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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.