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10.1186/1741-7007-4-8 | 16,678,698 | Abstract Background Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function o... | 10.1038/nn.4114 | This work demonstrated that CRF acts in the NAc to enhance the effects of Pavlovian stimuli on instrumental behavior |
10.1098/rstb.1985.0010 | 62,135,822 | The study of animal behaviour has been dominated by two general models. According to the mechanistic stimulus-response model, a particular behaviour is either an innate or an acquired habit which is simply triggered by the appropriate stimulus. By contrast, the teleological model argues that, at least, some activities ... | 10.1038/nn.4114 | This paper proposed that goal-directed actions could become habits depending on the nature and extent of training. This is now the predominant view of habit formation |
10.1126/science.1171203 | 20,514,530 | The ability to shift between different behavioral strategies is necessary for appropriate decision-making. Here, we show that chronic stress biases decision-making strategies, affecting the ability of stressed animals to perform actions on the basis of their consequences. Using two different operant tasks, we revealed ... | 10.1038/nn.4114 | This study found that chronic unpredictable stress causes habit formation in rats and concomitant anatomical alterations in corticostriatal circuits associated with goal-directed versus habitual behavior |
10.1073/pnas.1208342109 | 83,033,006 | Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, altho... | 10.1038/nn.4114 | This paper showed that exogenous elevation of stress-related signals promotes habitual behavior, whereas medial prefrontal neurotrophins mediate motivation to seek reward |
10.1073/pnas.1312011110 | 125,257,104 | Significance The physiological response evoked by short-lived stressful events, referred to as acute stress, impacts human decision-making. Past studies assume that stress causes people to fall back, from more cognitive or deliberative modes of choice, to more primitive or automatic modes of choice because stress impai... | 10.1038/nn.4114 | This paper reported that acute cold-pressor stress in humans selectively disrupted model-based valuation processes that underlie cognitive and deliberative decision-making |
10.1126/science.280.5366.1082 | 38,212,327 | RasGRP, a guanyl nucleotide–releasing protein for the small guanosine triphosphatase Ras, was characterized. Besides the catalytic domain, RasGRP has an atypical pair of “EF hands” that bind calcium and a diacylglycerol (DAG)-binding domain. RasGRP activated Ras and caused transformation in fibroblasts. A DAG analog ca... | 10.1038/nrc2960 | This study provided an important demonstration of an alternative mode of RasGEF regulation, by diacylglycerol-mediated recruitment to the plasma membrane. As PLC isoforms function downstream of cell surface receptors that are aberrantly activated in cancer, this provided another example of how Ras may be activated thro... |
10.1038/sj.embor.embor899 | 123,129,027 | The monomeric RAL (RAS‐like) GTPases have been indirectly implicated in mitogenic regulation and cell transformation. Here, we show that RALA and RALB collaborate to maintain tumorigenicity through regulation of both proliferation and survival. Remarkably, this task is divided between these highly homologous isoforms. ... | 10.1038/nrc2960 | This study showed that the two highly related substrates of RalGEFs may have highly divergent roles in normal and neoplastic cell growth and survival. |
10.1126/science.1173569 | 81,530,025 | Reigning In Tumor Suppression Mitogenic signaling through phosphoinositide-3 kinase generates the lipid second messenger phosphatidyl inositol 3,4,5-trisphosphate (PIP3). The tumor suppressor gene product and lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10) opposes such mitogenic signaling by de... | 10.1038/nrc2960 | This paper identified a function for a RacGEF that is distinct from its activation of Rac, in which direct association with the PTEN tumour suppressor caused activation of PI3K signalling. |
10.1073/pnas.040569197 | 84,481,321 | We have identified a gene at 11q23, telomeric to MLL , that encodes a guanine nucleotide exchange factor (GEF). This gene is transcribed into a 9.5-kb mRNA containing a 4.6-kb ORF. By Northern analysis, it was found to be expressed in all human tissues examined including peripheral blood leukocytes, spleen, prostate, t... | 10.1038/nrc2960 | This paper identified a rearranged gene in an acute myelogenous leukaemia that encoded a chimeric protein that altered the structure of a RhoGEF. |
10.1101/gad.1672608 | 16,830,175 | Deletions on chromosome 8p are common in human tumors, suggesting that one or more tumor suppressor genes reside in this region. Deleted in Liver Cancer 1 ( DLC1 ) encodes a Rho-GTPase activating protein and is a candidate 8p tumor suppressor. We show that DLC1 knockdown cooperates with Myc to promote hepatocellular ca... | 10.1038/nrc2960 | This study found that the rate of genetic loss of the RhoGAP DLC1 approaches that of the TP53 tumour suppressor in some cancers, and it demonstrated a clear role for RhoGAP loss in tumorigenesis in a mouse model of liver cancer. |
10.1126/science.280.5372.2112 | 79,485,769 | Signaling pathways that link extracellular factors to activation of the monomeric guanosine triphosphatase (GTPase) Rho control cytoskeletal rearrangements and cell growth. Heterotrimeric guanine nucleotide–binding proteins (G proteins) participate in several of these pathways, although their mechanisms are unclear. Th... | 10.1038/nrc2960 | This study identified a RhoGEF downstream of GPCR signalling through Gα 13 , and established another indirect mechanism for Rho GTPase activation in cancer. |
10.1152/physrev.00016.2011 | 62,657,377 | Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surro... | 10.1038/nrdp.2016.37 | A comprehensive paper providing new insights in coagulation physiology and pathology. |
10.1126/science.1092385 | 20,833,731 | Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) ... | 10.1038/nrdp.2016.37 | This study highlighted the importance of innate immune activation and its coupling to DIC. The study described important pathophysiological roles of NETs. |
10.1186/s13054-015-0810-3 | 20,372,976 | Abstract Introduction The safety and efficacy of recombinant human soluble thrombomodulin (rhTM) have been demonstrated, with promising evidence suggestive of efficacy for patients with severe sepsis involving coagulopathy in a phase IIb randomized controlled trial. However, the benefit profiles of rhTM have not been e... | 10.1038/nrdp.2016.37 | The results reported in this paper indirectly support the concept that the target of anticoagulant factor concentrates is not severe sepsis, but severe sepsis with established DIC. |
10.1073/pnas.0805270106 | 62,240,104 | Coronaviruses are enveloped viruses containing the largest reported RNA genomes. As a result of their pleomorphic nature, our structural insight into the coronavirion is still rudimentary, and it is based mainly on 2D electron microscopy. Here we report the 3D virion structure of coronaviruses obtained by cryo-electron... | 10.1038/nrmicro2147 | This paper and Ref. 3 use novel methodologies to obtain detailed models of the structure of the intact coronavirion. |
10.1126/science.1118391 | 62,602,310 | Severe acute respiratory syndrome (SARS) emerged in 2002 to 2003 in southern China. The origin of its etiological agent, the SARS coronavirus (SARS-CoV), remains elusive. Here we report that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak. These viruses, te... | 10.1038/nrmicro2147 | This paper and Ref. 80 show that SARS-CoV probably originated in bats. |
10.1073/pnas.0808116105 | 20,611,924 | Defining prospective pathways by which zoonoses evolve and emerge as human pathogens is critical for anticipating and controlling both natural and deliberate pandemics. However, predicting tenable pathways of animal-to-human movement has been hindered by challenges in identifying reservoir species, cultivating zoonotic... | 10.1038/nrmicro2147 | This manuscript describes the engineering of a non-cultivable bat SARS-like coronavirus using synthetic DNA technology. |
10.1073/pnas.0603144103 | 62,481,885 | Severe acute respiratory syndrome (SARS) coronavirus (SCoV) causes a recently emerged human disease associated with pneumonia. The 5′ end two-thirds of the single-stranded positive-sense viral genomic RNA, gene 1, encodes 16 mature proteins. Expression of nsp1, the most N-terminal gene 1 protein, prevented Sendai virus... | 10.1038/nrmicro2147 | Describes a novel mechanism of viral protein-induced inhibition of host gene expression. |
10.1002/ana.24019 | 82,790,001 | Objective Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake‐promoting system. As cerebrospinal fluid histamine levels may be low in patients wit... | 10.1038/nrdp.2016.100 | References 102 and 103 simultaneously describe that patients with NT1 have increased numbers of histaminergic neurons in the brain. |
10.1126/science.289.5480.739 | 41,560,733 | Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane α helices connected by six loops of varying lengths. We determined the struc... | 10.1038/nrd913 | This landmark paper showing the crystal structure of rhodopsin represents the first and only determination of a high-resolution, three-dimensional structure for a family 1 GPCR. |
10.1091/mbc.01-10-0525 | 103,742,494 | In many cells endosomal vacuoles show clathrin coats of which the function is unknown. Herein, we show that this coat is predominantly present on early endosomes and has a characteristic bilayered appearance in the electron microscope. By immunoelectron miscroscopy we show that the coat contains clathrin heavy as well ... | 10.1038/nrm2162 | References 21 and 24 provide evidence that ubiquitylated receptors are sorted at endosomes via HRS and clathrin, and clathrin in turn restricts the distribution of HRS (reference 26). |
10.1242/jcs.02421 | 125,091,099 | The early endosome comprises morphologically distinct regions specialised in sorting cargo receptors. A central question is whether receptors move through a predetermined structural pathway, or whether cargo selection contributes to the generation of endosome morphology and membrane flux. Here, we show that depletion o... | 10.1038/nrm2162 | References 15 and 54 show that in mammalian cells ESCRT-I depletion results in extensive tubulation and prevents ILVs formation, whereas HRS depletion produces enlarged, spherical MVBs with few ILVs. |
10.1091/mbc.11.10.3365 | 102,159,769 | The Saccharomyces cerevisiae DOA4 gene encodes a deubiquitinating enzyme that is required for rapid degradation of ubiquitin–proteasome pathway substrates. Both genetic and biochemical data suggest that Doa4 acts in this pathway by facilitating ubiquitin recycling from ubiquitinated intermediates targeted to the protea... | 10.1038/nrm2162 | References 77, 111 and 113 demonstrate a requirement for a DUB in the endocytic pathway in yeast. |
10.1083/jcb.200606113 | 59,412,724 | The sorting of transmembrane cargo proteins into the lumenal vesicles of multivesicular bodies (MVBs) depends on the recruitment of endosomal sorting complexes required for transport (ESCRTs) to the cytosolic face of endosomal membranes. The subsequent dissociation of ESCRT complexes from endosomes requires Vps4, a mem... | 10.1038/nrm2162 | Reference 80 demonstrates that Did2 has an important role in Vps4-mediated disassembly of ESCRT-III but not of ESCRT-I and-II, that ILV formation can be uncoupled from ESCRT-III disassembly and that class E compartments can have either multilammelar structures without ILVs ( vps4Δ ) or tubular structures with ILVs ( di... |
10.1083/jcb.200401141 | 102,304,884 | The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif has been proposed to provide the active site for isopeptidase activity associated with the Rpn11/POH1 subunit of the 19S-proteasome and the Csn5-subunit of the signalosome. We have looked for similar activity in associated molecule with the SH3 domain of STAM (AMSH), a JAMM... | 10.1038/nrm2162 | Reference 85 shows that AMSH is a Lys63-ubiquitin-chain specific DUB that has a role in sorting a growth-factor receptor at endosomes, and is recruited to CHMPs (shown in references 25, 84 and 88). |
10.1111/j.1600-0854.2006.00452.x | 29,293,773 | Monoubiquitination of endocytosed cell surface receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. The sorting of ubiquitinated proteins is executed by concerted actions of class E vacuolar protein sorting (Vps) proteins. Some proteins in the sorting machinery undergo monoubiquitinat... | 10.1038/nrm2162 | References 120, 121 and 75 report on a key role for the DUB UBPY in receptor downregulation and endosomal ubiquitin dynamics. |
10.1126/science.1092425 | 81,391,013 | What are the components that control the assembly of subcellular organelles in eukaryotic cells? Although membranes can clearly be distorted by cytosolic factors, very little is known about the intrinsic mechanisms that control the biogenesis, shape, and organization of organellar membranes. Here, we found that the unc... | 10.1038/nrm2162 | Highlights that not only proteins, but also lipids (lysobisphosphatidic acid (LBPA) in this case) can have crucial roles in forming MVBs. |
10.1126/science.277.5322.55 | 125,327,431 | Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell–specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mo... | 10.1038/nrc2894 | First report about the identification of ANGPT2, the overexpression of ANGPT2 is shown to be embyronically lethal similar to the loss of ANGPT1 or TIE2. |
10.7554/elife.02676 | 17,648,804 | Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somew... | 10.1038/nrg3897 | This study identifies a basic cluster in MeCP2 that binds to DNA, and shows that this interaction is impaired by the RTT-causing R306C mutation. |
10.1126/science.1138389 | 41,682,339 | Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns pheno... | 10.1038/nrg3897 | This study shows that the neurological deficits observed in MeCP2-mutant mice can be largely reversed by re-expression of the protein after symptoms have developed. |
10.1126/science.1153252 | 100,394,438 | Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorde... | 10.1038/nrg3897 | This expression analysis of brain regions from Mecp2 -null mice and MeCP2-overexpressing mice reveals many genes that are positively and negatively regulated by MeCP2. |
10.1111/apt.12052 | 80,935,686 | Summary Background Sustained acid inhibition with PPI stimulates gastrin secretion, exerting a proliferative drive on enterochromaffin‐like cells ( ECL cells) of the oxyntic mucosa. It may also accelerate development of gastric gland atrophy in H elicobacter pylori ‐infected individuals. Aims To evaluate gastric exocri... | 10.1038/nrgastro.2017.117 | A controlled study on the long-term effect of PPIs on endocrine and exocrine gastric cells. |
10.1111/apt.13324 | 20,587,865 | Summary Background Proton pump inhibitors ( PPI s) have a well‐established safety profile. However, concerns have been raised about a potential relationship between PPI ‐induced hypergastrinaemia and the development of enterochromaffin‐like ( ECL ) cell hyperplasia, neuroendocrine tumours and gastric cancer during long... | 10.1038/nrgastro.2017.117 | This systematic review reports on long-term PPI-induced moderate hypergastrinaemia in most patients and an increased prevalence of enterochromaffin-like cell hyperplasia; Helicobacter pylori -positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than were H. pylori -negative ... |
10.1017/ice.2016.194 | 122,901,690 | BACKGROUND Clostridium difficile is the principal infectious cause of antibiotic-associated diarrhea and accounts for 12% of hospital-acquired infections. Recent literature has shown an increased risk of C. difficile infection (CDI) with proton pump inhibitor (PPI) use. OBJECTIVE To conduct a systematic assessment of t... | 10.1038/nrgastro.2017.117 | A meta-analysis suggesting an almost twofold increased risk of hospital-acquired Clostridium difficile infection in patients on PPIs. |
10.1002/hep.28737 | 20,269,004 | Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis... | 10.1038/nrgastro.2017.117 | A relevant study showing that PPIs increase the risk of developing hepatic encephalopathy and spontaneous bacterial peritonitis in patients with liver cirrhosis. |
10.1111/apt.13304 | 18,314,443 | Summary Background Debate continues on whether a causal association exists between the use of proton pump inhibitors ( PPI s) and the risk of respiratory tract infections, in particular pneumonia. Aim To investigate the occurrence of community‐acquired respiratory tract infections, including pneumonia, in patients rece... | 10.1038/nrgastro.2017.117 | A large cohort study of a PPI (esomeprazole) that disproves the risk of community-acquired pneumonia. |
10.1111/apt.13194 | 20,364,710 | Summary Background Control of chronic gastro‐oesophageal reflux disease may be achieved either by anti‐reflux surgery ( ARS ) or by long‐term medical therapy with proton pump inhibitors ( PPI s). The primary efficacy results of the SOPRAN study, comparing long‐term omeprazole use with open ARS , and the LOTUS study, co... | 10.1038/nrgastro.2017.117 | This study shows data from controlled randomized trials with reassuring findings on long-term PPI use, electrolytes and micronutrients. |
10.1126/science.1204333 | 101,502,064 | A collective electron excitation displays an unusual dependence on an applied magnetic field. | 10.1038/nnano.2013.161 | This article presents combined theoretical and experimental work on the formation of Hubbard split bands in a 2DEG subject to a honeycomb periodic potential and a perpendicular magnetic field. |
10.1126/science.271.5256.1734 | 41,614,572 | One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activat... | 10.1038/nri2744 | The first report that CTLA4 blockade can enhance antitumour immunity and promote tumour clearance. |
10.1084/jem.20011097 | 1,353,298 | The mechanism of antitumor effect of monoclonal antibodies (mAbs) is not fully understood. Here we show that coating myeloma cells with anti–syndecan-1 antibody promotes cross-presentation of cellular antigens by dendritic cells (DCs) to autologous T cells from healthy donors. The tumor cells treated with anti–syndecan... | 10.1038/nri2744 | An important study describing cross-presentation as one potential mechanism of action of cancer-specific monoclonal antibodies. |
10.4049/jimmunol.1103253 | 84,364,925 | Abstract Systemic bacterial infection is rapidly recognized as an emergency state leading to neutrophil release into the circulation and increased myeloid cell production within the bone marrow. However, the mechanisms of sensing infection and subsequent translation into emergency myelopoiesis have not been defined. In... | 10.1038/nri3660 | This study reveals for the first time that, in contrast to popular belief, it is not haematopoietic but non- haematopoietic cells that are the primary cell type that translates the sensing of systemically disseminated LPS into an emergency granulopoiesis response, through an increase in the production of G-CSF. |
10.1182/blood.v84.6.1737.1737 | 103,673,682 | Abstract Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30%... | 10.1038/nri3660 | A seminal in vivo study showing that G-CSF is an essential haematopoietic growth factor for granulocyte homeostasis in the steady state and during emergency granulopoiesis. |
10.1182/blood-2009-12-259630 | 42,573,696 | Abstract Granulocyte colony-stimulating factor (G-CSF) mediates “emergency” granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional delet... | 10.1038/nri3660 | The authors show that G-CSF-induced signal transduction in myeloid progenitors during G-CSF- or L. monocytogenes -driven emergency granulopoiesis occurs via STAT3 and results in increased myeloid progenitor cell proliferation. |
10.1126/science.1171461 | 41,261,226 | Making the Choice The importance of cytokine signals for the generation of specific blood lineages is well known. However, whether cytokines only influence survival and proliferation of cells that have already committed to one lineage, or if they also influence the lineage choice is unclear. For decades, researchers di... | 10.1038/nri3660 | This elegant study shows that the haematopoietic cytokines G-CSF and M-CSF directly instruct lineage choice in bipotent granulocyte–macrophage progenitors. |
10.1073/pnas.94.2.569 | 41,599,601 | Transcription factors are master regulatory switches of differentiation, including the development of specific hematopoietic lineages from stem cells. Here we show that mice with targeted disruption of the CCAAT enhancer binding protein α gene ( C/EBPα ) demonstrate a selective block in differentiation of neutrophils. ... | 10.1038/nri3660 | This study shows that C/EBPα is essential for steady-state granulopoiesis. |
10.1084/jem.20041419 | 59,267,980 | The coordinated production of leukocytes in bone marrow is crucial for innate and adaptive immunity. Inflammation alters normal leukocyte production by promoting granulopoiesis over lymphopoiesis, a response that supports the reactive neutrophilia that follows infection. Here we demonstrate that this specialization for... | 10.1038/nri3660 | The authors of this study propose a model of competition for space and growth factors between B lymphopoiesis and granulopoiesis, in which inflammation depletes the B cell content in bone marrow leading to reactive granulopoiesis. |
10.1146/annurev-genet-111212-133424 | 62,527,467 | Cells use messenger RNAs (mRNAs) to ensure the accurate dissemination of genetic information encoded by DNA. Given that mRNAs largely direct the synthesis of a critical effector of cellular phenotype, i.e., proteins, tight regulation of both the quality and quantity of mRNA is a prerequisite for effective cellular home... | 10.1038/nrm.2015.7 | References 5–7 provided the first evidence of splicing-dependent NMD in mammals. |
10.1101/gad.1389006 | 123,066,873 | Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNA containing premature termination codons (PTCs). In mammalian cells, recognition of PTCs requires translation and depends on the presence on the mRNA with the splicing-dependent exon junction complex (EJC). While it is known that a key eve... | 10.1038/nrm.2015.7 | This study defines the stepwise assembly of NMD complexes in human. |
10.1101/gad.245829.114 | 39,832,993 | The exon junction complex (EJC) is a highly conserved ribonucleoprotein complex that binds RNAs during splicing and remains associated with them following export to the cytoplasm. While the role of this complex in mRNA localization, translation, and degradation has been well characterized, its mechanism of action in sp... | 10.1038/nrm.2015.7 | References 91 and 92 document studies in D. melanogaster showing that depositing EJC proteins at piwi transcripts can enhance the splicing of neighbouring weak introns. |
10.4049/jimmunol.179.6.3724 | 100,426,979 | Abstract In this study, we report a novel biological function of vitamin A metabolites in conversion of naive FoxP3− CD4+ T cells into a unique FoxP3+ regulatory T cell subset (termed “retinoid-induced FoxP3+ T cells”) in both human and mouse T cells. We found that the major vitamin A metabolite all-trans-retinoic acid... | 10.1038/nri2335 | These papers, together with reference 10, demonstrated an important role for populations of MLN DCs, lamina propria DCs and lamina propria macrophages in the generation of FOXP3 + T Reg cells from naive peripheral CD4 + T cells. This was found to be mediated in part by retinoic acid, which enhanced TGFβ-mediated induct... |
10.1126/science.1132742 | 104,150,595 | Normal intestinal mucosa contains abundant immunoglobulin A (IgA)–secreting cells, which are generated from B cells in gut-associated lymphoid tissues (GALT). We show that dendritic cells (DC) from GALT induce T cell–independent expression of IgA and gut-homing receptors on B cells. GALT-DC–derived retinoic acid (RA) a... | 10.1038/nri2335 | This study showed that gut-associated lymphoid tissue DCs could promote expression of gut-homing receptors by B cells. This was mediated by retinoic acid. Retinoic acid also synergized with IL-5 and IL-6 to promote secretion of IgA. |
10.1073/pnas.0237043100 | 80,459,018 | The recombination-activating gene (RAG)1 and RAG2 proteins comprise the lymphocyte-specific components of the V(D)J recombinase and are required for the assembly of antigen-receptor variable-region genes. A mutant truncated RAG2 protein (“core” RAG2) lacking the C-terminal 144 amino acids, together with core RAG1, is a... | 10.1038/nri1247 | References 17 and 18 describe the development of knock-in mice that express only the core of recombinase-activating gene 2 (Rag2), showing the absolute requirement of full length Rag2 for the proper rearrangement of endogenous immuno-globulin and T-cell receptor (TCR) loci in vivo |
10.1073/pnas.0437964100 | 102,740,415 | DNA nonhomologous end-joining (NHEJ) is the major pathway for repairing DNA double-strand breaks in mammalian cells. It also functions to carry out rearrangements at the specialized breaks introduced during V(D)J recombination. Here, we describe a patient with T − B − severe combined immunodeficiency, whose cells have ... | 10.1038/nri1247 | This report indicates the existence of additional unknown factors in V(D)J recombination/DNA repair. |
10.1073/pnas.0730835100 | 123,062,346 | The expression of activation-induced cytidine deaminase (AID) is prerequisite to a “trifecta” of key molecular events in B cells: class-switch recombination and somatic hypermutation in humans and mice and gene conversion in chickens. Although this critically important enzyme shares common sequence motifs with apolipop... | 10.1038/nri1247 | This paper shows the action of AID on single-stranded DNA. |
10.1101/gad.188284.112 | 20,488,991 | Protein ubiquitylation and sumoylation play key roles in regulating cellular responses to DNA double-strand breaks (DSBs). Here, we show that human RNF4, a small ubiquitin-like modifier (SUMO)-targeted ubiquitin E3 ligase, is recruited to DSBs in a manner requiring its SUMO interaction motifs, the SUMO E3 ligases PIAS1... | 10.1038/nrc.2016.143 | Using microscopy and in vivo laser microablation techniques, references 79–81 demonstrate the direct roles of sumoylation at DNA double-strand breaks through the recruitment of SUMO-targeted and SUMO-regulated ubiquitin ligases. |
10.1126/science.1212728 | 124,075,628 | Taking the Myc Despite nearly 30 years of research into the mechanisms by which Myc oncogene dysregulation contributes to tumorigenesis, there are still no effective therapies that inhibit Myc activity. Kessler et al. (p. 348 , published online 8 December; see the Perspective by Evan ) searched for gene products that s... | 10.1038/nrc.2016.143 | Provides evidence from a synthetic lethal screen in RAS-driven breast cancer cells of the concept of non-oncogene addiction pertaining to sumoylation. |
10.1073/pnas.1415569112 | 48,667,201 | The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant ... | 10.1038/nrc.2016.143 | Shows that growth of RAS-driven colorectal cancer cells require sumoylation of chromatin regulators such as KAP1, thus providing further evidence for the role of sumoylation in non-oncogene addiction. |
10.1083/jcb.201204161 | 67,249,030 | A growing number of transcriptional regulatory proteins are known to be modified by the small ubiquitin-like protein, SUMO. Posttranslational modification by SUMO may be one means by which transcriptional regulatory factors that play context-dependent roles in multiple processes can be regulated such that they direct t... | 10.1038/nrc.2016.143 | A nice illustration of the importance of sumoylation in attenuating synergy between two transcription factors, MITF and SOX9. |
10.1073/pnas.0804612105 | 17,716,392 | Low-cost and high-resolution on-chip microscopes are vital for reducing cost and improving efficiency for modern biomedicine and bioscience. Despite the needs, the conventional microscope design has proven difficult to miniaturize. Here, we report the implementation and application of two high-resolution (≈0.9 μm for t... | 10.1038/nmeth.2114 | This work introduces an optofluidic lens-free microscope that is based on sampling of flowing object shadows |
10.1073/pnas.1110681108 | 101,118,483 | We report a chip-scale lensless wide-field-of-view microscopy imaging technique, subpixel perspective sweeping microscopy, which can render microscopy images of growing or confluent cell cultures autonomously. We demonstrate that this technology can be used to build smart Petri dish platforms, termed ePetri, for cell c... | 10.1038/nmeth.2114 | This work introduces contact-mode lens-free shadow imaging of static objects |
10.1083/jcb.130.4.941 | 19,646,318 | During mitosis in Ptk1 cells anaphase is not initiated until, on average, 23 +/- 1 min after the last monooriented chromosome acquires a bipolar attachment to the spindle--an event that may require 3 h (Rieder, C. L., A. Schultz, R. W. Cole, and G. Sluder. 1994. J. Cell Biol. 127:1301-1310). To determine the nature of ... | 10.1038/nrm3132 | A classic paper showing that unattached kinetochores are the source of the signal that prevents anaphase. |
10.1242/dev.02883 | 62,326,744 | The embryonic heart and vessels are dynamic and form and remodel while functional. Much has been learned about the genetic mechanisms underlying the development of the cardiovascular system, but we are just beginning to understand how changes in heart and vessel structure are influenced by hemodynamic forces such as sh... | 10.1038/nrm2596 | Provides elegant evidence that fluid shear stress mediates the rearrangement of a primitive vascular plexus into a mature vascular tree in early mouse embryos. |
10.1073/pnas.102184999 | 109,160,555 | Endothelial cells (ECs) line the mammalian vascular system and respond to the hemodynamic stimulus of fluid shear stress, the frictional force produced by blood flow. When ECs are exposed to shear stress, one of the fastest responses is an increase of K + conductance, which suggests that ion channels are involved in th... | 10.1038/nrm2596 | Shows that an inward-rectifying K + channel opens in response to flow and analyzes the mechanism of activation. |
10.4049/jimmunol.155.3.1151 | 139,038,805 | Abstract Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inocu... | 10.1038/nri1806 | This paper proposed CD25 as a surface marker of CD4 + regulatory T cells. |
10.1084/jem.20011603 | 45,024,500 | Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid den... | 10.1038/nri1806 | References 17?19 report that human plasmacytoid dendritic cells can induce CD8 + regulatory T cells. |
10.4049/jimmunol.163.10.5211 | 139,067,451 | Abstract This study shows that removal of a T cell subpopulation can evoke effective tumor immunity in otherwise nonresponding animals. Elimination of CD25-expressing T cells, which constitute 5–10% of peripheral CD4+ T cells in normal naive mice, elicited potent immune responses to syngeneic tumors in vivo and eradica... | 10.1038/nri1806 | References 24 and 25 are the first reports that depletion of CD25 + cells, probably CD4 + CD25 + T cells, improves or promotes tumour immunity in mice. |
10.4049/jimmunol.174.5.2591 | 107,150,912 | Abstract CD4+ T cells control the effector function, memory, and maintenance of CD8+ T cells. Paradoxically, we found that absence of CD4+ T cells enhanced adoptive immunotherapy of cancer when using CD8+ T cells directed against a persisting tumor/self-Ag. However, adoptive transfer of CD4+CD25− Th cells (Th cells) wi... | 10.1038/nri1806 | References 40, 41 and 42 provide a direct functional link between CD4 + CD25 + T cells and tumour immunopathogenesis in tumour patients and in tumour-bearing mice, respectively. |
10.1073/pnas.0830997100 | 61,475,991 | A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cell... | 10.1038/nri1806 | References 53 and 54 report clinical trials that show that CTLA4 blockade can induce tumour regression as well as severe, but manageable, autoimmune diseases in patients with tumours. |
10.1084/jem.20051511 | 62,607,899 | Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling i... | 10.1038/nri1806 | The first in vivo study demonstrating a role of CD4 + CD25 + T cells in blunting the NK-cell arm of the innate immune system in tumour immunity. |
10.1126/science.1243982 | 62,591,516 | Unrestricted Travel in Solar Cells In the past 2 years, organolead halide perovskites have emerged as a promising class of light-harvesting media in experimental solar cells, but the physical basis for their efficiency has been unclear (see the Perspective by Hodes ). Two studies now show, using a variety of time-resol... | 10.1038/nnano.2015.90 | References 42 and 79 reported for the first time the long charge carrier diffusion lengths in perovskites. |
10.1126/science.1243167 | 20,831,971 | Unrestricted Travel in Solar Cells In the past 2 years, organolead halide perovskites have emerged as a promising class of light-harvesting media in experimental solar cells, but the physical basis for their efficiency has been unclear (see the Perspective by Hodes ). Two studies now show, using a variety of time-resol... | 10.1038/nnano.2015.90 | References 42 and 79 reported for the first time the long charge carrier diffusion lengths in perovskites. |
10.1146/annurev.cellbio.22.010305.104258 | 20,686,267 | For many years the extracellular matrix was viewed as a benign scaffold for arranging cells within connective tissues, but it is now being redefined as a dynamic, mobile, and flexible key player in defining cellular behavior. Gene targeting, transgene expression, and spontaneous mutations of extracellular matrix protei... | 10.1038/nrg2520 | Comprehensive review on the use of mutant mouse models to explore the structure and function of the ECM. |
10.1146/annurev.pathmechdis.3.121806.151434 | 83,056,358 | The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which, collectively, represent a large fraction of the total protein output of a mammalian cell. Therefore, the protein flux through the ER must be carefully monitored for abnormalities, including the buildup of misf... | 10.1038/nrg2520 | Review of how ER stress and the UPR play an important part in the pathogenesis of many human diseases. |
10.1073/pnas.200360997 | 29,293,858 | We have identified a type I cytokine receptor, which we have termed novel interleukin receptor (NILR), that is most related to the IL-2 receptor β chain (IL-2Rβ) and physically adjacent to the IL-4 receptor α chain gene on chromosome 16. NILR mRNA is most highly expressed in thymus and spleen, and is induced by phytohe... | 10.1038/nri1688 | This was the first report to identify the IL-21 receptor as a novel type I cytokine receptor and to describe its structural features and signal-transduction pathways. |
10.4049/jimmunol.173.1.657 | 83,319,272 | Abstract IL-21 costimulates B cell proliferation and cooperatively with IL-4 promotes T cell-dependent Ab responses. Somewhat paradoxically, IL-21 also induces apoptosis of B cells. The present study was undertaken to more precisely define the expression of the IL-21R, using a novel mAb, and the circumstances by which ... | 10.1038/nri1688 | This paper describes the context-dependent effects of IL-21 on the B-cell lineage and identifies a BIM-dependent, IL-21-mediated apoptotic pathway in T-cell-independent B-cell responses. |
10.1126/science.1077002 | 62,117,399 | The cytokine interleukin-21 (IL-21) is closely related to IL-2 and IL-15, and their receptors all share the common cytokine receptor γ chain, γ c , which is mutated in humans with X-linked severe combined immunodeficiency disease (XSCID). We demonstrate that, although mice deficient in the receptor for IL-21 (IL-21R) h... | 10.1038/nri1688 | This paper describes the defective antibody production in Il21r −/− mice and shows that IL-21 and IL-4 cooperate in the regulation of antibody production. |
10.4049/jimmunol.173.9.5361 | 83,317,093 | Abstract IL-21 is a type I cytokine whose receptor is expressed on T, B, and NK cells. Within the B cell lineage, IL-21 regulates IgG1 production and cooperates with IL-4 for the production of multiple Ab classes in vivo. Using IL-21-transgenic mice and hydrodynamics-based gene delivery of IL-21 plasmid DNA into wild-t... | 10.1038/nri1688 | This report shows that IL-21 initiates the development of B cells into plasma cells through directly inducing expression of the master regulator of this process, BLIMP1. |
10.4049/jimmunol.173.2.900 | 2,614,348 | Abstract Cytokines that use the common receptor γ-chain for regulating CD8+ T cell responses to Ag include IL-2, IL-15, and the recently identified IL-21. The ability of these cytokines to regulate antitumor activity in mice has generated considerable interest in understanding their mode of action. In this study we com... | 10.1038/nri1688 | This paper describes the unique ability of IL-21 to induce long-term immunity to tumours through its anti-apoptotic and survival effects on CD8 + T cells. |
10.1093/bioinformatics/btp266 | 62,032,444 | Abstract Summary: High-resolution, three-dimensional (3D) imaging of large biological specimens generates massive image datasets that are difficult to navigate, annotate and share effectively. Inspired by online mapping applications like GoogleMaps™, we developed a decentralized web interface that allows seamless navig... | 10.1038/nmeth.2476 | Online annotation platform for electron microscopy image data presented in successive 2D image planes |
10.1126/science.282.5397.2254 | 16,751,722 | Are nutrients available to microbial communities in micropatches long enough to influence growth and competition? And what are the sources of such patches? To answer these questions, the swimming behavior of chemotactic bacteria in seawater samples was examined. Clusters of bacteria formed in conjunction with cell lysi... | 10.1038/nrmicro1747 | An experimental demonstration of the response of marine bacteria to organic matter hot spots and a simulation by numerical modelling. |
10.4319/lo.2001.46.6.1309 | 61,766,461 | Leaking organic solutes form an elongated plume in the wake of a sinking aggregate. These solutes may both be assimilated by suspended bacteria and guide bacteria with chemokinetic swimming behavior toward the aggregate. We used modifications of previously published models of the flow and concentration fields around si... | 10.1038/nrmicro1747 | This paper presents a model of marine snow colonized by bacteria that solubilize organic matter, and shows that an extended plume of DOM persists behind the sinking marine snow, which attracts bacteria from surrounding seawater. It predicts that half of the organic matter that is used in the sea by bacteria is from the... |
10.1111/j.1462-2920.2006.01152.x | 104,175,660 | Summary Members of the Bacteroidetes , formerly known as the Cytophaga‐Flavobacteria‐Bacteroides (CFB) phylum, are among the major taxa of marine heterotrophic bacterioplankton frequently found on macroscopic organic matter particles (marine snow). In addition, they have been shown to also represent a significant part ... | 10.1038/nrmicro1747 | This paper presents whole-genome analyses of a marine Bacteroidetes spp. and makes a prediction about its adaptive biology that is important for the solubilization and degradation of particulate organic matter in the ocean. |
10.1101/gad.1252704 | 18,540,265 | Protein localization is crucial for cellular morphogenesis and intracellular signal transduction cascades. Here we describe an interaction between two membrane proteins expressed in different cells of the Bacillus subtilis sporangium, the mother cell protein SpoIIIAH and the forespore protein SpoIIQ. We used affinity c... | 10.1038/nrmicro1795 | Demonstration of a zipper-like interaction between proteins from the forespore and mother cell that allows the assembly of protein complexes at the septal membrane. |
10.1073/pnas.0604503103 | 58,375,710 | The actin cytoskeleton represents a key regulator of multiple essential cellular functions in both eukaryotes and prokaryotes. In eukaryotes, these functions depend on the orchestrated dynamics of actin filament assembly and disassembly. However, the dynamics of the bacterial actin homolog MreB have yet to be examined ... | 10.1038/nrmicro1795 | Analysis of the dynamics of MreB cables in C. crescentus by tracking the movement of single fluorescently labelled MreB subunits within the cell. |
10.1126/science.1101313 | 40,508,664 | Dynamic instability—the switching of a two-state polymer between phases of steady elongation and rapid shortening—is essential to the cellular function of eukaryotic microtubules, especially during chromosome segregation. Since the discovery of dynamic instability 20 years ago, no other biological polymer has been foun... | 10.1038/nrmicro1795 | Elaborate biochemical analysis of the mechanism that underlies the polymerization of the actin-like protein ParM. |
10.1126/science.1138527 | 61,024,053 | Multiple unrelated polymer systems have evolved to partition DNA molecules between daughter cells at division. To better understand polymer-driven DNA segregation, we reconstituted the three-component segregation system of the R1 plasmid from purified components. We found that the ParR/ parC complex can construct a sim... | 10.1038/nrmicro1795 | This paper reports the first successful reconstitution of a plasmid-partitioning system in vitro and provides detailed information on the R1 partitioning mechanism. |
10.1101/gad.1546107 | 101,171,470 | Prokaryotes rely on a distant tubulin homolog, FtsZ, for assembling the cytokinetic ring essential for cell division, but are otherwise generally thought to lack tubulin-like polymers that participate in processes such as DNA segregation. Here we characterize a protein (TubZ) from the Bacillus thuringiensis virulence p... | 10.1038/nrmicro1795 | First report of a bacterial tubulin homologue that performs a function in plasmid segregation. |
10.1073/pnas.0402606101 | 101,726,197 | The chromosomal origin and terminus of replication are precisely localized in bacterial cells. We examined the cellular position of 112 individual loci that are dispersed over the circular Caulobacter crescentus chromosome and found that in living cells each locus has a specific subcellular address and that these loci ... | 10.1038/nrmicro1795 | The first global analysis of chromosome organization and segregation in live bacterial cells. |
10.1126/science.1079914 | 19,533,883 | Eukaryotic chromosomes are anchored to a spindle apparatus during mitosis, but no such structure is known during chromosome segregation in bacteria. When sister chromosomes are segregated during sporulation in Bacillus subtilis , the replication origin regions migrate to opposite poles of the cell. If and how origin re... | 10.1038/nrmicro1795 | Identification of a B. subtilis sporulation-specific protein that serves to attach the chromosomal origin region to the cell pole in the incipient forespore compartment. |
10.1101/gad.1496506 | 79,684,499 | The mechanisms that mediate chromosome segregation in bacteria are poorly understood. Despite evidence of dynamic movement of chromosome regions, to date, mitotic-like mechanisms that act on the bacterial chromosome have not been demonstrated. Here we provide evidence that the Vibrio cholerae ParAI and ParBI proteins a... | 10.1038/nrmicro1795 | This paper proves the involvement of ParAB in the segregation and polar attachment of the chromosomal origin regions in V. cholerae and provides evidence for a partitioning mechanism that is based on a pulling force that is generated by dynamic ParA filaments. |
10.1126/science.1123231 | 102,285,510 | Magnetosomes are membranous bacterial organelles sharing many features of eukaryotic organelles. Using electron cryotomography, we found that magnetosomes are invaginations of the cell membrane flanked by a network of cytoskeletal filaments. The filaments appeared to be composed of MamK, a homolog of the bacterial acti... | 10.1038/nrmicro1795 | Analysis of the role of the actin-like protein MamK in the alignment of magnetosome vesicles. |
10.1126/science.aad0135 | 125,168,323 | A gut bacterial containment system Trillions of bacteria selectively inhabit our guts, but how do our bodies keep them contained? Spadoni et al. describe a “gut-vascular barrier” that prevents intestinal microbes from accessing the liver and the bloodstream in mice (see the Perspective by Bouziat and Jabri). Studies wi... | 10.1038/nri.2017.100 | This study demonstrates the existence of the GVB and shows that endothelial cells control the passage of antigens into the bloodstream and prohibit entry of the microbiota. |
10.1126/scitranslmed.3009759 | 125,176,188 | The intestinal microbiota helps to maintain the integrity of the blood-brain barrier in fetal and adult mice. | 10.1038/nri.2017.100 | This study demonstrates that the intestinal microbiota can shape BBB properties. It shows that mice lacking a normal intestinal microbiota have increased BBB permeability compared with pathogen-free mice and that recolonization of germ-free adult mice restores BBB functionality. |
10.1073/pnas.1010529108 | 125,332,481 | Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxi... | 10.1038/nri.2017.100 | This study provides evidence that microbial colonization regulates signalling mechanisms, neurotransmitter turnover and synaptic-related protein production to affect motor control and anxiety behaviour. |
10.1126/scitranslmed.3008618 | 124,322,970 | The liver forms a firewall that protects against vascular-borne gut microbes and is commonly impaired in liver disease. | 10.1038/nri.2017.100 | This study demonstrates that the liver acts as a vascular firewall that impedes intestinal bacteria from entering the bloodstream during intestinal pathology, spreading systemically and activating non-mucosal immune responses. |
10.1073/pnas.1000082107 | 104,263,789 | Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. A... | 10.1038/nri.2017.100 | This work demonstrates that intestinal bacteria influence inflammatory immune responses in the CNS, favouring EAE development. |
10.1126/science.3420403 | 124,253,031 | Predicting the extinction of single populations or species requires ecological and evolutionary information. Primary demographic factors affecting population dynamics include social structure, life history variation caused by environmental fluctuation, dispersal in spatially heterogeneous environments, and local extinc... | 10.1038/nrg1425 | This landmark paper was one of the first to discuss the relevance of genetics and demography in conservation biology. |
10.1046/j.1365-294x.1998.00308.x | 122,933,739 | Since the 1920s, population geneticists have had measures that describe how genetic variation is distributed spatially within a species’ geographical range. Modern genetic survey techniques frequently yield information on the evolutionary relationships among the alleles or haplotypes as well as information on allele fr... | 10.1038/nrg1425 | A clear description of the nested clade approach and how it can be applied to a better understanding of ecological, demographic and genetic aspects of populations. |
10.1046/j.1365-294x.2003.01860.x | 109,134,002 | Abstract Museum specimens from the late 19th and early 20th centuries were surveyed for the single nucleotide polymorphism identified previously and used to diagnose populations of the federally threatened Northeastern Beach Tiger Beetle Cicindela d. dorsalis (Coleoptera: Carabidae). Widespread polymorphism was reveale... | 10.1038/nrg1425 | The authors used century-old pinned tiger beetles to assess the phylogeographic patterns in this endangered insect along the north-east Atlantic coast. |
10.1146/annurev-biophys-060414-034248 | 38,210,289 | The formation of the autophagosome, a landmark event in autophagy, is accomplished by the concerted actions of Atg proteins. The initial step of starvation-induced autophagy in yeast is the assembly of the Atg1 complex, which, with the help of other Atg groups, recruits Atg conjugation systems and initiates the formati... | 10.1038/nrd.2017.22 | This comprehensive review describes the molecular mechanisms that control autophagic responses and their regulation. |
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