source_doi stringlengths 13 57 | source_mag_paper_id int64 490k 157M | source_abstract stringlengths 8 10.7k | target_doi stringlengths 14 27 | target_summary stringlengths 42 889 |
|---|---|---|---|---|
10.1038/s41467-021-24532-8 | 135,317,206 | Abstract Histone H3 lysine 9 (H3K9) methylation is a central epigenetic modification that defines heterochromatin from unicellular to multicellular organisms. In mammalian cells, H3K9 methylation can be catalyzed by at least six distinct SET domain enzymes: Suv39h1/Suv39h2, Eset1/Eset2 and G9a/Glp. We used mouse embryonic fibroblasts (MEFs) with a conditional mutation for Eset1 and introduced progressive deletions for the other SET domain genes by CRISPR/Cas9 technology. Compound mutant MEFs for all six SET domain lysine methyltransferase (KMT) genes lack all H3K9 methylation states, derepress nearly all families of repeat elements and display genomic instabilities. Strikingly, the 6KO H3K9 KMT MEF cells no longer maintain heterochromatin organization and have lost electron-dense heterochromatin. This is a compelling analysis of H3K9 methylation-deficient mammalian chromatin and reveals a definitive function for H3K9 methylation in protecting heterochromatin organization and genome integrity. | 10.1038/s41580-022-00483-w | This study describes the effect of losing all detectable H3K9me owing to the loss of the six redundant mammalian H3K9-specific HMTs; analogous ablations and their consequences in C. elegans are described by Towbin et al. (2012) and Zeller et al. (2016). |
10.1038/celldisc.2016.37 | 122,113,032 | Abstract The histone 3 lysine 9 methyltransferase Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on the roles of Setdb1 in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies on isolated single myofibres showed that Setdb1 is required for adult muscle stem cells expansion following activation. In vitro studies in skeletal myoblasts confirmed that Setdb1 suppresses terminal differentiation. Genomic binding analyses showed a release of Setdb1 from selected target genes upon myoblast terminal differentiation, concomitant to a nuclear export of Setdb1 to the cytoplasm. Both genomic release and cytoplasmic Setdb1 relocalisation during differentiation were dependent on canonical Wnt signalling. Transcriptomic assays in myoblasts unravelled a significant overlap between Setdb1 and Wnt3a regulated genetic programmes. Together, our findings revealed Wnt-dependent subcellular relocalisation of Setdb1 as a novel mechanism regulating Setdb1 functions and myogenesis. | 10.1038/s41580-022-00483-w | This study is the first description of a global regulation of SETDB1 through nuclear export; an analogous mechanism during the stress response in C. elegans is described by Delaney et al. (2019) |
10.1038/embor.2009.90 | 123,922,965 | Trimethylation of lysine 9 in histone H3 (H3K9me3) enrichment is a characteristic of pericentric heterochromatin. The hypothesis of a stepwise mechanism to establish and maintain this mark during DNA replication suggests that newly synthesized histone H3 goes through an intermediate methylation state to become a substrate for the histone methyltransferase Suppressor of variegation 39 (Suv39H1/H2). How this intermediate methylation state is achieved and how it is targeted to the correct place at the right time is not yet known. Here, we show that the histone H3K9 methyltransferase SetDB1 associates with the specific heterochromatin protein 1α (HP1α)–chromatin assembly factor 1 (CAF1) chaperone complex. This complex monomethylates K9 on non‐nucleosomal histone H3. Therefore, the heterochromatic HP1α–CAF1–SetDB1 complex probably provides H3K9me1 for subsequent trimethylation by Suv39H1/H2 in pericentric regions. The connection of CAF1 with DNA replication, HP1α with heterochromatin formation and SetDB1 for H3K9me1 suggests a highly coordinated mechanism to ensure the propagation of H3K9me3 in pericentric heterochromatin during DNA replication. | 10.1038/s41580-022-00483-w | Links SETDB1 to the replication machinery to maintain H3K9me in mitotic cells |
10.1038/s41586-021-04228-1 | 130,505,215 | Abstract All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 lysine 9 trimethylation (H3K9me3) 1–3 . How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveal how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Thus intronless cDNA—the hallmark of reverse transcription—provides a versatile way to distinguish invading retroelements from host genes and enables HUSH to protect the genome from ‘non-self’ DNA, despite there being no previous exposure to the invading element. Our findings reveal the existence of a transcription-dependent genome-surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes. | 10.1038/s41580-022-00483-w | An elegant study revealing the mechanism of HUSH-dependent SETDB1 recruitment, which was described earlier by Tchasovnikarova et al. (2015) and Robbez-Masson et al. (2018) |
10.1126/science.aau0583 | 41,764,301 | Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. Trimethylated histone 3 lysine 9 (H3K9me3)–marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein-coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low–cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein-coding genes in early, uncommitted cells at the germ-layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type–specific gene expression. Perturbation of the three H3K9me3-related methyltransferases revealed a pivotal role for H3K9me3 heterochromatin during lineage commitment at the onset of organogenesis and for lineage fidelity maintenance. | 10.1038/s41580-022-00483-w | Analysis of H3K9me3-dependent gene silencing in SETDB1–SUV39H1–SUV39H2 triple mutants after embryogenesis |
10.1126/science.aah6499 | 20,624,537 | After priming, naïve CD8 + T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8 + T cells activated after Listeria monocytogenes infection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell–related memory genes. Single-cell RNA sequencing revealed a defect in silencing of stem/memory genes selectively in Suv39h1 -defective T cell effectors. As a result, Suv39h1 -defective CD8 + T cells show sustained survival and increased long-term memory reprogramming capacity. Thus, Suv39h1 plays a critical role in marking chromatin to silence stem/memory genes during CD8 + T effector terminal differentiation. | 10.1038/s41580-022-00483-w | Describes the important role of SUV39H1 in CD8 + T cell fate commitment |
10.1126/scitranslmed.3004952 | 122,305,066 | Mutant DNA from ovarian and endometrial tumors can be detected in Pap smear specimens through massively parallel sequencing. | 10.1038/s41568-019-0177-x | First study to show that endometrial cancer-associated mutations can be detected during routine Pap tests; led to development of the prototype ‘PapGene’ test (2013) |
10.1126/scitranslmed.aap8793 | 59,273,426 | Endometrial and ovarian cancers can be detected through the analysis of DNA from Pap test fluids, intrauterine samples, and plasma. | 10.1038/s41568-019-0177-x | Publication demonstrating the detection of early-stage endometrial cancers from samples collected during routine Pap tests using the ‘PapSEEK’ test (2018) |
10.1126/science.aan6733 | 20,843,651 | Predicting responses to immunotherapy Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and Sharma). They found that a wide range of different cancer types with MMR deficiency also responded to PD-1 blockade. The trial included some patients with pancreatic cancer, which is one of the deadliest forms of cancer. The clinical trial is still ongoing, and around 20% of patients have so far achieved a complete response. MMR deficiency appears to be a biomarker for predicting successful treatment outcomes for several solid tumors and indicates a new therapeutic option for patients harboring MMR-deficient cancers. Science , this issue p. 409 ; see also p. 358 | 10.1038/s41568-019-0177-x | Study describing the efficacy of single-agent pembrolizumab in mismatch repair-deficient endometrial cancer patients |
10.1083/jcb.2.4.73 | 45,414,532 | 1. In most rat liver cells, no special topographical relationship between mitochondria and ergastoplasmic lamellae is to be observed. In some cells, nevertheless, the two organelles are grouped together in dense zones clearly separated from the hyaloplasm. 2. Such an association can be produced at will in the livers of animals refed after prolonged fasting, or in the regenerative phases after partial hepatectomy and intoxication with carbon tetrachloride. In all these cells, the ergastoplasm, after having disappeared, suddenly reappears in the cytoplasm, either along the nucleus or cell membranes, where the mitochondria are grouped. 3. It may be supposed that these topographical relationships between mitochondria and ergastoplasm during a definite period of cellular activity indicate a close functional link between chondrioma and basophilic structures. Mitochondria seem to play an important part in the elaboration of hepatic ergastoplasm. | 10.1038/s41467-019-09253-3 | This is the first paper describing a contact site in cells. |
10.1126/science.280.5370.1763 | 41,469,373 | The spatial relation between mitochondria and endoplasmic reticulum (ER) in living HeLa cells was analyzed at high resolution in three dimensions with two differently colored, specifically targeted green fluorescent proteins. Numerous close contacts were observed between these organelles, and mitochondria in situ formed a largely interconnected, dynamic network. A Ca 2+ -sensitive photoprotein targeted to the outer face of the inner mitochondrial membrane showed that, upon opening of the inositol 1,4,5-triphosphate (IP 3 )–gated channels of the ER, the mitochondrial surface was exposed to a higher concentration of Ca 2+ than was the bulk cytosol. These results emphasize the importance of cell architecture and the distribution of organelles in regulation of Ca 2+ signaling. | 10.1038/s41467-019-09253-3 | This is the first paper showing a role for contact sites in direct calcium transfer. |
10.1091/mbc.11.7.2445 | 82,847,916 | Vac8p is a vacuolar membrane protein that is required for efficient vacuole inheritance and fusion, cytosol-to-vacuole targeting, and sporulation. By analogy to other armadillo domain proteins, including β-catenin and importin α, we hypothesize that Vac8p docks various factors at the vacuole membrane. Two-hybrid and copurfication assays demonstrated that Vac8p does form complexes with multiple binding partners, including Apg13p, Vab2p, and Nvj1p. Here we describe the surprising role of Vac8p-Nvj1p complexes in the formation of nucleus–vacuole (NV) junctions. Nvj1p is an integral membrane protein of the nuclear envelope and interacts with Vac8p in the cytosol through its C-terminal 40–60 amino acids (aa). Nvj1p green fluorescent protein (GFP) concentrated in small patches or rafts at sites of close contact between the nucleus and one or more vacuoles. Previously, we showed that Vac8p-GFP concentrated in intervacuole rafts, where is it likely to facilitate vacuole-vacuole fusion, and in “orphan” rafts at the edges of vacuole clusters. Orphan rafts of Vac8p red-sifted GFP (YFP) colocalize at sites of NV junctions with Nvj1p blue-sifted GFP (CFP). GFP-tagged nuclear pore complexes (NPCs) were excluded from NV junctions. In vac8-Δ cells, Nvj1p-GFP generally failed to concentrate into rafts and, instead, encircled the nucleus. NV junctions were absent in both nvj1-Δ andvac8-Δ cells. Overexpression of Nvj1p caused the profound proliferation of NV junctions. We conclude that Vac8p and Nvj1p are necessary components of a novel interorganelle junction apparatus. | 10.1038/s41467-019-09253-3 | This is the first paper describing a contact site tether in yeast. |
10.1126/science.1207385 | 62,297,467 | Mitochondrial division occurs at positions where endoplasmic reticulum tubules contact mitochondria and mediate constriction. | 10.1038/s41467-019-09253-3 | This paper describes the association between contact sites and mitochondrial fission. |
10.1126/science.aah6171 | 103,693,677 | Understanding insulin release Insulin release takes place in two phases: a first rapid burst followed by a series of small exocytic bursts that coincide with pulsatile spikes in cytosolic Ca 2+ levels. The second phase is impaired in patients with type II diabetes, underscoring the importance of understanding its molecular basis. Lees et al. report a mechanism through which TMEM24, a lipid transport protein that concentrates at endoplasmic reticulum–plasma membrane contact sites, regulates the pulsatility of cytosolic Ca 2+ and phosphoinositide signaling. This process in turn regulates pulsatile insulin secretion during the slow insulin release phase. Science , this issue p. eaah6171 | 10.1038/s41467-019-09253-3 | This manuscript showes a role for contact sites in physiology of a tissue. |
10.1073/pnas.1503191112 | 28,006,140 | The close apposition between the endoplasmic reticulum (ER) and the plasma membrane (PM) plays important roles in Ca 2+ homeostasis, signaling, and lipid metabolism. The extended synaptotagmins (E-Syts; tricalbins in yeast) are ER-anchored proteins that mediate the tethering of the ER to the PM and are thought to mediate lipid transfer between the two membranes. E-Syt cytoplasmic domains comprise a synaptotagmin-like mitochondrial-lipid–binding protein (SMP) domain followed by five C2 domains in E-Syt1 and three C2 domains in E-Syt2/3. Here, we used cryo-electron tomography to study the 3D architecture of E-Syt–mediated ER–PM contacts at molecular resolution. In vitrified frozen-hydrated mammalian cells overexpressing individual E-Syts, in which E-Syt–dependent contacts were by far the predominant contacts, ER–PM distance (19–22 nm) correlated with the amino acid length of the cytosolic region of E-Syts (i.e., the number of C2 domains). Elevation of cytosolic Ca 2+ shortened the ER–PM distance at E-Syt1–dependent contacts sites. E-Syt–mediated contacts displayed a characteristic electron-dense layer between the ER and the PM. These features were strikingly different from those observed in cells exposed to conditions that induce contacts mediated by the stromal interaction molecule 1 (STIM1) and the Ca 2+ channel Orai1 as well as store operated Ca 2+ entry. In these cells the gap between the ER and the PM was spanned by filamentous structures perpendicular to the membranes. Our results define specific ultrastructural features of E-Syt–dependent ER–PM contacts and reveal their structural plasticity, which may impact on the cross-talk between the ER and the PM and the functions of E-Syts in lipid transport between the two bilayers. | 10.1038/s41467-019-09253-3 | This paper shows a high resolution structure of a contact site. |
10.7554/elife.31019 | 103,666,020 | Endoplasmic reticulum (ER) membrane contact sites (MCSs) are crucial regulatory hubs in cells, playing roles in signaling, organelle dynamics, and ion and lipid homeostasis. Previous work demonstrated that the highly conserved yeast Ltc/Lam sterol transporters localize and function at ER MCSs. Our analysis of the human family members, GRAMD1a and GRAMD2a, demonstrates that they are ER-PM MCS proteins, which mark separate regions of the plasma membrane (PM) and perform distinct functions in vivo. GRAMD2a, but not GRAMD1a, co-localizes with the E-Syt2/3 tethers at ER-PM contacts in a PIP lipid-dependent manner and pre-marks the subset of PI(4,5)P2-enriched ER-PM MCSs utilized for STIM1 recruitment. Data from an analysis of cells lacking GRAMD2a suggest that it is an organizer of ER-PM MCSs with pleiotropic functions including calcium homeostasis. Thus, our data demonstrate the existence of multiple ER-PM domains in human cells that are functionally specialized by GRAM-domain containing proteins. | 10.1038/s41467-019-09253-3 | This manuscript demonstrates that a contact site between two organelles can be formed by different tethers and have diverse functions. |
10.1083/jcb.72.3.714 | 122,788,784 | Low-speed centrifugation (640 g) of rat liver homogenates, prepared with a standard ionic medium, yielded a pellet from which a rapidly sedimenting fraction of rough endoplasmic reticulum (RSER) was recovered free of nuclei. This fraction contained 20-25% of cellular RNA and approximately 30% of total glucose-6-phosphatase (ER marker) activity. A major portion of total cytochrome c oxidase (mitochondrial marker) activity was also recovered in this fraction, with the remainder sedimenting between 640 and 6,000 g. Evidence is provided which indicates that RSER may be intimately associated with mitochondria. Complete dissociation of ER from mitochondria in the RSER fraction required very harsh conditions. Sucrose density gradient centrifugation analysis revealed that 95% dissociation could be achieved when the RSER fraction was first resuspended in buffer containing 500 mM KCl and 20 mM EDTA, and subjected to shearing. Excluding KCl, EDTA, or shearing from the procedure resulted in incomplete separation. Both electron microscopy and marker enzyme analysis of mitochondria purified by this procedure indicated that some structural damage and leakage of proteins from matrix and intermembrane compartments had occurred. Nevertheless, when mitochondria from RSER and postnuclear 6,000-g pellet fractions were purified in this way fromanimals injected with [35S]methionine +/- cycloheximide, mitochondria from the postnuclear 6,000-g pellet were found to incorporate approximately two times more cytoplasmically synthesized radioactive protein per milligram mitochondrial protein (or per unit cytochrome c oxidase activity) than did mitochondria from the RSER fraction. Mitochondria-RSER associations, therefore, do not appear to facilitate enhanced incorporation of mitochondrial proteins which are newly synthesized in the cytoplasm. | 10.1038/s41467-019-09253-3 | This paper identifies a fraction of rough er in association with mitochondria. |
10.1126/science.1191035 | 104,259,708 | Environment Matters Stem cells isolated from muscle can be used for muscle regeneration, but only if the stem cells are fresh. Under standard cell culture conditions in the laboratory, muscle stem cells fail to proliferate efficiently and lose their regenerative capacity. Gilbert et al. (p. 1078 , published online 15 July; see the Perspective by Bhatia ) built an in vitro–culture system that resembles the physical characteristics in which muscle stem cells normally reside: a squishy elastic bed (rather than the hard slab of a plastic culture flask). Laminin tethered to hydrogels was used to generate substrates of varying elasticity. When cultured on these substrates, muscle stem cells remained undifferentiated and were able to support muscle regeneration when transplanted back into mice. | 10.1038/s41586-018-0089-z | This study demonstrated that muscle stem cells best maintained their stem cell phenotype and regenerative potential when cultured on substrates with stiffness approximating that of healthy muscle. |
10.1038/ncomms15909 | 102,860,008 | Abstract Micelles formed by the self-assembly of block copolymers in selective solvents have attracted widespread attention and have uses in a wide variety of fields, whereas applications based on their electronic properties are virtually unexplored. Herein we describe studies of solution-processable, low-dispersity, electroactive fibre-like micelles of controlled length from π-conjugated diblock copolymers containing a crystalline regioregular poly(3-hexylthiophene) core and a solubilizing, amorphous regiosymmetric poly(3-hexylthiophene) or polystyrene corona. Tunnelling atomic force microscopy measurements demonstrate that the individual fibres exhibit appreciable conductivity. The fibres were subsequently incorporated as the active layer in field-effect transistors. The resulting charge carrier mobility strongly depends on both the degree of polymerization of the core-forming block and the fibre length, and is independent of corona composition. The use of uniform, colloidally stable electroactive fibre-like micelles based on common π-conjugated block copolymers highlights their significant potential to provide fundamental insight into charge carrier processes in devices, and to enable future electronic applications. | 10.1038/s41578-020-00233-4 | This is a detailed study on the effect of nanofibre length on device performance |
10.1126/science.aar8104 | 103,667,027 | A longer exciton pathway Organic semiconductors typically exhibit exciton diffusion lengths on the order of tens of nanometers. Jin et al. prepared nanofibers from block polymers consisting of emissive polyfluorene cores surrounded by coronas of polyethylene glycol and polythiophene (see the Perspective by Holmes). Excitons generated in the polyfluorene cannot enter the polyethylene glycol layer and so diffuse more than 200 nm. This distance can be tuned by varying the length of the polyethylene glycol—a feature that could potentially be exploited in the development of organic devices such as photovoltaics. Science , this issue p. 897 ; see also p. 854 | 10.1038/s41578-020-00233-4 | This study reports fibres made through CDSA that display exceptional exciton-diffusion lengths |
10.1002/adfm.201808365 | 101,925,236 | Abstract Methods for noninvasive brain imaging are highly desirable to study brain structures in neuroscience. Two‐photon fluorescence microscopy (2PFM) with near‐infrared (NIR) light excitation is a relatively noninvasive approach commonly used to study brain with high spatial resolution and large imaging depth. However, most of the current studies require cranial window implantation or skull‐thinning methods due to attenuation of excitation light. 2PFM through intact mouse skull is challenging due to strong scattering induced by skull bone. Herein, NIR‐II light excitable single‐chain conjugated polymer dots (CPdots) with bright fluorescence in NIR‐I region (peak at ≈725 nm and quantum yield of 20.6 ± 1.0%) are developed for deep in vivo two‐photon fluorescence (2PF) imaging of intact mouse brain. The synthesized CPdots exhibit good biocompatibility, high photostability, and large two‐photon absorption cross section. The CPdots allow 2PF images acquired upon excitation at 800, 1040 and 1200 nm with the highest signal‐to‐background ratio of 208 demonstrated for 1200 nm excitation. Moreover, a 3D reconstruction of the brain blood vessel network is obtained with a large vertical depth of 400 µm through intact skull. This work demonstrates great potential of bright NIR fluorophores for in vivo deep tissue imaging. | 10.1038/s41578-020-00233-4 | This study reports in vivo deep-tissue imaging with high contrast by using NIR |
10.1002/anie.201712550 | 123,858,373 | Abstract Nanoparticles for photothermal therapy: Real‐time temperature monitoring is critical to reduce the nonspecific damage during photothermal therapy (PTT); however, PTT agents that can emit temperature‐related signals are rare and limited to few inorganic nanoparticles. We herein synthesize a semiconducting polymer nanococktail (SPN CT ) that can not only convert photo‐energy to heat but also emit temperature‐correlated luminescence after cessation of light excitation. Such an afterglow luminescence of the SPN CT detects tumors more sensitively than fluorescence as a result of the elimination of tissue autofluorescence, while its temperature‐dependent nature allows tumor temperature to be optically monitored under near‐infrared (NIR) laser irradiation. Thus, SPN CT represents the first organic optical nanosystem that enables optical‐imaging guided PTT without real‐time light excitation. | 10.1038/s41578-020-00233-4 | This study demonstrates optical-imaging-guided photothermal therapy without real-time light excitation |
10.1002/anie.201705543 | 83,440,722 | Abstract Regulation of transgene systems is needed to develop innovative medicines. However, noninvasive remote control of gene expression has been rarely developed and remains challenging. We herein synthesize a near‐infrared (NIR) absorbing dendronized semiconducting polymer (DSP) and utilize it as a photothermal nanocarrier not only to efficiently deliver genes but also to spatiotemporally control gene expression in conjunction with heat‐inducible promoter. DSP has a high photothermal conversion efficiency (44.2 %) at 808 nm, permitting fast transduction of NIR light into thermal signals for intracellular activation of transcription. Such a DSP‐mediated remote activation can rapidly and safely result in 25‐ and 4.5‐fold increases in the expression levels of proteins in living cells and mice, respectively. This study thus provides a promising approach to optically regulate transgene systems for on‐demand therapeutic transgene dosing. | 10.1038/s41578-020-00233-4 | This work seeds the idea of remotely controlling gene expression |
10.1002/anie.201813066 | 62,043,357 | Abstract Semiconducting polymer dots (Pdots) have recently attracted considerable attention because of their photocatalytic activity as well as tunable optical band gap. In this contribution, we describe the therapeutic application of Pdots through in situ photocatalytic hydrogen generation. Liposomes were employed as nanoreactors to confine the Pdot photocatalyst, reactants, intermediates, and by‐products. Upon photon absorption by the Pdots, the catalytic cycle is initiated and repeated within the aqueous interior, while the H 2 product diffuses across the lipid bilayer to counteract reactive oxygen species (ROS) overexpressed in diseased tissues. Ensemble and single‐particle Förster resonance energy transfer microscopy confirmed the proposed nanoreactor model. We demonstrate that a liposomal nanoreactor containing Pdots and a sacrificial electron donor is a potential photocatalytic nanoreactor for in situ hydrogen therapy. | 10.1038/s41578-020-00233-4 | This paper demonstrates a promising and original approach to photothermal therapy |
10.1101/gr.246678.118 | 125,333,095 | Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans -acting regulatory proteins that control alternative splicing has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here show that the RNA components of the spliceosome likewise influence alternative splicing decisions. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and across cancer samples. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially misspliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many cancers, we propose that a full understanding of such dysregulated pre-mRNA processing requires study of snRNAs, as well as protein splicing factors. Together, our data show that the RNA components of the spliceosome are not merely basal factors, as has long been assumed. Instead, these noncoding RNAs constitute a previously uncharacterized layer of regulation of alternative splicing, and contribute to the establishment of global splicing programs in both healthy and malignant cells. | 10.1038/s41568-020-00306-0 | Dvinge et al. (2019) and Shuai et al. (2019) demonstrate that RNA components of the spliceosome are also altered in cancer |
10.1158/2159-8290.cd-16-1034 | 29,197,701 | Abstract Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation–positive advanced hematologic malignancies. Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478–93. ©2017 AACR. See related commentary by Thomas and Majeti, p. 459. See related article by Shih et al., p. 494. This article is highlighted in the In This Issue feature, p. 443 | 10.1038/s41589-022-00997-6 | This paper reports the discovery and application of an allosteric IDH2 inhibitor in AML. |
10.1158/2159-8290.cd-19-1228 | 83,282,890 | Abstract A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. Significance: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis. This article is highlighted in the In This Issue feature, p. 1241 | 10.1038/s41589-022-00997-6 | This paper describes the application of PH-755 in breast cancer metastasis models. |
10.1158/1535-7163.mct-13-0870 | 41,665,712 | Abstract Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor–positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2+ cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. Mol Cancer Ther; 13(4); 890–901. ©2014 AACR. | 10.1038/s41589-022-00997-6 | This paper describes the biochemical and cellular applications of CB-839. |
10.1126/science.aaf2786 | 104,021,261 | Quantitation of metabolic pathway regulation Although metabolic biochemical pathways are well understood, less is known about precisely how reaction rates or fluxes through the various enzymes are controlled. Hackett et al. developed a method to quantitate such regulatory influence in yeast. They monitored concentrations of metabolites, enzymes, and potential regulators by LC-MS/MS (liquid chromatography–tandem mass spectrometry) and isotope ratio measurements for 56 reactions, over 100 metabolites, and 370 metabolic enzymes in yeast in 25 different steady-state conditions. Bayesian analysis was used to examine the probability of regulatory interactions. Regulation of flux through the pathways was predominantly controlled by changes in the concentration of small-molecule metabolites rather than changes in enzyme abundance. The analysis also revealed previously unrecognized regulation between pathways. Science , this issue p. 432 | 10.1038/s41589-022-00997-6 | This paper describes the SIMMER method for identifying endogenous allosteric interactions. |
10.1126/scitranslmed.aay1063 | 104,393,236 | Atherosclerotic lesional macrophages express molecules that promote plaque progression, but lack of mechanisms to therapeutically target these molecules represents a major gap in translational cardiovascular research. Here, we tested the efficacy of a small interfering RNA (siRNA) nanoparticle (NP) platform targeting a plaque-destabilizing macrophage molecule—Ca 2+ /calmodulin-dependent protein kinase γ (CaMKIIγ). CaMKIIγ becomes activated in advanced human and mouse plaque macrophages and drives plaque necrosis by suppressing the expression of the efferocytosis receptor MerTK. When macrophage-targeted siCamk2g NPs were administered to Western diet–fed Ldlr −/− mice, the atherosclerotic lesions showed decreased CaMKIIγ and increased MerTK expression in macrophages, improved phagocytosis of apoptotic cells (efferocytosis), decreased necrotic core area, and increased fibrous cap thickness—all signs of increased plaque stability—compared with mice treated with control siRNA NPs. These findings demonstrate that atherosclerosis-promoting genes in plaque macrophages can be targeted with siRNA NPs in a preclinical model of advanced atherosclerosis. | 10.1038/s41569-021-00629-x | This study shows that macrophage-targeted siRNA nanoparticles can restore efferocytic capacity of atherosclerotic lesional macrophages and, therefore, reduce plaque burden in a preclinical model of advanced atherosclerosis. |
10.2217/fca-2017-0009 | 62,592,077 | Aim: The safety options in nanomedicine raise an issue of the optimal niche at the real-world clinical practice. Methods: This is an observational prospective cohort analysis of the 5-year clinical outcomes at the intention-to-treat population (nano vs ferro vs stenting; n = 180) of NANOM first-in-man trial (NCT01270139). Results: Mortality (6 vs 9 vs 10 cases of cardiac death in groups, p < 0.05), major adverse cardiovascular events (14.3 vs 20.9 vs 22.9%, p = 0.04), late thrombosis (2 vs 4 vs 6, p < 0.05) and target lesion revascularization (3.8 vs 4.8 vs 5.7%, p = 0.04) were significantly higher in ferro group and stent control at 60 months. Conclusion: NANOM first-in-man trial demonstrates high safety with better rate of mortality, major adverse cardiovascular events and target lesion revascularization at the long-term follow-up if compare with stent XIENCE V. | 10.1038/s41569-021-00629-x | Together with Kharlamov et al. (2015), this is the first-in-human trial that demonstrates that plasmonic photothermal therapy can reduce atherosclerotic plaque burden and major adverse cardiovascular events. |
10.1126/sciimmunol.aat1482 | 83,433,077 | Deeper insights into the biology of interleukin-2 and its receptors are leading to therapeutic strategies for selective T reg stimulation. | 10.1038/s41573-019-0041-4 | A comprehensive review discussing the discovery, biology and therapeutic potential of the cytokine IL-2 |
10.1084/jem.20060468 | 83,281,170 | Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases. | 10.1038/s41573-019-0041-4 | Together with Liu et al. (2006) this article describes the use of CD127 (IL-7 receptor subunit-α) as a surface marker, the exclusion of which dramatically enhances peripheral blood human T reg cell purity after FACS |
10.1126/scitranslmed.aad4134 | 103,721,459 | Autologous regulatory T cells can be expanded and are well tolerated in patients with recent-onset type 1 diabetes. | 10.1038/s41573-019-0041-4 | First clinical trial demonstrating up to 1 year survival of infused T reg cells in patients with T1D |
10.1084/jem.20040139 | 83,080,620 | The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity. | 10.1038/s41573-019-0041-4 | Seminal study showing that antigen-specific T reg cells can be expanded ex vivo and cure T1D in mice |
10.1182/blood-2004-09-3579 | 123,181,209 | Abstract We developed an approach that increases CD4+CD25+ regulatory T-cell potency by antigen-specifically redirecting them against pathologic T lymphocytes. The regulatory cells are transgenically modified with chimeric receptors that link antigen–major histocompatibility complex (MHC) extracellular and transmembrane domains with the cytoplasmic signaling tail of T-cell receptor ζ (TCR-ζ). The receptors' antigen-MHC recognizes the TCR of cognate T lymphocytes. Receptor engagement stimulates the receptor-modified T cell (RMTC) through the linked ζ chain. CD4+CD25+ RMTCs expressing a myelin basic protein (MBP) 89-101-IAs-ζ receptor, unlike unmodified CD4+CD25+ T cells or CD4+CD25- RMTCs, prevented and treated experimental allergic encephalomyelitis (EAE) induced with MBP89-101. The RMTCs were effective even after the autoreactive T-cell repertoire had diversified to include specificities not directly targeted by the chimeric receptor. Remissions were sustained and mortality was decreased from more than 50% to 0%. These results provide proof of principal for a novel approach to enforce the interaction of regulatory and pathologic T lymphocytes, thereby facilitating the treatment of autoimmune disease. | 10.1038/s41573-019-0041-4 | First study redirecting T reg cells using a chimeric receptor, designed to recognize autoreactive T cells in EAE |
10.2337/db08-1168 | 4,860,455 | OBJECTIVE—Regulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells—a need forming the basis for these studies. RESEARCH DESIGN AND METHODS—Tregs from recent-onset type 1 diabetic patients and healthy control subjects were isolated by fluorescence-activated cell sorting and compared for their capacity to expand in vitro in response to anti-CD3–anti-CD28–coated microbeads and IL-2. Expanded cells were examined for suppressive function, lineage markers and FOXP3, and cytokine production. RESULTS—Both CD4+CD127lo/− and CD4+CD127lo/−CD25+ T-cells could be expanded and used as Tregs. However, expansion of CD4+CD127lo/− cells required the addition of rapamycin to maintain lineage purity. In contrast, expansion of CD4+CD127lo/−CD25+ T-cells, especially the CD45RA+ subset, resulted in high yield, functional Tregs that maintained higher FOXP3 expression in the absence of rapamycin. Tregs from type 1 diabetic patients and control subjects expanded similarly and were equally capable of suppressing T-cell proliferation. Regulatory cytokines were produced by Tregs after culture; however, a portion of FOXP3+ cells were capable of producing interferon (IFN)-γ after reactivation. IFN-γ production was observed from both CD45RO+ and CD45RA+ Treg populations. CONCLUSIONS—The results support the feasibility of isolating Tregs for in vitro expansion. Based on expansion capacity, FOXP3 stability, and functional properties, the CD4+CD127lo/−CD25+ T-cells represent a viable cell population for cellular therapy in this autoimmune disease. | 10.1038/s41573-019-0041-4 | This article describes the good manufacturing practice manufacture of T reg cells isolated from patients with T1D for T reg cell therapy |
10.1126/science.aar3246 | 4,860,145 | Engineering cytokine-receptor pairs Interleukin-2 (IL-2) is an important cytokine that helps T cells destroy tumors and virus-infected cells. IL-2 has great therapeutic promise but is limited by toxic side effects and its capacity to both activate and repress immune responses. Sockolosky et al. set out to improve IL-2–based immunotherapy by engineering synthetic IL-2–receptor pairs (i.e., IL-2 and its receptor, IL-2R) (see the Perspective by Mackall). Engineered complexes transmitted IL-2 signals but only interacted with each other and not with endogenous IL-2/IL-2R. Treatment of mice with IL-2 improved the ability of engineered T cells to reject tumors with no obvious side effects. This type of approach may provide a way to mitigate toxicities associated with some cytokine-based immunotherapies. Science , this issue p. 1037 ; see also p. 990 | 10.1038/s41573-019-0041-4 | This study reports the generation of an orthogonal IL-2–IL-2 receptor pair that could be used to trigger IL-2 signalling specifically in infused engineered T reg cells |
10.1126/science.aad2791 | 62,290,395 | T cells target peptide combos One of the enduring mysteries of autoimmunity is the identity of the specific proteins targeted by autoimmune T cells. Delong et al. used mass spectrometry to elucidate the peptide targets of autoimmune T cells isolated from a mouse model of type 1 diabetes. T cells targeted hybrid peptides formed by the covalent linking of a peptide derived from pro-insulin to other peptides derived from proteins found in pancreatic beta cells. T cells isolated from the pancreatic islets of two individuals with type 1 diabetes also recognized such hybrid peptides, suggesting that they may play an important role in driving disease. Science , this issue p. 711 | 10.1038/s41573-019-0041-4 | This article shows that some diabetogenic T cells recognize epitopes formed by fusion of proinsulin peptides to other peptides that are found in the secretory vesicles of beta cells |
10.1073/pnas.1902566116 | 82,979,762 | Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage “don’t-eat me” signal CD47 from the AAVS1 safe harbor locus. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells were minimal. Our results describe an approach that effectively targets adaptive as well as innate immune responses and may therefore enable cell therapy on a broader scale. | 10.1038/s41573-019-0041-4 | This article describes the development of gene-edited hypoimmunogenic human pluripotent stem cells, which could in the future be used as an inexhaustible source for universally compatible T reg cells |
10.4049/jimmunol.167.3.1245 | 20,436,631 | Abstract Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD+CD25+ T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4+ population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4+CD25+ regulatory cells isolated in mice. With TCR cross-linking, CD4+CD25high cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4+CD25− responder T cells in a contact-dependent manner. The CD4+CD25high regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RBlow on murine CD4+CD25+ regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4+CD25high regulatory cells and CD4+CD25− responder cells. Whereas higher ratios of CD4+CD25high T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders. | 10.1038/s41573-019-0041-4 | Together with Levings et al. (2001), Jonuleit et al. (2001), Dieckmann et al. (2001), Ng et al. (2001) and Stephens et al. (2001), this article is a seminal study, the first to describe T reg cells in humans |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.