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10.1101/gad.242002 | 20,610,271 | Branching morphogenesis in the mammalian lung and Drosophila trachea relies on the precise localization of secreted modulators of epithelial growth to select branch sites and direct branch elongation, but the intercellular signals that control blood vessel branching have not been previously identified. We found that VE... | 10.1038/nrg1158 | A genetic study that documents the role of VEGF isoforms in vessel patterning and branching. |
10.1159/000049150 | 81,165,419 | Current evidence suggests that the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of Alzheimer disease (AD) cases may exhibit significant cerebrovascular pathology, which constitutes distinct small vessel disease (SVD). Cerebral amyloid ang... | 10.1038/nrg1158 | An overview that highlights the role of blood vessels in neurodegenerative Alzheimer Disease. |
10.1073/pnas.0832373100 | 59,302,016 | Genomic sequencing is no longer a novelty, but gene function annotation remains a key challenge in modern biology. A variety of functional genomics experimental techniques are available, from classic methods such as affinity precipitation to advanced high-throughput techniques such as gene expression microarrays. In th... | 10.1038/nrc2036 | The authors present an effective computational method to integrate different functional-association data sets for gene-function prediction. |
10.1093/bioinformatics/btl390 | 81,166,248 | Abstract Motivation: The study of interactomes, or networks of protein-protein interactions, is increasingly providing valuable information on biological systems. Here we report a study of cancer proteins in an extensive human protein-protein interaction network constructed by computational methods. Results: We show th... | 10.1038/nrc2036 | The authors show that human proteins translated from known cancer genes have a protein–protein interaction network topology that is different from that of proteins not documented as being mutated in cancer. |
10.1186/1471-2164-7-187 | 83,109,210 | Abstract Background Accurate evaluation of the quality of genomic or proteomic data and computational methods is vital to our ability to use them for formulating novel biological hypotheses and directing further experiments. There is currently no standard approach to evaluation in functional genomics. Our analysis of e... | 10.1038/nrc2036 | The authors discuss the deficiencies of current computational methods to infer functions from functional-association data, and outline new approaches to deal with these problems. |
10.1073/pnas.0806993105 | 81,949,494 | Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linea... | 10.1038/nrd3757 | This study is the first to suggest that the effects of leptin on glucose homeostasis can be independent of the effects of insulin. |
10.1126/science.7624776 | 104,326,115 | C57BL/6J mice with a mutation in the obese ( ob )gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. ... | 10.1038/nrd3757 | This study is the first to suggest that the effects of leptin on glucose homeostasis are direct and not secondary to its effects on food intake or body weight. |
10.1073/pnas.221269198 | 79,590,639 | Inflammation in asthma, sepsis, transplant rejection, and many neurodegenerative diseases associates an up-regulation of NO synthesis with increased protein nitration at tyrosine. Nitration can cause protein dysfunction and is implicated in pathogenesis, but few proteins that appear nitrated in vivo have been identifie... | 10.1038/nrc1046 | Important report of vast protein nitration following an inflammatory challenge in animals. |
10.1073/pnas.92.10.4392 | 80,660,276 | A subclone of the human colon adenocarcinoma cell line DLD-1, which grew reproducibly as subcutaneous tumors in nude mice, was isolated. Such cells, when engineered to generate nitric oxide (NO) continuously, grew more slowly in vitro than the wild-type parental cells. This growth retardation was reversed by the additi... | 10.1038/nrc1046 | Key study showing the dual roles of nitric oxide in animals. |
10.1084/jem.80.2.101 | 105,430,293 | Benzpyrene brings about neoplastic changes in rabbit epidermis much sooner than has been supposed. The long interval that elapses before visible growths appear is due in the main to the relatively slight power of the carcinogen to encourage multiplication of the cells it renders neoplastic. Yet some slight power of thi... | 10.1038/nrc1046 | References 71 and 72 are important papers describing a role for chronic irritation and associated inflammation in tumorigenesis in animals. |
10.1126/science.1218835 | 80,126,180 | Epithelial Defense Force The nature of the cells that maintain and heal the epithelium lining the esophagus has been controversial. Doupé et al. (p. 1091 , published online 19 July; see the Perspective by Kushner ) show that, unlike many other tissues, mouse esophagus is devoid of slow cycling stem cells. Instead, the ... | 10.1038/nrc3460 | Lineage tracing and other approaches reveal that murine oesophagus has no quiescent stem cells, and is healed by the same progenitor cells that maintain the tissue. |
10.1073/pnas.0909738107 | 61,645,489 | UV B (UVB) radiation induces clones of cells mutant for the p53 tumor suppressor gene in human and murine epidermis. Here we reanalyze large datasets that report the fate of clones in mice subjected to a course of UVB radiation, to uncover how p53 mutation affects epidermal progenitor cell behavior. We show that p53 mu... | 10.1038/nrc3460 | Quantitative analysis reveals that UV light drives the exponential expansion of p53-mutant clones in mouse and human epidermis. |
10.1126/science.1224676 | 103,771,555 | Cancer Stem Cells in Color One of the liveliest debates in contemporary cancer research centers on whether cancer stem cells (CSCs) exist and, if so, how these cells are defined phenotypically. CSCs are hypothesized to be a small population of cells within a tumor that are endowed with the unique capacity to drive tumo... | 10.1038/nrc3460 | Multicolour lineage tracing reveals that adenoma growth is underpinned by Lgr5 -expressing cells that have escaped the confines of the niche. |
10.1073/pnas.0511307103 | 41,720,604 | Given that retroposed copies of genes are presumed to lack the regulatory elements required for their expression, retroposition has long been considered a mechanism without functional relevance. However, through an in silico assay for transcriptional activity, we identify here >1,000 transcribed retrocopies in the h... | 10.1038/nrg2487 | This study shows that retrocopy transcription is widespread, predominant in the testis and often relies on regulatory elements from nearby genes. It also provides an estimate of the number of functional retrogenes in the human genome. |
10.1126/science.1090042 | 20,586,558 | Mammalian sex chromosomes have undergone profound changes since evolving from ancestral autosomes. By examining retroposed genes in the human and mouse genomes, we demonstrate that, during evolution, the mammalian X chromosome has generated and recruited a disproportionately high number of functional retroposed genes, ... | 10.1038/nrg2487 | This global survey of retroposition in human and mouse genomes reveals that the X chromosome has both produced and accepted an excess of retrogenes, thus demonstrating a similar pattern to that previously discovered in fruitflies. |
10.1073/pnas.0800693105 | 109,016,646 | New genes can originate by the combination of sequences from unrelated genes or their duplicates to form a chimeric structure. These chimeric genes often evolve rapidly, suggesting that they undergo adaptive evolution and may therefore be involved in novel phenotypes. Their functions, however, are rarely known. Here, w... | 10.1038/nrg2487 | The first retrogene for which a behavioural phenotype is described (in this case, behaviour related to courtship). |
10.1016/j.febslet.2004.11.025 | 61,498,232 | Imaging of biochemical processes in living cells and organisms is essential for understanding how genes and gene products work together in space and time and in health and disease. Such imaging depends crucially on indicator molecules designed to maximize sensitivity and specificity. These molecules can be entirely syn... | 10.1038/nmeth.1483 | A concise review of fluorescence reporters and probes for in vivo imaging |
10.1126/science.1162912 | 125,216,272 | The molecular mechanism by which a mechanical stimulus is translated into a chemical response in biological systems is still unclear. We show that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules. We used magnetic tweezers, total internal reflection fluorescence, and atomic f... | 10.1038/nrm2957 | This paper confirms the prediction from structural studies that applying force to talin exposes vinculin binding sites. |
10.1128/mcb.01324-07 | 40,482,659 | ABSTRACT Focal adhesion kinase (FAK) is an essential kinase that regulates developmental processes and functions in the pathology of human disease. An intramolecular autoinhibitory interaction between the FERM and catalytic domains is a major mechanism of regulation. Based upon structural studies, a fluorescence resona... | 10.1038/nrm2957 | This paper developed a fluorescence-based biosensor for FAK activation and used it to describe a stimulus-dependent local FAK activation in cells that depends on FAK binding to acidic phospholipids. |
10.1126/science.1168441 | 123,117,067 | The cytoskeleton, integrin-mediated adhesion, and substrate stiffness control a common set of cell functions required for development and homeostasis that are often deranged in cancer. The connection between these mechanical elements and chemical signaling processes is not known. Here, we show that α 5 β 1 integrin swi... | 10.1038/nrm2957 | This paper presents evidence that α5β1integrin responds to mechanical tension by conversion to a high affinity state that is required for binding to the synergy site in fibronectin. |
10.1182/blood-2009-07-235176 | 64,289,048 | Abstract Heritable epigenetic signatures are proposed to serve as an important regulatory mechanism in lineage fate determination. To investigate this, we profiled chromatin modifications in murine hematopoietic stem cells, lineage-restricted progenitors, and CD4+ T cells using modified genome-scale mini-chromatin immu... | 10.1038/nri2991 | References 78 and 79 identified genome-wide changes in gene expression and histone modification during haematopoiesis, emphasizing that developmentally regulated genes are specifically epigenetically primed in HSCs for subsequent activation or repression during lineage commitment. |
10.1101/gad.1861209 | 60,233,870 | We reported previously that well-characterized enhancers but not promoters for typical tissue-specific genes, including the classic Alb1 gene, contain unmethylated CpG dinucleotides and evidence of pioneer factor interactions in embryonic stem (ES) cells. These properties, which are distinct from the bivalent histone m... | 10.1038/nri2991 | This study demonstrated that enhancer sequences are already epigenetically pre-marked in ES cells.These marks may be essential for maintaining competence for transcriptional activation. |
10.1073/pnas.1202970109 | 26,976,265 | Animals living in social communities typically harbor a characteristic gut microbiota important for nutrition and pathogen defense. Accordingly, in the gut of the honey bee, Apis mellifera , a distinctive microbial community, composed of a taxonomically restricted set of species specific to social bees, has been identi... | 10.1038/nrmicro.2016.43 | This metagenomic study reveals the broad set of functions that are attributable to each member of the gut microbial community in honey bees and provides the first evidence of extensive strain diversity within each species of the community; strains that are essentially identical in 16S rDNA sequences can be highly diver... |
10.1126/science.1146498 | 82,950,343 | In colony collapse disorder (CCD), honey bee colonies inexplicably lose their workers. CCD has resulted in a loss of 50 to 90% of colonies in beekeeping operations across the United States. The observation that irradiated combs from affected colonies can be repopulated with naive bees suggests that infection may contri... | 10.1038/nrmicro.2016.43 | Large-scale honey bee deaths occurred in 2006–2007: this study uses early next-generation sequencing technology to identify causative agents. Although bee deaths could not be attributed to a single disease, this analysis reveals the widespread presence of the core members of the bacterial gut community across diverse p... |
10.1111/mec.12966 | 107,388,179 | Abstract Honey bee hives are filled with stored pollen, honey, plant resins and wax, all antimicrobial to differing degrees. Stored pollen is the nutritionally rich currency used for colony growth and consists of 40–50% simple sugars. Many studies speculate that prior to consumption by bees, stored pollen undergoes lon... | 10.1038/nrmicro.2016.43 | It has long been suspected that hive-stored pollen was gradually degraded into a more nutritious food source by microbial action. However, this study finds few bacteria in stored pollen, which implies that digestion occurs in the worker gut. |
10.1073/pnas.1405838111 | 103,615,611 | Significance Gut microbes are increasingly recognized as influential components of animal biology. Genomic, mechanistic, and evolutionary aspects of gut symbiont specialization remain understudied, however, largely due to the complexity of gut communities, especially in vertebrate systems. We show that the simple micro... | 10.1038/nrmicro.2016.43 | The sequencing of S. alvi and G. apicola isolates from honey bees and bumble bees indicates that they occupy distinct metabolic niches and have diverse gene sets. In vivo experiments demonstrate barriers to host-switching for S. alvi strains, which suggests specialization to hosts. |
10.1111/j.1461-0248.2012.01831.x | 82,373,783 | Abstract Specific interactions between parasite genotypes and host genotypes (G p × G h ) are commonly found in invertebrate systems, but are largely lacking a mechanistic explanation. The genotype of invertebrate hosts can be complemented by the genomes of microorganisms living on or within the host (‘microbiota’). We... | 10.1038/nrmicro.2016.43 | This study shows that the infection of bumble bees by different strains of a trypanosomatid parasite is more dependent on the source of the gut microbiota than on host genotype, which suggests that bacteria in the guts of bees are undergoing a co-evolutionary 'arms race' with the parasites. |
10.1101/gad.283499.116 | 25,910,849 | The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras -driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened ( Smo ) in stromal fibroblas... | 10.1038/nrc.2017.68 | In this study, the importance of SHH signalling from stromal fibroblasts in pancreatic ADM is demonstrated. |
10.1084/jem.20110308 | 83,303,153 | The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was up-regulated in lymphocytes by antigen receptor stimulation but not... | 10.1038/nri3155 | By using Nur77 –GFP as a reporter for TCR stimulation, this study correlated the level of TCR signal received with the potential for T Reg cell differentiation. |
10.1073/pnas.1103810108 | 65,453,688 | CD4 + CD25 + Foxp3 + regulatory T (Treg) cells are generated during thymocyte development and play a crucial role in preventing the immune system from attacking the body's cells and tissues. However, how the formation of these cells is directed by T-cell receptor (TCR) recognition of self-peptide:major histocompatibili... | 10.1038/nri3155 | This study demonstrated that, in addition to avidity, the quality or affinity of the interaction between a TCR and a peptide–MHC complex is important for thymic T Reg cell selection. |
10.1084/jem.20100004 | 105,411,563 | The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4+ T cells from Cbl-b RING finger mutant knockin or Cbl-b–deficient mice show impaired TGF-β–induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-β... | 10.1038/nri3155 | References 58–60 were three independent studies that demonstrated the importance of FOXO in the thymic development of T Reg cells. |
10.4049/jimmunol.178.1.280 | 20,882,270 | Abstract IL-2 −/− mice develop autoimmunity despite having relatively normal numbers of regulatory T cells (Tregs). In contrast, we demonstrate that IL-2−/− × IL-15−/− and IL-2Rβ−/− mice have a significant decrease in Treg numbers. Ectopic expression of foxp3 in a subset of CD4+ T cells rescued Treg development and pre... | 10.1038/nri3155 | Together with reference 70, this study demonstrates that the development of thymic T Reg cells can be divided into at least two steps based on the dependence on TCR stimulation: a proper TCR signal probably instructs thymocytes to develop into FOXP3 − T Reg cell precursors, which then express FOXP3 after acquiring an I... |
10.1084/jem.185.12.2157 | 39,287,227 | The role of the spleen and of other organized secondary lymphoid organs for the induction of protective antiviral immune responses was evaluated in orphan homeobox gene 11 knockout mice (Hox11−/−) lacking the spleen, and in homozygous alymphoplastic mutant mice (aly/aly) possessing a structurally altered spleen but lac... | 10.1038/nri2414 | This study shows that lymph nodes are crucial for the induction of antiviral immune responses. In the absence of lymph nodes, cytopathic virus infection resulted in death of the animals, whereas infection with a non-cytopathic virus led to viral persistence. |
10.1084/jem.20021801 | 18,435,378 | Access to the splenic white pulp is restricted to lymphocytes and dendritic cells. Here we show that movement of molecules from the blood into these confined areas is also limited. Large molecules, such as bovine serum albumin (68 kD), immunoglobulin G (150 kD), and 500 kD dextran are unable to enter the white pulp, wh... | 10.1038/nri2414 | This study reveals that the conduit system in the spleen has an important role in the distribution of both blood-borne and locally produced molecules, and provides a framework for directing lymphocyte migration and the organization of the white pulp of the spleen. |
10.1126/science.1146291 | 20,502,960 | Mounting a protective immune response is critically dependent on the orchestrated movement of cells within lymphoid organs. We report here the visualization, using major histocompatability complex class I tetramers, of the CD8-positive (CD8) T cell response in the spleens of mice to Listeria monocytogenes infection. A ... | 10.1038/nri2414 | This study uses MHC class I tetramers to visualize the CD8 + T-cell response in the spleens of mice to L. monocytogenes antigens following infection in situ . Initial CTL activation occurred at the borders of the B- and T-cell zones followed by prolonged cluster formation with APCs, and eventually, CD8 + T-cell exit fr... |
10.1126/science.1144830 | 102,951,472 | The chemokines CCL21 and CXCL13 are immune factors that dictate homing and motility of lymphocytes and dendritic cells in lymphoid tissues. However, the means by which these chemokines are regulated and how they influence cell trafficking during immune responses remain unclear. We show that CCL21 and CXCL13 are transie... | 10.1038/nri2414 | This paper shows that viral infection can lead to the downregulation of constitutive chemokine expression, thereby precipitating a transient period of immunosuppression. |
10.1126/science.1199484 | 107,319,200 | A search for substrates of a growth-promoting kinase revealed a regulatory feedback loop involved in tumor suppression. | 10.1038/nrm3330 | References 35 and 36 report GRB10 as an mTORC1 substrate and an effector of the mTORC1–PI3K feedback loop. |
10.1126/science.1160809 | 20,879,499 | Fuel Economy for Growing Cells Sophisticated 21st-century analyses of the signaling pathways that control cell growth have led researchers back to the seminal work of Otto Warburg, who discovered in the 1920s that tumor cells generate their energy in an unusual way—by switching from mitochondrial respiration to glycoly... | 10.1038/nrm3330 | This review comprehensively discusses the links between cell metabolism and cancer. |
10.1111/j.1365-2958.2012.08206.x | 26,837,619 | Summary Pathogenic mycobacteria require type VII secretion ( T7S ) systems to transport virulence factors across their complex cell envelope. These bacteria have up to five of these systems, termed ESX ‐1 to ESX ‐5. Here, we show that ESX ‐5 of M ycobacterium tuberculosis mediates the secretion of EsxN , PPE and PE_PGR... | 10.1038/nrmicro.2016.131 | A paper that describes the first insights into the components that form the ESX secretion apparatus of ESX systems. |
10.1073/pnas.1406693111 | 104,322,216 | Significance In 1901, when Robert Koch proposed that the bacilli causing human and bovine tuberculosis were not identical, this view caused much controversy. Now, 113 y later, we know that the bovine tuberculosis agent, Mycobacterium bovis , together with other animal strains, forms a separate phylogenetic lineage apar... | 10.1038/nrmicro.2016.131 | A study that reveals the role of compensatory mutations in preserving ESX-1 functions in PhoP–PhoR-mutated lineages of the M. tuberculosis complex. |
10.1111/mmi.12707 | 29,236,372 | Summary The Type VII protein secretion system, found in G ram‐positive bacteria, secretes small proteins, containing a conserved W ‐x‐ G amino acid sequence motif, to the growth medium. S taphylococcus aureus has a conserved Type VII secretion system, termed Ess , which is dispensable for laboratory growth but required... | 10.1038/nrmicro.2016.131 | A paper that provides novel insights into the ESX-like secretion system that is found in strains of Staphylococcus aureus |
10.1101/gr.8.3.195 | 62,624,571 | Sequencing of large clones or small genomes is generally done by the shotgun approach (Anderson et al. 1982). This has two phases: (1) a shotgun phase in which a number of reads are generated from random subclones and assembled into contigs, followed by (2) a directed, or finishing phase in which the assembly is inspec... | 10.1038/nmeth.1422 | A widely used finishing tool that was the first to use error probabilities as an objective criterion to guide the finishing process |
10.1101/gr.403602 | 81,918,621 | The Generic Model Organism System Database Project (GMOD) seeks to develop reusable software components for model organism system databases. In this paper we describe the Generic Genome Browser (GBrowse), a Web-based application for displaying genomic annotations and other features. For the end user, features of the br... | 10.1038/nmeth.1422 | The Generic Model Organism Database project is the most widely used framework for developing software tools to support genome analysis and curation. Three synteny-specific tools have been developed within the GMOD framework: SynBrowse, SynView and GBrowseSyn |
10.1002/ajhb.20590 | 29,320,596 | Abstract Biomedical science has little considered the relevance of life history theory and evolutionary and ecological developmental biology to clinical medicine. However, the observations that early life influences can alter later disease risk—the “developmental origins of health and disease” (DOHaD) paradigm—have led... | 10.1038/nrg2045 | References 1–4 discuss evidence for the early origins of the adult disease susceptibility hypothesis. |
10.1192/bjp.172.4.324 | 4,856,268 | Background It has been suggested that prenatal exposure to maternal stress increases the risk of subsequently developing schizophrenia. Method The five-day invasion and defeat of The Netherlands by the German army in May 1940 constituted a severe, well-circumscribed national stressful event. Individuals exposed and non... | 10.1038/nrg2045 | References 5 and 6 discuss epidemiological evidence that the adult incidence of schizophrenia is significantly increased in humans who were exposed prenatally to famine conditions. |
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/nrg2045 | This study demonstrates the ability of environmental factors to induce an epigenetic transgenerational disease phenotype for four generations. |
10.1111/j.1420-9101.2006.01091.x | 82,707,389 | Abstract We describe a new hypothesis for the development of autism, that it is driven by imbalances in brain development involving enhanced effects of paternally expressed imprinted genes, deficits of effects from maternally expressed genes, or both. This hypothesis is supported by: (1) the strong genomic-imprinting c... | 10.1038/nrg2045 | These authors propose that human neurological disorders, such as autism, result from an imbalanced expression of imprinted genes during development. |
10.1126/science.1080902 | 83,060,636 | Loss of imprinting (LOI), an epigenetic alteration affecting the insulin-like growth factor II gene ( IGF2 ), is found in normal colonic mucosa of about 30% of colorectal cancer (CRC) patients, but it is found in only 10% of healthy individuals. In a pilot study to investigate the utility of LOI as a marker of CRC risk... | 10.1038/nrg2045 | This paper reports that some humans have IGF2 LOI in peripheral lymphocytes, which is correlated with biallelic expression in normal colonic mucosa and a personal history of colorectal cancer. |
10.1210/en.2006-0987 | 107,956,049 | Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the ... | 10.1038/nrg2045 | This report demonstrates the ability of vinclozolin to induce the reprogramming of the germ line, and the formation of genes and DNA sequences that contain paternal-allele alterations in DNA methylation associated with transgenerational disease. |
10.1101/gr.3303505 | 109,118,250 | Imprinted genes are epigenetically modified genes whose expression is determined according to their parent of origin. They are involved in embryonic development, and imprinting dysregulation is linked to cancer, obesity, diabetes, and behavioral disorders such as autism and bipolar disease. Herein, we train a statistic... | 10.1038/nrg2045 | These authors demonstrate that imprinted genes and their parental expression bias can be predicted genome-wide with the use of machine learning algorithms. |
10.1073/pnas.96.17.9533 | 16,752,436 | The yeast two-hybrid system is a powerful technique that detects interactions between two proteins and has been useful in identifying new binding partners. However, the system fails to detect protein–protein interactions that require the presence of additional components of a multisubunit complex. Here we demonstrate t... | 10.1038/nrd1199 | Provides insight into how VHL targets HIF-1α for ubiquitin-mediated degradation. |
10.1126/science.1059817 | 62,609,790 | HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel–Lindau tumor suppressor protein (pVHL). We found that human pVHL bin... | 10.1038/nrd1199 | One of two important papers that initially demonstrated that the oxygen sensor for HIF-1 degradation is hydroxylation of a crucial proline residue. |
10.1126/science.1059796 | 104,432,460 | Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-α subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel–Lindau tumor suppressor (pVHL) E3 ligase complex.... | 10.1038/nrd1199 | The other important paper showing that proline hydroxylation regulates the oxygen lability of HIF-1α. |
10.1126/science.1068592 | 104,434,037 | The hypoxia-inducible factors (HIFs) 1α and 2α are key mammalian transcription factors that exhibit dramatic increases in both protein stability and intrinsic transcriptional potency during low-oxygen stress. This increased stability is due to the absence of proline hydroxylation, which in normoxia promotes binding of ... | 10.1038/nrd1199 | Indicates that hydroxylation of different residues can regulate HIF-1 transactivation as well as stability. |
10.1242/dev.129.10.2507 | 41,690,305 | Neural tube closure is a fundamental embryonic event whose molecular regulation is poorly understood. As mouse neurulation progresses along the spinal axis, there is a shift from midline neural plate bending to dorsolateral bending. Here, we show that midline bending is not essential for spinal closure since, in its ab... | 10.1038/nrg1181 | This study produced the first evidence of a role for sonic hedgehog signalling in regulating the pattern of neural plate bending during mouse spinal neurulation. |
10.1126/science.277.5329.1109 | 104,296,555 | The PATCHED ( PTC ) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS). Functions of PTC were investigated by inactivating the mouse gene. Mice homozygous for the ptc mutation died during embryogenesis and were found to have open and overgro... | 10.1038/nrg1181 | This paper gives a description of the knockout phenotype of the Patched1 gene, including the finding of severe neural tube defects in homozygotes and the development of medulloblastomas, which are important brain tumours of childhood, in heterozygotes. |
10.1002/tera.1420470112 | 124,689,310 | Abstract Development of the neural tube is often described as a continuous process that begins in the cervical region of the embryo and proceeds both rostrally and caudally. Examination of neural tube closure in the cranial region of LM/Bc and SWV/Bc mice revealed an intermittent pattern with four distinct areas of clo... | 10.1038/nrg1181 | This was the first study to show that neural tube closure initiates at three distinct locations in the mouse embryo, with an intermittent pattern of subsequent closure. This contradicted the traditional textbook belief that neural tube closure comprises a simple 'zipping up' in both directions from a starting point mid... |
10.1126/science.aaf6659 | 103,765,714 | Wreaking havoc while (growth-)arrested Cells enter a state of senescence in response to certain stresses. Studying mouse models, Childs et al. examined the role of senescent lipid-loaded macrophages (so-called “foam cells”) in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells... | 10.1038/nrd.2017.116 | This study links the pro-inflammatory, proteolytic properties of plaque SNCs to progression and destabilization of atherosclerosis. |
10.1073/pnas.92.20.9363 | 62,247,869 | Normal somatic cells invariably enter a state of irreversibly arrested growth and altered function after a finite number of divisions. This process, termed replicative senescence, is thought to be a tumor-suppressive mechanism and an underlying cause of aging. There is ample evidence that escape from senescence, or imm... | 10.1038/nrd.2017.116 | This study reports the development of the SA- β -Gal stain, which is a widely used biomarker for detecting SNCs in vitro and in vivo |
10.1101/gad.290635.116 | 104,284,550 | Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. How... | 10.1038/nrd.2017.116 | This work implicated signals arising from the SNC secretome to stemness during tissue regeneration. |
10.15252/embr.201439245 | 41,477,138 | Abstract In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence‐inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, s... | 10.1038/nrd.2017.116 | This review gives a broad overview of the possible advantages of senescence compared with apoptosis as a fate for damaged cells. |
10.1073/pnas.211053698 | 62,257,322 | Mammalian cells can respond to damage or stress by entering a state of arrested growth and altered function termed cellular senescence. Several lines of evidence suggest that the senescence response suppresses tumorigenesis. Cellular senescence is also thought to contribute to aging, but the mechanism is not well under... | 10.1038/nrd.2017.116 | This study provided early support for the hypothesis that SNCs promote carcinogenesis in a cell non-autonomous fashion. |
10.4049/jimmunol.143.10.3200 | 139,045,702 | Abstract The immune response to polysaccharide Ag as present in the capsule of certain virulent bacteria has been demonstrated to be related to a functionally intact spleen. This immune response is almost completely defective in infancy. Because of this the development of cellular compartments in the human spleen was s... | 10.1038/nri2508 | This seminal work identifies crucial maturation stages for the development of the marginal zone of the spleen. |
10.4049/jimmunol.170.6.2824 | 20,797,068 | Abstract The factors limiting neonatal and infant IgG Ab responses to T-dependent Ags are only partly known. In this study, we assess how these B cell responses are influenced by the postnatal development of the spleen and lymph node microarchitecture. When BALB/c mice were immunized with alum-adsorbed tetanus toxoid a... | 10.1038/nri2508 | This work provides a mechanistic explanation for the delayed and limited antibody responses in early life by identifying the slow postnatal maturation of FDCs as a crucial factor that decreases germinal centre responses. |
10.1182/blood-2007-09-110858 | 41,668,868 | The persistence of serum IgG antibodies elicited in human infants is much shorter than when such responses are elicited later in life. The reasons for this rapid waning of antigen-specific antibodies elicited in infancy are yet unknown. We have recently shown that adoptively transferred tetanus toxoid (TT)–specific pla... | 10.1038/nri2508 | This work identifies a unique pro-survival effect of APRIL on antigen-specific plasmablasts and shows that its limited production by bone marrow stromal cells is associated with the defective establishment of the plasma-cell pool. |
10.1182/blood-2007-11-123844 | 81,637,447 | Abstract The fact that you can vaccinate a child at 5 years of age and find lymphoid B cells and antibodies specific for this vaccination 70 years later remains an immunologic enigma. It has never been determined how these long-lived memory B cells are maintained and whether they are protected by storage in a special n... | 10.1038/nri2508 | This paper reports the differential distribution of memory B cells between blood and spleen, and the lack of any significant correlation between specific memory B cells in the blood and the serum titres of their specific antibody. |
10.1111/j.1474-9726.2008.00443.x | 83,252,023 | Summary Older people suffer from a decline in immune system, which affects their ability to respond to infections and to raise efficient responses to vaccines. Effective and specific antibodies in responses from older individuals are decreased in favour of non‐specific antibody production. We investigated the B‐cell re... | 10.1038/nri2508 | A spectratype analysis across the complementarity-determining region 3 in individuals of different ages that shows the decline in the B-cell repertoire in older individuals and at the same time maps their health status on the analysis, thereby linking frailty with repertoire distortion. |
10.1126/science.1221489 | 104,119,825 | How to Make a Place Cell Hippocampal place cells have been studied for more than 40 years, yet the mechanisms underlying their remarkable spatial tuning are still not established. Using whole-cell patch-clamp recordings in freely moving rats, Lee et al. (p. 849 ) changed the baseline membrane potential in hippocampal p... | 10.1038/nn.4652 | This work reveals surprisingly nonlinear properties of place cells. The authors obtained intracellular recordings from hippocampal neurons in freely navigating mice. They show that silent cells without any spatial modulation of membrane potential can be turned into place cells by sustained depolarization |
10.1126/science.aan3846 | 62,339,567 | A different form of synaptic plasticity How do synaptic or other neuronal changes support learning? This subject has been dominated by Hebb's postulate of synaptic change. Although there is strong experimental support for Hebbian plasticity in a number of preparations, alternative ideas have also been developed over th... | 10.1038/nn.4652 | This study reports an unusual form of synaptic plasticity in CA1 pyramidal cells, whereby a single pairing of pre- and postsynaptic activity within a time window of several seconds produces long-term potentiation of the synaptic response. Such a pairing paradigm may store events that occur at behavioral timescales |
10.2337/dc13-2743 | 18,123,128 | Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The gr... | 10.1038/nrd.2015.36 | A panel of specialists provides guidelines to initiating insulin therapy in the context of recent findings and novel treatment options. |
10.1111/dom.12498 | 62,541,619 | Aims To confirm, in a 26‐week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide ( IDegLira ) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes. Methods Insulin‐naïve adults with type 2 diabetes randomized to once‐dail... | 10.1038/nrd.2015.36 | This extended clinical study underscores the benefits of combination therapy of insulin with GLP1 analogues. |
10.1002/bip.20734 | 123,184,549 | Abstract Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a fou... | 10.1038/nrd.2015.36 | This review focuses on the history of insulin chemical synthesis and the insulin structure–activity relationship. |
10.1111/dom.12087 | 80,778,110 | Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under‐appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this gluc... | 10.1038/nrd.2015.36 | The identification of inter-and intra-patient variability as the major issue of the current insulin therapies and establishing it as a primary consideration for future treatments. |
10.1111/j.1463-1326.2012.01628.x | 4,679,545 | Abstract Due to the increasing prevalence of type 2 diabetes mellitus ( T2DM ), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians an... | 10.1038/nrd.2015.36 | A review discussing the benefits of insulin and GLP1A combination therapy with early clinical examples. |
10.1126/scitranslmed.3007218 | 123,917,763 | Compared to best-in-class GLP-1 mono-agonists, unimolecular co-agonists of GLP-1 and GIP with optimized pharmacokinetics enhance glycemic and metabolic benefits in mammals. | 10.1038/nrd.2015.36 | An example of improved pharmacology obtained through combination of two incretin hormones. |
10.1093/genetics/139.3.1455 | 41,623,687 | Abstract We present a new parameterization of physiological epistasis that allows the measurement of epistasis separate from its effects on the interaction (epistatic) genetic variance component. Epistasis is the deviation of two-locus genotypic values from the sum of the contributing single-locus genotypic values. Thi... | 10.1038/nrg3627 | This is the first paper to clearly articulate the difference between the effect of epistasis on individual genotypes — which is independent of allele frequency — and the contribution of epistasis to epistatic variance for a quantitative trait, which does depend on allele frequency. |
10.1126/science.1091317 | 19,073,938 | A genetic interaction network containing ∼1000 genes and ∼4000 interactions was mapped by crossing mutations in 132 different query genes into a set of ∼4700 viable gene yeast deletion mutants and scoring the double mutant progeny for fitness defects. Network connectivity was predictive of function because interactions... | 10.1038/nrg3627 | This paper describes the first high-throughput analysis of synthetic lethal genetic interaction mapping in yeast, from which the first large-scale genetic interaction network was derived. |
10.1093/genetics/144.4.1559 | 41,542,071 | A molecular mapping experiment shows that a major gene effect on a quantitative trait, the level of alcohol dehydrogenase expression in Drosophila melanogaster, is due to multiple polymorphisms within the Adh gene. These polymorphisms are located in an intron, the coding sequence, and the 3′ untranslated region. Becaus... | 10.1038/nrg3627 | This classic paper uses P-element transformation to create all possible combinations of three segments of the Adh gene and showed that each of the three segments affects Adh activity, and that there is, surprisingly, epistasis between two different regions within the gene. |
10.1111/j.1365-2958.1992.tb02202.x | 125,154,176 | Summary Up to 36% of Neurospora crassa transformants showing an albino phenotype were recovered by transforming a wild‐type strain with different portions of the carotenogenic albino‐3 (al‐3) and albino‐1 (al‐1) genes. The presence of the exogenous sequences (which were randomly integrated in ectopic locations) provoke... | 10.1038/nrm1129 | Evidence that the ectopic expression of segments of transgenes leads to silencing of the endogenous homologues. This process is known as 'quelling' in Neurospora and is related to PTGS in plants and RNAi in animals. |
10.1126/science.287.5462.2494 | 79,651,251 | In Caenorhabditis elegans , the introduction of double-stranded RNA triggers sequence-specific genetic interference (RNAi) that is transmitted to offspring. The inheritance properties associated with this phenomenon were examined. Transmission of the interference effect occurred through a dominant extragenic agent. The... | 10.1038/nrm1129 | This study begins to assemble the genes that are involved in RNAi into a pathway and explain the genetic requirements of inheritance of RNAi phenotypes from parents to offspring. |
10.1126/science.1062961 | 125,244,068 | The 21-nucleotide small temporal RNA (stRNA) let-7 regulates developmental timing in Caenorhabditis elegans and probably in other bilateral animals. We present in vivo and in vitro evidence that in Drosophila melanogaster a developmentally regulated precursor RNA is cleaved by an RNA interference-like mechanism to prod... | 10.1038/nrm1129 | MicroRNAs are genetically related to siRNAs by Dicer processing, and the silencing of Dicer led to accumulation of the prototype microRNA precursor of let-7 |
10.1126/science.1067081 | 122,348,256 | Single-cell mouse embryos were infected in vitro with recombinant lentiviral vectors to generate transgenic mice carrying the green fluorescent protein (GFP) gene driven by a ubiquitously expressing promoter . Eighty percent of founder mice carried at least one copy of the transgene, and 90% of these expressed GFP at h... | 10.1038/nrm1129 | Lentiviral vectors are efficient vehicles for gene delivery to embryos and they enable the efficient production of transgenic animals. The lentiviral vector described is the parent vector for many of the lentiviral vectors being used at present to deliver small RNAs. |
10.1126/science.1062538 | 81,044,023 | Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of ... | 10.1038/nrc3317 | This paper describes the T315I point mutation and BCR-ABL1 gene amplification as mechanisms of clinical resistance to BCR-ABL1 tyrosine kinase inhibitors. |
10.1126/science.1099480 | 62,262,965 | Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive t... | 10.1038/nrc3317 | This study that introduced dasatinib underscores the importance of rational design for the production of second-generation targeted therapies. |
10.1038/srep12298 | 17,349,983 | Abstract Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we... | 10.1038/nrd.2016.233 | Network analysis of transcriptomic data pinpointed response-associated molecular modules and hubs that could be targeted to improve the response rate. |
10.1126/science.1158013 | 101,021,260 | In T cells, the stochasticity of protein expression could contribute to the useful diversification of biological functions within a clonal population or interfere with accurate antigen discrimination. Combining computer modeling and single-cell measurements, we examined how endogenous variation in the expression levels... | 10.1038/nrd.2016.233 | This paper provides an example of how randomness at a cellular level is managed to enable controlled variability at a population level. |
10.1038/sj.icb.7100061 | 77,471,608 | Regulating the strength and class of an immune response requires lymphocytes to act as complex signal integrating ‘machines’, taking information from multiple sources while making decisions that affect the final outcome. Describing and understanding the decision‐making behaviour of lymphocytes within the context of the... | 10.1038/nrd.2016.233 | References 44 63 and 65 provide insightful perspectives on how the immune system functions on a systems level and how this function is shaped on a lower level through random and probabilistic events. |
10.1038/srep17501 | 122,104,901 | Abstract Identifying early-warning signals of a critical transition for a complex system is difficult, especially when the target system is constantly perturbed by big noise, which makes the traditional methods fail due to the strong fluctuations of the observed data. In this work, we show that the critical transition ... | 10.1038/nrd.2016.233 | References 72 73 74 75 report on the development of mathematical models to identify dynamic network biomarkers that can predict a critical transition from a healthy to a disease state. |
10.1126/science.aaa1193 | 125,099,511 | The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interc... | 10.1038/nrm.2017.66 | References 17 and 18 resolve the structure of the intact mammalian 55S mitochondrial ribosome using cryo-electron microscopy. |
10.1126/science.1112125 | 103,816,998 | Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulati... | 10.1038/nrm.2017.66 | References 26 and 27 show that accumulation of mtDNA mutations in mice leads to premature ageing. |
10.1083/jcb.201504062 | 80,628,866 | Mitochondrial ribosomes synthesize a subset of hydrophobic proteins required for assembly of the oxidative phosphorylation complexes. This process requires temporal and spatial coordination and regulation, so quality control of mitochondrial protein synthesis is paramount to maintain proteostasis. We show how impaired ... | 10.1038/nrm.2017.66 | This report shows how defects in the quality control of de novo synthesized mitochondrial proteins triggers OMA1 activation and OPA1 processing because of a proteotoxic stress in the membrane. |
10.1126/science.aac6054 | 18,945,947 | Spatial control of cellular enzymes Purine is a building block of DNA and also a component of ATP that is used as an energy source in the cell. Enzymes involved in purine biosynthesis organize into dynamic bodies called purinosomes. French et al. found that purinosomes colocalize with mitochondria, organelles that gene... | 10.1038/nrm.2017.66 | References 90 and 91 establish the link between mitochondrial folate cycle, mTORC1 and purine synthesis. |
10.1126/science.aad9642 | 62,246,695 | Thriving on a breath of low oxygen Mitochondrial diseases are debilitating and largely untreatable. Most are caused by genetic mutations that impair the mitochondrial respiratory chain, which generates cellular energy. Because these diseases do not affect all tissues equally, it is thought that endogenous mechanisms ex... | 10.1038/nrm.2017.66 | This report indicates that oxygen may have a role in mitochondrial disease progression, and that induction of hypoxia-signalling pathways by chronic hypoxia improves the condition of mice that have mitochondrial disease. |
10.1126/science.277.5332.1669 | 62,007,714 | Cytotrophoblasts, specialized placental cells, proliferate early in pregnancy and then differentiate into tumor-like cells that establish blood flow to the placenta by invading the uterus and its vasculature. In this study, cytotrophoblasts cultured under hypoxic conditions (2 percent oxygen), mimicking the environment... | 10.1038/nrm2354 | This article was the first to demonstrate that progenitor cell proliferation and differentiation is regulated in response to changes in O 2 availability. |
10.1101/gad.934301 | 128,873,053 | Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1α. A key ... | 10.1038/nrm2354 | This is among the first of many articles using a conditional allele of HIF1α to show that hypoxic microenvironments specifically regulate developing progenitor cells during organ formation. |
10.1101/gad.1399906 | 39,300,782 | The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including oxygen availability. Using a genetic “knock-in” strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1α with HIF-2α re... | 10.1038/nrm2354 | This article first connected the pluripotent OCT4 transcription factor to changes in O 2 availability. |
10.1073/pnas.93.18.9493 | 83,244,087 | We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and from other more hypoxia sensitive systems. We propose that the response of hypoxia tolerant systems to oxygen lack occurs i... | 10.1038/nrm2354 | Among the first articles to show that O 2 deprivation is tolerated by altered intracellular metabolic pathways to conserve ATP. |
10.1126/science.284.5423.2124 | 18,691,057 | From comparative analyses of the nucleotide sequences of genes encoding ribosomal RNAs and several proteins, molecular phylogeneticists have constructed a “universal tree of life,” taking it as the basis for a “natural” hierarchical classification of all living things. Although confidence in some of the tree's early br... | 10.1038/nrg929 | Describes how the finding of large amounts of horizontal gene transfer, as inferred from phylogenetic analyses of sequence data, has reshaped our view of the 'tree of life'. |
10.1073/pnas.94.24.13028 | 60,222,798 | A recent study of the divergence times of the major groups of organisms as gauged by amino acid sequence comparison has been expanded and the data have been reanalyzed with a distance measure that corrects for both constraints on amino acid interchange and variation in substitution rate at different sites. Beyond that,... | 10.1038/nrg929 | An update of the influential 1996 Science paper from the laboratory of Russell Doolittle, one of the first to use large numbers of genes or proteins to date early events in the history of life. |
10.1128/mmbr.62.4.1435-1491.1998 | 28,226,106 | SUMMARY The presence of shared conserved insertion or deletions (indels) in protein sequences is a special type of signature sequence that shows considerable promise for phylogenetic inference. An alternative model of microbial evolution based on the use of indels of conserved proteins and the morphological features of... | 10.1038/nrg929 | Provides a detailed and often overlooked critique of the evidence bearing on the origin of mitochondria and on the number of symbiotic events (and gene transfers) that occurred in the origin of eukaryotes. |
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