of population extinction. Our results strengthen the importance of adopting prominent environmental policies to conserve this important biodiversity facet.

10.1038/s41467-023-40104-4

biorxiv

10.1101/2019.12.20.884262

Cognitive control of behavior and hippocampal information processing without medial prefrontal cortex

Park, E.; Reilly, K. O.; Grubbs, G.; Taborga, D.; Nicholas, K.; Ahmeda, A. S.; Ruiz, N.; Kim, N.; Segura-Carrillo, S.; Fenton, A. A.

Kally O'Reilly

Columbia University

2024-04-11T00:00:00

3

new results

cc_by_nd

neuroscience

https://www.biorxiv.org/content/early/2024/04/11/2019.12.20.884262.source.xml

Cognitive control tasks require using one class of information and ignoring competing classes of information. A central role for the medial prefrontal cortex (mPFC) in cognitive control is well established because mPFC damage impairs tasks that may require cognitive control, as inferred, typically from the task design. We tested the "central-computation" hypothesis that rat mPFC is essential for cognitive control. Ibotenic acid lesion of the mPFC was effective and altered the coordination of metabolic activity in remaining structures. The lesion did not impair an active place avoidance task that requires cognitive control, nor did it impair concurrent alternation between task-relevant and task-irrelevant hippocampal CA1 representations of space. Conflict avoidance learning that tests cognitive flexibility was impaired, but not initial learning or long-term memory. These findings support an alternative "local-computation" hypothesis: the computations required for cognitive control can occur locally in brain networks independently of the mPFC, as demonstrated.

NA

biorxiv

10.1101/2020.01.03.893776

A long tail of truth and beauty: A zigzag pattern of feather formation explains the symmetry, complexity, and beauty of the peacock's tail

Singh, R. S.; Jagadeeshan, S.

Rama Shankar Singh

McMaster University

2023-08-17T00:00:00

3

new results

cc_by_nc_nd

evolutionary biology

https://www.biorxiv.org/content/early/2023/08/17/2020.01.03.893776.source.xml

One hundred and fifty years after the publication of Darwins sexual selection theory, the problem of the peacocks train remains unsolved. Darwin assumed that the peacocks long train was maladaptive and was the indirect effect of selection by female mate choice based on the trains beauty. While a relationship between the feathers elaborate features and mating success has been shown, the concept of eyespots as the basis of female choice remains controversial. We examined the anatomical plan underlying feather development using museum specimens and observed a zigzag pattern of feather follicles that determined both the number and the hexagonal arrangement of eyespots on the train as well as, strikingly, the individual eyespots color rings. While the zigzag pattern explains the symmetry, complexity, and structural beauty of the peacocks train, it also precludes individual eyespot variation. The only available variation in eyespot number is expected to be due to annual addition of new rows of 10/11 feathers as a function of age, giving rise to an inherently determined eyespot number. New insights show that eyespot number and feather length are developmentally correlated and an asymptotic function of a males age, that their effects on female choice would be confounded and inseparable, and that male vigor would be a crucial factor affecting male fitness. Females may not always choose males with the largest number of eyespots, as older males may lack vigor. We propose a multimodal model of female choice based on male size, vigor, and beauty where females see eyespot and train size not as separate traits but as one complex trait combining both. The new model may be able to explain conflicting results and why eyespot number alone may not be sufficient to explain female choice. Beauty is truth, truth beauty. Keats

NA

biorxiv

10.1101/2020.01.04.894907

Genome-wide Functional Characterization of Escherichia coli Promoters and Sequence Elements Encoding Their Regulation

Urtecho, G.; Insigne, K.; Tripp, A. D.; Brinck, M.; Lubock, N. B.; Acree, C.; Kim, H.; Chan, T.; Kosuri, S.

Sriram Kosuri

UCLA

2023-10-12T00:00:00

2

new results

cc_by_nc

microbiology

https://www.biorxiv.org/content/early/2023/10/12/2020.01.04.894907.source.xml

Despite decades of intense genetic, biochemical, and evolutionary characterizations of bacterial promoters, we lack the ability to identify or predict transcriptional activities of promoters using primary sequence. Even in simple, well-characterized organisms such as E. coli there is little agreement on the number, location, and strength of promoters. We use a genomically-encoded massively parallel reporter assay to perform the first full characterization of autonomous promoter activity across the E. coli genome. We measure promoter activity of >300,000 sequences spanning the entire genome and map 2,228 promoters active in rich media. Surprisingly, 944 of these promoters were found within intragenic sequences and are associated with conciliatory sequence adaptations by both the protein-coding regions and overlapping RNAP binding sites. Furthermore, we perform a scanning mutagenesis of 2,057 promoters to uncover sequence elements regulating promoter activity, revealing 3,317 novel regulatory elements. Finally, we show that despite these large datasets and modern machine learning algorithms, predicting endogenous promoter activity from primary sequence is still challenging.

NA

biorxiv

10.1101/2020.01.09.900514

Defective Function of α-Ketoglutarate Dehydrogenase Exacerbates Mitochondrial ATP Deficits during Complex I Deficiency

Piroli, G. G.; Manuel, A. M.; McCain, R. S.; Smith, H. H.; Ozohanics, O.; Mellid, S.; Cotham, W. E.; Walla, M. D.; Cascon, A.; Ambrus, A.; Frizzell, N.

Norma Frizzell

University of South Carolina

2023-08-10T00:00:00

3

new results

cc_by_nc_nd

biochemistry

https://www.biorxiv.org/content/early/2023/08/10/2020.01.09.900514.source.xml

The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration, suggesting a mechanistic role in neurodegenerative decline. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the -ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the OXPHOS ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.

10.1016/j.redox.2023.102932

biorxiv

10.1101/2020.01.11.899559

Macromolecular and cytological changes in fission yeast G0 nuclei

Tan, Z. Y.; Cai, S.; Paithankar, S. A.; Nie, X.; Shi, J.; Gan, L.

Lu Gan

National University of Singapore

2024-04-10T00:00:00

2

new results

cc_by_nc_nd

cell biology

https://www.biorxiv.org/content/early/2024/04/10/2020.01.11.899559.source.xml

When starved of nitrogen, fission yeast Schizosaccharomyces pombe cells enter a quiescent "G0" state with smaller nuclei and transcriptional repression. The genomics of S. pombe G0 cells has been well studied, but much of its nuclear cell biology remains unknown. Here we use confocal microscopy, immunoblots, and electron cryotomography to investigate the cytological, biochemical, and ultrastructural differences between S. pombe proliferating, G1-arrested, and G0 cell nuclei, with an emphasis on the histone acetylation, RNA polymerase II fates, and macromolecular complex packing. Compared to proliferating cells, G0 cells have lower levels of histone acetylation, nuclear RNA polymerase II, and active transcription. The G0 nucleus has similar macromolecular crowding yet fewer chromatin-associated multi-megadalton globular complexes. Induced histone hyperacetylation in G0 results in cells that have larger nuclei and therefore less compact chromatin. However, these histone-hyperacetylated G0 cells remain transcriptionally repressed with similar nuclear crowding. Canonical nucleosomes - those that resemble the crystal structure - are rare in proliferating, G1-arrested, and G0 cells. Our study therefore shows that extreme changes in nucleus physiology are possible without extreme reorganisation at the macromolecular level. SummaryWe use multiple cell-biological techniques to compare proliferating and quiescent G0 fission yeast cell nucleus transcription, histone acetylation, macromolecular packing.

NA

biorxiv

10.1101/2020.01.12.903393

Calcium-independent lipid release from astrocytes modulates neuronal excitability

Wang, F.; Bradshaw, H. B.; Jablonska, B.; Pena, S. E.; Xavier, J.; Gong, S.; Li, B.; Chandler-Militello, D.; Bekar, L. K.; Smith, N. A.

Nathan A Smith

Children's National Research Institute

2024-05-19T00:00:00

6

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2024/05/19/2020.01.12.903393.source.xml

An accumulating amount of data suggests that Ca2+-dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE2). Surprisingly, the buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca2+-independent pathway regulates the release of PGE2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCEUntil now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.

NA

biorxiv

10.1101/2020.01.12.903393

Calcium-independent lipid release from astrocytes modulates neuronal excitability

Wang, F.; Bradshaw, H. B.; Jablonska, B.; Pena, S. E.; Chittaranjan, S.; Xavier, J.; Gong, S.; Li, B.; Chandler-Militello, D.; Bekar, L. K.; Smith, N. A.

Nathan A Smith

Children's National Research Institute

2024-07-30T00:00:00

7

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2024/07/30/2020.01.12.903393.source.xml

An accumulating amount of data suggests that Ca2+-dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE2). Surprisingly, the buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca2+-independent pathway regulates the release of PGE2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCEUntil now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.

NA

biorxiv

10.1101/2020.01.29.926022

CopyMix: Mixture Model Based Single-Cell Clustering and Copy Number Profiling using Variational Inference

Safinianaini, N.; P. E. de Souza, C.; Roth, A.; Koptagel, H.; Toosi, H.; Lagergren, J.

Negar Safinianaini

School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, Stockholm, Sweden

2023-10-17T00:00:00

6

new results

cc_by

bioinformatics

https://www.biorxiv.org/content/early/2023/10/17/2020.01.29.926022.source.xml

Investigating tumor heterogeneity using single-cell sequencing technologies is imperative to understand how tumors evolve since each cell subpopulation harbors a unique set of genomic features that yields a unique phenotype, which is bound to have clinical relevance. Clustering of cells based on copy number data obtained from single-cell DNA sequencing provides an opportunity to identify different tumor cell subpopulations. Accordingly, computational methods have emerged for single-cell copy number profiling and clustering; however, these two tasks have been handled sequentially by applying various ad-hoc pre- and post-processing steps; hence, a procedure vulnerable to introducing clustering artifacts. Moreover, clonal copy number profiling has been missing except for one method, CONET, which unfortunately computes it by a post-processing tool. Finally, a common copy number profiling tool, HMMcopy, requires parameter tuning. We avoid the clustering artifact issues and provide clonal copy number profiles without the labor of parameter tuning in our method, CopyMix, a Variational Inference for a novel mixture model, by jointly inferring cell clusters and their underlying copy number profile. We evaluate CopyMix using simulated data and published biological data from ovarian cancer. The results reveal high clustering performance and low errors in copy number profiling. These favorable results indicate a considerable potential to obtain clinical impact by using CopyMix in studies of cancer tumor heterogeneity.

NA

biorxiv

10.1101/2020.01.30.926790

Alu insertion-mediated dsRNA structure formation with pre-existing Alu elements as a novel disease-causing mechanism

Masson, E.; Maestri, S.; Bordeau, V.; Cooper, D. N.; Ferec, C.; Chen, J.-M.

Jian-Min Chen

Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200 Brest, France

2024-04-03T00:00:00

2

new results

cc_by_nc_nd

genetics

https://www.biorxiv.org/content/early/2024/04/03/2020.01.30.926790.source.xml

We previously identified a homozygous Alu insertion variant (Alu_Ins) in the 3-UTR of the SPINK1 gene as the cause of a novel pediatric disease. Although we established that Alu_Ins leads to the complete loss of SPINK1 mRNA expression, the precise mechanisms remained elusive. Here we aimed to elucidate these mechanisms through a hypothesis-driven approach. Initially, we speculated that Alu_Ins could independently disrupt mRNA 3 end formation and/or affect other post-transcriptional processes such as nuclear export and translation, due to its particular location. However, the presence of Alu_Ins in the 3-UTR resulted in only an ~50% reduction in luciferase reporter activity compared to the wild-type, suggesting the involvement of additional mechanisms. Using RepeatMasker, we identified two Alu elements within SPINK1s third intron, both of which resided in an orientation opposite to that of Alu_Ins. Through RNAfold predictions and full-length gene expression assays designed to examine orientation-dependent interactions between Alu repeats, we present evidence linking the detrimental effect of Alu_Ins to extensive double-stranded RNA structures formed between Alu_Ins and pre-existing intronic Alu sequences. Our results reveal a novel pathogenetic mechanism involving an Alu insertion, highlighting the importance of considering interactions between new and pre-existing Alu elements in inverted orientations within disease-associated genes.

NA

biorxiv

10.1101/2020.02.03.926295

The hidden cost of receiving favors: A theory of indebtedness

Gao, X.; Jolly, E.; Yu, H.; Liu, H.; Zhou, X.; Chang, L. J.

Luke J Chang

Peking University

2023-05-26T00:00:00

4

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2023/05/26/2020.02.03.926295.source.xml

Receiving help or a favor from another person can sometimes have a hidden cost for the beneficiary. In this study, we explore these hidden costs by developing and validating a conceptual model of indebtedness across three studies that combine a large scale online questionnaire, an interpersonal game, computational modeling, and neuroimaging. Our model captures how individuals perceive the altruistic and strategic intentions of the benefactor. These inferences produce distinct feelings of guilt and obligation that together comprise indebtedness and motivate reciprocity. Perceived altruistic intentions convey care and concern and are associated with activity in insula, ventromedial prefrontal cortex and dorsolateral prefrontal cortex, while inferred strategic intentions convey expectations of future reciprocity and are associated with activation in temporal parietal junction and dorsomedial prefrontal cortex. We further develop a neural utility model of indebtedness using multivariate patterns of brain activity that captures the tradeoff between these feelings and reliably predicts reciprocity behavior.

NA

biorxiv

10.1101/2020.02.09.940494

Pathogen community composition and co-infection patterns in a wild community of rodents

Abbate, J. L.; Galan, M.; Razzauti, M.; Sironen, T.; Voutilainen, L.; Henttonen, H.; Gasqui, P.; Cosson, J.-F.; Charbonnel, N.

Nathalie Charbonnel

CBGP, INRAE, CIRAD, IRD, Montpellier SupAgro, Univ Montpellier, Montpellier, France

2023-07-21T00:00:00

3

new results

cc_by_nc_nd

ecology

https://www.biorxiv.org/content/early/2023/07/21/2020.02.09.940494.source.xml

Rodents are major reservoirs of pathogens that can cause disease in humans and livestock. It is therefore important to know what pathogens naturally circulate in rodent populations, and to understand the factors that may influence their distribution in the wild. Here, we describe the occurrence and distribution patterns of a range of endemic and zoonotic pathogens circulating among rodent communities in northern France. The community sample consisted of 713 rodents, including 11 host species from diverse habitats. Rodents were screened for virus exposure (hantaviruses, cowpox virus, Lymphocytic choriomeningitis virus, Tick-borne encephalitis virus) using antibody assays. Bacterial communities were characterized using 16S rRNA amplicon sequencing of splenic samples. Multiple correspondence (MCA), multiple regression and association screening (SCN) analyses were used to determine the degree to which extrinsic factors (study year and site; host habitat, species, sex and age class) contributed to pathogen community structure, and to identify patterns of associations between pathogens within hosts. We found a rich diversity of bacterial genera, with 36 known or suspected to be pathogenic. We revealed that host species is the most important determinant of pathogen community composition, and that hosts that share habitats can have very different pathogen communities. Pathogen diversity and co-infection rates also vary among host species. Aggregation of pathogens responsible for zoonotic diseases suggests that some rodent species may be more important for transmission risk than others. Moreover, we detected positive associations between several pathogens, including Bartonella, Mycoplasma species, Cowpox virus (CPXV) and hantaviruses, and these patterns were generally specific to particular host species. Altogether, our results suggest that host and pathogen specificity is the most important driver of pathogen community structure, and that interspecific pathogen-pathogen associations also depend on host species.

10.24072/pcjournal.370

biorxiv

10.1101/2020.02.09.940494

Pathogen community composition and co-infection patterns in a wild community of rodents

Abbate, J. L.; Galan, M.; Razzauti, M.; Sironen, T.; Voutilainen, L.; Henttonen, H.; Gasqui, P.; Cosson, J.-F.; Charbonnel, N.

Nathalie Charbonnel

CBGP, INRAE, CIRAD, IRD, Montpellier SupAgro, Univ Montpellier, Montpellier, France

2023-11-14T00:00:00

4

new results

cc_by_nc_nd

ecology

https://www.biorxiv.org/content/early/2023/11/14/2020.02.09.940494.source.xml

Rodents are major reservoirs of pathogens that can cause disease in humans and livestock. It is therefore important to know what pathogens naturally circulate in rodent populations, and to understand the factors that may influence their distribution in the wild. Here, we describe the occurrence and distribution patterns of a range of endemic and zoonotic pathogens circulating among rodent communities in northern France. The community sample consisted of 713 rodents, including 11 host species from diverse habitats. Rodents were screened for virus exposure (hantaviruses, cowpox virus, Lymphocytic choriomeningitis virus, Tick-borne encephalitis virus) using antibody assays. Bacterial communities were characterized using 16S rRNA amplicon sequencing of splenic samples. Multiple correspondence (MCA), multiple regression and association screening (SCN) analyses were used to determine the degree to which extrinsic factors (study year and site; host habitat, species, sex and age class) contributed to pathogen community structure, and to identify patterns of associations between pathogens within hosts. We found a rich diversity of bacterial genera, with 36 known or suspected to be pathogenic. We revealed that host species is the most important determinant of pathogen community composition, and that hosts that share habitats can have very different pathogen communities. Pathogen diversity and co-infection rates also vary among host species. Aggregation of pathogens responsible for zoonotic diseases suggests that some rodent species may be more important for transmission risk than others. Moreover, we detected positive associations between several pathogens, including Bartonella, Mycoplasma species, Cowpox virus (CPXV) and hantaviruses, and these patterns were generally specific to particular host species. Altogether, our results suggest that host and pathogen specificity is the most important driver of pathogen community structure, and that interspecific pathogen-pathogen associations also depend on host species.

10.24072/pcjournal.370

biorxiv

10.1101/2020.02.13.946517

Protein interaction mapping reveals widespread targeting of development-related host transcription factors by phytoplasma effectors

Correa Marrero, M.; Capdevielle, S.; Huang, W.; Al-Subhi, A. M.; Busscher, M.; Busscher-Lange, J.; van der Wal, F.; de Ridder, D.; van Dijk, A. D. J.; Hogenhout, S. A.; Immink, R. G. H.

Richard G.H. Immink

Wageningen University & Research

2023-07-23T00:00:00

2

new results

cc_by_nc_nd

plant biology

https://www.biorxiv.org/content/early/2023/07/23/2020.02.13.946517.source.xml

Phytoplasmas are pathogenic bacteria that reprogram plant host development for their own benefit. Previous studies have characterized a few different phytoplasma effector proteins that destabilize specific plant transcription factors. However, these are only a small fraction of the potential effectors used by phytoplasmas; therefore, the molecular mechanisms through which phytoplasmas modulate their hosts require further investigation. To obtain further insights into the phytoplasma infection mechanisms, we generated a protein-protein interaction network between a broad set of phytoplasma effectors and a large, unbiased collection of Arabidopsis thaliana transcription factors and transcriptional regulators. We found widespread, but specific, interactions between phytoplasma effectors and host transcription factors, especially those related to host developmental processes. In particular, many unrelated effectors target specific sets of TCP transcription factors, which regulate plant development and immunity. Comparison with other host-pathogen protein interaction networks shows that phytoplasma effectors have unusual targets, indicating that phytoplasmas have evolved a unique and unusual infection strategy. This study contributes a rich and solid data source that guides further investigations of the functions of individual effectors, as demonstrated for some herein. Moreover, the dataset provides insights into the underlying molecular mechanisms of phytoplasma infection.

10.1111/tpj.16546

biorxiv

10.1101/2020.02.13.948539

Slow oscillation-spindle coupling predicts sequence-based language learning

Cross, Z. R.; Helfrich, R. F.; Corcoran, A. W.; Kohler, M. J.; Coussens, S.; Zou-Williams, L.; Schlesewsky, M.; Gaskell, M. G.; Knight, R. T.; Bornkessel-Schlesewsky, I.

Zachariah R Cross

Cognitive and Systems Neuroscience Research Hub, University of South Australia

2023-11-27T00:00:00

3

new results

cc_by_nd

neuroscience

https://www.biorxiv.org/content/early/2023/11/27/2020.02.13.948539.source.xml

Sentence comprehension involves the rapid decoding of semantic and grammatical information, a process fundamental to communication. As with other cognitive processes, language comprehension relies partly on long-term memory. However, the electrophysiological mechanisms underpinning the initial encoding and generalisation of higher-order linguistic knowledge remains elusive, particularly from a sleep-based consolidation perspective. One candidate mechanism that may subserve the consolidation of language is the temporal coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement sleep (NREM). To examine this hypothesis, we analysed electroencephalographic (EEG) data recorded from 35 participants (Mage = 25.4, SD = 7.10; 16 males) during an artificial language learning task, contrasting performance between individuals who were given an 8hr nocturnal sleep period or an equivelant period of wake. We found that sleep relative to wake was associated with superior performance for rules that followed a sequence-based word order. Post-sleep sequence-based word order processing was associated with an increase in task-related theta power, an electrophysiological signature of successful memory consolidation. Frontal NREM SO-spindle coupling was also positively associated with behavioural sensitivity to sequence-based word order rules, as well as with task-related theta power. As such, theta activity during retrieval of previously learned information correlates with SO-spindle coupling, thus linking neural activity in the sleeping and waking brain. Taken together, this study presents converging behavioural and neurophysiological evidence for a role of NREM SO-spindle coupling and task-related theta activity as signatures of successful memory consolidation and retrieval in the context of higher-order language learning. SIGNIFICANCE STATEMENTThe endogenous temporal coordination of neural oscillations supports information processing during both wake and sleep states. Here we demonstrate that slow oscillation-spindle coupling during non-rapid eye movement sleep predicts the consolidation of complex grammatical rules and modulates task-related oscillatory dynamics previously implicated in sentence processing. We show that increases in theta power predict enhanced sensitivity to grammatical violations after a period of sleep and strong slow oscillation-spindle coupling modulates subsequent task-related theta activity to influence behaviour. Our findings reveal a complex interaction between both wake- and sleep-related oscillatory dynamics during the early stages of language learning beyond the single word level.

NA

biorxiv

10.1101/2020.02.19.955351

Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knock-out, and LacZ knock-in mice.

Kwak, H.; Cho, E.-H.; Cho, E. B.; Lee, Y.-N.; Shahapal, A.; Yong, H. J.; Reyes-Alcaraz, A.; Jeong, Y.; Lee, Y.; Lee, M.; Ha, N.; Oh, S.; Lee, J. K.; Lee, W. S.; Kim, W. K.; Hwang, J.-I.; Seong, J. Y.

Jae Young Seong

Graduate School of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea

2024-07-26T00:00:00

2

contradictory results

cc_by_nd

genetics

https://www.biorxiv.org/content/early/2024/07/26/2020.02.19.955351.source.xml

FAM19A5 is a novel secretory protein primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function through sphingosine-1-phosphate receptor 2 (S1PR2). In our study, we investigated FAM19A5 transcript and protein levels in peripheral tissues, including adipose tissues, from wild-type, FAM19A5 knockout, and FAM19A5 LacZ knockin mice. We found that FAM19A5 transcript levels in the central nervous system were much greater than those in any of the peripheral tissues, including adipose tissues. Furthermore, the FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for Western blot analysis. Additionally, we found that the FAM19A5 protein did not interact with S1PR2 in terms of G protein-mediated signal transduction, {beta}-arrestin recruitment, or ligand-mediated internalization. Taken together, our findings revealed basal levels of FAM19A5 transcripts and proteins in peripheral tissues, confirming its primary expression in the central nervous system and lack of significant interaction with S1PR2.

NA

biorxiv

10.1101/2020.02.20.957548

A New World begomovirus infecting Cotton in Argentina

Delfosse, V.; Debat, H.; Zavallo, D.; Moyano, S.; Luna, F.; Bonacic Kresic, I.; Asurmendi, S.; Gomez-Talquenca, S.; Distefano, A. J.

Humberto Debat

IPAVE-CIAP-INTA

2023-08-08T00:00:00

2

new results

cc_by_nc_nd

microbiology

https://www.biorxiv.org/content/early/2023/08/08/2020.02.20.957548.source.xml

Cotton (Gossypium spp.) is a globally significant cash crop cultivated for its versatile fiber, widely used in the textile industry. Cotton, as other crops, is vulnerable to infectious pathogens. Several of them, including viruses, are a major threat to cotton production. Geminiviruses (family Geminiviridae) are insect transmitted, small non-enveloped viruses, with circular single-stranded DNA genomes, which are encapsidated in quasi-icosahedral geminated virions. Here we present evidence of a novel begomovirus (genus Begomovirus) infecting cotton from Argentina. Two circular ssDNA virus sequences were assembled from high-throughput sequencing data from Gossyipium hirsutum cotton samples showing mosaic symptoms from Argentina. Structural and functional annotation indicated that the virus sequences corresponded to complete DNA components A and B of a novel New World bipartite begomovirus. Genetic distance and evolutionary analyses support that the detected sequences correspond to a new virus, a tentative prototype member of a novel species which we propose the name "Cotton mosaic virus" (CoMV).

NA

biorxiv

10.1101/2020.02.25.965376

A rapid, accurate approach to inferring pedigrees in endogamous populations

Williams, C. M.; Scelza, B.; Slack, S. D.; Mathias, R. A.; Watson, H.; Barnes, K. C.; Lange, E.; Johnson, R. K.; Gignoux, C. R.; Ramachandran, S.; Henn, B. M.

Brenna M Henn

Dept. of Anthropology and UC Davis Genome Center, University of California, Davis

2024-07-16T00:00:00

3

new results

cc_by_nc_nd

bioinformatics

https://www.biorxiv.org/content/early/2024/07/16/2020.02.25.965376.source.xml

Accurate reconstruction of pedigrees from genetic data remains a challenging problem. Pedigree inference algorithms are often trained only on European-descent families in urban locations. Many relationship categories can be difficult to distinguish (e.g. half-sibships versus avuncular) without external information. Furthermore, existing methods perform poorly in endogamous populations for which there may be reticulations within the pedigrees and elevated haplotype sharing. We present a simple, rapid algorithm which initially uses only high-confidence first-degree relationships to seed a machine learning step based on summary statistics of identity-by-descent (IBD) sharing. One of these statistics, our "haplotype score", is novel and can be used to: (1) distinguish half-sibling pairs from avuncular or grandparent-grandchildren pairs; and (2) assign individuals to ancestor versus descendant generation. We test our approach in a sample of 700 individuals from northern Namibia, sampled from an endogamous population called the Himba. Due to a culture of concurrent relationships in the Himba, there is a high proportion of half-sibships. We accurately identify first through fourth-degree relationships and distinguish between various second-degree relationships: half-sibships, avuncular pairs, and grandparent-grandchildren. We further validate our approach in a second diverse African-descent dataset, the Barbados Asthma Genetics Study (BAGS). Accurate reconstruction of pedigrees holds promise for tracing allele frequency trajectories, improved phasing and other population genomic questions.

NA

biorxiv

10.1101/2020.02.27.968339

Spiking attractor model of motor cortex explains modulation of neural and behavioral variability by prior target information

Rostami, V.; Rost, T.; Schmitt, F. J.; van Albada, S. J.; Riehle, A.; P. Nawrot, M.

Vahid Rostami

Computational Systems Neuroscience, Institute of Zoology, University of Cologne, Cologne, Germany

2024-03-05T00:00:00

4

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2024/03/05/2020.02.27.968339.source.xml

When preparing a movement, we often rely on partial or incomplete information, which can decrement task performance. In behaving monkeys we show that the degree of cued target information is reflected in both, neural variability in motor cortex and behavioral reaction times. We study the underlying mechanisms in a spiking motor-cortical attractor model. By introducing a novel and biologically realistic network topology where excitatory neuron clusters are locally balanced with inhibitory neuron clusters we robustly achieve metastable network activity across a wide range of network parameters. In application to the monkey task, the model performs target-specific action selection and accurately reproduces the task-epoch dependent reduction of trial-to-trial variability in vivo where the degree of reduction directly reflects the amount of processed target information, while spiking irregularity remained constant throughout the task. In the context of incomplete cue information, the increased target selection time of the model can explain increased behavioral reaction times . We conclude that context-dependent neural and behavioral variability is a signum of attractor computation in the motor cortex.

10.1038/s41467-024-49889-4

biorxiv

10.1101/2020.02.29.971424

Trypanosoma brucei ultra-structure cell modifications caused by knockdown of the ribonuclease Rrp44/Dis3

Cesaro, G.; Hiraiwa, P. M.; Carneiro, F. R. G.; Rouam, V.; Legrand, P.; Conesa, J. J.; Refregiers, M.; Pereiro, E.; Guimaraes, B. G.; Jamme, F.; Zanchin, N. I. T.

Nilson I. T. Zanchin

Carlos Chagas Institute, Oswaldo Cruz Foundation, FIOCRUZ-PR, Curitiba-PR, Brazil

2024-01-31T00:00:00

2

new results

cc_by_nc_nd

cell biology

https://www.biorxiv.org/content/early/2024/01/31/2020.02.29.971424.source.xml

Rrp44/Dis3 is an essential protein conserved in all eukaryotes that functions in the maturation of many different RNA precursors and RNA surveillance. The Trypanosoma brucei Rrp44/Dis3 homologue (TbRRP44) is required for maturation of pre-rRNA, spliced leader, and U3 snoRNA precursors. Its depletion leads to inhibition of cell proliferation and eventually to cell death. In this work, we showed that TbRRP44 depletion causes a massive expansion of acidic and lysosome-derived vacuoles, enlargement of cell and nuclei sizes without changes in DNA content, mitochondrial inactivation, and autophagy induction. Consistently, 3D reconstructions using cryo-soft X-ray tomography revealed extreme vacuolation of the cytoplasm and numerous cellular alterations, including an increase in size and number of calcium-containing vesicles and lipid droplets. These multiple defects indicate that a combination of alterations converge to induce lysosome expansion. With time, the cytoplasm is taken up by lysosome-derived vacuoles, which may be a final stage leading to the cell death triggered by TbRRP44 depletion. These studies provide the first evidence on the ultra-structure cell modifications caused by deficiency of this essential ribonuclease in T. brucei.

NA

biorxiv

10.1101/2020.03.05.979468

Neurons in the ventral striatopallidal complex modulate lateral hypothalamic orexin/hypocretin neuron activity: Implications for reward-seeking

Mitchell, C. S.; Mohammadkhani, A.; Manning, E. E.; Campbell, E. J.; Fisher, S. D.; Yeoh, J. W.; Pearl, A. J.; Iredale, J. A.; Burton, N. J.; Qiao, M.; Bains, J. S.; McNally, G. P.; Andrews, Z. A.; Graham, B. A.; Scammel, T. E.; Lowell, B. B.; Kong, D.; Borgland, S. L.; Dayas, C. V.

Christopher V Dayas

School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia.

2024-03-03T00:00:00

2

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2024/03/03/2020.03.05.979468.source.xml

Reward-seeking involves the engagement and computation of multiple physiological and motivational parameters. The lateral hypothalamus (LH) is a necessary node in the circuits that control food-seeking and motivation. One group of cells that plays an important yet incompletely understood role in these processes are the orexin/hypocretin (OX/HT) neurons. OX/HT cells are located exclusively within the LH and are implicated in feeding, arousal, and reward-seeking behavior. Importantly, the role of OX/HT neurons in consummatory versus reward-seeking actions is not fully defined, nor are the circuits that control the activity of these neurons under different behavioral states. Here we show that OX/HT neurons respond in real time to food presentation and that this response is modulated by differences in metabolic state. We observed increased OX/HT neuron activity on approach to food, but this activity trended towards pre-approach levels by the start of the consummatory phase. Next, we studied ventrostriatopallidal (VSP) inputs to the OX/HT neurons. Using optogenetics and cell type-specific electrophysiology, we found that ventral pallidum inputs onto OX/HT neurons exert strong inhibitory (and weak excitatory) effects whereas the lateral nucleus accumbens shell provides weaker direct inhibitory connections with OX/HT neurons. These findings reveal that the activity of OX/HT neurons is strongly modulated by metabolic and hedonic state. Further, OX/HT neurons is primarily associated with food approach and that the effect of VSP-terminal output is to suppress OX/HT activity.

NA

biorxiv

10.1101/2020.03.11.988238

Immune Digital Twin Blueprint: A Comprehensive Simulatable Model of the Human Immune System

Moore, R.; Amin, R.; Aghamiri, S.; Mohammed, A.; La Fleur, A.; Puniya, B. L.; Helikar, T.

Tomas Helikar

University of Nebraska - Lincoln

2023-05-16T00:00:00

2

new results

cc_by_nd

systems biology

https://www.biorxiv.org/content/early/2023/05/16/2020.03.11.988238.source.xml

The immune system is a complex and dynamic network, crucial for combating infections and maintaining health. Developing a comprehensive digital twin of the immune system requires incorporating essential cellular components and their interactions. This study presents the first blueprint for an immune system digital twin, consisting of a comprehensive and simulatable mechanistic model. It integrates 51 innate and adaptive immune cells, 37 secretory factors, and 11 disease conditions, providing the foundation for developing a multi-scale model. The cellular-level model demonstrates its potential in characterizing immune responses to various single and combinatorial disease conditions. By making the model available in easy-to-use formats directly in the Cell Collective platform, the community can easily and further expand it. This blueprint represents a significant step towards developing general-purpose immune digital twins, with far-reaching implications for the future of digital twin technology in life sciences and healthcare, advancing patient care, and accelerating precision medicine.

NA

biorxiv

10.1101/2020.03.11.988238

Immune Digital Twin Blueprint: A Comprehensive Mechanistic Model of the Human Immune System

Amin, R.; Aghamiri, S.; Puniya, B. L.; Mayo, L.; Startsev, D.; Poore, K.; Helikar, R. M.; Helikar, T.

Tomas Helikar

University of Nebraska - Lincoln

2024-07-31T00:00:00

3

new results

cc_by_nd

systems biology

https://www.biorxiv.org/content/early/2024/07/31/2020.03.11.988238.source.xml

The immune system is a complex and dynamic network, crucial for combating infections and maintaining health. Developing a comprehensive digital twin of the immune system requires incorporating essential cellular components and their interactions. This study presents the first blueprint for an immune system digital twin, consisting of a comprehensive and simulatable mechanistic model. It integrates 51 innate and adaptive immune cells, 37 secretory factors, and 11 disease conditions, providing the foundation for developing a multi-scale model. The cellular-level model demonstrates its potential in characterizing immune responses to various single and combinatorial disease conditions. By making the model available in easy-to-use formats directly in the Cell Collective platform, the community can easily and further expand it. This blueprint represents a significant step towards developing general-purpose immune digital twins, with far-reaching implications for the future of digital twin technology in life sciences and healthcare, advancing patient care, and accelerating precision medicine.

NA

biorxiv

10.1101/2020.03.17.995431

pyComBat, a Python tool for batch effects correction in high-throughput molecular data using empirical Bayes methods

Behdenna, A.; Colange, M.; Haziza, J.; Gema, A. P.; Appe, G.; Azencott, C.-A.; Nordor, A.

Akpéli Nordor

Epigene Labs, Paris, France

2023-08-29T00:00:00

3

confirmatory results

cc_by_nc_nd

bioinformatics

https://www.biorxiv.org/content/early/2023/08/29/2020.03.17.995431.source.xml

BackgroundVariability in datasets is not only the product of biological processes: they are also the product of technical biases. ComBat and ComBat-Seq are among the most widely used tools for correcting those technical biases, called batch effects, in, respectively, microarray and RNA-Seq expression data. ResultsIn this technical note, we present a new Python implementation of ComBat and ComBat-Seq. While the mathematical framework is strictly the same, we show here that our implementations: (i) have similar results in terms of batch effects correction; (ii) are as fast or faster than the original implementations in R and; (iii) offer new tools for the bioinformatics community to participate in its development. pyComBat is implemented in the Python language and is distributed under GPL-3.0 (https://www.gnu.org/licenses/gpl-3.0.en.html) license as a module of the inmoose package. Source code is available at https://github.com/epigenelabs/inmoose and Python package at https://pypi.org/project/inmoose. ConclusionsWe present a new Python implementation of state-of-the-art tools ComBat and ComBat-Seq for the correction of batch effects in microarray and RNA-Seq data. This new implementation, based on the same mathematical frameworks as ComBat and ComBat-Seq, offers similar power for batch effect correction, at reduced computational cost. Contactakpeli@epigenelabs.com

10.1186/s12859-023-05578-5

biorxiv

10.1101/2020.03.22.002618

Solving the where problem in neuroanatomy: a generative framework with learned mappings to register multimodal, incomplete data into a reference brain

Tward, D. J.; Gray, B. D. P.; Li, X.; Huo, B.; Banerjee, S.; Savoia, S.; Mezias, C.; Das, S.; Miller, M.; Mitra, P. P.

Daniel Jacob Tward

Johns Hopkins University

2024-02-28T00:00:00

2

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2024/02/28/2020.03.22.002618.source.xml

A current focus of research in neuroscience is to enumerate, map and annotate neuronal cell types in whole vertebrate brains using different modalities of data acquisition. Mapping these molecular and anatomical datasets into a common reference space remains a key challenge. While several brain-to-atlas mapping workflows exist, they do not adequately address challenges of modern high throughput neuroimaging, including multimodal and multiscale signals, missing data or non reference signals, and geometric quantification of individual variation. Our solution is to implement a generative statistical model that describes the likelihood of imaging data given a sequence of transforms of an atlas image, and a framework for maximum a posteriori estimation of unknown parameters capturing the issues listed above. The key idea in our approach is to minimize the difference between synthetic image volumes and real data over these parameter. Rather than merely using mappings as a "normalization" step, we implement tools for using their local metric changes as an opportunity for geometric quantification of technical and biological sources of variation in an unprecedented manner. While the framework is used to compute pairwise mappings, our approach particularly allows for easy compositions across chains of multimodality datasets. We apply these methods across a broad range of datasets including various combinations of in-vivo and ex-vivo MRI, 3D STP and fMOST data sets, 2D serial histology sections, and brains processed for snRNAseq with tissue partially removed. We show biological utility by quantifying cell density and diffeomorphic characterization of brain shape fluctuations across biological covariates. We note that the magnitude of individual variation is often greater than differences between different sample preparation techniques. To facilitate community accessibility, we implement our algorithm as open source, include a web based framework, and implement input and output dataset standards. Our work establishes a quantitative, scalable and streamlined workflow for unifying a broad spectrum of multi-modal whole-brain light microscopic data volumes into a coordinate-based atlas framework. This work enables large scale integration of whole brain data sets that are essential in modern neuroscience.

NA

biorxiv

10.1101/2020.03.23.003962

Flagellar dynamics reveal fluctuations and kinetic limit in the Escherichia coli chemotaxis network

Bano, R.; Mears, P.; Golding, I.; Chemla, Y. R.

Yann R Chemla

University of Illinois at Urbana-Champaign

2023-12-03T00:00:00

3

new results

cc_by_nc_nd

biophysics

https://www.biorxiv.org/content/early/2023/12/03/2020.03.23.003962.source.xml

The Escherichia coli chemotaxis network, by which bacteria modulate their random run/tumble swimming pattern to navigate their environment, must cope with unavoidable number fluctuations ("noise") in its molecular constituents like other signaling networks. The probability of clockwise (CW) flagellar rotation, or CW bias, is a measure of the chemotaxis networks output, and its temporal fluctuations provide a proxy for network noise. Here we quantify fluctuations in the chemotaxis signaling network from the switching statistics of flagella, observed using time-resolved fluorescence microscopy of individual optically trapped E. coli cells. This approach allows noise to be quantified across the dynamic range of the network. Large CW bias fluctuations are revealed at steady state, which may play a critical role in driving flagellar switching and cell tumbling. When the network is stimulated chemically to higher activity, fluctuations dramatically decrease. A stochastic theoretical model, inspired by work on gene expression noise, points to CheY activation occurring in bursts, driving CW bias fluctuations. This model also shows that an intrinsic kinetic ceiling on network activity places an upper limit on activated CheY and CW bias, which when encountered suppresses network fluctuations. This limit may also prevent cells from tumbling unproductively in steep gradients.

NA

biorxiv

10.1101/2020.03.23.003061

Modality-independent effect of gravity in shaping the internal representation of 3D space

Theo, M.; Gabriela, H. A.; Leonardo, A.; Gilles, C.; Mathieu, B.; Joseph, M.; Michele, T.

Michele Tagliabue

Université de Paris, Integrative Neuroscience and Cognition Center, CNRS UMR 8002, F-75270 Paris, France.

2023-06-11T00:00:00

2

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2023/06/11/2020.03.23.003061.source.xml

Human 3D perception of visual objects is flawed by distortions, which are influenced by non-visual factors, such as gravitational vestibular signals. Whether gravity acts specifically on the visual system or at a higher, modality-independent, level of information processing remains unknown. To test these modality-specific vs modality-independent hypotheses, we performed experiments comparing visual versus haptic 3D shape perception in normo-gravity and microgravity. The results obtained for upright and supine posture in 1g show that visual and haptic perceptual anisotropies are systematically in opposing ego-centered, but not gravity-centered, directions suggesting they share a common origin. On the other hand, microgravity significantly modulates both visual and haptic perceptual distortion in the same direction. Overall, our results show a clear link between the visual and haptic perceptual distortions and demonstrate a role of gravity-related signals on a modality-independent internal representation of 3D space used to interpret incoming sensory inputs.

10.1523/JNEUROSCI.2457-20.2023

biorxiv

10.1101/2020.03.26.009795

Fifty shades of The Virtual Brain: Converging optimal working points yield biologically plausibleelectrophysiological and imaging features

Triebkorn, P.; Meier, J.; Zimmermann, J.; Stefanovski, L.; Roy, D.; Solodkin, A.; Jirsa, V.; Deco, G.; Breakspear, M.; Schirner, M.; McIntosh, A. R.; Ritter, P.

Paul Triebkorn

Charite Universitatsmedizin Berlin

2024-05-15T00:00:00

2

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2024/05/15/2020.03.26.009795.source.xml

Brain network modeling studies are often limited with respect to the number of data features fitted, although capturing multiple empirical features is important to validate the models overall biological plausibility. Here we construct personalized models from multimodal data of 50 healthy individuals (18-80 years) with The Virtual Brain and demonstrate that an individuals brain has its own converging optimal working point in the parameter space that predicts multiple empirical features in functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). We further show that bimodality in the alpha band power - as an explored novel feature - arises as a function of global coupling and exhibits inter-regional differences depending on the degree. Reliable inter-individual differences with respect to these optimal working points were found that seem to be driven by the individual structural rather than by the functional connectivity. Our results provide the groundwork for future multimodal brain modeling studies.

NA

biorxiv

10.1101/2020.04.06.028092

Post-transcriptional splicing can occur in a slow-moving zone around the gene

Cote, A. J.; O'Farrell, A.; Dardani, I.; Dunagin, M.; Cote, C. J.; Wan, Y.; Bayatpour, S.; Drexler, H. L.; Alexander, K. A.; Chen, F.; Wassie, A. T.; Patel, R.; Pham, K.; Boyden, E. S.; Berger, S.; Phillips-Cremins, J.; Churchman, L. S.; Raj, A.

Arjun Raj

University of Pennsylvania

2023-06-13T00:00:00

3

new results

cc_by

cell biology

https://www.biorxiv.org/content/early/2023/06/13/2020.04.06.028092.source.xml

Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription site proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.

10.7554/eLife.91357

biorxiv

10.1101/2020.04.06.028092

Post-transcriptional splicing can occur in a slow-moving zone around the gene

Cote, A. J.; O'Farrell, A.; Dardani, I.; Dunagin, M.; Cote, C. J.; Wan, Y.; Bayatpour, S.; Drexler, H. L.; Alexander, K. A.; Chen, F.; Wassie, A. T.; Patel, R.; Pham, K.; Boyden, E. S.; Berger, S.; Phillips-Cremins, J.; Churchman, L. S.; Raj, A.

Arjun Raj

University of Pennsylvania

2023-11-13T00:00:00

4

new results

cc_by

cell biology

https://www.biorxiv.org/content/early/2023/11/13/2020.04.06.028092.source.xml

Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription site proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.

10.7554/eLife.91357

biorxiv

10.1101/2020.04.07.029009

Disseminating cells in human tumours acquire an EMT cancer stem cell state that is predictive of metastasis

Youssef, G.; Gammon, L.; Ambler, L.; Lunetto, S.; Scemama, A.; Cottom, H.; Piper, K.; Mackenzie, I. C.; Philpott, M. P.; Biddle, A.

Adrian Biddle

Queen Mary University of London

2023-05-03T00:00:00

2

new results

cc_by

cancer biology

https://www.biorxiv.org/content/early/2023/05/03/2020.04.07.029009.source.xml

Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as markers of EMT CSCs with enhanced plasticity. This afforded the opportunity to investigate whether retention of EpCAM and CD24 alongside upregulation of the EMT marker Vimentin can identify disseminating EMT CSCs in human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 84 human oral cancer specimens, we see a significant enrichment of single EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.

10.7554/eLife.90298

biorxiv

10.1101/2020.04.20.049866

The accelerated infectious disease risk in the Anthropocene: more outbreaks and wider global spread

Morand, S.; Walther, B. A.

Bruno Andreas Walther

National Sun Yat-sen University

2023-08-24T00:00:00

2

confirmatory results

cc_by_nc_nd

ecology

https://www.biorxiv.org/content/early/2023/08/24/2020.04.20.049866.source.xml

The greatly accelerated economic growth during the Anthropocene has resulted in astonishing improvements in many aspects of human well-being, but has also caused the acceleration of risks, such as the interlinked biodiversity and climate crisis. Here, we report on another risk: the accelerated infectious disease risk associated with the number and geographic spread of human infectious disease outbreaks. Using the most complete, reliable, and up-to-date database on human infectious disease outbreaks (GIDEON), we show that the number of disease outbreaks, the number of diseases involved in these outbreaks, and the number of countries affected have increased during the entire Anthropocene. Furthermore, the spatial distribution of these outbreaks is becoming more globalized in the sense that the overall modularity of the disease networks across the globe has decreased, meaning disease outbreaks have become increasingly pandemic in their nature. This decrease in modularity is associated with tremendous increases in mobility, especially in air traffic. We also show that those countries and regions which are most central within these disease networks tend to be countries and global regions with higher GDPs. Therefore, one cost of greater economic growth and the associated increased global mobility is the increased risk of disease outbreaks and their wider spread. Finally, the recent global outbreaks of Covid-19 and monkeypox allowed us to demonstrate that the time of first occurrence in each country was correlated with each countrys centrality value in the disease network. We briefly discuss three different scenarios of how mobility may develop in the future which decision-makers might discuss in light of our results.

NA

biorxiv

10.1101/2020.04.22.043422

Phenotypic innovation in one tooth induced concerted developmental evolution in another

Semon, M.; Gueguen, L.; Steklikova, K.; Mouginot, M.; Peltier, M.; Veber, P.; Pantalacci, S.

Marie Semon

LBMC / ENS Lyon

2023-05-02T00:00:00

3

new results

cc_by_nc_nd

evolutionary biology

https://www.biorxiv.org/content/early/2023/05/02/2020.04.22.043422.source.xml

Serial appendages are similar organs found at different places in the body, such as fore/hindlimbs or different teeth. They are bound to develop with the same pleiotropic genes, apart from identity genes. These identity genes have logically been implicated in cases where a single appendage evolved a drastically new shape while the other retained an ancestral shape, by enabling developmental changes specifically in one organ. Here, we showed that independent evolution involved developmental changes happening in both organs, in two well characterized model systems. Mouse upper molars evolved a new dental plan with two more cusps on the lingual side, while the lower molar kept a much more ancestral morphology, as did the molars of hamster, our control species. We obtained quantitative timelines of cusp formation and corresponding transcriptomic timeseries in the 4 molars. We found that a molecular and morphogenetic identity of lower and upper molars predated the mouse and hamster divergence and likely facilitated the independent evolution of molars lingual side in the mouse lineage. We found 3 morphogenetic changes which could combine to cause the supplementary cusps in the upper molar and a candidate gene, Bmper. Unexpectedly given its milder morphological divergence, we observed extensive changes in mouse lower molar development. Its transcriptomic profiles diverged as much as, and co-evolved extensively with, those of the upper molar. Consistent with the transcriptomic quantifications, two out of the three morphogenetic changes also impacted lower molar development. Moving to limbs, we show the drastic evolution of the bat wing also involved gene expression co-evolution and a combination of specific and pleiotropic changes. Independent morphological innovation in one organ therefore involves concerted developmental evolution of the other organ. This is facilitated by evolutionary flexibility of its development, a phenomenon known as Developmental System Drift. AUTHOR SUMMARYSerial organs, such as the different wings of an insect or the different limbs or teeth of a vertebrate, can develop into drastically different shapes due to the position-specific expression of so-called "identity" genes. Often during evolution, one organ evolves a new shape while another retains a conserved shape. It was thought that identity genes were responsible for these cases of independent evolution, by enabling developmental changes specifically in one organ. Here, we showed that developmental changes evolved in both organs to enable the independent evolution of the upper molar in mice and the wing in bats. In the organ with the new shape, several developmental changes combine. In the organ with the conserved shape, part of these developmental changes are seen as well. This modifies the development but is not sufficient to drastically change the phenotype, a phenomenon known as "Developmental System Drift", DSD. Thus, the independent evolution of one organ relies on concerted molecular changes, which will contribute to adaptation in one organ and be no more than DSD in another organ. This concerted evolution could apply more generally to very different body parts and explain previous observations on gene expression evolution.

NA

biorxiv

10.1101/2020.04.24.014852

HiTaC: a Hierarchical Taxonomic Classifier for Fungal ITS Sequences

Miranda, F. M.; Azevedo, V. A. C.; Ramos, R. T. J.; Renard, B. Y.; C. Piro, V.

Vitor C. Piro

Hasso Plattner Institut

2023-06-04T00:00:00

4

new results

cc_by

bioinformatics

https://www.biorxiv.org/content/early/2023/06/04/2020.04.24.014852.source.xml

BackgroundFungi play a key role in several important ecological functions, ranging from organic matter decomposition to symbiotic associations with plants. Moreover, fungi naturally inhabit the human body and can be beneficial when administered as probiotics. In mycology, the internal transcribed spacer (ITS) region was adopted as the universal marker for classifying fungi. Hence, an accurate and robust method for ITS classification is not only desired for the purpose of better diversity estimation, but it can also help us gain a deeper insight into the dynamics of environmental communities and ultimately comprehend whether the abundance of certain species correlate with health and disease. Although many methods have been proposed for taxonomic classification, to the best of our knowledge, none of them fully explore the taxonomic tree hierarchy when building their models. This in turn, leads to lower generalization power and higher risk of committing classification errors. ResultsHere we introduce HiTaC, a robust hierarchical machine learning model for accurate ITS classification, which requires a small amount of data for training and can handle imbalanced datasets. HiTaC was thoroughly evaluated with the established TAXXI benchmark and could correctly classify fungal ITS sequences of varying lengths and a range of identity differences between the training and test data. HiTaC outperforms state-of-the-art methods when trained over noisy data, consistently achieving higher F1-score and sensitivity across different taxonomic ranks, improving sensitivity by 6.9 percentage points over top methods in the most noisy dataset available on TAXXI. ConclusionsHiTaC is publicly available at the Python package index, BIO-CONDA and Docker Hub. It is released under the new BSD license, allowing free use in academia and industry. Source code and documentation, which includes installation and usage instructions, are available at https://gitlab.com/dacs-hpi/hitac.

10.1186/s12859-024-05839-x

biorxiv

10.1101/2020.04.24.014852

HiTaC: a hierarchical taxonomic classifier for fungal ITS sequences compatible with QIIME2

Miranda, F. M.; Azevedo, V. A. C.; Ramos, R. T. J.; Renard, B. Y.; C. Piro, V.

Vitor C. Piro

Hasso Plattner Institut

2024-03-15T00:00:00

5

new results

cc_by

bioinformatics

https://www.biorxiv.org/content/early/2024/03/15/2020.04.24.014852.source.xml

BackgroundFungi play a key role in several important ecological functions, ranging from organic matter decomposition to symbiotic associations with plants. Moreover, fungi naturally inhabit the human body and can be beneficial when administered as probiotics. In mycology, the internal transcribed spacer (ITS) region was adopted as the universal marker for classifying fungi. Hence, an accurate and robust method for ITS classification is not only desired for the purpose of better diversity estimation, but it can also help us gain a deeper insight into the dynamics of environmental communities and ultimately comprehend whether the abundance of certain species correlate with health and disease. Although many methods have been proposed for taxonomic classification, to the best of our knowledge, none of them fully explore the taxonomic tree hierarchy when building their models. This in turn, leads to lower generalization power and higher risk of committing classification errors. ResultsHere we introduce HiTaC, a robust hierarchical machine learning model for accurate ITS classification, which requires a small amount of data for training and can handle imbalanced datasets. HiTaC was thoroughly evaluated with the established TAXXI benchmark and could correctly classify fungal ITS sequences of varying lengths and a range of identity differences between the training and test data. HiTaC outperforms state-of-the-art methods when trained over noisy data, consistently achieving higher F1-score and sensitivity across different taxonomic ranks, improving sensitivity by 6.9 percentage points over top methods in the most noisy dataset available on TAXXI. ConclusionsHiTaC is publicly available at the Python package index, BIO-CONDA and Docker Hub. It is released under the new BSD license, allowing free use in academia and industry. Source code and documentation, which includes installation and usage instructions, are available at https://gitlab.com/dacs-hpi/hitac.

10.1186/s12859-024-05839-x

biorxiv

10.1101/2020.04.24.059097

Characterising a stable five-species microbial community for use in experimental evolution and ecology.

Castledine, M.; Pennycook, J.; Newbury, A.; Lear, L.; Erdos, Z.; Lewis, R.; Kay, S.; Sanders, D.; Sunderhauf, D.; Buckling, A.; Hesse, E.; Padfield, D.

Daniel Padfield

University of Exeter

2024-04-11T00:00:00

2

new results

cc_by_nd

ecology

https://www.biorxiv.org/content/early/2024/04/11/2020.04.24.059097.source.xml

Model microbial communities are regularly used to test ecological and evolutionary theory as they are easy to manipulate and have fast generation times, allowing for large-scale, high throughput experiments. A key assumption for most model microbial communities is that they stably coexist, but this is rarely tested experimentally. Here we report the (dis)assembly of a five-species microbial community from a metacommunity of soil microbes that can be used for future experiments. Using reciprocal invasion from rare experiments we show that all species can coexist and we demonstrate that the community is stable for a long time ([~]600 generations). Crucially for future work, we show that each species can be identified by their plate morphologies, even after >1 year in co-culture. We characterise pairwise species interactions and produce high-quality reference genomes for each species. This stable five-species community can be used to test key questions in microbial ecology and evolution.

NA

biorxiv

10.1101/2020.04.25.061531

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder

Singh, A. K.; Praharaj, M.; Lombardo, K. A.; Yoshida, T.; Matoso, A.; Baras, A. S.; Zhao, L.; Prasad, P.; Powell, J. D.; Kates, M.; McConkey, D.; Pardoll, D. M.; Bishai, W. R.; Bivalacqua, T. J.

Trinity J. Bivalacqua

Johns Hopkins School of Medicine

2023-12-20T00:00:00

4

withdrawn

cc_by

cancer biology

https://www.biorxiv.org/content/early/2023/12/20/2020.04.25.061531.source.xml

Withdrawal StatementThe authors have withdrawn their manuscript owing to irregularities in the Source Data supporting some figures. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding authors.

10.1038/s41467-022-28509-z

biorxiv

10.1101/2020.04.27.063628

Toxoplasma FER1 is a versatile and dynamic mediator of differential microneme trafficking and microneme exocytosis

Tagoe, D. N.; Ribeiro E Silva, A.; Drozda, A. A.; Coppens, I.; Coleman, B. I.; Gubbels, M.-J.

Marc-Jan Gubbels

Boston College

2024-06-11T00:00:00

2

new results

cc_by_nc_nd

cell biology

https://www.biorxiv.org/content/early/2024/06/11/2020.04.27.063628.source.xml

Toxoplasma gondii is a polarized cell concentrating several secretory organelles at the apical pole. The secretory micronemes come in two sub-populations differentiated by dependence on the Rab5A/C in their biogenesis. Calcium-dependent exocytosis of micronemes occurs at the very apical tip and is critical for parasite egress from its host cell, adhesion and invasion of the next cell. Ferlins represent a protein family with roles in exocytosis containing multiple Ca2+-sensing C2 domains. We determined that T. gondiis ferlin 1 (FER1) localized dynamically to the parasites secretory pathway. FER1 function was dissected by dominant negative overexpression strategies. We demonstrated that FER1 traffics microneme organelles along the following trajectories:1. From the trans-Golgi-endosomes network to the subpellicular cortex; 2. Along the cortex to the apical end; 3. To the apical tip for fusion with the plasma membrane; 4. Retrograde transport allowing microneme recycling from mother to daughter; 5. Differential microneme sub-population traffic. Finally, FER1 overexpression triggers a microneme exocytosis burst, supporting the notion that the radially organized micronemes at the apical tip comprise a readily-releasable microneme pool. In summary, FER1 is pivotal for dynamic microneme trafficking, acts differently on the two microneme subpopulations, and acts on the plasma membrane fusion step during microneme exocytosis.

NA

biorxiv

10.1101/2020.04.28.065755

Single-cell copy number calling and event history reconstruction

Kuipers, J.; Tuncel, M. A.; Ferreira, P. F.; Jahn, K.; Beerenwinkel, N.

Niko Beerenwinkel

D-BSSE, ETH Zurich

2024-06-03T00:00:00

2

new results

cc_by_nc_nd

cancer biology

https://www.biorxiv.org/content/early/2024/06/03/2020.04.28.065755.source.xml

Copy number alterations are driving forces of tumour development and the emergence of intra-tumour heterogeneity. A comprehensive picture of these genomic aberrations is therefore essential for the development of personalised and precise cancer diagnostics and therapies. Single-cell sequencing offers the highest resolution for copy number profiling down to the level of individual cells. Recent high-throughput protocols allow for the processing of hundreds of cells through shallow whole-genome DNA sequencing. The resulting low read-depth data poses substantial statistical and computational challenges to the identification of copy number alterations. We developed SCICoNE, a statistical model and MCMC algorithm tailored to single-cell copy number profiling from shallow whole-genome DNA sequencing data. SCICoNE reconstructs the history of copy number events in the tumour and uses these evolutionary relationships to identify the copy number profiles of the individual cells. We show the accuracy of this approach in evaluations on simulated data and demonstrate its practicability in applications to two breast cancer samples from different sequencing protocols.

NA

biorxiv

10.1101/2020.04.29.069138

Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Ceddia, R. P.; Zurawski, Z.; Thompson Gray, A.; Adegboye, F.; McDonald-Boyer, A.; Shi, F.; Liu, D.; Maldonado, J.; Feng, J.; Li, Y.; Alford, S.; Ayala, J. E.; McGuinness, O. P.; Collins, S.; Hamm, H. E.

Heidi E Hamm

Vanderbilt University

2023-06-06T00:00:00

4

new results

cc_by_nc_nd

physiology

https://www.biorxiv.org/content/early/2023/06/06/2020.04.29.069138.source.xml

Negative regulation of exocytosis from secretory cells throughout the body is accomplished through inhibitory signals from Gi/o G protein-coupled receptors by G{beta}{gamma} subunit inhibition of two common mechanisms: (i) decreased calcium entry and (ii) direct interaction of G{beta}{gamma} with the Soluble N-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. We have previously shown that disabling the second mechanism with a truncation of SNAP25 (SNAP25{Delta}3/{Delta}3) decreases the affinity of G{beta}{gamma} for the SNARE complex, leaving exocytotic fusion as well as modulation of calcium entry intact but disabling GPCR inhibition of exocytosis. Here we report significant beneficial metabolic remodeling in mice carrying this mutation. Chow-fed SNAP25{Delta}3/{Delta}3 mice exhibit enhanced insulin sensitivity and increased beiging of white fat. In response to a high fat diet, the metabolic protection was amplified in SNAP25{Delta}3/{Delta}3 mice. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. This metabolic protection in SNAP25{Delta}3/{Delta}3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting basal autonomic activity is required. Direct electrode stimulation of sympathetic neurons exocytosis from SNAP25{Delta}3/{Delta}3 inguinal adipose depot resulted in enhanced and prolonged norepinephrine release. Thus, the G{beta}{gamma}-SNARE interaction represents a cellular mechanism that deserves further exploration as a new avenue for combatting metabolic disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/069138v4_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@2c1fa0org.highwire.dtl.DTLVardef@d076ceorg.highwire.dtl.DTLVardef@27e351org.highwire.dtl.DTLVardef@bce219_HPS_FORMAT_FIGEXP M_FIG C_FIG

NA

biorxiv

10.1101/2020.05.04.075119

Single-cell RNA sequencing reveals subset-specific functional reprogramming of CD4+ T-cells from PLHIV upon ex vivo HDAC inhibition and biomarkers of cells harbouring non-silent proviruses

Kazmierski, J.; Postmus, D.; Wyler, E.; Fadejeva, J.; Steijaert, T.; Fischer, C.; Jansen, J.; Koppe, U.; Gunsenheimer-Bartmeyer, B.; Meixenberger, K.; Vitcetz, S.; Sohn, M.; Loyal, L.; Thiel, A.; Sauer, S.; Bannert, N.; Landthaler, M.; GOFFINET, C.

Christine GOFFINET

Charite - Universitaetsmedizin Berlin

2023-06-04T00:00:00

2

new results

cc_by_nc

microbiology

https://www.biorxiv.org/content/early/2023/06/04/2020.05.04.075119.source.xml

Shock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcription in vitro, ex vivo and in vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+ T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+ T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+ T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivation per se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-{beta} and -14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies.

NA

biorxiv

10.1101/2020.05.04.075119

Type I interferons sensitise HIV-1-reactivating T-cells for NK cell-mediated elimination despite HDACi-imposed dysregulation of innate immunity

Prigann, J.; Postmus, D.; Pietrobon, A. J.; Wyler, E.; Jansen, J.; Moeller, L.; Fadejeva, J.; Steijaert, T.; Fischer, C.; Koppe, U.; Gunsenheimer-Bartmeyer, B.; Meixenberger, K.; Vitcetz, S.; Sohn, M.; Loyal, L.; Thiel, A.; Sauer, S.; Sutter, K.; Dittmer, U.; Laue, M.; Bannert, N.; Landthaler, M.; GOFFINET, C.

Christine GOFFINET

Charite - Universitaetsmedizin Berlin

2023-11-19T00:00:00

3

new results

cc_by_nc

microbiology

https://www.biorxiv.org/content/early/2023/11/19/2020.05.04.075119.source.xml

Shock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcription in vitro, ex vivo and in vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+ T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+ T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+ T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivation per se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-{beta} and -14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies.

NA

biorxiv

10.1101/2020.05.08.080929

The evolution of sex allocation in metapopulations

Roux, C.; Mullon, C. D. L.; Pannell, J.

John Pannell

Univ. of Lausanne

2024-04-08T00:00:00

2

new results

cc_by_nc_nd

evolutionary biology

https://www.biorxiv.org/content/early/2024/04/08/2020.05.08.080929.source.xml

Selection in inbred populations is expected to favor female-biased sex ratios in dioecious populations as a result of local mate competition, a prediction that finds strong support in situations where females have control of the sex ratio. Local mate competition due to inbreeding should also promote female-biased sex allocation in hermaphrodites, with reduced emphasis on the production and dispersal of sperm or pollen relative to that of eggs, ovules or seeds. While inbreeding can be the direct result of the mating system in local populations, it can also be brought about by population turnover in metapopulations with frequent local extinction and recolonization. This effect of population turnover has previously been considered for species with separate sexes. Here, we use both formal analysis and individual-based simulations to explore the effect of population turnover on sex allocation in partially self-fertilizing hermaphroditic metapopulations. Using simulations, we also assess the extent to which different genetic measures of inbreeding and population differentiation predict the equilibrium sex allocation. We find that population turnover can select for strongly female-biased sex allocation in hermaphroditic metapopulations, particularly if amongdeme dispersal is low, even where local demes are fully outcrossing. In such situations, FST is a good predictor of the equilibrium sex allocation, and much better than the alternative differentiation measures GST and Josts D. Our study extends predictions for sex allocation in subdivided populations to hermaphroditic species, and draws attention in general to the power of Wrights hierarchical inbreeding statistics to predict the sex allocation in metapopulations at equilibrium.

NA

biorxiv

10.1101/2020.05.08.084848

Generating Synthetic Signaling Networks for in Silico Modeling Studies

Xu, J.; Wiley, H. S.; Sauro, H. M.

Herbert M. Sauro

University of Washington

2023-05-15T00:00:00

2

new results

cc_by_nc_nd

systems biology

https://www.biorxiv.org/content/early/2023/05/15/2020.05.08.084848.source.xml

Predictive models of signaling pathways have proven to be difficult to develop. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. To meet this need, we developed a method for generating artificial signaling networks that were reasonably realistic and thus could be treated as ground truth models. These synthetic models could then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. We defined the reaction degree and reaction distance to measure the topology of reaction networks, especially to consider enzymes. To determine whether our generated signaling networks displayed meaningful behavior, we compared them with signaling networks from the BioModels Database. This comparison indicated that our generated signaling networks had high topological similarities with BioModels signaling networks with respect to the reaction degree and distance distributions. In addition, our synthetic signaling networks had similar behavioral dynamics with respect to both steady states and oscillations, suggesting that our method generated synthetic signaling networks comparable with BioModels and thus could be useful for building network evaluation tools. HighlightsO_LIWe provided a Julia script to generate synthetic signaling networks. C_LIO_LIWe defined reaction degree and distance to measure the reaction network topology. C_LIO_LIWe provided the Python scripts to calculate the reaction network topology. C_LIO_LIThe synthetic signaling networks had topological similarities with the BioModels. C_LIO_LIThe synthetic signaling networks had dynamic similarities with the BioModels. C_LI

NA

biorxiv

10.1101/2020.05.08.084848

Generating synthetic signaling networks for in silico modeling studies

Xu, J.; Wiley, S.; Sauro, H. M.

Herbert M. Sauro

University of Washington

2024-02-01T00:00:00

3

new results

cc_by_nc_nd

systems biology

https://www.biorxiv.org/content/early/2024/02/01/2020.05.08.084848.source.xml

Predictive models of signaling pathways have proven to be difficult to develop. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. To meet this need, we developed a method for generating artificial signaling networks that were reasonably realistic and thus could be treated as ground truth models. These synthetic models could then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. We defined the reaction degree and reaction distance to measure the topology of reaction networks, especially to consider enzymes. To determine whether our generated signaling networks displayed meaningful behavior, we compared them with signaling networks from the BioModels Database. This comparison indicated that our generated signaling networks had high topological similarities with BioModels signaling networks with respect to the reaction degree and distance distributions. In addition, our synthetic signaling networks had similar behavioral dynamics with respect to both steady states and oscillations, suggesting that our method generated synthetic signaling networks comparable with BioModels and thus could be useful for building network evaluation tools. HighlightsO_LIWe provided a Julia script to generate synthetic signaling networks. C_LIO_LIWe defined reaction degree and distance to measure the reaction network topology. C_LIO_LIWe provided the Python scripts to calculate the reaction network topology. C_LIO_LIThe synthetic signaling networks had topological similarities with the BioModels. C_LIO_LIThe synthetic signaling networks had dynamic similarities with the BioModels. C_LI

NA

biorxiv

10.1101/2020.05.08.084848

Generating synthetic signaling networks for in silico modeling studies

Xu, J.; Wiley, S.; Sauro, H. M.

Herbert M. Sauro

University of Washington

2024-06-07T00:00:00

4

new results

cc_by_nc_nd

systems biology

https://www.biorxiv.org/content/early/2024/06/07/2020.05.08.084848.source.xml

Predictive models of signaling pathways have proven to be difficult to develop. Traditional approaches to developing mechanistic models rely on collecting experimental data and fitting a single model to that data. This approach works for simple systems but has proven unreliable for complex systems such as biological signaling networks. Thus, there is a need to develop new approaches to create predictive mechanistic models of complex systems. To meet this need, we developed a method for generating artificial signaling networks that were reasonably realistic and thus could be treated as ground truth models. These synthetic models could then be used to generate synthetic data for developing and testing algorithms designed to recover the underlying network topology and associated parameters. We defined the reaction degree and reaction distance to measure the topology of reaction networks, especially to consider enzymes. To determine whether our generated signaling networks displayed meaningful behavior, we compared them with signaling networks from the BioModels Database. This comparison indicated that our generated signaling networks had high topological similarities with BioModels signaling networks with respect to the reaction degree and distance distributions. In addition, our synthetic signaling networks had similar behavioral dynamics with respect to both steady states and oscillations, suggesting that our method generated synthetic signaling networks comparable with BioModels and thus could be useful for building network evaluation tools. HighlightsO_LIWe provided a Julia script to generate synthetic signaling networks. C_LIO_LIWe defined reaction degree and distance to measure the reaction network topology. C_LIO_LIWe provided the Python scripts to calculate the reaction network topology. C_LIO_LIThe synthetic signaling networks had topological similarities with the BioModels. C_LIO_LIThe synthetic signaling networks had dynamic similarities with the BioModels. C_LI

NA

biorxiv

10.1101/2020.05.12.079863

Haplotype-based analysis distinguishes maternal-fetal genetic contribution to pregnancy-related outcomes

Srivastava, A. K.; Juodakis, J.; Sole-Navais, P.; Chen, J.; Bacelis, J.; Teramo, K.; Hallman, M.; Njolstad, P. R.; Evans, D. M.; Jacobsson, B.; Muglia, L. J.; Zhang, G.

Ge Zhang

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, USA

2023-06-30T00:00:00

2

new results

cc_by_nc_nd

genetics

https://www.biorxiv.org/content/early/2023/06/30/2020.05.12.079863.source.xml

AbstractGenotype-based approaches for the estimation of SNP-based narrow-sense heritability [Formula] have limited utility in pregnancy-related outcomes due to confounding by the shared alleles between mother and child. Here, we propose a haplotype-based approach to estimate the genetic variance attributable to three haplotypes - maternal transmitted [Formula], maternal non-transmitted [Formula] and paternal transmitted [Formula] in mother-child pairs. We show through extensive simulations that our haplotype-based approach outperforms the conventional and contemporary approaches for resolving the contribution of maternal and fetal effects, particularly when m1 and p1 have different effects in the offspring. We apply this approach to estimate the explicit and relative maternal-fetal genetic contribution to the phenotypic variance of gestational duration and gestational duration adjusted fetal size measurements at birth in 10,375 mother-child pairs. The results reveal that variance of gestational duration is mainly attributable to m1 and m2 ([Formula]= 17.3%, S. E. = 5.2%; [Formula] = 12.2%, S. E. = 5.2%; [Formula] = 0.0%, S. E. = 5.0%). In contrast, variance of fetal size measurements at birth are mainly attributable to m1 and p1 ([Formula] = 18.6 - 36.4%, [Formula] = 0.0 - 5.2% and [Formula] = 4.4 - 13.6%). Our results suggest that gestational duration and fetal size measurements are primarily genetically determined by the maternal and fetal genomes, respectively. In addition, a greater contribution of m1 as compared to m2 and p1 [Formula] to birth length and head circumference suggests a substantial influence of correlated maternal-fetal genetic effects on these traits. Our newly developed approach provides a direct and robust alternative for resolving explicit maternal and fetal genetic contributions to the phenotypic variance of pregnancy-related outcomes.

NA

biorxiv

10.1101/2020.05.14.096032

Mycobacteria inhibit neutrophil recruitment to avoid neutrophil-assisted killing by macrophages

Candel, S.; Ramakrishnan, L.

Lalita Ramakrishnan

University of Cambridge

2023-07-26T00:00:00

4

withdrawn

cc_by

molecular biology

https://www.biorxiv.org/content/early/2023/07/26/2020.05.14.096032.source.xml

This article was withdrawn on 29 July 2020 after inaccuracies were identified in the experiments reported in the manuscript. The corresponding author, Professor Lalita Ramakishnan, reported concerns regarding data in the manuscript to the University of Cambridge. An investigation by the University of Cambridge concluded that data related to Alox5 -/-; mpx-/- double knockout zebrafish included in the manuscript had been fabricated. If you have any questions, please contact the corresponding author (Lalita Ramakrishnan, lr404@cam.ac.uk).

NA

biorxiv

10.1101/2020.05.14.096230

scRNA-seq analysis of colon and esophageal tumors uncovers abundant microbial reads in myeloid cells undergoing proinflammatory transcriptional alterations

Robinson, W.; Stone, J. K.; Schischlik, F.; Gasmi, B.; Kelly, M. C.; Seibert, C.; Dadkhah, K.; Gertz, E. M.; Lee, J. S.; Zhu, K.; Ma, L.; Wang, X. W.; Sahinalp, C.; Patro, R.; Leiserson, M. D.; Harris, C. C.; Schäffer, A. A.; Ruppin, E.

Eytan Ruppin

Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute

2023-04-28T00:00:00

3

new results

cc0

cancer biology

https://www.biorxiv.org/content/early/2023/04/28/2020.05.14.096230.source.xml

The study of the tumor microbiome has been garnering increased attention. We developed a computational pipeline (CSI-Microbes) for identifying microbial reads from single-cell RNA sequencing (scRNA-seq) data. Using a series of controlled experiments and analyses, we performed the first systematic evaluation of the efficacy of recovering microbial UMIs by multiple scRNA-seq technologies, which identified the newer 10x chemistries (3 v3 and 5) as the best suited approach. Based on these findings, we analyzed patient esophageal and colorectal carcinomas and found that reads from distinct genera tend to co-occur in the same host cells, testifying to possible intracellular polymicrobial interactions. Microbial reads are disproportionately abundant within myeloid cells that upregulate proinflammatory cytokines like IL1B and CXCL8 and downregulate antigen processing and presentation (APP) pathways. The latter, however, are markedly upregulated in infected tumor cells. These results testify that intracellular bacteria predominately reside within co-opted myeloid cells, which inflame the tumor microenvironment and may influence immunotherapy response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/096230v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@16399a5org.highwire.dtl.DTLVardef@1fc464dorg.highwire.dtl.DTLVardef@16ba6c5org.highwire.dtl.DTLVardef@91fa4c_HPS_FORMAT_FIGEXP M_FIG C_FIG

NA

biorxiv

10.1101/2020.05.15.097907

HerpesDRG: a comprehensive resource for human herpesvirus antiviral drug resistance genotyping

Charles, O. J.; Venturini, C.; Goldstein, R. A.; Breuer, J.

Judith Breuer

University College London

2023-10-24T00:00:00

2

new results

cc_by_nc_nd

bioinformatics

https://www.biorxiv.org/content/early/2023/10/24/2020.05.15.097907.source.xml

The prevention and treatment of many herpesvirus associated diseases is based on the utilization of antiviral therapies, however therapeutic success is limited by the development of drug resistance. A comprehensive point of truth of resistance conferring mutations has been missing but would be important to aid the development of antiviral drugs and in management of infections. We therefore developed HerpesDRG, a drug resistance mutation database for all the known important genes and current treatment options, built from a systematic review of available genotype to phenotype literature. The database is released along with an R package to provide a low barrier of entry to variant resistance annotation and clinical implication analysis from common sanger and NGS sequence data. This represents the first openly available and community maintainable knowledgebase of drug resistance mutations for the human herpes viruses (HHV), developed for the community of researchers and clinicians tackling HHV drug resistance. AvailabilityThe HerpesDRG database is available at github.com/ojcharles/herpesdrg-db. The R package for resistance genotyping data is available at github.com/ojcharles/herpesdrg. A user-friendly webserver is available at cmv-resistance.ucl.ac.uk/herpesdrg

NA

biorxiv

10.1101/2020.05.20.106930

WITHDRAWN: Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific

Salter, E. W.; Lei, G.; Choi, S.-L.; Ralph, L. T.; Zhang, L.; Jin, F.; Kadia, A.; Wang, J.; Georgiou, J.; Collingridge, G. L.

Graham L Collingridge

Lunenfeld-Tanenbaum Research Institute/University of Toronto/University of Bristol/TANZ Centre for Research in Neurodegenerative Diseases

2023-09-26T00:00:00

2

withdrawn

cc_by

neuroscience

https://www.biorxiv.org/content/early/2023/09/26/2020.05.20.106930.source.xml

Withdrawal statementThe authors have withdrawn their manuscript owing to the results of this pre-print being based on experiments performed prior to COVID-19 shutdowns, which required a near complete culling of the mouse colony. Upon re-initiating the colony, the phenotype outlined in the pre-print could no longer be observed and as such we have decided to withdraw the pre-print. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

NA

biorxiv

10.1101/2020.05.25.114959

Improvements in task performance after practice are associated with scale-free dynamics of brain activity

Kardan, O.; Stier, A. J.; Layden, E. A.; Choe, K. W.; Lyu, M.; Zhang, X.; Beilock, S. L.; Rosenberg, M. D.; Berman, M. G.

Omid Kardan

University of Chicago

2023-04-04T00:00:00

2

new results

cc_by_nc_nd

neuroscience

https://www.biorxiv.org/content/early/2023/04/04/2020.05.25.114959.source.xml

Although practicing a task generally benefits later performance on that same task, there are individual differences in practice effects. One avenue to model such differences comes from research showing that brain networks extract functional advantages from operating in the vicinity of criticality, a state in which brain network activity is more scale-free. We hypothesized that higher scale-free signal from fMRI data, measured with the Hurst exponent (H), indicates closer proximity to critical states. We tested whether individuals with higher H during repeated task performance would show greater practice effects. In Study 1, participants performed a dual-n-back task (DNB) twice during MRI (n = 56). In Study 2, we used two runs of n-back task (NBK) data from the Human Connectome Project sample (n = 599). In Study 3, participants performed a word completion task (CAST) across 6 runs (n = 44). In all three studies, multivariate analysis was used to test whether higher H was related to greater practice-related performance improvement. Supporting our hypothesis, we found patterns of higher H that reliably correlated with greater performance improvement across participants in all three studies. However, the predictive brain regions were distinct, suggesting that the specific spatial H{uparrow} patterns are not task-general.

10.1162/netn_a_00319

biorxiv

10.1101/2020.05.26.104687

Pictorial balance is a bottom-up aesthetic property mediated by eye movements. A model of a primitive visual operating system explains balance and visual properties of pictures

Corwin, D. M.

David M Corwin

David Corwin MD

2023-08-22T00:00:00

18

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2023/08/22/2020.05.26.104687.source.xml

Pictorial balance has been used to explain why some paintings evoke feelings of unity and harmony. This study shows how it is calculated and proposes an evolutionary reason for its existence. The concept of pictorial balance as a center of mass effect, i.e. the feeling that somehow a person on the left seems to be balanced by a tree on the right, originated at the beginning of the 20th century. It had never been mentioned in art commentary of the previous 500 years, and yet has become a widely assumed but unsubstantiated explanation of why some paintings evoke feelings of unity and harmony. Despite the lack of historical documentation, the perception of pictorial balance exists. This study shows how the low-level visual system calculates balance, how it evokes feelings of unity and harmony, and its evolutionary importance in visualizing the world of moving organisms. It is done by means of a study of an elusive pictorial effect known to painters, in which these feelings are evoked. In such pictures the image seems to be perceived as a whole without the need to fixate on individual depicted objects. The effect was first described by a 17th century critic Roger de Piles and subsequently by a few renowned artists. The author hypothesized that this response was due to the painting being in a state of perfect balance. Computer modeling found that such a picture must have bilateral luminance symmetry with a lighter lower half by [~]1.07. A study was conducted in which the identical picture seen sequentially in slightly different frames could seem different to observers because of the change in balance created by the frames. The results indicate that the extent to which the pairs were seen as different correlated with two methods of calculating balance. One of them could be understood as a possible primitive visual operating system for identifying other moving organisms as ever-changing vectors of balance. The more balanced the painting, the more it will be seen as a whole object by emphasizing peripheral vision and decreasing the tendency to fixate on what is in the picture, causing the painting to be perceived as unified and harmonious. It is proposed that in the evolution of vision there is a luminance pathway that was later superseded by other pathways using color vision. This explains the percept of balance and other visual phenomena.

NA

biorxiv

10.1101/2020.05.26.104687

Pictorial balance is a bottom-up aesthetic property mediated by eye movements. A model of a primitive visual operating system explains balance and visual properties of pictures

Corwin, D. M.

David M Corwin

David Corwin MD

2024-04-18T00:00:00

19

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2024/04/18/2020.05.26.104687.source.xml

Pictorial balance has been used to explain why some paintings evoke feelings of unity and harmony. This study shows how it is calculated and proposes an evolutionary reason for its existence. The concept of pictorial balance as a center of mass effect, i.e. the feeling that somehow a person on the left seems to be balanced by a tree on the right, originated at the beginning of the 20th century. It had never been mentioned in art commentary of the previous 500 years, and yet has become a widely assumed but unsubstantiated explanation of why some paintings evoke feelings of unity and harmony. Despite the lack of historical documentation, the perception of pictorial balance exists. This study shows how the low-level visual system calculates balance, how it evokes feelings of unity and harmony, and its evolutionary importance in visualizing the world of moving organisms. It is done by means of a study of an elusive pictorial effect known to painters, in which these feelings are evoked. In such pictures the image seems to be perceived as a whole without the need to fixate on individual depicted objects. The effect was first described by a 17th century critic Roger de Piles and subsequently by a few renowned artists. The author hypothesized that this response was due to the painting being in a state of perfect balance. Computer modeling found that such a picture must have bilateral luminance symmetry with a lighter lower half by [~]1.07. A study was conducted in which the identical picture seen sequentially in slightly different frames could seem different to observers because of the change in balance created by the frames. The results indicate that the extent to which the pairs were seen as different correlated with two methods of calculating balance. One of them could be understood as a possible primitive visual operating system for identifying other moving organisms as ever-changing vectors of balance. The more balanced the painting, the more it will be seen as a whole object by emphasizing peripheral vision and decreasing the tendency to fixate on what is in the picture, causing the painting to be perceived as unified and harmonious. It is proposed that in the evolution of vision there is a luminance pathway that was later superseded by other pathways using color vision. This explains the percept of balance and other visual phenomena.

NA

biorxiv

10.1101/2020.05.26.104687

Pictorial balance is a bottom-up neuro-aesthetic property mediating attention and eye movements. A model of a primitive visual operating system explains the property of balance and some visual properties of pictures

Corwin, D. M.

David M Corwin

David Corwin MD

2024-08-26T00:00:00

20

new results

cc_by

neuroscience

https://www.biorxiv.org/content/early/2024/08/26/2020.05.26.104687.source.xml

Pictorial balance has been used to explain why some paintings evoke feelings of unity and harmony. This study shows how it is calculated and proposes an evolutionary reason for its existence. The concept of pictorial balance as a center of mass effect, i.e. the feeling that somehow a person on the left seems to be balanced by a tree on the right, originated at the beginning of the 20th century. It had never been mentioned in art commentary of the previous 500 years, and yet has become a widely assumed but unsubstantiated explanation of why some paintings evoke feelings of unity and harmony. Despite the lack of historical documentation, the perception of pictorial balance exists. This study shows how the low-level visual system calculates balance, how it evokes feelings of unity and harmony, and its evolutionary importance in visualizing the world of moving organisms. It is done by means of a study of an elusive pictorial effect known to painters, in which these feelings are evoked. In such pictures the image seems to be perceived as a whole without the need to fixate on individual depicted objects. The effect was first described by a 17th century critic Roger de Piles and subsequently by a few renowned artists. The author hypothesized that this response was due to the painting being in a state of perfect balance. Computer modeling found that such a picture must have bilateral luminance symmetry with a lighter lower half by [~]1.07. A study was conducted in which the identical picture seen sequentially in slightly different frames could seem different to observers because of the change in balance created by the frames. The results indicate that the extent to which the pairs were seen as different correlated with two methods of calculating balance. One of them could be understood as a possible primitive visual operating system for identifying other moving organisms as ever-changing vectors of balance. The more balanced the painting, the more it will be seen as a whole object by emphasizing peripheral vision and decreasing the tendency to fixate on what is in the picture, causing the painting to be perceived as unified and harmonious. It is proposed that in the evolution of vision there is a luminance pathway that was later superseded by other pathways using color vision. This explains the percept of balance and other visual phenomena.

NA

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Biorxiv Abstracts from the our ICML 2025 paper "Private federated learning using preference-optimized synthetic data"

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