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161. Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis.

作者: Luke E Berchowitz.;Greg Kabachinski.;Margaret R Walker.;Thomas M Carlile.;Wendy V Gilbert.;Thomas U Schwartz.;Angelika Amon.
来源: Cell. 2015年163卷2期406-18页
Message-specific translational control is required for gametogenesis. In yeast, the RNA-binding protein Rim4 mediates translational repression of numerous mRNAs, including the B-type cyclin CLB3, which is essential for establishing the meiotic chromosome segregation pattern. Here, we show that Rim4 forms amyloid-like aggregates and that it is the amyloid-like form of Rim4 that is the active, translationally repressive form of the protein. Our data further show that Rim4 aggregation is a developmentally regulated process. Starvation induces the conversion of monomeric Rim4 into amyloid-like aggregates, thereby activating the protein to bring about repression of translation. At the onset of meiosis II, Rim4 aggregates are abruptly degraded allowing translation to commence. Although amyloids are best known for their role in the etiology of diseases such as Alzheimer's, Parkinson's, and diabetes by forming toxic protein aggregates, our findings show that cells can utilize amyloid-like protein aggregates to function as central regulators of gametogenesis.

162. An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses.

作者: Teruyuki Sano.;Wendy Huang.;Jason A Hall.;Yi Yang.;Alessandra Chen.;Samuel J Gavzy.;June-Yong Lee.;Joshua W Ziel.;Emily R Miraldi.;Ana I Domingos.;Richard Bonneau.;Dan R Littman.
来源: Cell. 2015年163卷2期381-93页
RORγt(+) Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt(+) T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt(+) T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.

163. Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells.

作者: Koji Atarashi.;Takeshi Tanoue.;Minoru Ando.;Nobuhiko Kamada.;Yuji Nagano.;Seiko Narushima.;Wataru Suda.;Akemi Imaoka.;Hiromi Setoyama.;Takashi Nagamori.;Eiji Ishikawa.;Tatsuichiro Shima.;Taeko Hara.;Shoichi Kado.;Toshi Jinnohara.;Hiroshi Ohno.;Takashi Kondo.;Kiminori Toyooka.;Eiichiro Watanabe.;Shin-Ichiro Yokoyama.;Shunji Tokoro.;Hiroshi Mori.;Yurika Noguchi.;Hidetoshi Morita.;Ivaylo I Ivanov.;Tsuyoshi Sugiyama.;Gabriel Nuñez.;J Gray Camp.;Masahira Hattori.;Yoshinori Umesaki.;Kenya Honda.
来源: Cell. 2015年163卷2期367-80页
Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.

164. SnapShot: CRISPR-RNA-guided adaptive immune systems.

作者: Joshua Carter.;Blake Wiedenheft.
来源: Cell. 2015年163卷1期260-260.e1页
Bacteria and archaea have evolved sophisticated adaptive immune systems that reply on CRISPR loci and a diverse cassette of Cas genes that are classified into three main types and at least eleven subtypes. All CRISPR-Cas immune systems operate through three main stages: acquisition, biogenesis, and interference. This SnapShot summarizes our current knowledge of these fascinating immune systems.

165. A high-resolution imaging approach to investigate chromatin architecture in complex tissues.

作者: Michael W Linhoff.;Saurabh K Garg.;Gail Mandel.
来源: Cell. 2015年163卷1期246-55页
We present ChromATin, a quantitative high-resolution imaging approach for investigating chromatin organization in complex tissues. This method combines analysis of epigenetic modifications by immunostaining, localization of specific DNA sequences by FISH, and high-resolution segregation of nuclear compartments using array tomography (AT) imaging. We then apply this approach to examine how the genome is organized in the mammalian brain using female Rett syndrome mice, which are a mosaic of normal and Mecp2-null cells. Side-by-side comparisons within the same field reveal distinct heterochromatin territories in wild-type neurons that are altered in Mecp2-null nuclei. Mutant neurons exhibit increased chromatin compaction and a striking redistribution of the H4K20me3 histone modification into pericentromeric heterochromatin, a territory occupied normally by MeCP2. These events are not observed in every neuronal cell type, highlighting ChromATin as a powerful in situ method for examining cell-type-specific differences in chromatin architecture in complex tissues.

166. Tracing dynamic changes of DNA methylation at single-cell resolution.

作者: Yonatan Stelzer.;Chikdu Shakti Shivalila.;Frank Soldner.;Styliani Markoulaki.;Rudolf Jaenisch.
来源: Cell. 2015年163卷1期218-29页
Mammalian DNA methylation plays an essential role in development. To date, only snapshots of different mouse and human cell types have been generated, providing a static view on DNA methylation. To enable monitoring of methylation status as it changes over time, we establish a reporter of genomic methylation (RGM) that relies on a minimal imprinted gene promoter driving a fluorescent protein. We show that insertion of RGM proximal to promoter-associated CpG islands reports the gain or loss of DNA methylation. We further utilized RGM to report endogenous methylation dynamics of non-coding regulatory elements, such as the pluripotency-specific super enhancers of Sox2 and miR290. Loci-specific DNA methylation changes and their correlation with transcription were visualized during cell-state transition following differentiation of mouse embryonic stem cells and during reprogramming of somatic cells to pluripotency. RGM will allow the investigation of dynamic methylation changes during development and disease at single-cell resolution.

167. CDK7-dependent transcriptional addiction in triple-negative breast cancer.

作者: Yubao Wang.;Tinghu Zhang.;Nicholas Kwiatkowski.;Brian J Abraham.;Tong Ihn Lee.;Shaozhen Xie.;Haluk Yuzugullu.;Thanh Von.;Heyuan Li.;Ziao Lin.;Daniel G Stover.;Elgene Lim.;Zhigang C Wang.;J Dirk Iglehart.;Richard A Young.;Nathanael S Gray.;Jean J Zhao.
来源: Cell. 2015年163卷1期174-86页
Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing kinase inhibitors and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not hormone receptor-positive breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An "Achilles cluster" of TNBC-specific genes is especially sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be a useful therapy for this challenging cancer.

168. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.

作者: Alan Serrels.;Tom Lund.;Bryan Serrels.;Adam Byron.;Rhoanne C McPherson.;Alexander von Kriegsheim.;Laura Gómez-Cuadrado.;Marta Canel.;Morwenna Muir.;Jennifer E Ring.;Eleni Maniati.;Andrew H Sims.;Jonathan A Pachter.;Valerie G Brunton.;Nick Gilbert.;Stephen M Anderton.;Robert J B Nibbs.;Margaret C Frame.
来源: Cell. 2015年163卷1期160-73页
Focal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8(+) T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8(+) T cell activity, permitting growth of FAK-expressing tumors. Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Furthermore, FAK's immuno-modulatory nuclear activities may be specific to cancerous squamous epithelial cells, as normal keratinocytes do not have nuclear FAK. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8(+) T cell-mediated anti-tumor response. Therefore, FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic opportunities.

169. A hierarchical multi-oscillator network orchestrates the Arabidopsis circadian system.

作者: Nozomu Takahashi.;Yoshito Hirata.;Kazuyuki Aihara.;Paloma Mas.
来源: Cell. 2015年163卷1期148-59页
Short- and long-distance circadian communication is essential for integration of temporal information. However, a major challenge in plant biology is to decipher how individual clocks are interconnected to sustain rhythms in the whole plant. Here we show that the shoot apex is composed of an ensemble of coupled clocks that influence rhythms in roots. Live-imaging of single cells, desynchronization of dispersed protoplasts, and mathematical analysis using barycentric coordinates for high-dimensional space show a gradation in the strength of circadian communication in different tissues, with shoot apex clocks displaying the highest coupling. The increased synchrony confers robustness of morning and evening oscillations and particular capabilities for phase readjustments. Rhythms in roots are altered by shoot apex ablation and micrografting, suggesting that signals from the shoot apex are able to synchronize distal organs. Similarly to the mammalian suprachiasmatic nucleus, shoot apexes play a dominant role within the plant hierarchical circadian structure.

170. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.

作者: Amandine Molliex.;Jamshid Temirov.;Jihun Lee.;Maura Coughlin.;Anderson P Kanagaraj.;Hong Joo Kim.;Tanja Mittag.;J Paul Taylor.
来源: Cell. 2015年163卷1期123-33页
Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.

171. Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel.

作者: Neelendu Dey.;Vitas E Wagner.;Laura V Blanton.;Jiye Cheng.;Luigi Fontana.;Rashidul Haque.;Tahmeed Ahmed.;Jeffrey I Gordon.
来源: Cell. 2015年163卷1期95-107页
To understand how different diets, the consumers' gut microbiota, and the enteric nervous system (ENS) interact to regulate gut motility, we developed a gnotobiotic mouse model that mimics short-term dietary changes that happen when humans are traveling to places with different culinary traditions. Studying animals transplanted with the microbiota from humans representing diverse culinary traditions and fed a sequence of diets representing those of all donors, we found that correlations between bacterial species abundances and transit times are diet dependent. However, the levels of unconjugated bile acids-generated by bacterial bile salt hydrolases (BSH)-correlated with faster transit, including during consumption of a Bangladeshi diet. Mice harboring a consortium of sequenced cultured bacterial strains from the Bangladeshi donor's microbiota and fed a Bangladeshi diet revealed that the commonly used cholekinetic spice, turmeric, affects gut motility through a mechanism that reflects bacterial BSH activity and Ret signaling in the ENS. These results demonstrate how a single food ingredient interacts with a functional microbiota trait to regulate host physiology.

172. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis.

作者: Wenwen Zeng.;Roksana M Pirzgalska.;Mafalda M A Pereira.;Nadiya Kubasova.;Andreia Barateiro.;Elsa Seixas.;Yi-Hsueh Lu.;Albina Kozlova.;Henning Voss.;Gabriel G Martins.;Jeffrey M Friedman.;Ana I Domingos.
来源: Cell. 2015年163卷1期84-94页
Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine β-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.

173. Molecular identity of human outer radial glia during cortical development.

作者: Alex A Pollen.;Tomasz J Nowakowski.;Jiadong Chen.;Hanna Retallack.;Carmen Sandoval-Espinosa.;Cory R Nicholas.;Joe Shuga.;Siyuan John Liu.;Michael C Oldham.;Aaron Diaz.;Daniel A Lim.;Anne A Leyrat.;Jay A West.;Arnold R Kriegstein.
来源: Cell. 2015年163卷1期55-67页
Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex.

174. Preclinical mouse cancer models: a maze of opportunities and challenges.

作者: Chi-Ping Day.;Glenn Merlino.;Terry Van Dyke.
来源: Cell. 2015年163卷1期39-53页
Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This Primer explores the current status, promise, and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development.

175. Mitochondrial DNA variation in human radiation and disease.

作者: Douglas C Wallace.
来源: Cell. 2015年163卷1期33-8页
Environmental adaptation, predisposition to common diseases, and, potentially, speciation may all be linked through the adaptive potential of mitochondrial DNA (mtDNA) alterations of bioenergetics. This Perspective synthesizes evidence that human mtDNA variants may be adaptive or deleterious depending on environmental context and proposes that the accrual of mtDNA variation could contribute to animal speciation via adaptation to marginal environments.

176. Revealing the complexity of retroviral repression.

作者: Gernot Wolf.;Todd S Macfarlan.
来源: Cell. 2015年163卷1期30-2页
Retroviral restriction is a complex phenomenon that, despite remarkable recent progress, is far from being well understood. In this Preview, we introduce an insightful study by Yang et al. that represents the first attempt to identify the global determinants of retroviral repression in pluripotent mammalian cells.

177. No driver behind the wheel? Targeting transcription in cancer.

作者: Hector L Franco.;W Lee Kraus.
来源: Cell. 2015年163卷1期28-30页
Exploiting the dependence of cancer cells on transcription can be used as an effective strategy for targeting aggressive and therapeutically recalcitrant tumors. Wang et al. show that inhibiting transcription using THZ1, a small-molecule inhibitor of cyclin-dependent kinase CDK7, induces apoptotic cell death in triple-negative breast cancers.

178. A sympathetic view on fat by leptin.

作者: Luis Varela.;Tamas L Horvath.
来源: Cell. 2015年163卷1期26-7页
Zeng et al. reveal that the lipolytic effect of the hormone leptin is mediated by sympathetic nerve fibers that directly "envelope" white adipocytes. Local activation of the sympathetic input to the fat opens new venues to circumvent central leptin resistance in obesity.

179. Coordinating the human looks.

作者: Vanja Haberle.;Alexander Stark.
来源: Cell. 2015年163卷1期24-6页
Prescott et al. take a step forward in studying primate morphological evolution by a cellular anthropology approach. Through epigenomic profiling of in-vitro-derived cells, the authors identify and characterize candidate cis-regulatory elements underlying divergence in facial morphology between human and chimp, shedding new light on what makes us (look) human.

180. From scientific discovery to cures: bright stars within a galaxy.

作者: R Sanders Williams.;Samad Lotia.;Alisha K Holloway.;Alexander R Pico.
来源: Cell. 2015年163卷1期21-3页
We propose that data mining and network analysis utilizing public databases can identify and quantify relationships between scientific discoveries and major advances in medicine (cures). Further development of such approaches could help to increase public understanding and governmental support for life science research and could enhance decision making in the quest for cures.
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