source_doi stringlengths 13 57 | source_mag_paper_id int64 490k 157M | source_abstract stringlengths 8 10.7k | target_doi stringlengths 14 27 | target_summary stringlengths 42 889 |
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10.1666/0094-8373(2000)026<0386:bpngns>2.0.co;2 | 45,549,969 | Multicellular filaments from the ca. 1200-Ma Hunting Formation (Somerset Island, arctic Canada) are identified as bangiacean red algae on the basis of diagnostic cell-division patterns. As the oldest taxonomically resolved eukaryote on record Bangiomorpha pubescens n. gen. n. sp. provides a key datum point for constrai... | 10.1038/nrg929 | Describes the oldest taxonomically resolved eukaryotic group (red algae): it arose 1.2 Gyr ago, and therefore has helped to constrain molecular clocks. The article also discusses the significance of this ancient group for understanding the origin of sex and multicellularity. |
10.1126/science.1067179 | 4,756,232 | Molecular phylogenetic studies have resolved placental mammals into four major groups, but have not established the full hierarchy of interordinal relationships, including the position of the root. The latter is critical for understanding the early biogeographic history of placentals. We investigated placental phylogen... | 10.1038/nrg929 | Presents a phylogenetic analysis of the most taxonomically diverse sequence data set for placental mammals. |
10.1182/blood-2006-08-041384 | 40,585,287 | Abstract Early B lymphopoiesis in mammals is induced within the bone marrow (BM) microenvironment, but which cells constitute this niche is not known. Previous studies had shown that osteoblasts (OBs) support hematopoietic stem cell (HSC) proliferation and myeloid differentiation. We now find that purified primary muri... | 10.1038/nri2279 | References 41 and 42 conditionally ablated osteoblasts using Col1a1-TK transgenic mice, observing an acute disruption of haematopoiesis in the bone marrow, including the loss of B-cell lineage progenitors, followed by a slower reduction in the absolute number of LIN − SCA1 + KIT + cells (which are enriched for HSCs). |
10.1182/blood-2005-02-0671 | 60,472,671 | In vitro studies suggest that bone marrow endothelial cells contribute to multilineage hematopoiesis, but this function has not been studied in vivo. We used a Cre/loxP-mediated recombination to produce mice that lacked the cytokine receptor subunit gp130 in hematopoietic and endothelial cells. Although normal at birth... | 10.1038/nri2279 | This study shows that conditional loss of GP130 in endothelial cells leads to a reduction in bone-marrow cellularity, particularly around sinusoids, demonstrating that endothelial-cell function is required for maintaining haematopoiesis in vivo |
10.1126/science.1215802 | 41,514,186 | Choosing a Path The β 2 -adrenergic receptor (β 2 AR) is a G protein–coupled receptor that recognizes diverse ligands to trigger signaling in the cell. Besides binding G proteins, activated β 2 AR can be phosphorylated and bind arrestin, which redirects signaling to other pathways. Some β 2 AR ligands are “biased” in t... | 10.1038/nrd.2018.180 | Based on observation of CF 3 NMR signals of TET at C265 and C327, this study identifies local conformational equilibria of TMVI and TMVII, which are then related to variable efficacy and biased signalling of β 2 AR. |
10.1038/s41467-017-02008-y | 62,130,295 | Abstract A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., G s and β-arrestin. Using 13 C methyl methionine NMR for the β 1 -adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-... | 10.1038/nrd.2018.180 | Based on observation of methionine methyl NMR signals, efficacy-dependent local conformational equilibria are identified for β 1 AR, and it is shown that a single conformation is present after binding to a G protein-mimicking nanobody. |
10.1002/anie.201406603 | 102,191,858 | Abstract G‐protein‐coupled receptors (GPCRs) exist in conformational equilibrium between active and inactive states, and the former population determines the efficacy of signaling. However, the conformational equilibrium of GPCRs in lipid bilayers is unknown owing to the low sensitivities of their NMR signals. To incre... | 10.1038/nrd.2018.180 | In this study, observation of methionine methyl group NMR signals of partially deuterated β 2 AR reveals variations in the relative populations of different conformers and the rates of conformational exchange between β 2 AR reconstituted in detergent micelles and in lipid nanodiscs, respectively. |
10.1038/s41467-017-02632-8 | 50,827,424 | Abstract The C-terminal region of G-protein-coupled receptors (GPCRs), stimulated by agonist binding, is phosphorylated by GPCR kinases, and the phosphorylated GPCRs bind to arrestin, leading to the cellular responses. To understand the mechanism underlying the formation of the phosphorylated GPCR-arrestin complex, we ... | 10.1038/nrd.2018.180 | In this study, observation of segmentally labelled β 2 AR containing the [u- 2 H, 13 C, 15 N]-labelled C-terminal polypeptide segment of residues 349 to 413 attached to the unlabelled β 2 AR polypeptide 1–348 reveals a phosphorylation-induced conformation of β 2 AR that preferentially interacts with β-arrestin. |
10.1002/anie.201508794 | 102,903,024 | Abstract G‐protein‐coupled receptor (GPCR) ligands impart differing degrees of signaling in the G‐protein and arrestin pathways, in phenomena called “biased signaling”. However, the mechanism underlying the biased signaling of GPCRs is still unclear, although crystal structures of GPCRs bound to the G protein or arrest... | 10.1038/nrd.2018.180 | Observation of methionine methyl NMR signals in deuterated and methionine methyl-labelled MOR identifies conformational equilibria related to biased signalling. |
10.1073/pnas.96.24.13744 | 28,213,770 | We report high resolution solution 19 F NMR spectra of fluorine-labeled rhodopsin mutants in detergent micelles. Single cysteine substitution mutants in the cytoplasmic face of rhodopsin were labeled by attachment of the trifluoroethylthio (TET), CF 3 -CH 2 -S, group through a disulfide linkage. TET-labeled cysteine mu... | 10.1038/nrd.2018.180 | This is the first report using extrinsic trifluoromethyl groups for solution 19 F NMR studies of integral membrane proteins. |
10.1073/pnas.95.10.5730 | 86,316,362 | We have demonstrated chromosomal instability in the clonal descendants of hemopoietic stem cells after irradiating murine bone marrow with α-particles. However, because cells that are irradiated by α-particles are defined by a Poisson distribution of individual particle traversals, there is an inevitable proportion of ... | 10.1038/nrc1735 | This study reports that IR with α-particles can elicit persistent genomic instability in non-irradiated cells. |
10.1126/science.1060191 | 61,470,174 | Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the prim... | 10.1038/nrc1735 | This study described a novel mechanism of tissue damage through the loss of endothelial cells from IR-induced signalling through the ceramide pathway. |
10.1126/science.959840 | 62,297,808 | It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from acti... | 10.1038/nrc2013 | The seminal description of cancer as an evolutionary process. Predicts sequences of clonal expansions, individual variation in response to interventions and therapeutic resistance. |
10.1073/pnas.97.3.1236 | 103,798,672 | It is difficult to observe human tumor progression as precursor lesions are systematically removed. Alternatives to direct observations, commonly used to reveal the hidden past of species and populations, are sequence comparisons or molecular clocks. Noncoding microsatellite (MS) loci were employed as molecular tumor c... | 10.1038/nrc2013 | Uses phylogenetic methods to trace the common ancestor of microsatellite-unstable clones in colorectal cancer back to a date before an adenoma was detected. |
10.1158/1055-9965.1375.13.8 | 128,027,862 | Abstract Cells in neoplasms evolve by natural selection. Traditional cytotoxic chemotherapies add further selection pressure to the evolution of neoplastic cells, thereby selecting for cells resistant to the therapies. An alternative proposal is a benign cell booster. Rather than trying to kill the highly dysplastic or... | 10.1038/nrc2013 | Uses computational models to develop prevention and therapeutic strategies for avoiding the evolution of resistance. |
10.1142/s0219198905000557 | 83,372,584 | We present two different mathematical models that examine the role of cellular evolution in the development and treatment of cancer. The first is a Lotka-Volterra model of an invasive cancer subjected to chemotherapy that demonstrates rapid evolution of drug-resistant phenotypes. The second model represents a major ref... | 10.1038/nrc2013 | Describes the use of evolutionary and ecological models to develop new approaches to therapy. |
10.1073/pnas.202139299 | 109,137,505 | With the advent of drugs targeting specific molecular defects in cancerous cells [Gorre, M. E., et al . (2001) Science 293, 876–880], it is important to understand the degree of genetic heterogeneity present in tumor cell populations and the rules that govern microdiversity in human cancer. Here, we first show that pop... | 10.1038/nrc2013 | Shows genetic heterogeneity within a neoplasm, and how clones can be intertwined in complex patterns. |
10.1073/pnas.96.26.15121 | 58,564,796 | Cancer cell genomes contain alterations beyond known etiologic events, but their total number has been unknown at even the order of magnitude level. By sampling colorectal premalignant polyp and carcinoma cell genomes through use of the technique inter-(simple sequence repeat) PCR, we have found genomic alterations to ... | 10.1038/nrc2013 | Measures the frequency of genomic alterations in colorectal cancer at approximately 11,000 per clone. |
10.1073/pnas.68.4.820 | 20,848,282 | Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, ... | 10.1038/nrc2013 | Uses a Poisson model to deduce the requirement of two mutations to generate retinoblastoma. |
10.1073/pnas.2535419100 | 19,684,616 | Cancer is the consequence of an unwanted evolutionary process. Cells receive mutations that alter their phenotype. Especially dangerous are those mutations that increase the net reproductive rate of cells, thereby leading to neoplasia and later to cancer. The standard models of evolutionary dynamics consider well mixed... | 10.1038/nrc2013 | Uses a mathematical model to analyse the evolutionary dynamics of cells in structured tissues. |
10.1073/pnas.1415518111 | 62,591,367 | Significance Cell death by regulated necrosis causes tremendous tissue damage in a wide variety of diseases, including myocardial infarction, stroke, sepsis, and ischemia–reperfusion injury upon solid organ transplantation. Here, we demonstrate that an iron-dependent form of regulated necrosis, referred to as ferroptos... | 10.1038/nrd.2015.6 | This paper indicates that in vivo inhibition of ferroptosis leads to a protective effect in a pathophysiological setting, such as IRI in the kidney. |
10.1073/pnas.1405158111 | 41,649,476 | Significance Excessive activation of poly(ADP-ribose) (PAR) polymerase (PARP) is intimately linked to cell death in a variety of organ systems. It has long been thought that the cell death caused by excessive activation of PARP occurs through the catalytic consumption of NAD + followed by reduction of ATP and bioenerge... | 10.1038/nrd.2015.6 | Although parthanatos still lacks a clear core cell death pathway, this paper indicates that overactivation of PARP1 is caused by PAR-dependent inhibition of glycolysis through the inhibition of HK, explaining the bioenergetic collapse that results in necrotic cell death. |
10.1073/pnas.0505294102 | 62,353,986 | Mitochondrial permeability transition (PT) is a phenomenon induced by high levels of matrix calcium and is characterized by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochondrial membrane potential, expansion of the matrix, and rupture of the mitochondrial outer membrane. Consequently,... | 10.1038/nrd.2015.6 | References 126–128 characterize the requirement of CypD for the formation of the MPTP, and its inhibition as a pharmacologically amenable approach. |
10.1126/science.273.5274.503 | 59,635,469 | B and T lymphocytes undergoing apoptosis in response to anti-immunoglobulin M antibodies and dexamethasone, respectively, were found to have increased amounts of messenger RNA for the inositol 1,4,5-trisphosphate receptor (IP 3 R) and increased amounts of IP 3 R protein. Immunohistochemical analysis revealed that the a... | 10.1038/nrm1150 | This report links apoptosis to upregulation of type 3 Ins(1,4,5)P 3 receptors in the lymphocyte plasma membrane. |
10.1126/science.8235595 | 38,399,490 | Microdomains of high intracellular calcium ion concentration, [Ca 2+ ] i , have been hypothesized to occur in living cells exposed to stimuli that generate inositol 1,4,5-trisphosphate (IP 3 ). Mitochondrially targeted recombinant aequorin was used to show that IP 3 -induced Ca 2+ mobilization from intracellular stores... | 10.1038/nrm1150 | Early report of ER–mitochondrial Ca 2+ fluxes originating from microdomains with elevated Ca 2+ in the cytoplasm. |
10.1126/science.284.5412.339 | 38,244,201 | The Ca 2+ -activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-x L and promoting apoptosis. The Ca 2+ -induced dephosphorylation of BAD correlat... | 10.1038/nrm1150 | This report links apoptosis to calcineurin-mediated dephosphorylation and activation of the pro-apoptotic Bcl-2 family protein Bad. |
10.1073/pnas.97.11.5723 | 103,821,285 | The antiapoptotic protein Bcl-2 localizes not only to mitochondria but also to the endoplasmic reticulum (ER). However, the function of Bcl-2 at the level of the ER is poorly understood. In this study, we have investigated the effects of Bcl-2 expression on Ca 2+ storage and release by the ER. The expression of Bcl-2 d... | 10.1038/nrm1150 | Early evidence that Bcl-2 decreases the ER Ca 2+ pool by increasing the permeability of the ER membrane. |
10.1126/science.1081208 | 20,860,170 | BAX and BAK are “multidomain” proapoptotic proteins that initiate mitochondrial dysfunction but also localize to the endoplasmic reticulum (ER). Mouse embryonic fibroblasts deficient for BAX and BAK (DKO cells) were found to have a reduced resting concentration of calcium in the ER ([Ca 2+ ] er ) that results in decrea... | 10.1038/nrm1150 | Evidence that Bax and Bak are required for the maintenance of ER Ca 2+ homeostasis, and that certain stimuli (for example, oxidative stress) induce apoptosis by promotion of ER–mitochondrial Ca 2+ translocation. |
10.1111/j.1365-2958.2006.05410.x | 4,609,089 | Summary Conversion of pyruvate to acetate via the phosphotransacetylase‐acetate kinase pathway generates ATP and is a major overflow pathway under conditions of carbon and nitrogen excess. In Bacillus subtilis , this pathway is positively regulated by CcpA, a global regulator of carbon metabolism genes. Transcription o... | 10.1038/nrmicro1772 | This study was the first to demonstrate positive regulation by CodY, and highlighted the interesting and important role of CodY in carbon-overflow pathways. |
10.1111/j.1365-2958.1995.tb02280.x | 4,829,399 | Summary CcpA, the repressor/activator mediating carbon catabolite repression and glucose activation in many Gram‐positive bacteria, has been purified from Bacillus megaterium after fusing it to a His tag. CcpA‐his immobilized on a Ni‐NTA resin specifically interacted with HPr phosphorylated at seryl residue 46. HPr, a ... | 10.1038/nrmicro1772 | This paper was the first to establish a connection between CcpA activity, fructose-1,6-bisphosphate and the seryl phosphorylation of HPr. |
10.1101/gad.874201 | 81,472,972 | CodY, a highly conserved protein in the low G + C, gram-positive bacteria, regulates the expression of many Bacillus subtilis genes that are induced as cells make the transition from rapid exponential growth to stationary phase and sporulation. This transition has been associated with a transient drop in the intracellu... | 10.1038/nrmicro1772 | The first demonstration that GTP binds to CodY and increases its activity as a transcription factor. |
10.1111/j.1365-2958.2004.04135.x | 45,319,784 | Summary CodY, a GTP‐activated global transcriptional regulator of early stationary phase genes, is conserved in many Gram‐positive bacterial species. Recently, a number of novel targets regulated by CodY have been identified, including three Bacillus subtilis operons involved in branched‐chain amino acid (BCAA) biosynt... | 10.1038/nrmicro1772 | The first evidence that BCAAs interact directly with CodY and increase its affinity for DNA. |
10.1111/j.1365-2958.2007.05816.x | 4,829,654 | Summary Glutamate synthesis is the link between carbon and nitrogen metabolism . In Bacillus subtilis , glutamate is exclusively synthesized by the glutamate synthase encoded by the gltAB operon. The glutamate dehydrogenase RocG from B. subtilis is exclusively devoted to glutamate degradation rather than to its synthes... | 10.1038/nrmicro1772 | This recent paper shows that glutamate dehydrogenase interacts with GltC, thereby reducing glutamate synthesis. |
10.1111/j.1365-2958.2005.04635.x | 82,539,666 | Summary The Bacillus subtilis ilv‐leu operon involved in the biosynthesis of branched‐chain amino acids is under negative regulation mediated by TnrA and CodY, which recognize and bind to their respective cis ‐elements located upstream of the ilv‐leu promoter. This operon is known to be under CcpA‐dependent positive re... | 10.1038/nrmicro1772 | This paper reported simultaneously with reference 88 that CodY and CcpA have antagonistic effects on ilvB transcription, so establishing a crucial interaction between the two regulons. |
10.1046/j.1365-2958.2001.02470.x | 27,909,674 | Proteolysis is essential for supplying Lactococcus lactis with amino acids during growth in milk. Expression of the major components of the L. lactis proteolytic system, including the cell wall proteinase (PrtP), the oligopeptide transport system (Opp) and at least four intracellular peptidases (PepO1, PepN, PepC, PepD... | 10.1038/nrmicro1772 | The first evidence that CodY responds in vivo to BCAAs. |
10.1111/j.1365-2958.2007.05906.x | 45,319,726 | Summary CodY, a global regulator of gene expression in low G + C Gram‐positive bacteria, was found to repress toxin gene expression in Clostridium difficile . Inactivation of the codY gene resulted in derepression of all five genes of the C. difficile pathogenicity locus during exponential growth and stationary phase. ... | 10.1038/nrmicro1772 | This paper presents the first example of direct interaction between CodY and a virulence-gene locus. |
10.1126/science.1075958 | 41,666,351 | Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire - deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue– restricted antigens in me... | 10.1038/nrg1944 | This seminal paper demonstrates the importance of AIRE in regulating the thymic expression of self antigens and its role in autoimmunity. |
10.1126/science.1092138 | 19,612,856 | Protein tyrosine kinases and phosphatases cooperate to regulate normal immune cell function. We examined the role of PEST domain–enriched tyrosine phosphatase (PEP) in regulating T cell antigen–receptor function during thymocyte development and peripheral T cell differentiation. Although normal naïve T cell functions ... | 10.1038/nrg1944 | These two papers present contrasting evidence for the mechanisms by which PTPN22 alleles predispose to autoimmunity. Vang et al . provide evidence for the gain of function of PTPN22 risk alleles, whereas studies in knockout mice (Hasegawa et al .) indicate that PTPN22 has predominantly negative regulatory effects in T ... |
10.1126/science.1124978 | 20,584,170 | Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator ( Yaa ) locus are intrinsically biased toward nucleolar antigens because of increase... | 10.1038/nrg1944 | These two recent studies provide direct evidence for the involvement of TLRs ( Tlr7 ) in mouse models of autoimmunity, setting the stage for a further investigation of the role of TLR7 in humans, and further supporting the involvement of innate immune mechanisms in the development of autoimmunity. |
10.1002/art.21575 | 104,376,881 | Abstract Objective To investigate whether smoking and HLA–DR shared epitope (SE) genes may interact in triggering immune reactions to citrulline‐modified proteins. Methods In a case–control study involving patients with recent‐onset rheumatoid arthritis (RA), we studied interactions between a major environmental risk f... | 10.1038/nrg1944 | This report provides a compelling recent example of a gene–environment interaction in the development of autoimmunity. |
10.1083/jcb.134.5.1283 | 102,576,843 | Armadillo, the Drosophila homologue of vertebrate beta-catenin, plays a pivotal role both in Wingless signaling and in assembly of adherens junctions. We performed the first in vivo structure-function study of an adherens junction protein, by generating and examining a series of Armadillo mutants in the context of the ... | 10.1038/nrm2654 | A seminal structure–function study carried out in D. melanogaster that yielded far-reaching insights into the function of β-catenin. |
10.1101/gad.1385806 | 82,975,640 | The APC tumor suppressor controls the stability and nuclear export of β-catenin (β-cat), a transcriptional coactivator of LEF-1/TCF HMG proteins in the Wnt/ Wg signaling pathway. We show here that β-cat and APC have opposing actions at Wnt target genes in vivo. The β-cat C-terminal activation domain associates with TRR... | 10.1038/nrm2654 | One of the first studies to apply time-course ChIP analysis to study the dynamics at a WRE. |
10.1128/mcb.02175-07 | 80,653,649 | ABSTRACT Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding T-cell factors (TCFs) and the transcriptional coactivator β-catenin. In colorectal cancer, activating Wnt pathway mutations transform epithelial cells through the inappropriate activation of a TCF7L2/TCF4 tar... | 10.1038/nrm2654 | Information on TCF occupancy on a genomic level, such as binding site distribution at target gene loci and their structure. |
10.1146/annurev.biochem.75.103004.142422 | 41,587,933 | It is more evident now than ever that nucleosomes can transmit epigenetic information from one cell generation to the next. It has been demonstrated during the past decade that the posttranslational modifications of histone proteins within the chromosome impact chromatin structure, gene transcription, and epigenetic in... | 10.1038/nrm2654 | A good introduction to the mechanisms that underlie histone ubiquitylation and methylation, chromatin modification crosstalk and the catalysing protein complexes. |
10.1016/j.febslet.2004.12.007 | 124,109,830 | Transcriptional regulation in eukaryotes involves structurally and functionally distinct nuclear RNA polymerases, corresponding general initiation factors, gene‐specific (DNA‐binding) regulatory factors, and a variety of coregulatory factors that act either through chromatin modifications (e.g. histone acetyltransferas... | 10.1038/nrm2654 | A comprehensive review of how transcription factors use their auxiliary cofactors to achieve transcriptional activation. |
10.1126/science.290.5497.1768 | 123,035,429 | OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neuro... | 10.1038/nri1105 | CD200–CD200R-mediated interactions between neurons and microglia are essential for maintenance of the anti-inflammatory state in the central nervous system (CNS). |
10.1126/science.8009221 | 125,114,982 | Mice lacking the known subunit of the type I interferon (IFN) receptor were completely unresponsive to type I IFNs, suggesting that this receptor chain is essential for type I IFN-mediated signal transduction. These mice showed no overt anomalies but were unable to cope with viral infections, despite otherwise normal i... | 10.1038/nri1105 | This paper reports the development of mice that are deficient in receptors for interferon-α/β (IFN-α/β) and IFN-γ and indicates the essential role of these receptors in the control of virus replication. |
10.1084/jem.186.12.2023 | 86,313,797 | We explored expression and possible function of interferon-γ (IFN-γ) in cultured fetal (E15) rat dorsal root ganglion neurons combining whole cell patch-clamp electrophysiology with single cell reverse transcriptase polymerase chain reaction and confocal laser immunocytochemistry. Morphologically, we located IFN-γ prot... | 10.1038/nri1105 | This paper describes for the first time that neurons produce IFN-γ. |
10.4049/jimmunol.161.6.2746 | 139,046,011 | Abstract SJL mice develop immune-mediated disorders of the central nervous system (CNS) when infected with certain neurotropic viruses or when immunized with myelin Ags. Other strains including BALB/c are more resistant to these diseases. During Sindbis virus-induced encephalitis, both mice are easily infected and elic... | 10.1038/nri1105 | This paper shows that brain gangliosides regulate T-cell responses in the CNS. |
10.1126/science.1658936 | 101,046,534 | Humoral immunity is important for protection against viral infection and neutralization of extracellular virus, but clearance of virus from infected tissues is thought to be mediated solely by cellular immunity. However, in a SCID mouse model of persistent alphavirus encephalomyelitis, adoptive transfer of hyperimmune ... | 10.1038/nri1105 | This was the first paper to show that antibody can mediate non-cytolytic clearance of virus from neurons. |
10.1126/science.7624779 | 38,196,862 | Whether neurons express major histocompatibility complex (MHC) class I genes has not been firmly established. The techniques of confocal laser microscopy, patch clamp electrophysiology, and reverse transcriptase-polymerase chain reaction were combined here to directly examine the inducibility of MHC class I genes in in... | 10.1038/nri1105 | This paper describes that damaged neurons can express MHC class I molecules in response to IFN-γ. |
10.4049/jimmunol.153.2.818 | 139,000,326 | Abstract Borna disease (BD) is a virus-induced immunopathologic disease of the central nervous system in a variety of species from birds to primates and probably in humans. Severe inflammatory reactions lead to tissue destruction and finally to cortical brain atrophy. After experimental infection of the rat, intraparen... | 10.1038/nri1105 | This study provides evidence that populations of neurons differ in their susceptibility to IFN-γ-mediated virus clearance. |
10.4049/jimmunol.168.3.1204 | 99,477,359 | Abstract Contributions of humoral and cellular immunity in controlling neurotropic mouse hepatitis virus persistence within the CNS were determined in B cell-deficient JHD and syngeneic H-2d B cell+ Ab-deficient mice. Virus clearance followed similar kinetics in all mice, confirming initial control of virus replication... | 10.1038/nri1105 | A report showing that B cells are required to prevent renewed replication of coronavirus in glial cells after initial T-cell-mediated control of replication. |
10.1182/blood-2011-09-379412 | 123,985,001 | Abstract Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient pati... | 10.1038/nri.2017.67 | References 7 and 8 show that B cell hyperactivity underlies the autoimmune features of Wiskott–Aldrich syndrome in mouse models. |
10.1126/science.1237572 | 102,951,301 | The generation of high-affinity antibodies depends on the ability of B cells to extract antigens from the surfaces of antigen-presenting cells. B cells that express high-affinity B cell receptors (BCRs) acquire more antigen and obtain better T cell help. However, the mechanisms by which B cells extract antigen remain u... | 10.1038/nri.2017.67 | This study demonstrates that B cells use mechanical forces to extract antigens from immune synapses and that the forces regulate affinity discrimination. |
10.4049/jimmunol.1102233 | 18,945,800 | Abstract When lymphocytes encounter APCs bearing cognate Ag, they spread across the surface of the APC to scan for additional Ags. This is followed by membrane contraction and the formation of Ag receptor microclusters that initiate the signaling reactions that lead to lymphocyte activation. Breakdown of the submembran... | 10.1038/nri.2017.67 | This study shows an important role for cofilin 1-mediated actin severing in BCR-induced actin remodelling. |
10.1126/scisignal.2005887 | 82,560,012 | Antigen stimulates the dispersion and remodeling of preformed distinct clusters of B cell receptors on the cell surface. | 10.1038/nri.2017.67 | References 49 and 92 reveal the nanoscopic organization of the BCR and its relationship to the actin cytoskeleton. |
10.1084/jem.20101125 | 103,907,229 | Signaling microclusters are a common feature of lymphocyte activation. However, the mechanisms controlling the size and organization of these discrete structures are poorly understood. The Ezrin-Radixin-Moesin (ERM) proteins, which link plasma membrane proteins with the actin cytoskeleton and regulate the steady-state ... | 10.1038/nri.2017.67 | This paper demonstrates the importance of ezrin-mediated coupling of the plasma membrane to the cytoskeleton in the regulation of BCR signalling. |
10.15252/embj.201593027 | 124,500,869 | Abstract Receptor organization and dynamics at the cell membrane are important factors of signal transduction regulation. Using super‐resolution microscopy and single‐particle tracking, we show how the negative coreceptor CD 22 works with the cortical cytoskeleton in restraining BCR signalling. In naïve B cells, we fou... | 10.1038/nri.2017.67 | This paper shows the importance of the regulation of CD22 diffusion in the inhibition of BCR signalling. |
10.1084/jem.20160528 | 91,207,890 | FcγRIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of FcγRIIB, FcγRIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of FcγRIIB-T232 at both functional and structural levels. Our results showed that Fc... | 10.1038/nri.2017.67 | This paper demonstrates that rapid FcRγIIB diffusion is important for terminating BCR signalling that is induced by IgG-containing immune complexes. |
10.1126/science.1123940 | 18,937,211 | B cells recognize foreign antigens by virtue of cell surface immunoglobulin receptors and are most effectively activated by membrane-bound ligands. Here, we show that in the early stages of this process, B cells exhibit a two-phase response in which they first spread over the antigen-bearing membrane and then contract,... | 10.1038/nri.2017.67 | This is a landmark paper that describes the cellular and cytoskeletal changes that occur during B cell immune synapse formation. |
10.1083/jcb.201607064 | 18,117,281 | Antibody production and affinity maturation are driven by B cell extraction and internalization of antigen from immune synapses. However, the extraction mechanism remains poorly understood. Here we develop DNA-based nanosensors to interrogate two previously proposed mechanisms, enzymatic liberation and mechanical force... | 10.1038/nri.2017.67 | This paper shows that APC stiffness promotes B cell affinity discrimination. |
10.1126/science.1214100 | 83,101,659 | Antigen Polarity in B Cell Differentiation Communication received through cell contact is critical for the differentiation of specialized effector cell populations during the immune response. For example, B lymphocytes acquire antigen that they present to helper T lymphocytes. T lymphocytes, in turn, provide key differ... | 10.1038/nri.2017.67 | This paper shows that the polarized localization of the antigen-processing compartment leads to its asymmetric division during B cell proliferation. |
10.1126/science.277.5331.1497 | 59,289,275 | In response to DNA damage, mammalian cells prevent cell cycle progression through the control of critical cell cycle regulators. A human gene was identified that encodes the protein Chk1, a homolog of the Schizosaccharomyces pombe Chk1 protein kinase, which is required for the DNA damage checkpoint. Human Chk1 protein ... | 10.1038/nrc1296 | This paper describes the cloning, and preliminary biochemical characterization of CHK1, particularly its role in the G2–M transition |
10.1101/gad.14.12.1439 | 133,907,527 | The recent discovery of checkpoint kinases has suggested the conservation of checkpoint mechanisms between yeast and mammals. In yeast, the protein kinase Chk1 is thought to mediate signaling associated with the DNA damage checkpoint of the cell cycle. However, the function of Chk1 in mammals has remained unknown. Targ... | 10.1038/nrc1296 | Work described in this reference and reference 16 indicates that Chk1 in mammals might have an essential role during the normal cell cycle. |
10.1126/science.287.5459.1824 | 26,930,737 | Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2 −/− embryonic stem cells failed to maintain γ-irradiation–induced arrest in the G 2 phase of the cell cycle. Chk2 −/− thymocytes were resistant to DNA ... | 10.1038/nrc1296 | Work described in this reference and references 67–69 show that CHK2 is crucial for IR-induced apoptosis and indicates that CHK2 could be a radioprotection target. |
10.1126/science.285.5434.1733 | 39,248,130 | Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient ... | 10.1038/nrc1296 | This reference describes the identification — by chemical library screening — and in vitro and in vivo testing of a p53 inhibitor, and indicates that inhibition of the p53 pathway could reduce IR-induced DNA damage and lead to radioprotection. |
10.1083/jcb.200802105 | 80,088,320 | Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablati... | 10.1038/nrc3318 | References 22 and 23 show that inhibition of DICER1 expression promotes metastasis, and that DICER1 loss elicits a p53-dependent arrest. |
10.1073/pnas.242606799 | 38,332,408 | Micro-RNAs ( miR genes) are a large family of highly conserved noncoding genes thought to be involved in temporal and tissue-specific gene regulation. MiRs are transcribed as short hairpin precursors (≈70 nt) and are processed into active 21- to 22-nt RNAs by Dicer, a ribonuclease that recognizes target mRNAs via base-... | 10.1038/nrc3318 | This paper provides the initial identification of a genetic inactivation of an miRNA-encoding gene. |
10.1084/jem.20110235 | 20,391,832 | p53 suppresses tumor progression and metastasis. Epithelial–mesenchymal transition (EMT) is a key process in tumor progression and metastasis. The transcription factors ZEB1 and ZEB2 promote EMT. Here, we show that p53 suppresses EMT by repressing expression of ZEB1 and ZEB2. By profiling 92 primary hepatocellular carc... | 10.1038/nrc3318 | References 47 and 48 are the first demonstrations that p53 suppresses EMT and metastasis by inducing the miR-200 family genes. |
10.1083/jcb.201103097 | 41,088,565 | Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial–mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonst... | 10.1038/nrc3318 | Together with reference 57 this study shows the regulation of the EMT-inducing factor SNAIL by miR-34. |
10.1073/pnas.1017536108 | 58,395,590 | Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that c... | 10.1038/nrc3318 | This paper provides a convincing in vivo idenification and analysis of a coherent forward feedback regulation of the MET gene by the combined activity of p53 and miR-34. |
10.1101/gad.1790409 | 18,573,161 | Unusually for a eukaryote, genes transcribed by RNA polymerase II (pol II) in Trypanosoma brucei are arranged in polycistronic transcription units. With one exception, no pol II promoter motifs have been identified, and how transcription is initiated remains an enigma. T. brucei has four histone variants: H2AZ, H2BV, H... | 10.1038/nrm2861 | Reports that trypanosomes have two versions of each of the four core histones, which form unique combinations at transcription initiation sites and termination sites. This suggests the existence of an ancestral mode of gene regulation based on histone variants and an ancient function for H2A.Z in marking promoters. |
10.1083/jcb.200604141 | 125,149,400 | During male germ cell postmeiotic maturation, dramatic chromatin reorganization occurs, which is driven by completely unknown mechanisms. For the first time, we describe a specific reprogramming of mouse pericentric heterochromatin. Initiated when histones undergo global acetylation in early elongating spermatids, this... | 10.1038/nrm2861 | Describes new H2A variants enriched in pericentric heterochromatin in spermatids that form sub-nucleosomal chromatin particles lacking H3 and H4. |
10.1073/pnas.1512503112 | 18,395,205 | T-cell genome engineering holds great promise for cell-based therapies for cancer, HIV, primary immune deficiencies, and autoimmune diseases, but genetic manipulation of human T cells has been challenging. Improved tools are needed to efficiently “knock out” genes and “knock in” targeted genome modifications to modulat... | 10.1038/nrd.2016.238 | This paper demonstrates high-efficiency editing of primary human cells using Cas9 RNPs. |
10.1126/science.aaf8729 | 103,685,794 | INTRODUCTION To combat invading pathogens, cells develop an adaptive immune response by changing their own genetic information. In vertebrates, the generation of genetic variation (somatic hypermutation) is an essential process for diversification and affinity maturation of antibodies that function to detect and seques... | 10.1038/nrd.2016.238 | References 56 and 57 show the engineering of chimeric Cas enzymes for position-specific base editing. |
10.1158/2159-8290.cd-16-0154 | 83,076,386 | Abstract The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased ce... | 10.1038/nrd.2016.238 | References 64, 68 and 69 show that CRISPR–Cas9 can generate false-positive effects at amplified loci. |
10.1534/genetics.115.176594 | 20,398,543 | Abstract The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) system is an adaptive immune system in bacteria and archaea that has recently been exploited for genome engineering. Mutant mice can be generated in one step through direct delivery of the CRISPR/Cas9 componen... | 10.1038/nrd.2016.238 | References 87–89 show direct zygote editing by electroporation of Cas9 RNP or Cas9 mRNA and sgRNA. |
10.1126/science.aad5227 | 20,680,038 | Making the correct cut The CRISPR/Cas system is a prokaryotic immune system that targets and cuts out foreign DNA in bacteria. It has been adopted for gene editing because it can be designed to recognize and cut specific locations in the genome. A challenge in developing clinical applications is the potential for off-t... | 10.1038/nrd.2016.238 | References 129 and 130 describe the development of a Cas9 nuclease with reduced off-target activity. |
10.1084/jem.20091983 | 38,400,308 | Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33... | 10.1038/nri3493 | References 81–83 were the first to highlight the remarkably limited infectious phenotype (that is, increased susceptibility to chronic mucocutaneous candidiasis) that occurs in patients with focal defects in IL-17-mediated signalling. By contrast, IL-17 has been shown to protect against a wider range of infections in m... |
10.1002/cncr.24121 | 62,275,521 | Abstract BACKGROUND: Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents, but there is a second incidence peak among individuals aged >60 years. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors or focused on cases occurring in... | 10.1038/nrendo.2017.16 | This is a detailed epidemiological study describing the incidence and survival of osteosarcoma among different ages and ethnicities using the SEER database. |
10.1038/ncomms9940 | 4,698,515 | Abstract Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpret... | 10.1038/nrendo.2017.16 | This study used whole-exome sequencing on osteosarcoma tumours, and identified 13 main drivers and a BRCA-like phenotype in >80% of samples. |
10.1126/science.1181369 | 41,754,439 | Chromosomal Mapping The conformation of the genome in the nucleus and contacts between both proximal and distal loci influence gene expression. In order to map genomic contacts, Lieberman-Aiden et al. (p. 289 , see the cover) developed a technique to allow the detection of all interactions between genomic loci in the e... | 10.1038/nrm.2016.104 | The original study describing Hi-C technology. This study was also the first to describe the genome compartments A and B, which respectively mark colocalizing active and repressed regions of the genome. |
10.1101/gr.5571506 | 125,229,796 | Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Her... | 10.1038/nrm.2016.104 | The original study describing 5C, which explores the interaction profiles of several contiguous loci with each other at high resolution. |
10.1101/gr.185272.114 | 83,288,649 | The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulat... | 10.1038/nrm.2016.104 | The first application of Capture-HiC to capture all promoters in the genome, demonstrating the feasibility and quality of obtaining high-resolution promoter interaction profiles for >20,000 loci in a single assay. |
10.1101/gr.175034.114 | 104,407,718 | Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor ... | 10.1038/nrm.2016.104 | The original study describing Capture-HiC technology and its use to interrogate the interaction landscapes of several disease-associated risk loci. |
10.1182/blood-2009-12-257832 | 125,166,102 | Abstract Blood vessel networks expand in a 2-step process that begins with vessel sprouting and is followed by vessel anastomosis. Vessel sprouting is induced by chemotactic gradients of the vascular endothelial growth factor (VEGF), which stimulates tip cell protrusion. Yet it is not known which factors promote the fu... | 10.1038/nrd.2015.2 | This study demonstrates for the first time the role of tissue resident macrophages in vessel fusion in the developing brain. |
10.1084/jem.20120690 | 37,493,096 | Adult neovascularization relies on the recruitment of monocytes to the target organ or tumor and functioning therein as a paracrine accessory. The exact origins of the recruited monocytes and the mechanisms underlying their plasticity remain unclear. Using a VEGF-based transgenic system in which genetically tagged mono... | 10.1038/nrd.2015.2 | This study demonstrates that local VEGF 're-educates' monocytes to attain a pro-angiogenic phenotype. |
10.1182/blood-2010-01-266072 | 40,520,380 | Abstract During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced int... | 10.1038/nrd.2015.2 | This study demonstrates that an intravascular chemokine gradient on endothelial heparan sulfate directs crawling neutrophils towards the site of chemokine origin and accelerates their transmigration. |
10.1084/jem.20111622 | 39,421,977 | Neutrophil transmigration through venular walls that are composed of endothelial cells (ECs), pericytes, and the venular basement membrane is a key component of innate immunity. Through direct analysis of leukocyte–pericyte interactions in inflamed tissues using confocal intravital microscopy, we show how pericytes fac... | 10.1038/nrd.2015.2 | This study demonstrates that pericytes support neutrophil migration to inflamed tissue by providing a surface for neutrophil crawling and by enlarging the inter-pericyte spaces by contraction. |
10.1084/jem.20080305 | 38,403,539 | Biological functions of proteins are influenced by posttranslational modifications such as on/off switching by phosphorylation and modulation by glycosylation. Proteolytic processing regulates cytokine and chemokine activities. In this study, we report that natural posttranslational citrullination or deimination alters... | 10.1038/nrd.2015.2 | This study demonstrates that inflammation can be regulated by post-translational modifications of chemokines to greatly affect chemokine activity and stability. |
10.1152/ajpcell.00024.2014 | 62,521,416 | Resolution of acute inflammation is an active process locally controlled by a novel genus of specialized pro-resolving mediators (SPM) that orchestrate key resolution responses. Hence, it is of general interest to identify individual bioactive mediators and profile their biosynthetic pathways with related isomers as we... | 10.1038/nrd.2015.2 | This study identifies the mediators involved in resolution of acute inflammation, including lipoxins, resolvins, protectins and maresins in human plasma and lymphoid organs. |
10.1073/pnas.1119964109 | 100,358,244 | Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl 4 -induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B hi F... | 10.1038/nrd.2015.2 | This paper describes the first identification and characterization of the 'restorative macrophage', which can promote tissue remodelling and resolution of fibrosis. |
10.1126/science.1070051 | 62,103,897 | Lymphocyte motility is vital for trafficking within lymphoid organs and for initiating contact with antigen-presenting cells. Visualization of these processes has previously been limited to in vitro systems. We describe the use of two-photon laser microscopy to image the dynamic behavior of individual living lymphocyte... | 10.1038/nri935 | The first use of two-photon microscopy to observe the dynamics of T- and B-cell motility in an intact lymphoid organ; T cells were observed with and without antigen challenge. |
10.1126/science.1070945 | 103,790,844 | Thymocytes are selected to mature according to their ability to interact with self major histocompatibility complex (MHC)–peptide complexes displayed on the thymic stroma. Using two-photon microscopy, we performed real-time analysis of the cellular contacts made by developing thymocytes undergoing positive selection in... | 10.1038/nri935 | Two-photon microscopy was used to image interactions between thymocytes and stromal cells in a reaggregated thymic organ culture system during positive selection. |
10.1126/science.1071065 | 20,374,889 | T cell immune responses begin within organized lymphoid tissues. The pace, topology, and outcomes of the cellular interactions that underlie these responses have, so far, been inferred from static imaging of sectioned tissue or from studies of cultured cells. Here we report dynamic visualization of antigen-specific T c... | 10.1038/nri935 | Confocal imaging of T cells interacting with dendritic cells in intact lymph nodes. |
10.1017/s0962279900000776 | 120,004,341 | The establishment of a pregnancy depends upon mechanisms of forming close contacts between embryonic/fetal and maternal tissues. The starting point is the attachment of the blastocyst to the uterine wall, and this critical step is followed by a series of different morphogenetic events leading to placentation. These pro... | 10.1038/nri886 | A detailed review of how placental cells invade maternal arteries. |
10.1084/jem.20021183 | 40,504,283 | The production of interleukin (IL)-12 is critical for the development of interferon (IFN)-γ–dependent resistance to Toxoplasma gondii. Nevertheless, when this response is dysregulated, such as occurs in the absence of IL-10, the uncontrolled inflammation that results can have lethal consequences for the host. Recently,... | 10.1038/nri1547 | An original report on the role of endogenous lipoxins in modulating pro-inflammatory responses during infection with T. gondii |
10.1084/jem.20031325 | 62,586,529 | Lipoxin A4 (LXA4) is a potent endogenous lipoxygenase-derived eicosanoid with antiinflammatory and proresolving properties. Supraphysiological levels of LXA4 are generated during infection by Toxoplasma gondii, which in turn reduces interleukin (IL) 12 production by dendritic cells, thus dampening Th1-type cell-mediate... | 10.1038/nri1547 | Identification of a lipoxygenase activity in T. gondii that has immunomodulatory effects in vivo |
10.1073/pnas.0307308101 | 83,432,580 | In mammals, lipoxygenases play key roles in inflammation by initiating the transformation of arachidonic acid into potent bioactive lipid mediators such as leukotrienes and lipoxins. In general, most bacteria are believed to lack lipoxygenases and their polyunsaturated fatty acid substrates. It is therefore of interest... | 10.1038/nri1547 | Identification of a 15-lipoxygenase in the cystic-fibrosis-causing pathogen P. aeruginosa |
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