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10.1126/science.1058092 | 20,005,880 | The macrocyclic core of the antibiotic erythromycin, 6-deoxyerythronolide B (6dEB), is a complex natural product synthesized by the soil bacterium Saccharopolyspora erythraea through the action of a multifunctional polyketide synthase (PKS). The engineering potential of modular PKSs is hampered by the limited capabilit... | 10.1038/nrmicro1287 | Describes the production of 6-dEB in an adapted strain of E. coli |
10.1073/pnas.0400146101 | 103,216,188 | Little is known about the mutational fitness effects associated with single-nucleotide substitutions on RNA viral genomes. Here, we used site-directed mutagenesis to create 91 single mutant clones of vesicular stomatitis virus derived from a common ancestral cDNA and performed competition experiments to measure the rel... | 10.1038/nrg2146 | Estimates the DFE for an RNA virus by measuring the fitness consequences of single mutations. |
10.1126/science.285.5434.1748 | 38,581,984 | Deleterious mutations with very small phenotypic effects could be important for several evolutionary phenomena, but the extent of their contribution has been unknown. Fitness effects of induced mutations in lines of Caenorhabditis elegans were measured using a system for which the number of deleterious point mutations ... | 10.1038/nrg2146 | Shows that most mutations are undectable in a mutation accumulation study and that the DFE of deleterious mutations must be complex and multi-modal. |
10.1101/gr.178701 | 109,156,972 | Comparative genomic approaches to gene and cis -regulatory prediction are based on the principle that differential DNA sequence conservation reflects variation in functional constraint. Using this principle, we analyze noncoding sequence conservation in Drosophila for 40 loci with known or suspected cis -regulatory fun... | 10.1038/nrg2146 | Provided the first indication that extensive amounts of Drosophila non-coding DNA is subject to selection. |
10.1093/genetics/163.4.1519 | 38,206,977 | Abstract We know little about the distribution of fitness effects among new beneficial mutations, a problem that partly reflects the rarity of these changes. Surprisingly, though, population genetic theory allows us to predict what this distribution should look like under fairly general assumptions. Using extreme value... | 10.1038/nrg2146 | An extension of the work of Gillespie showing that the DFE of advantageous mutations should be an exponential distribution under certain simplifying assumptions. |
10.1534/genetics.104.039248 | 16,668,833 | Abstract Beneficial mutations are the driving force of evolution by natural selection. Yet, relatively little is known about the distribution of the fitness effects of beneficial mutations in populations. Recent work of Gillespie and Orr suggested some of the first generalizations for the distributions of beneficial fi... | 10.1038/nrg2146 | Provided evidence that the DFE of advantageous mutations is not an exponential distribution. |
10.1126/science.1240988 | 62,585,957 | Move Over, TLR4 The innate immune system senses bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) (see the Perspective by Kagan ). However, Kayagaki et al. (p 1246 , published online 25 July) and Hagar et al. (p. 1250 ) report that the hexa-acyl lipid A component of LPS from Gramnegative bacteria i... | 10.1038/nri.2015.7 | References 35 and 36 identify an unknown cytoplasmic sensor that mediates recognition of cytosolic LPS independently of TLR4. This sensor was later shown to be caspase 11 (see reference 73). |
10.4049/jimmunol.1400501 | 85,603,033 | Abstract Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1β and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose ... | 10.1038/nri.2015.7 | References 69–71independently identify a role for caspase 11 in mediating protection against colitis-associated colorectal cancer. |
10.1126/science.1104765 | 109,274,534 | Caspase-8, a proapoptotic protease, has an essential role in lymphocyte activation and protective immunity. We show that caspase-8 deficiency (CED) in humans and mice specifically abolishes activation of the transcription factor nuclear factor κB (NF-κB) after stimulation through antigen receptors, Fc receptors, or Tol... | 10.1038/nri.2015.7 | This study identifies a human mutation in caspase 8 that leads to impaired activation of NF-κB signalling, demonstrating a role for caspase 8 in inflammation. |
10.1084/jem.20071632 | 38,745,875 | The cytokine interleukin (IL)-1β is a key mediator of the inflammatory response and has been implicated in the pathophysiology of acute and chronic inflammation. IL-1β is synthesized in response to many stimuli as an inactive pro–IL-1β precursor protein that is further processed by caspase-1 into mature IL-1β, which is... | 10.1038/nri.2015.7 | This study demonstrates a requirement for TRIF in the processing of IL-1β by caspase 8, but not by caspase 1, in vitro |
10.1038/ncomms8515 | 39,243,210 | Abstract TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activ... | 10.1038/nri.2015.7 | References 95–97, 112–118 and 157 are important studies that decipher the functional relevance of caspase 8 in controlling the activities of various caspase 1 inflammasomes. |
10.1186/1756-9966-29-78 | 36,268,571 | Abstract Patients with cervical carcinoma (CC) are frequently immunocompromised. Dendritic cells (DCs) are potent antigen-presenting cells. Using multicolor flow cytometry, the percentages of CD11c+ (DC1) and CD123+ (DC2) subsets, were determined in the peripheral blood of 37 patients with cervical carcinoma (CC), 54 p... | 10.1038/nri1498 | References 20 and 21 report that DC defects in cancer patients are confined to the population of myeloid DCs and not pDCs or lymphoid DCs. |
10.1084/jem.20021598 | 103,734,174 | To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was p... | 10.1038/nri1498 | This paper reports that non-activated DCs loaded with antigen in vivo can induce peripheral T-cell tolerance. |
10.4049/jimmunol.172.1.464 | 19,372,058 | Abstract Abnormal differentiation of myeloid cells is one of the hallmarks of cancer. However, the molecular mechanisms of this process remain elusive. In this study, we investigated the effect of tumor-derived factors on Janus kinase (Jak)/STAT signaling in myeloid cells during their differentiation into dendritic cel... | 10.1038/nri1498 | This paper shows a crucial role for STAT3 in tumour-induced abnormalities in the differentiation of myeloid cells. |
10.1182/blood-2004-04-1309 | 108,666,716 | Abstract Interleukin-10-deficient (IL-10-/-) mice develop an IL-12-mediated intestinal inflammation in the absence of endogenous IL-10. The molecular mechanisms of the dysregulated IL-12 responses in IL-10-/- mice are poorly understood. In this study, we investigated the role of nuclear factor-κ B (NF-κB) and signal tr... | 10.1038/nri1498 | References 103 and 104 show that direct interaction occurs between STAT3 and NF-κB and that NF-κB activation is inhibited by STAT3. |
10.1091/mbc.e09-03-0231 | 119,993,646 | Endoplasmic reticulum (ER) quality control mechanisms monitor the folding of nascent polypeptides of the secretory pathway. These are dynamic processes that retain folding proteins, promote the transport of conformationally mature proteins, and target misfolded proteins to ER-associated degradation (ERAD) pathways. Aid... | 10.1038/nrm3383 | Describes the roles of key N -linked glycan sites that mark structural determinants that are sensitive to the overall folding state of the molecule and mediate targeting of misfolded proteins for ER-associated degradation. |
10.1083/jcb.201003055 | 41,625,867 | After growth factor stimulation, kinases are activated to regulate multiple aspects of cell physiology. Activated Src is present on Golgi membranes, but its function here remains unclear. We find that Src regulates mucin-type protein O-glycosylation through redistribution of the initiating enzymes, polypeptide N-acetyl... | 10.1038/nrm3383 | SRC-dependent growth factor stimulation drives the relocation of polypeptide GalNAc transferases to earlier secretory compartments, enhancing the production of GalNAc initiated O -linked glycans. |
10.1242/dev.055376 | 80,068,905 | Precise glycan structures on specific glycoproteins impart functionalities essential for neural development. However, mechanisms controlling embryonic neural-specific glycosylation are unknown. A genetic screen for relevant mutations in Drosophila generated the sugar-free frosting (sff) mutant that reveals a new functi... | 10.1038/nrm3383 | A partial loss-of-function mutation in a neural specific kinase decreases expression of a set of neural-specific glycans, demonstrating a direct link between protein phosphorylation, Golgi architecture and glycan end-products. |
10.1083/jcb.200912082 | 109,054,015 | To what extent the secretory pathway is regulated by cellular signaling is unknown. In this study, we used RNA interference to explore the function of human kinases and phosphatases in controlling the organization of and trafficking within the secretory pathway. We identified 122 kinases/phosphatases that affect endopl... | 10.1038/nrm3383 | An RNA interference screen for kinases and phosphatases that alter ER and Golgi trafficking identified 122 such proteins, indicating a broad role for cell signaling in sculpting flux through the secretory pathway with subsequent, but not yet demonstrated, glycomic consequences. |
10.1126/science.1180512 | 123,027,956 | Modifying Protein Modification Alpha-dystroglycan (α-DG) is a cell-surface receptor that anchors the basal lamina to the sarcolemma by binding proteins containing laminin-G domains. This binding is essential for protecting muscle from contraction-induced injury, and defective binding is thought to cause a subclass of c... | 10.1038/nrm3383 | First description of a novel GAG-like structure containing Xyl and GlcA in unknown linkage to an essential extracellular protein that interacts with the extracellular matrix. |
10.1126/science.1214115 | 81,772,482 | Posttranslational modification of alpha-dystroglycan (α-DG) by the like-acetylglucosaminyltransferase (LARGE) is required for it to function as an extracellular matrix (ECM) receptor. Mutations in the LARGE gene have been identified in congenital muscular dystrophy patients with brain abnormalities. However, the precis... | 10.1038/nrm3383 | Reports the bifunctional glycosyltransferase activity of LARGE1 on O -Man-containing glycans of αDG. |
10.1002/sim.973 | 4,715,621 | Abstract Consideration of gene–environment ( G × E ) interaction is becoming increasingly important in the design of new epidemiologic studies. We present a method for computing required sample size or power to detect G × E interaction in the context of three specific designs: the standard matched case‐control; the cas... | 10.1038/nrg2764 | This paper describes a general approach to sample size and power calculations for G×E studies and the capabilities of the freely available Quanto program for this purpose. |
10.1159/000073735 | 59,255,390 | There is increasing awareness that epistasis or gene-gene interaction plays a role in susceptibility to common human diseases. In this paper, we formulate a working hypothesis that epistasis is a ubiquitous component of the genetic architecture of common human diseases and that complex interactions are more important t... | 10.1038/nrg2764 | The creator of the MDR algorithm for identifying higher-order interactions gives a spirited argument in support of the notion that many such effects would be overlooked by limiting attention to factors showing significant main effects. |
10.1002/sim.4780130206 | 103,069,890 | Abstract This article describes how genetic components of disease susceptibility can be evaluated in case‐control studies, where cases and controls are sampled independently from the population at large. Subjects are assumed unrelated, in contrast to studies of familial aggregation and linkage. The logistic model can b... | 10.1038/nrg2764 | The paper that introduced the case-only design for testing G×E interactions. |
10.1111/1467-9876.00165 | 100,470,505 | SUMMARY Two-phase stratified sampling is used to select subjects for the collection of additional data, e.g. validation data in measurement error problems. Stratification jointly by outcome and covariates, with sampling fractions chosen to achieve approximately equal numbers per stratum at the second phase of sampling,... | 10.1038/nrg2764 | Arguably the most accessible summary of a major series of papers on the design and analysis of two-phase case–control studies. |
10.1002/gepi.20334 | 59,997,938 | Abstract In genomewide genetic association studies, prior biological knowledge may help distinguish variation that is truly associated with a quantitative trait from the vast majority of unassociated variation that may be significant in hypothesis testing due to chance. However, formal methods for integrating prior bio... | 10.1038/nrg2764 | This paper provides a clear discussion of the use of GSEA as a way of prioritizing hits from a GWA study and interpreting the ensemble of SNP associations in relation to pathways. |
10.1158/1055-9965.1013.13.6 | 132,256,281 | Abstract Background: Genetic association studies are generating much information, usually in the form of single nucleotide polymorphisms in candidate genes. Analyzing such data is challenging, and raises issues of multiple comparisons and potential false-positive associations. Using data from a case-control study of bl... | 10.1038/nrg2764 | One of the first examples of the use of hierarchical modelling for the study of G×E interactions. A set of pathway indicator variables are used as prior covariates to classify specific combinations of genes and environmental exposures. |
10.1158/1055-9965.epi-07-2937 | 119,457,853 | Abstract Low-folate status and genetic polymorphisms in folate metabolism have been linked to several cancers. Possible biological mechanisms for this association include effects on purine and thymidine synthesis, DNA methylation, or homocysteine concentrations. The influence of genetic variation in folate metabolism o... | 10.1038/nrg2764 | One of a long series of papers on mathematical modelling of the folate pathway. This article focuses specifically on the use of the authors' model to predict the effects of variation in metabolic rate parameters for polymorphisms in specific genes on various outcomes, such as homocysteine concentration or DNA methylati... |
10.1126/science.1094068 | 20,256,643 | High-throughput genome-wide molecular assays, which probe cellular networks from different perspectives, have become central to molecular biology. Probabilistic graphical models are useful for extracting meaningful biological insights from the resulting data sets. These models provide a concise representation of comple... | 10.1038/nrg2764 | An important paper that popularized the use of Bayesian network analysis for the reconstruction of gene networks from gene co-expression data. |
10.1002/gepi.1370070302 | 124,380,220 | Abstract This paper illustrates how epidemiologic principles can be used to investigate relationships between genetic susceptibility and other risk factors for disease. Five plausible models are described for relationships between genetic and environmental effects, and an example of a simple mendelian disorder that fit... | 10.1038/nrg2764 | This widely quoted paper was one of the first to offer a classification of different types of G×E interactions, and gives classic examples of each type. |
10.1073/pnas.0630592100 | 122,403,629 | Vaccine efficacy is determined largely by cellular and humoral immunity as well as long-lasting immunological memory. IL-2 and IL-15 were evaluated in vaccinia vectors expressing HIV gp160 for the establishment of an effective vaccine strategy. Both IL-2 and IL-15 in the vaccinia vector induced strong and long-lasting ... | 10.1038/nri1901 | In this study, vaccines that express IL-15 were found to induce long-lasting CD8 + T-cell-mediated immunity, whereas vaccines incorporating IL-2 elicited short-lived immunity. |
10.1073/pnas.0402653101 | 46,131,643 | Identifying effective treatment combinations for MS patients failing standard therapy is an important goal. We report the results of a phase II open label baseline-to-treatment trial of a humanized monoclonal antibody against CD25 (daclizumab) in 10 multiple sclerosis patients with incomplete response to IFN-β therapy ... | 10.1038/nri1901 | This paper shows that treatment with daclizumab leads to a 78% reduction in new contrast-enhancing lesions in patients with multiple sclerosis who have failed to respond to treatment with IFNβ. |
10.1126/science.1164097 | 109,445,740 | Chromatin Modifier Modulates Gene Expression Modification of chromatin structure is usually thought of as a global, relatively nonspecific way of modulating gene expression. However, Wellen et al. (p. 1076 ; see the Perspective by Rathmell and Newgard ) demonstrate that such regulation helps link growth factor–stimulat... | 10.1038/nrd3137 | Identification of a novel molecular link between cellular metabolism and gene regulation through histone acetylation. |
10.1126/science.1126863 | 83,436,024 | The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance b... | 10.1038/nrd3137 | This is the first demonstration that the absence of a single p53 target gene, synthesis of SCO2, recapitulates the metabolic switch towards glycolysis that is exhibited by p53-deficient cells, thereby providing a possible explanation for the Warburg effect. |
10.1126/science.2945253 | 80,282,868 | The Golgi complex is a series of membrane compartments through which proteins destined for the plasma membrane, secretory vesicles, and lysosomes move sequentially. A model is proposed whereby these three different classes of proteins are sorted into different vesicles in the last Golgi compartment, the trans Golgi net... | 10.1038/nrm2378 | A seminal review that introduced the concept of the TGN as the exit and sorting station of the Golgi complex. |
10.1083/jcb.148.1.45 | 109,159,550 | Transport intermediates (TIs) have a central role in intracellular traffic, and much effort has been directed towards defining their molecular organization. Unfortunately, major uncertainties remain regarding their true structure in living cells. To address this question, we have developed an approach based on the comb... | 10.1038/nrm2378 | The first study to analyse specifically the ultrastructure of TGN-derived carriers. |
10.1083/jcb.144.6.1135 | 104,215,857 | Three-dimensional reconstructions of portions of the Golgi complex from cryofixed, freeze-substituted normal rat kidney cells have been made by dual-axis, high-voltage EM tomography at ∼7-nm resolution. The reconstruction shown here (∼1 × 1 × 4 μm3) contains two stacks of seven cisternae separated by a noncompact regio... | 10.1038/nrm2378 | The first study to report the 3D reconstruction of the TGN. |
10.1002/ar.1092420302 | 60,080,623 | Abstract Background : The trans‐Golgi network (TGN) is generally considered as a distinct and permanent structural compartment of the Golgi apparatus of various cell types. To verify this postulate we examined and compared the three‐dimensional characteristics of the TGNs of 14 different mammalian cell types as present... | 10.1038/nrm2378 | An extensive study of the TGN in different cell types. |
10.1083/jcb.108.2.277 | 60,224,438 | The intracellular transport of newly synthesized G protein of vesicular stomatitis virus is blocked at 20 degrees C and this spanning membrane glycoprotein accumulates in the last Golgi compartment, the trans Golgi-network (TGN). Previous morphological evidence suggested that the TGN enlarged significantly under this c... | 10.1038/nrm2378 | The first study to report the structural changes induced in the TGN by blocking the export of secretory cargoes. |
10.1083/jcb.143.6.1485 | 59,310,840 | Quantitative time-lapse imaging data of single cells expressing the transmembrane protein, vesicular stomatitis virus ts045 G protein fused to green fluorescent protein (VSVG–GFP), were used for kinetic modeling of protein traffic through the various compartments of the secretory pathway. A series of first order rate l... | 10.1038/nrm2378 | The first study to report the existence and dynamics of the large tubular carriers that derive from the TGN. |
10.1083/jcb.200408165 | 84,368,567 | The AP-1B clathrin adaptor complex is responsible for the polarized transport of many basolateral membrane proteins in epithelial cells. Localization of AP-1B to recycling endosomes (REs) along with other components (exocyst subunits and Rab8) involved in AP-1B–dependent transport suggested that RE might be an intermed... | 10.1038/nrm2378 | Shows a transendosomal pathway for the transport of VSVG to the basolateral PM in epithelial cells. |
10.4049/jimmunol.1001176 | 41,319,599 | Abstract Recent evidence demonstrating that exposure to rapamycin during viral infection increased the quantity and quality of Ag-specific T cells poses an intriguing paradox, because rapamycin is used in transplantation to dampen, rather than enhance, donor-reactive T cell responses. In this report, we compared the ef... | 10.1038/nri3215 | This study demonstrated that the immunosuppressive drug rapamycin augments the magnitude of CD8 + T cell responses to L. monocytogenes infection but suppresses the response to skin grafts, thereby highlighting a fundamental difference between responses to infectious agents and allografts that can potentially be exploit... |
10.1242/dev.124.12.2463 | 104,246,974 | Germline stem cells play a pivotal role in gametogenesis; yet little is known about how they are formed, how they divide to self-renew, and how these processes are genetically controlled. Here we describe the self-renewing asymmetric division of germline stem cells in the Drosophila ovarian germline, as marked by the s... | 10.1038/nrm2321 | References 1–3 are seminal works that originally described the Argonaute gene family. |
10.1126/science.1102514 | 125,260,708 | Argonaute proteins and small interfering RNAs (siRNAs) are the known signature components of the RNA interference effector complex RNA-induced silencing complex (RISC). However, the identity of “Slicer,” the enzyme that cleaves the messenger RNA (mRNA) as directed by the siRNA, has not been resolved. Here, we report th... | 10.1038/nrm2321 | The first crystal structure of a complete Argonaute protein, revealing its function as the catalytic component of RISC. |
10.1126/science.1102513 | 20,686,233 | Gene silencing through RNA interference (RNAi) is carried out by RISC, the RNA-induced silencing complex. RISC contains two signature components, small interfering RNAs (siRNAs) and Argonaute family proteins. Here, we show that the multiple Argonaute proteins present in mammals are both biologically and biochemically d... | 10.1038/nrm2321 | Demonstrates that disruption of specific amino acids found in the cryptic ribonuclease H domain abrogates RISC activity. Also shows that AGO2 is essential for mouse development. |
10.1126/science.1115079 | 83,423,363 | MicroRNAs (miRNAs) are ∼21-nucleotide-long RNA molecules regulating gene expression in multicellular eukaryotes. In metazoa, miRNAs act by imperfectly base-pairing with the 3′ untranslated region of target messenger RNAs (mRNAs) and repressing protein accumulation by an unknown mechanism. We demonstrate that endogenous... | 10.1038/nrm2321 | Demonstrates that tethering Argonaute proteins to the 3′-UTR region of a mRNA can mimic miRNA translational inhibition, suggesting that miRNAs function to guide Argonautes to mRNAs. |
10.1126/science.1064023 | 125,244,029 | Double-stranded RNA induces potent and specific gene silencing through a process referred to as RNA interference (RNAi) or posttranscriptional gene silencing (PTGS). RNAi is mediated by RNA-induced silencing complex (RISC), a sequence-specific, multicomponent nuclease that destroys messenger RNAs homologous to the sile... | 10.1038/nrm2321 | Reports the purification of the RNAi effector nuclease previously described in 2000, revealing Argonaute-2 in the complex. |
10.1084/jem.20111502 | 38,930,087 | In nonobese diabetic (NOD) mice, two sets of autoreactive CD4+ T cells recognize the B:9–23 segment of the insulin B chain. One set, type A, recognizes insulin presented by antigen-presenting cells (APCs). These T cells are highly deleted in the thymus. The second set, type B, does not recognize insulin protein but rea... | 10.1038/nri3422 | This study describes a mechanism whereby autoreactive T cells that escape thymic selection can be activated by antigen-presenting cells that bear antigenic insulin peptides. |
10.1084/jem.20111187 | 60,608,884 | A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ... | 10.1038/nri3422 | Human insulitis is characterized in this analysis of autopsy material from patients with T1D. Diabetes-antigen-specific T cells could be identified within the insulitis. |
10.2337/dc09-0934 | 83,118,594 | OBJECTIVE There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AN... | 10.1038/nri3422 | This clinical study shows the effects of CTLA4–Ig on attenuation of the decline in C peptide in the first 2 years of T1D. |
10.4049/jimmunol.167.2.641 | 8,313,904 | Abstract Chemokine-induced polarization of lymphocytes involves the rapid collapse of vimentin intermediate filaments (IFs) into an aggregate within the uropod. Little is known about the interactions of lymphocyte vimentin with other cytoskeletal elements. We demonstrate that human peripheral blood T lymphocytes expres... | 10.1038/nri2021 | References 3, 4 and 5 describe a role for intermediate filaments in leukocyte function, and indicate that vimentin is an important structural component of the cytoskeleton during adhesion and migration. |
10.1084/jem.20051182 | 83,422,914 | T cell receptor (TCR) microclusters form within seconds of T cell contact with supported planar bilayers containing intercellular adhesion molecule-1 and agonist major histocompatibility complex (MHC)–peptide complexes, and elevation of cytoplasmic Ca2+ is observed within seconds of the first detectable microclusters. ... | 10.1038/nri2021 | This paper, along with references 22 and 80, describes the formation of dynamic and highly motile TCR microclusters at the periphery of the cSMAC, and indicate that they serve as platforms for active signalling during TCR–peptide–MHC interaction. Surprisingly, TCR microclusters move towards the cSMAC from the periphery... |
10.1126/science.1130563 | 41,075,782 | The evolutionarily conserved actin-related protein (Arp2/3) complex is a key component of actin filament networks that is dynamically regulated by nucleation-promoting and inhibitory factors. Although much is known about actin assembly, the physiologic functions of inhibitory proteins are unclear. We generated coronin ... | 10.1038/nri2021 | This is the first study characterizing T cells from coronin-1-deficient mice, indicating that coronin-1 inhibits ARP2/3-driven actin polymerization leading to defects in migration and cell survival. |
10.1111/j.1365-2567.2005.02222.x | 104,317,260 | Summary In this study, we examined the contribution of the actin cytoskeleton to T‐cell receptor (TCR)‐initiated signalling in cytotoxic T lymphocytes (CTLs). We demonstrate that cytoskeletal remodelling is required for sustaining TCR‐stimulated signals that lead to degranulation by CTLs. Disruption of the actin cytosk... | 10.1038/nri2021 | This study shows that continuous actin polymerization and depolymerization is required for ongoing tyrosine kinase activity, which leads to degranulation by CTLs. |
10.1182/blood-2004-05-2051 | 18,499,419 | Abstract Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T-cell function (T-CVID). We have previously identified a subset of patients with T-CVID characterized by defective T-cell receptor (TCR)-depende... | 10.1038/nri2021 | Describes a subset of T-cell defective patients with CVID whose syndrome is caused by the loss of expression of the RHO-family GEF and adaptor molecule VAV1. Patients showed loss of TCR-induced cell signalling, F-actin reorganization and upregulation of the lipid-raft constituent GM1 following TCR–CD28 engagement. |
10.1083/jcb.200711053 | 104,421,597 | Since the discovery of γ-tubulin, attention has focused on its involvement as a microtubule nucleator at the centrosome. However, mislocalization of γ-tubulin away from the centrosome does not inhibit mitotic spindle formation in Drosophila melanogaster, suggesting that a critical function for γ-tubulin might reside el... | 10.1038/nrm.2016.162 | References 62 and 63 identified the 5-subunit Augmin complex in flies that promotes microtubule nucleation within the spindle. |
10.1073/pnas.0901587106 | 20,809,570 | The mitotic spindle is constructed from microtubules (MTs) nucleated from centrosomes, chromosome proximal regions, and preexisting spindle MTs. Augmin, a recently identified protein complex, is a critical factor in spindle MT-based MT generation in Drosophila S2 cells. Previously, we identified one subunit of human au... | 10.1038/nrm.2016.162 | References 66 and 67 identified and functionally characterized the human Augmin complex. |
10.1126/science.1243110 | 102,399,329 | Scaling Spindle Size The difficulty of modulating cell size in vivo has made it hard to test hypotheses for organelle size scaling during development. To this end, Hazel et al. (p. 853 ) and Good et al. (p. 856 ) developed microfluidic systems in which cytoplasmic extracts are encapsulated in compartments with definabl... | 10.1038/nrm.2016.162 | Using droplets to restrict cytoplasmic volume and shape, references 124 and 125 show that spindle length correlates with cytoplasmic volume rather than diameter. |
10.1073/pnas.1400568111 | 19,570,288 | Significance Centrioles form the core of centrosomes, which organize cilia and interphase and spindle microtubules in animal cells, but centrosome function has not been defined in mammals in vivo. We show that mouse embryos that lack centrioles and centrosomes survive to midgestation, when they lack primary cilia and c... | 10.1038/nrm.2016.162 | References 134, 140 and 141 demonstrate that centrosome removal by genetic manipulation in a range of systems does not preclude spindle assembly in somatic cells. |
10.1126/science.aaa5111 | 103,611,943 | Giving an old organelle the old heave-ho Centrioles are ancient cellular organelles that build centrosomes, the major microtubule-organizing centers in animal cells. Duplication of centrioles is tightly controlled to ensure that each dividing cell has precisely two centrosomes. Human cancer cells often have extra centr... | 10.1038/nrm.2016.162 | This paper shows that p53-deficient cells can continue to proliferate without centrioles. |
10.1083/jcb.110.1.81 | 122,901,233 | During mitosis in cultured newt pneumocytes, one or more chromosomes may become positioned well removed (greater than 50 microns) from the polar regions during early prometaphase. As a result, these chromosomes are delayed for up to 5 h in forming an attachment to the spindle. The spatial separation of these chromosome... | 10.1038/nrm.2016.162 | This paper demonstrated the attachment of a microtubule to a kinetochore in live cells for the first time. |
10.1016/0014-5793(86)81424-7 | 41,538,342 | Enzyme kinetics Uncompetitive inhibition Catastrophic response Pesticide design | 10.1038/nrd.2017.219 | This paper provides insight into why uncompetitive inhibition is rarely encountered and suggests that it is a useful approach, as these inhibitors may have greater pharmacological effects. |
10.1177/1087057116671509 | 41,689,905 | The clinical and commercial success of covalent drugs has prompted a renewed and more deliberate pursuit of covalent and irreversible mechanisms within drug discovery. A covalent mechanism can produce potent inhibition in a biochemical, cellular, or in vivo setting. In many cases, teams choose to focus on the consequen... | 10.1038/nrd.2017.219 | This paper provides a detailed explanation of the characterization of irreversible inhibition. |
10.1126/science.275.5303.1129 | 104,015,345 | Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-... | 10.1038/nrm2434 | This paper and reference 6 describe the ability of BCL2 to block OMM permeabilization as its mechanism of inhibiting apoptosis. These papers form the foundation of the studies of the mitochondrial pathway. |
10.1126/science.1059108 | 125,115,620 | Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a “BH3-domain–only” BCL-2 family member, triggers the homooligomerization of “multidomain” conserved proapoptotic family members B... | 10.1038/nrm2434 | Describes the effects on mitochondria of BAX–BAK-double-knockout in mice and shows that BAX and BAK are the effectors of OMM permeabilization. |
10.1083/jcb.147.4.809 | 62,075,622 | During apoptosis, an important pathway leading to caspase activation involves the release of cytochrome c from the intermembrane space of mitochondria. Using a cell-free system based on Xenopus egg extracts, we examined changes in the outer mitochondrial membrane accompanying cytochrome c efflux. The pro-apoptotic prot... | 10.1038/nrm2434 | References 61 and 62 show that the activation of BAX by active BID leads to its insertion and oligomerization, forming a basis for the mechanism of action of BAX and, by extension, BAK. |
10.1126/science.286.5445.1735 | 107,243,398 | Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells a... | 10.1038/nrm2434 | Described BIM-knockout mice and indicated that BIM is an important protein in the control of apoptosis in several settings. |
10.1242/dev.01907 | 20,390,012 | The functions of the Snail family of zinc-finger transcription factors are essential during embryonic development. One of their best-known functions is to induce epithelial to mesenchymal transitions (EMTs), which convert epithelial cells into migratory mesenchymal cells. In recent years, many orthologues of the Snail ... | 10.1038/nrm1835 | An excellent review of the different facets of the snail genes. |
10.1126/science.1090772 | 41,636,777 | The Rho family of small guanosine triphosphatases regulates actin cytoskeleton dynamics that underlie cellular functions such as cell shape changes, migration, and polarity. We found that Smurf1, a HECT domain E3 ubiquitin ligase, regulated cell polarity and protrusive activity and was required to maintain the transfor... | 10.1038/nrm1835 | Exploited an advanced technique to discover new critical partners in tight junctions that couple signalling and morphogenesis. |
10.1091/mbc.e13-12-0745 | 38,398,511 | The nuclear pore complex (NPC) regulates transport between the nucleus and cytoplasm. Soluble cargo-protein complexes navigate through the pore by binding to phenylalanine-glycine (FG)-repeat proteins attached to the channel walls. The Nup62 complex contains the FG-repeat proteins Nup62, Nup54, and Nup58 and is located... | 10.1038/nrm.2016.147 | This work demonstrates a 1:1:1 stoichiometry of the NUP62 complex, but non-canonical stoichiometries when a coiled-coil partner is absent. |
10.1126/science.aaa4136 | 62,190,927 | A closeup view of the nuclear pore's coat The precise molecular architecture of the nuclear pore complex (NPC), which mediates traffic between the cytoplasm and the nucleus, has been difficult to ascertain owing to the size and complexity of this subcellular structure. Now, Stuwe et al. describe the crystal structure o... | 10.1038/nrm.2016.147 | This study reports the crystal structure of the yeast S. cerevisiae hexameric Y-complex. |
10.1073/pnas.1112846108 | 99,087,253 | So far, only a few of the interactions between the ≈30 nucleoporins comprising the modular structure of the nuclear pore complex have been defined at atomic resolution. Here we report the crystal structure, at 2.6 Å resolution, of a heterotrimeric complex, composed of fragments of three cytoplasmically oriented nucleop... | 10.1038/nrm.2016.147 | The authors report the crystal structure of a cytoplasmically oriented NUP complex, clarifying the mode of NUP interactions. |
10.1126/science.aac9176 | 123,198,259 | The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. We present the reconstitution and interdisciplinary analyses of the ~425-kilodalton inner ring complex (IRC), which forms the central transport channel and diffusion barrier of the NPC, revealing its interaction n... | 10.1038/nrm.2016.147 | References 122 and 123 reveal the crystal structures of the NUP62 and Nsp1 channel complexes from X. laevis and C thermophilum , respectively. |
10.1083/jcb.201411003 | 103,697,089 | Nuclear pore complexes (NPCs) are huge assemblies formed from ∼30 different nucleoporins, typically organized in subcomplexes. One module, the conserved Nup82 complex at the cytoplasmic face of NPCs, is crucial to terminate mRNA export. To gain insight into the structure, assembly, and function of the cytoplasmic pore ... | 10.1038/nrm.2016.147 | The authors develop an integrated 3D structural model of the Nup82 complex and propose how it embeds into the NPC scaffold, showing that it projects towards the central channel in agreement with reference 125. |
10.1126/science.aaf1015 | 125,072,335 | Blueprint for a macromolecular machine Nuclear pore complexes (NPCs) consist of around 1000 protein subunits, are embedded in the membrane that surrounds the nucleus, and regulate transport between the nucleus and the cytoplasm. Although the overall shape of NPCs is known, the details of this macromolecular complex hav... | 10.1038/nrm.2016.147 | This study reports the X-ray structure of scaffold NUPs with bound SLMs from linker NUPs and the docking of these structures into the tomographic map of the human NPC. |
10.1126/science.2305263 | 81,643,436 | Identification of a mutant epidermal growth factor (EGF) receptor that does not undergo downregulation has provided a genetic probe to investigate the role of internalization in ligand-induced mitogenesis. Contact-inhibited cells expressing this internalization-defective receptor exhibited a normal mitogenic response a... | 10.1038/nrm883 | The first demonstration of the role of RTK endocytosis in attenuation of the mitogenic signalling by growth factors. |
10.1242/dev.127.7.1373 | 41,774,581 | Endocytosis of the ligand delta; is required for activation of the receptor Notch during Drosophila development. The Notch extracellular domain (NotchECD) dissociates from the Notch intracellular domain (NotchICD) and is trans-endocytosed into delta;-expressing cells in wild-type imaginal discs. Reduction of dynamin-me... | 10.1038/nrm883 | This paper provided the first evidence for the role of endocytosis in regulation of Notch signalling during Drosophila development. |
10.1126/science.290.5496.1574 | 59,416,221 | β-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein–coupled receptor (GPCR) desensitization, also function in internalization and signaling of these receptors. We identified c-Jun amino-terminal kinase 3 (JNK3) as a binding partner of β-arrestin 2 using a yeast two-hyb... | 10.1038/nrm883 | This study concluded that β-arrestins have a general role as molecular scaffolds to organize MAPK modules around endocytosed GPCRs. |
10.1083/jcb.148.6.1267 | 45,372,825 | Recently, a requirement for β-arrestin–mediated endocytosis in the activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2) by several G protein–coupled receptors (GPCRs) has been proposed. However, the importance of this requirement for function of ERK1/2 is unknown. We report that agonists of Gαq-coupled... | 10.1038/nrm883 | Evidence that β-arrestin controls the selectivity of GPCR signalling from the endocytic pathway by physically restricting the localization of a GPCR-activated MAPK. |
10.1126/science.277.5329.1097 | 83,259,416 | Nerve growth factor (NGF) is a neurotrophic factor secreted by cells that are the targets of innervation of sympathetic and some sensory neurons. However, the mechanism by which the NGF signal is propagated from the axon terminal to the cell body, which can be more than 1 meter away, to influence biochemical events cri... | 10.1038/nrm883 | Evidence that neurotrophin signalling from the axon to the neural cell body is mediated by the retrograde movement of activated neurotrophin receptors after endocytosis. |
10.1126/science.274.5295.2086 | 41,621,939 | Epidermal growth factor receptor (EGFR) signaling was analyzed in mammalian cells conditionally defective for receptor-mediated endocytosis. EGF-dependent cell proliferation was enhanced in endocytosis-defective cells. However, early EGF-dependent signaling events were not uniformly up-regulated. A subset of signal tra... | 10.1038/nrm883 | The first demonstration of the role of clathrin-mediated endocytosis of RTKs in the activation of the ERK/MAPK signalling pathway. |
10.1126/science.283.5402.655 | 123,334,781 | The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of β 2 adrenergic receptors resulted in the assembly of a protein complex conta... | 10.1038/nrm883 | Evidence that β-arrestins function as a scaffold that links GPCRs to activation of a non-receptor tyrosine kinase. |
10.1083/jcb.200110132 | 122,881,747 | Nonvisual arrestins (arr) modulate G protein–coupled receptor (GPCR) desensitization and internalization and bind to both clathrin (CL) and AP-2 components of the endocytic coated pit (CP). This raises the possibility that endocytosis of some GPCRs may be a consequence of arr-induced de novo CP formation. To directly t... | 10.1038/nrm883 | This study provides evidence that activated GPCRs, through interaction with arrestins, can change the properties of clathrin-coated pits through which they are endocytosed. |
10.1083/jcb.150.4.905 | 102,376,821 | Membrane receptors are internalized either constitutively or upon ligand engagement. Whereas there is evidence for differential regulation of the two processes, little is known about the molecular machinery involved. Previous studies have shown that an unidentified kinase substrate is required for endocytosis of the ep... | 10.1038/nrm883 | This study highlights an interesting example of the specific role of Eps15, a component of clathrin-coated pits, in the growth-factor-induced endocytosis of EGF receptors. |
10.1162/106454604773563612 | 103,974,921 | Avida is a software platform for experiments with self-replicating and evolving computer programs. It provides detailed control over experimental settings and protocols, a large array of measurement tools, and sophisticated methods to analyze and post-process experimental data. We explain the general principles on whic... | 10.1038/nrg1771 | This article is a user's guide for digital geneticists, outlining many of the options that are available to the experimenter along with a description of analysis tools. |
10.1098/rspb.2005.3338 | 62,328,782 | Modularity and epistasis, as well as other aspects of genetic architecture, have emerged as central themes in evolutionary biology. Theory suggests that modularity promotes evolvability, and that aggravating (synergistic) epistasis among deleterious mutations facilitates the evolution of sex. Here, by contrast, we inve... | 10.1038/nrg1771 | An ingenious study of the emergence of modules as a response to code recombination in digital organisms. |
10.1126/science.1096307 | 61,424,296 | Species richness often peaks at intermediate productivity and decreases as resources become more or less abundant. The mechanisms that produce this pattern are not completely known, but several previous studies have suggested environmental heterogeneity as a cause. In experiments with evolving digital organisms and pop... | 10.1038/nrg1771 | A study of the selective pressures that give rise to stably co-existing 'ecotypes', by varying resource availability to force negative frequency-dependent selection. |
10.1073/pnas.91.15.6808 | 38,429,820 | We followed evolutionary change in 12 populations of Escherichia coli propagated for 10,000 generations in identical environments. Both morphology (cell size) and fitness (measured in competition with the ancestor) evolved rapidly for the first 2000 generations or so after the populations were introduced into the exper... | 10.1038/nrg1771 | This landmark paper introduces the modern experimental evolution philosophy of replicate populations evolving for thousands of generations in controlled environments, with accurate fitness measurements and a perfect 'fossil record'. |
10.1126/science.7809610 | 4,847,164 | The contributions of adaptation, chance, and history to the evolution of fitness and cell size were measured in two separate experiments using bacteria. In both experiments, populations propagated in identical environments achieved similar fitnesses, regardless of prior history or subsequent chance events. In contrast,... | 10.1038/nrg1771 | Another landmark study that introduces statistical tests for disentangling the effects of history, chance and adaptation on evolution using microorganisms. |
10.1073/pnas.96.24.13910 | 62,604,215 | The rate of spontaneous mutation is a key parameter in modeling the genetic structure and evolution of populations. The impact of the accumulated load of mutations and the consequences of increasing the mutation rate are important in assessing the genetic health of populations. Mutation frequencies are among the more d... | 10.1038/nrg1771 | A thorough compilation of mutation rates in RNA viruses that indicates that evolution optimizes the product of per-site mutation rate and genome length, but not each independently. |
10.1042/bj2480765 | 61,399,604 | Previous work demonstrated the existence of phosphatidylinositol kinase and phosphatidylinositol phosphate kinase in rat liver nuclei, with the suggestion that these activities are in the nuclear membrane [Smith & Wells (1983) J. Biol. Chem. 258, 9368-9373]. Here we show that highly purified nuclei from Friend cell... | 10.1038/nrm1100 | This paper, together with references 9 and 10, provides the first evidence that nuclei contain a PtdIns(4,5)P 2 -based signalling system that is distinct from that in the cytoplasm. |
10.1242/jcs.114.13.2501 | 41,610,347 | Phosphoinositide turnover regulates multiple cellular processes. Compared with their well-known cytosolic roles, limited information is available on the functions of nuclear phosphoinositides. Here, we show that phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2) stably associates with electron-dense particles withi... | 10.1038/nrm1100 | This paper provides the particularly intriguing suggestion for the involvement of PtdIns(4,5)P 2 in some aspect of pre-mRNA splicing. |
10.1126/science.1078062 | 19,304,459 | Chromatin remodeling is required for efficient transcription of eukaryotic genes. In a genetic selection for budding yeast mutants that were defective in induction of the phosphate-responsive PHO5 gene, we identified mutations in ARG82/IPK2 , which encodes a nuclear inositol polyphosphate kinase. In arg82 mutant strain... | 10.1038/nrm1100 | References 50–53 document another potentially important insight into the physiological function of the PI-PLC pathway in nuclei: to liberate Ins(1,4,5)P 3 , which is then phosphorylated to higher inositol phosphates. These in turn might have functions in mRNA export, transcriptional regulation and/or chromatin structur... |
10.1126/science.1065173 | 80,350,724 | DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyl... | 10.1038/nrc1045 | The first paper to report the targeted recruitment of a DNA methyltransferase in the hypermethylation of a CpG island. |
10.1073/pnas.89.5.1827 | 41,610,722 | The modulation of DNA-protein interactions by methylation of protein-binding sites in DNA and the occurrence in genomic imprinting, X chromosome inactivation, and fragile X syndrome of different methylation patterns in DNA of different chromosomal origin have underlined the need to establish methylation patterns in ind... | 10.1038/nrc1045 | Revolutionized the field of DNA methylation analysis by introducing the sodium bisulphite conversion technique. |
10.1073/pnas.93.18.9821 | 125,305,933 | Precise mapping of DNA methylation patterns in CpG islands has become essential for understanding diverse biological processes such as the regulation of imprinted genes, X chromosome inactivation, and tumor suppressor gene silencing in human cancer. We describe a new method, MSP (methylation-specific PCR), which can ra... | 10.1038/nrc1045 | Introduced a technique that made DNA methylation analysis in human tumours widely accessible. |
10.1111/j.1365-2141.1994.tb04828.x | 38,331,989 | Summary. Oncogene mutations are frequently found in several tumour types and, among these, point mutations of the ras gene are particularly significant. A predominance of N‐ ras mutations has been found in the bone marrow DNA of patients with myelodysplatic syndrome (MDS) or acute myelogenous leukaemia (AML). On the ot... | 10.1038/nrc1045 | Provided the first proof that the free DNA in serum was of tumour origin. |
10.1126/scitranslmed.3003310 | 61,973,916 | Applying next-generation sequencing to 42 infants with mitochondrial disease highlights both the potential and the challenge of using this technology in clinical diagnosis. | 10.1038/nrg3275 | This was one of the first applications of sequencing the 'mitochondrial exome' (that is, ∼ 1,500 nuclear genes encoding mitochondrial-targeted proteins) to identify pathogenic mutations causing mitochondrial disease. |
10.1073/pnas.89.16.7370 | 41,469,011 | An assay that selectively amplifies a specific deletion of the mitochondrial genome has been used to study the extent of the deletion's accumulation in a variety of human tissues. The deletion occurs at much higher levels in nervous and muscle tissues than in all other tissues studied. The variation in deletion level b... | 10.1038/nrg3275 | This was among the first reports that called attention to the accumulation of somatic mtDNA deletions in normal ageing. |
10.1111/j.1474-9726.2010.00607.x | 104,038,938 | Summary Migration of fragmented mitochondrial DNA (mtDNA) to the nucleus has been shown to occur in multiple species including yeast, plants, and mammals. Several human diseases, including Pallister–Hall syndrome and mucolipidosis, can be initiated by mtDNA insertion mutagenesis of nuclear DNA. In yeast, we demonstrate... | 10.1038/nrg3275 | This is a fascinating example of how mtDNA fragments can be transferred to the nucleus in 'real time' (that is, during the lifetime of an individual). |
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