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10.1126/science.285.5428.727 | 125,332,529 | Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for γδ T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most γδ T cells, CD8 + αβ T cells, and natural killer (NK) cells and was identified as NKG2D. Effector ... | 10.1038/nrc928 | Demonstration that NKG2D recognizes stress-inducible MICA, a distant homologue of MHC class I, and previously shown to function as an antigen for γδ T cells and frequently expressed in epithelial tumours. These data first indicated an activating-immunoreceptor–MHC-ligand interaction that might promote antitumour NK- an... |
10.4049/jimmunol.168.9.4472 | 81,969,789 | Abstract We have investigated the primary and secondary immunity generated in vivo by a MHC class I-deficient tumor cell line that expressed CD80 (B7-1). CD80 expression enhanced primary NK cell-mediated tumor rejection in vivo and T cell immunity against secondary tumor challenge. CD80 expression enhanced primary NK c... | 10.1038/nrc928 | Direct demonstration that NK-cell-mediated rejection of tumours via CD27–CD70 co-stimulatory interactions subsequently evoke the development of tumour-specific cytotoxic and T helper type 1 responses, providing a key link between innate NK-cell responses and adaptive T-cell immunity. |
10.1126/science.1134053 | 107,324,687 | Chromatin plays roles in processes governed by different time scales. To assay the dynamic behavior of chromatin in living cells, we used genomic tiling arrays to measure histone H3 turnover in G1-arrested Saccharomyces cerevisiae at single-nucleosome resolution over 4% of the genome, and at lower (∼265 base pair) reso... | 10.1038/nrg3484 | This study measured the turnover rates of core histones on a genome-wide scale and reported dwell times on the order of tens of minutes that varied substantially between genomic locations. |
10.1126/science.1141319 | 62,248,418 | In vivo protein-DNA interactions connect each transcription factor with its direct targets to form a gene network scaffold. To map these protein-DNA interactions comprehensively across entire mammalian genomes, we developed a large-scale chromatin immunoprecipitation assay (ChIPSeq) based on direct ultrahigh-throughput... | 10.1038/nrg3484 | The first article to report genome-wide binding of a chromatin-interacting factor by ChIP followed by high-throughput sequencing (ChIP–seq). |
10.1126/science.1202142 | 62,066,217 | In yeast, the initiation of gene expression is stochastic and is controlled by transcription factor search times. | 10.1038/nrg3484 | The first direct observation of RNA synthesis in living cells at the single-transcript level, which revealed the kinetics of initiation and elongation. |
10.1126/science.1198817 | 125,292,736 | Real-time monitoring of gene expression reveals transcription kinetics of mammalian genes. | 10.1038/nrg3484 | This study presents inference of single-gene activity from fluctuations of protein expression levels. Distributions of active and inactive times in gene bursting indicate refractoriness in gene reactivation, thus reflecting a multistep sequential process. |
10.1126/science.1200508 | 122,772,928 | Genome-wide nucleosome positioning is a self-organizing system amenable to in vitro reconstitution. | 10.1038/nrg3484 | This study reports an in vitro reconstitution of nucleosome positioning patterns over gene bodies that mimic in vivo positions. The need for ATP to obtain this result demonstrates the non-equilibrium nature of nucleosome positioning. |
10.1126/science.287.5456.1262 | 104,363,091 | Steroid receptors bind to site-specific response elements in chromatin and modulate gene expression in a hormone-dependent fashion. With the use of a tandem array of mouse mammary tumor virus reporter elements and a form of glucocorticoid receptor labeled with green fluorescent protein, targeting of the receptor to res... | 10.1038/nrm715 | References 33 and 34 are recent descriptions of dynamic movement of proteins in the nucleus studied in vivo |
10.1073/pnas.92.17.7686 | 104,079,710 | Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl... | 10.1038/nrm715 | This was the first description of an inhibitor of ERK/MAPK cascade. |
10.1126/science.aad7977 | 38,377,117 | Offspring affected by sperm small RNAs Paternal dietary conditions in mammals influence the metabolic phenotypes of offspring. Although prior work suggests the involvement of epigenetic pathways, the mechanisms remains unclear. Two studies now show that altered paternal diet affects the level of small RNAs in mouse spe... | 10.1038/nrg.2016.106 | This study demonstrates that zygotic injection of sperm total RNAs or tsRNAs from males fed a HFD can induce metabolic disorders in offspring, and that RNA modifications in sperm tsRNAs are sensitive to a HFD. |
10.1073/pnas.1207169109 | 82,856,722 | Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Dea... | 10.1038/nrg.2016.106 | This report shows that APOBEC1 is involved in transgenerational epigenetic inheritance of a phenotype. |
10.1126/science.aab2006 | 82,857,152 | Generations affected by histone changes Parent and even grandparent environmental exposure can transmit adverse health effects to offspring. The mechanism of transmission is unclear, but some studies have implicated variations in DNA methylation. In a mouse model, Siklenka et al. found that alterations in histone methy... | 10.1038/nrg.2016.106 | This study demonstrates that defects induced by genetically disrupting histone methylation cause transgenerational inheritance of phenotypes in mammals. |
10.1093/bioinformatics/btg015 | 125,269,745 | Abstract Motivation: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. Results: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, X... | 10.1038/nrg1922 | SBML has been evolving since the early 2000s through the efforts of an international group of software developers and users. Today, SBML is supported by over 90 software systems. |
10.1126/science.1233913 | 20,642,942 | On the Origin of Tumor T regs The tumor microenvironment is often seeded with regulatory T cells (T regs ), which inhibit antitumor immunity. Using mice with genetically driven prostate cancer, Malchow et al. (p. 1219 ; see the Perspective by Joshi and Jacks ) found a population of T regs that were enriched in the pros... | 10.1038/nri.2016.26 | This study reports that T Reg cells that are reactive to a prostate-associated self antigen are highly enriched in oncogene-induced prostate tumours. Differentiation of these T Reg cells in the thymus is determined by AIRE-dependent expression of prostate tissue antigens by mTECs. |
10.1073/pnas.89.1.444 | 17,609,489 | Endothelium-derived relaxing factor (EDRF) activity has been attributed to the highly labile nitric oxide radical (NO). In view of the fact that the plasma and cellular milieux contain reactive species that can rapidly inactivate NO, it has been postulated that NO is stabilized by a carrier molecule that preserves its ... | 10.1038/nrm3391 | The first study demonstrating protein S -nitrosylation on Cys residues both in vitro and in vivo |
10.1523/jneurosci.16-03-01066.1996 | 103,834,689 | Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously from L-cysteine in mammalian tissues. H2S is present at relatively high levels in the brain, suggesting that it has a physiological function. Two other gases, nitric oxide and carbon monoxide, are also endogenously produced and have be... | 10.1038/nrm3391 | The first evidence for a functional role of H 2 S in the brain. |
10.1126/science.1162667 | 104,326,574 | Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H 2 S) is now receiving increasing attention. Here we show that H 2 S is physiological... | 10.1038/nrm3391 | The first study demonstrating a physiological role of H 2 S in vasorelaxation. This paper used CSE-deficient mice to establish that H 2 S is endogenously generated by CSE. |
10.1073/pnas.1119658109 | 60,978,452 | Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon... | 10.1038/nrm3391 | Demonstrates a crosstalk between the CO and H 2 S systems in regulation of cerebral vasodilation. |
10.1126/scisignal.2000464 | 62,607,345 | The gaseous messenger hydrogen sulfide regulates target proteins through S-sulfhydration of cysteine residues. | 10.1038/nrm3391 | The first study demonstrating protein sulfhydration in vivo by using a CSE-deficient mice model. |
10.1126/scisignal.2002329 | 83,074,229 | Reversible inactivation by sulfhydration of the protein tyrosine phosphatase PTP1B activates the kinase PERK to promote the ER stress response. | 10.1038/nrm3391 | Links protein sulfhydration to ER stress signalling, and demonstrates that sulfhydration is reversible by the thioredoxin system. |
10.1126/science.1209855 | 104,438,792 | Sulfide formation helps to protect various bacteria from antibiotic toxicity. | 10.1038/nrm3391 | Demonstrates that H 2 S acts as a bacterial cytoprotectant, implying that inhibitors of its biogenesis may facilitate antibiotic therapy. |
10.1126/science.274.5286.430 | 125,092,047 | Cigarette smoke carcinogens such as benzo[ a ]pyrene are implicated in the development of lung cancer. The distribution of benzo[ a ]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct f... | 10.1038/nrc1190 | Proposes a role for benzo[ a ]pyrene-7,8-diol-9,10-epoxide–DNA adducts as causes of mutations found in the TP53 gene in lung cancer. |
10.1073/pnas.81.20.6271 | 62,283,173 | The mutagenicity of O6-methylguanine (O6MeGua), a chemical carcinogen-DNA adduct, has been studied in vivo by using a single-stranded M13mp8 genome in which a single O6MeGua residue was positioned in the unique recognition site for the restriction endonuclease Pst I. Transformation of Escherichia coli MM294A cells with... | 10.1038/nrc1190 | Shows that O 6 -methylguanine specifically causes G to A mutations during cell replication. |
10.1126/science.982061 | 36,535,089 | The binding of benzo[ a ]pyrene to DNA in cultured human bronchus was measured in specimens from 37 patients. The binding values ranged from 2 to 151 picomoles of benzo[ a ]pyrene per milligram of DNA with an overall mean ± standard error of 34.2 ± 5.2. This 75-fold interindividual variation in the binding of benzo[ a ... | 10.1038/nrc1190 | Shows large inter-individual differences in the ability to metabolically activate benzo[ a ]pyrene to DNA adducts. |
10.1126/science.288.5475.2351 | 83,389,528 | A conserved domain in the extracellular region of the 60- and 80-kilodalton tumor necrosis factor receptors (TNFRs) was identified that mediates specific ligand-independent assembly of receptor trimers. This pre–ligand-binding assembly domain (PLAD) is physically distinct from the domain that forms the major contacts w... | 10.1038/nri1184 | This report refutes the previous theory proposing that the ligand induces oligomerization of the receptor. The authors identified a domain in the receptor that mediates ligand-independent assembly of the receptor. |
10.1101/gr.6557307 | 122,758,917 | Given the evolutionary importance of gene duplication to the emergence of species-specific traits, we have extended the application of cDNA array-based comparative genomic hybridization (aCGH) to survey gene duplications and losses genome-wide across 10 primate species, including human. Using human cDNA arrays that con... | 10.1038/nrg2593 | This paper traces the history of copy number variation through the evolution of the primate lineage. |
10.1128/mcb.24.19.8504-8518.2004 | 29,097,027 | ABSTRACT There is an emerging concept that acquired genetic instability in cancer cells can arise from the dysregulation of critical DNA repair pathways due to cell stresses such as inflammation and hypoxia. Here we report that hypoxia specifically down-regulates the expression of RAD51 , a key mediator of homologous r... | 10.1038/nrg2593 | This paper shows that HR enzymes are downregulated by stress in human cells, and that this is accompanied by reduction in HR. |
10.1084/jem.20100199 | 28,249,115 | Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88−/− mice to he... | 10.1038/nri2891 | A demonstration of the protective role of MYD88 and IL-18 in colitis-associated colorectal cancer. |
10.1084/jem.20100050 | 60,020,182 | Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and ... | 10.1038/nri2891 | A demonstration of the role of caspase 1, ASC and NLRP3 in colitis-associated colorectal cancer. |
10.1126/science.1140488 | 62,390,890 | Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms and pathways involved are not well understood. Tumor development is regulated by products of several modifier genes, but instructions for their tumor-specific expression are currently unknown. We show that the si... | 10.1038/nri2891 | This article describes a role for MYD88 and TLRs in the regulation of intestinal homeostasis and carcinogenesis. |
10.1002/dvdy.21309 | 40,258,228 | Abstract To study the role of Cdc42 in the establishment of epithelial polarity during mammalian development, we generated murine Cdc42‐null embryonic stem cells and analyzed peri‐implantation development using embryoid bodies (EBs). Mutant EBs developed endoderm and underlying basement membrane, but exhibited defects ... | 10.1038/nrm2476 | Describes the earliest effects of CDC42 deletion during embryogenesis, including defects in cell polarity and cell–cell adhesion. These correlate with CDC42-mediated changes in polarity proteins such as aPKC and GSK3β. |
10.1101/gad.361406 | 38,506,769 | Differentiation of skin stem cells into hair follicles (HFs) requires the inhibition of β-catenin degradation, which is controlled by a complex containing axin and the protein kinase GSK3β. Using conditional gene targeting in mice, we show now that the small GTPase Cdc42 is crucial for differentiation of skin progenito... | 10.1038/nrm2476 | The first demonstration that CDC42 is essential for the formation of hair follicles in the skin, a process which is dependent on β-catenin. |
10.1182/blood-2007-03-079582 | 38,490,146 | Abstract The Rho GTPase Cdc42 regulates adhesion, migration, and homing, as well as cell cycle progression, of hematopoietic stem cells, but its role in multilineage blood development remains unclear. We report here that inducible deletion of cdc42 in cdc42-floxed mouse bone marrow by the interferon-responsive, Mx1-Cre... | 10.1038/nrm2476 | Describes the effect of CDC42 on cell fate in the haematopoietic system: loss of CDC42 leads to inhibition of erythropoiesis and hyperproliferation of myeloid cells. |
10.1083/jcb.200705122 | 40,520,877 | Actin assembly at the leading edge of migrating cells depends on the availability of high-affinity free barbed ends (FBE) that drive actin filament elongation and subsequent membrane protrusion. We investigated the specific mechanisms through which the Rac1 and Rac2 small guanosine triphosphatases (GTPases) generate fr... | 10.1038/nrm2476 | Describes the different roles for RAC1 and RAC2 in stimulating actin polymerization in neutrophils. |
10.1182/blood-2006-03-005942 | 100,582,252 | Abstract Actin oligomers are a significant structural component of the erythrocyte cytoskeleton. Rac1 and Rac2 GTPases regulate actin structures and have multiple overlapping as well as distinct roles in hematopoietic cells; therefore, we studied their role in red blood cells (RBCs). Conditional gene targeting with a l... | 10.1038/nrm2476 | Provides the first evidence that RAC1 and RAC2 are essential for the correct assembly of the membrane-associated cytoskeleton in erythrocytes. |
10.1101/gr.180801 | 62,434,694 | The exponential growth in the volume of accessible biological information has generated a confusion of voices surrounding the annotation of molecular information about genes and their products. The Gene Ontology (GO) project seeks to provide a set of structured vocabularies for specific biological domains that can be u... | 10.1038/nrg2363 | This paper describes in more detail how the GO ontology is built and maintained in more detail. |
10.1093/bioinformatics/btl140 | 20,739,403 | Abstract Motivation: The result of a typical microarray experiment is a long list of genes with corresponding expression measurements. This list is only the starting point for a meaningful biological interpretation. Modern methods identify relevant biological processes or functions from gene expression data by scoring ... | 10.1038/nrg2363 | This paper explains some of the problems related to the structure of GO and proposes an approach that can be used to address them. |
10.1093/bioinformatics/bti565 | 18,869,933 | Abstract Summary: Independent of the platform and the analysis methods used, the result of a microarray experiment is, in most cases, a list of differentially expressed genes. An automatic ontological analysis approach has been recently proposed to help with the biological interpretation of such results. Currently, thi... | 10.1038/nrg2363 | This includes a detailed comparison of 14 functional profiling tools using a number of different criteria, including scope of the analysis, visualization capabilities, statistical model(s) used, correction for multiple comparisons, reference microarrays available, installation issues and sources of annotation data. |
10.1073/pnas.0608424104 | 60,872,209 | Our understanding of the genetic basis of host specialization in insects is limited to basic information on the number and location of genetic factors underlying changes in conspicuous phenotypes. We know nothing about general patterns of molecular evolution that may accompany host specialization but are not traceable ... | 10.1038/nrg2339 | This paper highlights the rapid gene loss and DNA decay that can occur when insects become specialized. |
10.1111/j.1420-9101.2007.01348.x | 124,934,695 | Abstract The present study extends evidence that Drosophila heat‐shock genes are distinctively evolvable because of insertion of transposable elements by examining the genotypic diversity and phenotypic consequences of naturally occurring P element insertions in the proximal promoter regions of two small heat‐shock gen... | 10.1038/nrg2339 | This paper shows that changes in promoter regions are common in heat shock protein genes and are likely to underlie some aspects of thermal adaptation. |
10.1073/pnas.97.3.1206 | 79,469,052 | We have imaged, in real time, fluorescent tumors growing and metastasizing in live mice. The whole-body optical imaging system is external and noninvasive. It affords unprecedented continuous visual monitoring of malignant growth and spread within intact animals. We have established new human and rodent tumors that sta... | 10.1038/nrc1717 | The first paper to demonstrate whole-body imaging using GFP-expressing tumours. |
10.1073/pnas.2436101100 | 100,773,292 | We have developed a simple yet powerful technique for delineating the morphological events of tumor-induced angiogenesis and other tumor-induced host processes with dual-color fluorescence. The method clearly images implanted tumors and adjacent stroma, distinguishing unambiguously the host and tumor-specific component... | 10.1038/nrc1717 | First dual-colour tumour–host model. The model uses RFP-tumours transplanted into GFP mice. |
10.1126/science.1106148 | 41,669,313 | Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr 308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser 473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We sho... | 10.1038/nrm3025 | References 42–44 show that mTORC2 mediates the phosphorylation and activation of AGC family kinases. |
10.1158/0008-5472.can-09-0299 | 124,216,078 | Abstract The mammalian target of rapamycin (mTOR) is centrally involved in cell growth, metabolism, and angiogenesis. While showing clinical efficacy in a subset of tumors, rapamycin and rapalogs are specific and allosteric inhibitors of mTOR complex 1 (mTORC1), but they do not directly inhibit mTOR complex 2 (mTORC2),... | 10.1038/nrm3025 | References 35 and 138–141 report the synthesis of catalytic inhibitors of mTOR. |
10.1126/science.1115535 | 125,098,176 | Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae . From a large-scale analysis of 564 single-gene–deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nut... | 10.1038/nrm3025 | This article provides evidence that reducing the activity of the TOR pathway extends the lifespan of S. cerevisiae and that DR acts through TOR. |
10.1073/pnas.1009798107 | 79,797,974 | The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function scree... | 10.1038/nri.2016.40 | This study highlights the role of several miRNAs in regulating HSC function as measured by bone marrow engraftment. |
10.1126/science.1216557 | 20,587,598 | Making Immune Cells Young Again Hematopoiesis, the development of the immune system, occurs in distinct waves. The immune system is first populated by cells that arise from fetal hematopoietic stem cells (HSCs) and then later by cells derived from adult HSCs. Furthermore, fetal HSCs give rise to lymphocytes with innate... | 10.1038/nri.2016.40 | This study demonstrates how altering the post-transcriptional processing of a specific miRNA can reprogramme adult haematopoietic cells to fetal haematopoiesis. |
10.1073/pnas.0605298103 | 125,306,911 | Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 20... | 10.1038/nri.2016.40 | This is the first study to demonstrate induction of miRNAs in response to inflammatory stimuli. |
10.1084/jem.20072108 | 121,862,475 | Mammalian microRNAs are emerging as key regulators of the development and function of the immune system. Here, we report a strong but transient induction of miR-155 in mouse bone marrow after injection of bacterial lipopolysaccharide (LPS) correlated with granulocyte/monocyte (GM) expansion. Demonstrating the sufficien... | 10.1038/nri.2016.40 | This is one of the first studies to demonstrate that aberrant miRNA expression can lead to myeloproliferative disorders. |
10.1126/science.1091903 | 62,305,227 | MicroRNAs (miRNAs) are an abundant class of ∼22-nucleotide regulatory RNAs found in plants and animals. Some miRNAs of plants, Caenorhabditis elegans , and Drosophila play important gene-regulatory roles during development by pairing to target mRNAs to specify posttranscriptional repression of these messages. We identi... | 10.1038/nri.2016.40 | This is the first study to show that miRNAs can modulate immune cell development. |
10.1084/jem.20101823 | 41,709,047 | Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse bio... | 10.1038/nri.2016.40 | This study describes how the loss of an anti-inflammatory miRNA can lead to autoimmunity and cancer. |
10.1126/science.1139253 | 19,011,092 | MicroRNAs are a class of small RNAs that are increasingly being recognized as important regulators of gene expression. Although hundreds of microRNAs are present in the mammalian genome, genetic studies addressing their physiological roles are at an early stage. We have shown that mice deficient for bic/microRNA-155 ar... | 10.1038/nri.2016.40 | This is one of the first studies to demonstrate the role of an inflammatory miRNA in the germinal centre response. |
10.1084/jem.20050678 | 83,457,363 | Dicer is an RNaseIII-like enzyme that is required for generating short interfering RNAs and microRNAs. The latter have been implicated in regulating cell fate determination in invertebrates and vertebrates. To test the requirement for Dicer in cell-lineage decisions in a mammalian organism, we have generated a conditio... | 10.1038/nri.2016.40 | References 179 and 180 demonstrate the impact of miRNA deletion on T cell development. |
10.7554/elife.05005 | 20,851,915 | MicroRNA targets are often recognized through pairing between the miRNA seed region and complementary sites within target mRNAs, but not all of these canonical sites are equally effective, and both computational and in vivo UV-crosslinking approaches suggest that many mRNAs are targeted through non-canonical interactio... | 10.1038/nri.2016.40 | This paper describes the algorithm used by Targetscan, a popular miRNA target prediction software. |
10.1126/science.1108190 | 82,938,903 | Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compou... | 10.1038/nrg3964 | The first experimental demonstration that exposure to environmental factors during embryogenesis (the endocrine disruptor vinclozolin) can have transgenerational consequences on offspring physiology in rats. |
10.1073/pnas.1321195111 | 62,103,457 | Significance Increasing evidence suggests that certain acquired traits can be transmitted to the next generation. However, controversy over the inheritance of acquired traits remains, as the exact molecular and mechanistic basis for these observations remains largely unclear. In this study, using a nongenetic prediabet... | 10.1038/nrg3964 | A thorough analysis of DNA methylation across three generations in sperm and peripheral tissues, including a demonstration in blastocysts that changes in DNA methylation persist during embryogenesis in mice. |
10.1126/science.1261754 | 82,224,180 | Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epitheliu... | 10.1038/nri.2016.27 | This is the first study challenging the concept that the anti-inflammatory effect of NRTIs is through inhibition of retroviral reverse transcription. |
10.1073/pnas.1116110108 | 20,697,352 | In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population ... | 10.1038/nri3547 | This report shows that human HSCs from aged adults show a bias towards myeloid differentiation, at the expense of lymphoid differentiation, as was also observed in mice. |
10.4049/jimmunol.178.11.6912 | 20,668,953 | Abstract Aging represents a state of paradox where chronic inflammation is associated with declining immune responses. Dendritic cells (DCs) are the major APCs responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. In this study, we have compared the innate immune... | 10.1038/nri3547 | This study shows an age-associated increase in TLR4- and TLR8-dependent cytokine production by human MDDCs, which occurs together with impaired phagocytosis and chemotaxis that is associated with decreased PI3K activation. |
10.1111/j.1474-9726.2012.00839.x | 20,556,697 | Summary Physiological aging is accompanied by a marked reduction in natural killer (NK) cell cytotoxicity (NKCC) at the single cell level, but the underlying mechanisms are unknown. To address this issue, we isolated NK cells from healthy young (≤ 35 years) and old (≤ 60 years) subjects and examined the effect of age o... | 10.1038/nri3547 | This is the first study to implicate defective perforin mobilization to the immunological synapse in age-associated impairment of NK cell cytotoxicity. |
10.1111/j.1474-9726.2012.00867.x | 101,078,439 | Summary Age‐associated decline in immunity to infection has been documented across multiple pathogens, yet the relative contributions of the aged priming environment and of lymphocyte‐intrinsic defects remain unclear. To address the impact of the aging environment on T‐cell priming, adult naïve OT‐I TCR transgenic CD8 ... | 10.1038/nri3547 | This study indicates that ageing mouse CD8α + DCs have impaired migration and upregulation of co-stimulatory molecules, and that this also impairs in vivo T cell responses in a model of bacterial infection. |
10.4049/jimmunol.178.2.970 | 29,192,920 | Abstract The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21–30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokin... | 10.1038/nri3547 | This study uses multivariable mixed effects modelling to show an age-related decrease in TLR1–TLR2-mediated cytokine production and TLR1 expression by monocytes from 159 human volunteers. |
10.4049/jimmunol.0901022 | 41,691,653 | Abstract We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21–30 y) and older (≥65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young indiv... | 10.1038/nri3547 | This paper shows an extensive, age-associated decrease in TLR-dependent cytokine production by primary human mDCs and pDCs that reflects elevated basal levels of cytokine production in aged adults and that is strongly associated with antibody responses to influenza virus vaccination. |
10.1084/jem.20090896 | 41,107,828 | Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymph... | 10.1038/nri3547 | Using skin biopsy and suction blister samples, this study shows an age-associated impairment in human delayed-type hypersensitivity responses, reduced TNF production by dermal macrophages and an associated increase in regulatory T cell infiltration of the skin of older individuals, compared with that of young individua... |
10.4049/jimmunol.181.10.6747 | 103,278,440 | Abstract Plasmacytoid dendritic cells (pDCs) are innate sensors that produce IFN-α in response to viral infections. Determining how aging alters the cellular and molecular function of these cells may provide an explanation of increased susceptibility of older people to viral infections. Hence, we examined whether aging... | 10.1038/nri3547 | This study shows that pDCs from aged mice have a TLR9-dependent defect in type I IFN production that is associated with impaired IRF7 upregulation. The defect in type I IFN production could be rescued by antioxidants or caloric restriction. |
10.4049/jimmunol.1103051 | 20,713,064 | Abstract The NLRP3 inflammasome is activated in the lung during influenza viral infection; however, the impact of aging on inflammasome function during influenza infection has not been examined. In this study, we show that elderly mice infected with a mouse-adapted strain of influenza produced lower levels of IL-1β dur... | 10.1038/nri3547 | This paper is the first to show an age-associated impairment in induced NLRP3 function in mice. |
10.4049/jimmunol.1003597 | 122,623,771 | Abstract IL-1β plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1–targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhan... | 10.1038/nri3095 | This study defined a role for PAMP-induced IL-18 and IL-1 in driving IL-17 production by CD4 + and γδ T cells that are pathogenic in autoimmune diseases. |
10.4049/jimmunol.169.5.2781 | 81,161,078 | Abstract Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4+ T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals... | 10.1038/nri3095 | This study demonstrated that innate immune cell activation and IL-12 induction through TLR9 induces T cells that are pathogenic in EAE. |
10.1083/jcb.151.7.1353 | 38,301,217 | Phagocytosis requires localized and transient remodeling of actin filaments. Phosphoinositide signaling is believed to play an important role in cytoskeletal organization, but it is unclear whether lipids, which can diffuse along the membrane, can mediate the focal actin assembly required for phagocytosis. We used imag... | 10.1038/nri1053 | This study used an elegant approach to show the rapid remodelling of the membranes that are used during phagocytosis. |
10.1083/jcb.135.5.1249 | 41,560,606 | Phosphoinositide 3-kinase (PI 3-kinase) has been implicated in growth factor signal transduction and vesicular membrane traffic. It is thought to mediate the earliest steps leading from ligation of cell surface receptors to increased cell surface ruffling. We show here that inhibitors of PI 3-kinase inhibit endocytosis... | 10.1038/nri1053 | The first demonstration of the role of phosphatidylinositol 3-kinase in phagocytosis. |
10.1083/jcb.152.1.165 | 81,715,066 | Phagosomes are key organelles for the innate ability of macrophages to participate in tissue remodeling, clear apoptotic cells, and restrict the spread of intracellular pathogens. To understand the functions of phagosomes, we initiated the systematic identification of their proteins. Using a proteomic approach, we iden... | 10.1038/nri1053 | This study is the first global characterization of a complex intracellular organelle by a proteomic approach. Several new characteristics and functions for phagosomes are proposed. |
10.1083/jcb.124.5.677 | 39,251,238 | We have examined the modifications occurring during the transformation of phagosomes into phagolysosomes in J-774 macrophages. The use of low density latex beads as markers of phagosomes (latex bead compartments, LBC) allowed the isolation of these organelles by flotation on a simple sucrose gradient. Two-dimensional g... | 10.1038/nri1053 | This study indicated that phagolysosome biogenesis is a maturation process involving sequential interaction with endocytic organelles through transient fusion events ('kiss and run'). |
10.1084/jem.158.4.1319 | 28,042,861 | Previous studies have shown that L. pneumophila multiplies intracellularly in human monocytes and alveolar macrophages within a membrane-bound cytoplasmic vacuole studded with ribosomes. In this paper, the formation of this novel vacuole is examined. After entry into monocytes, L. pneumophila resides in a membrane-boun... | 10.1038/nri1053 | This article describes a new process of phagocytosis used to internalize a new pathogen. |
10.1182/blood-2004-03-1040 | 81,777,944 | Abstract Graft-versus-host disease (GVHD) is characterized by an impairment of mechanisms that underlie the development of immunologic tolerance. Although the cytokine storm associated with GVHD leads to expression of cell surface markers on both effector and regulatory T cells, regulatory CD4+ T cells that play an ins... | 10.1038/nri2138 | This study shows for the first time a significant reduction of FOXP3 mRNA levels in PBMCs from patients with GVHD compared with those without GVHD. |
10.1084/jem.179.2.493 | 125,094,286 | Transplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunodeficiency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocyt... | 10.1038/nri2138 | This study describes the successful isolation of CD4 + host-reactive T-cell clones from SCID patients transplanted with allogeneic HSCs, which produce high amounts of IL-10 in the absence of IL-4 after antigen-specific stimulation in vitro . The presence of these IL-10-producing CD4 + T cells correlated with the absenc... |
10.1084/jem.20020399 | 41,407,329 | Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4+CD25+ regulatory T (Treg) cells have recently been shown to suppress proliferative responses of CD4+CD25− T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization... | 10.1038/nri2138 | References 35, 36 and 96 are the first to show that the adoptive transfer of CD4 + CD25 + regulatory T cells significantly delays or even prevents GVHD in preclinical mouse models of BMT. |
10.1182/blood-2004-10-3932 | 123,130,012 | Abstract Rapamycin is an immunosuppressive compound that is currently used to prevent acute graft rejection in humans. In addition, rapamycin has been shown to allow operational tolerance in murine models. However, a direct effect of rapamycin on T regulatory (Tr) cells, which play a key role in induction and maintenan... | 10.1038/nri2138 | In this study, we showed, for the first time, that rapamycin has the ability to allow the selective proliferation of T Reg cells. |
10.1182/blood-2003-04-1164 | 61,800,471 | Abstract Although CD4+CD25+ regulatory T cells are pivotal in the prevention of autoimmunity and appear to mediate transplantation tolerance, little is known concerning their antigen specificity. Here we describe the induction of a human CD4+CD25+ regulatory T-cell line specific for a defined peptide alloantigen (human... | 10.1038/nri2138 | References 50 and 51 show that CD4 + CD25 + T Reg cells are CD127 low/− and open new venues for a better isolation and purification of T Reg cells. |
10.1126/science.279.5356.1528 | 29,303,691 | Growth and repair of skeletal muscle are normally mediated by the satellite cells that surround muscle fibers. In regenerating muscle, however, the number of myogenic precursors exceeds that of resident satellite cells, implying migration or recruitment of undifferentiated progenitors from other sources. Transplantatio... | 10.1038/nrg1109 | This seminal study documents the capacity for transplanted bone-marrow cells from transgenic mice to migrate to sites of muscle degeneration and differentiate into muscle. This report proposes the possibility that bone-marrow cells might be used as a source of myogenic progenitors to treat muscle disease. |
10.1242/dev.126.5.1041 | 62,609,649 | Embryonic muscle growth requires a fine balance between proliferation and differentiation. In this study we have investigated how this balance is achieved during chick development. Removal of ectoderm from trunk somites results in the down-regulation of Pax-3 expression and cell division of myogenic precursors is halte... | 10.1038/nrg1109 | This paper proposes the hypothesis that embryonic myogenesis requires a temporal balance between proliferation and differentiation that is achieved through the presence of external cues, such as BMP and Shh signalling, and regulation of the expression of Pax3 and MyoD |
10.1101/gad.940702 | 122,836,505 | Sonic hedgehog (Shh) is a secreted signaling molecule for tissue patterning and stem cell specification in vertebrate embryos. Shh mediates both long-range and short-range signaling responses in embryonic tissues through the activation and repression of target genes by its Gli transcription factor effectors. Despite th... | 10.1038/nrg1109 | This study is the first to provide a direct association between environmental cues that regulate myogenesis and the activation of a muscle-specification gene. Specifically, the authors show that long-range Shh signalling activates Myf5 through Gli1 binding sites in the Myf5 epaxial somite enhancer. |
10.1126/sciadv.1600492 | 102,912,165 | Viruses are the most abundant biological entities in the world’s oceans, and they play a crucial role in global biogeochemical cycles. In deep-sea ecosystems, archaea and bacteria drive major nutrient cycles, and viruses are largely responsible for their mortality, thereby exerting important controls on microbial dynam... | 10.1038/nrmicro.2017.125 | This study shows that archaeal viruses have a profound role in the functioning of deep-sea ecosystems and in global biogeochemical cycles. |
10.1126/science.aaa4181 | 107,203,845 | A viral DNA form that survives extremes The prokaryote Sulfolobus islandicus lives at extreme temperatures (∼80°C) and acidity (pH 3). It is infected by the rudivirus SIRV2. DiMaio et al. determined the structure of the SIRV2 virus using cryo–electron microscopy to understand how the virus survives these brutal conditi... | 10.1038/nrmicro.2017.125 | Near-atomic-resolution structure of the rod-shaped archaeal virus reveals the A-form of DNA in a biological entity and provides clues about the thermostability of the viral particle. |
10.1073/pnas.1303047110 | 60,314,138 | It has been proposed that viruses can be divided into a small number of structure-based viral lineages. One of these lineages is exemplified by bacterial virus Hong Kong 97 (HK97), which represents the head-tailed dsDNA bacteriophages. Seemingly similar viruses also infect archaea. Here we demonstrate using genomic ana... | 10.1038/nrmicro.2017.125 | Cryo-EM reconstruction of the archaeal podovirus HSTV-1 capsid reveals a major capsid protein fold found in tailed bacteriophages and eukaryotic herpesviruses. |
10.1073/pnas.1300601110 | 37,447,106 | Sulfolobus turreted icosahedral virus (STIV) was isolated in acidic hot springs where it infects the archeon Sulfolobus solfataricus . We determined the STIV structure using near-atomic resolution electron microscopy and X-ray crystallography allowing tracing of structural polypeptide chains and visualization of transm... | 10.1038/nrmicro.2017.125 | Near-atomic-resolution structure of the turrivirus STIV reveals fine details of the virion organization and strengthens the evolutionary connection between STIV and bacterial and eukaryotic viruses with double jelly-roll capsid proteins. |
10.1073/pnas.1319245111 | 78,865,648 | Viruses have developed a wide range of strategies to escape from the host cells in which they replicate. For egress some archaeal viruses use a pyramidal structure with sevenfold rotational symmetry. Virus-associated pyramids (VAPs) assemble in the host cell membrane from the virus-encoded protein PVAP and open at the ... | 10.1038/nrmicro.2017.125 | This study presents a three-dimensional reconstruction of the virus-associated pyramids employed by rod-shaped virus SIRV2 during the egress. |
10.1111/1462-2920.13079 | 124,832,758 | Summary Limited by culture‐dependent methods the number of viruses identified from thermophilic A rchaea and B acteria is still very small. In this study we retrieved viral sequences from six hot spring metagenomes isolated worldwide, revealing a wide distribution of four archaeal viral families, A mpullaviridae , B ic... | 10.1038/nrmicro.2017.125 | The study describes several novel hyperthermophilic archaeal virus genomes assembled from metagenomic data. |
10.1126/science.1566048 | 122,873,176 | Colorectal (CR) tumors are usually curable if detected before metastasis. Because genetic alterations are associated with the development of these tumors, mutant genes may be found in the stool of individuals with CR neoplasms. The stools of nine patients whose tumors contained mutations of K- ras were analyzed. In eig... | 10.1038/nrc755 | References 13 and 14 establish the ability to detect oncogene mutations in body fluids. |
10.9734/ajmah/2021/v19i630338 | 132,865,246 | Objective: To study the sensitivity and specificity of peritumoral isosulfan blue dye injection for localization of suspected metastatic lymph nodes.
 Materials and methods: The study included all patients diagnosed with early-stage oral cancer between January 2018 and March 2020. After elevation of the skin flap,... | 10.1038/nrc755 | References 22 and 23 establish the use of oncogene mutations in the staging of cancer. |
10.1073/pnas.0602831103 | 20,441,130 | Since their discovery as key regulators of early animal development, microRNAs now are recognized as widespread regulators of gene expression. Despite their abundance, little is known regarding the regulation of microRNA biogenesis. We show that three highly conserved muscle-specific microRNAs, miR-1, miR-133 and miR-2... | 10.1038/nrm3854 | Provides examples of how master transcriptional regulators of a specific cell fate act upstream of tissue-specific miRNAs. |
10.1126/science.1216557 | 20,587,598 | Making Immune Cells Young Again Hematopoiesis, the development of the immune system, occurs in distinct waves. The immune system is first populated by cells that arise from fetal hematopoietic stem cells (HSCs) and then later by cells derived from adult HSCs. Furthermore, fetal HSCs give rise to lymphocytes with innate... | 10.1038/nrm3854 | Demonstrates that let-7 and LIN28 control the transition between fetal and adult haematopoiesis, a theme that is also seen in neurogenesis, as described in this Review. |
10.1126/science.1084398 | 83,399,916 | Myosin V is a dimeric molecular motor that moves processively on actin, with the center of mass moving ∼37 nanometers for each adenosine triphosphate hydrolyzed. We have labeled myosin V with a single fluorophore at different positions in the light-chain domain and measured the step size with a standard deviation of &l... | 10.1038/nrm3248 | Describes the use of super-resolution light microscopy to follow the movement of one head of myosin V as it moved along an actin filament bound to a coverslip surface, demonstrating a hand-over-hand walking mechanism. |
10.1083/jcb.200110086 | 18,555,054 | Myosins are molecular motors that exert force against actin filaments. One widely conserved myosin class, the myosin-Vs, recruits organelles to polarized sites in animal and fungal cells. However, it has been unclear whether myosin-Vs actively transport organelles, and whether the recently challenged lever arm model de... | 10.1038/nrm3248 | By showing that the speed of secretory vesicle transport decreases in yeast Myo2-null cells complemented with 'slower' versions of Myo2 (that is, the first application of the acid test referred to in this Review), these authors provide unequivocal evidence that this class V myosin drives secretory vesicle transport. |
10.1083/jcb.200912011 | 16,885,372 | In Saccharomyces cerevisiae, ASH1 mRNA is transported to the bud tip by the class V myosin Myo4. In vivo, Myo4 moves RNA in a rapid and continuous fashion, but in vitro Myo4 is a nonprocessive, monomeric motor that forms a complex with She3. To understand how nonprocessive motors generate continuous transport, we used ... | 10.1038/nrm3248 | Shows how the clustering of multiple monomeric Myo4 molecules by the self-association of the adaptor proteins that link it to mRNA allows this non-processive motor to drive processive mRNA transport in vivo |
10.1083/jcb.143.7.1899 | 59,302,826 | Unlike wild-type mouse melanocytes, where melanosomes are concentrated in dendrites and dendritic tips, melanosomes in dilute (myosin Va−) melanocytes are concentrated in the cell center. Here we sought to define the role that myosin Va plays in melanosome transport and distribution. Actin filaments that comprise a cor... | 10.1038/nrm3248 | Shows, by comparing melanosome distribution and dynamics in wild-type versus dilute (myosin Va-null) melanocytes, that melanosome positioning is driven by a cooperation between long-range, microtubule-dependent melanosome transport and myosin Va-dependent melanosome capture (and possibly local movement) in the cell per... |
10.1126/science.1138684 | 108,187,481 | Pleckstrin homology (PH) domain–mediated protein recruitment to cellular membranes is of paramount importance for signal transduction. The recruitment of many PH domains is controlled through production and turnover of their membrane ligand, phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ). We show that phosphorylatio... | 10.1038/nri2745 | Reference 17 described the identification of ITK as the first physiological InsP 4 effector. InsP 4 promoted ITK PH domain binding to the membrane-bound lipid PtdInsP 3 , probably through a cooperative allosteric mechanism involving ITK PH domain oligomerization. This is essential for thymocyte positive selection. |
10.4049/jimmunol.0802850 | 64,244,946 | Abstract Inositol 1,4,5-trisphosphate 3-kinase B (or Itpkb) converts inositol 1,4,5-trisphosphate to inositol 1,3,4,5-tetrakisphosphate upon Ag receptor activation and controls the fate and function of lymphocytes. To determine the role of Itpkb in B cell tolerance, Itpkb−/− mice were crossed to transgenic mice that ex... | 10.1038/nri2745 | This study follows up on references 16 and 21 and described the effects of Itpkb deficiency on B cell selection in BCR-transgenic mice. |
10.1073/pnas.0800218105 | 15,780,907 | Inositol trisphosphate 3-kinase B (InsP3KB) belongs to a family of kinases that convert inositol 1,4,5-trisphosphate (Ins(1,4,5)P3 or IP3) to inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4). Previous studies have shown that disruption of InsP3KB leads to impaired T cell and B cell development as well as hyperactiva... | 10.1038/nri2745 | This study showed that Itpkb deficiency results in granulocyte–monocyte progenitor accumulation and increased neutrophil production, probably through mechanisms involving AKT hyperactivation secondary to impaired InsP 4 -mediated inhibition of interactions between the AKT PH domain and PtdInsP 3 |
10.1084/jem.161.3.446 | 61,045,649 | Antibodies against the T3-antigen receptor complex can activate the human T cell line, Jurkat, to produce interleukin 2 (2-5). This activation is initiated by a receptor-mediated increase in the concentration of free cytoplasmic calcium ions [Ca2+]i (3, 4). In this communication, we investigate the mechanism by which t... | 10.1038/nri2745 | References 62, 63, 65 and 66 showed for the first time that lymphocyte antigen-receptor stimulation induces the accumulation of InsPs, including InsP 3 and InsP 4 , and Ca 2+ release from intracellular stores. |
10.1177/1087057108317062 | 80,117,500 | One of the most fundamental challenges in genome-wide RNA interference (RNAi) screens is to glean biological significance from mounds of data, which relies on the development and adoption of appropriate analytic methods and designs for quality control (QC) and hit selection. Currently, a Z-factor-based QC criterion is ... | 10.1038/nmeth.1351 | This article describes the use of SSMD for quality assessment and suggests appropriate thresholds, as well as provides an in-depth discussion of plate layout issues |
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