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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10.1177/1087057107312035 | 27,997,489 | High-throughput screening (HTS) of large-scale RNA interference (RNAi) libraries has become an increasingly popular method of functional genomics in recent years. Cell-based assays used for RNAi screening often produce small dynamic ranges and significant variability because of the combination of cellular heterogeneity... | 10.1038/nmeth.1351 | This article describes experimental and computational studies validating the effectiveness of median ± k median absolute deviations as a hit identification approach for RNAi screens |
10.1126/science.279.5349.381 | 62,456,696 | Circulating lymphocytes are recruited from the blood to the tissue by rolling along the endothelium until being stopped by a signaling event linked to the G i α subunit of a heterotrimeric GTP-binding protein; that event then triggers rapid integrin-dependent adhesion. Four chemokines are now shown to induce such adhes... | 10.1038/nri1354 | The first evidence that chemokines can induce arrest of rolling lymphocytes under flow conditions. |
10.4049/jimmunol.171.4.1642 | 122,237,164 | Abstract While CCR7 ligands direct T cell trafficking into lymph nodes (LNs) and Peyer’s patches (PPs), chemokines that regulate B cell trafficking across high endothelial venules (HEVs) remain to be fully elucidated. Here we report that CXC chemokine ligand (CXCL)13 (B lymphocyte chemoattractant) is detected immunohis... | 10.1038/nri1354 | The first paper to describe that the expression of CXCL13 in the HEV lumen is important for B-cell trafficking across HEVs in both lymph nodes and Peyer's patches. |
10.1084/jem.20020201 | 123,816,537 | B cell entry to lymph nodes and Peyer's patches depends on chemokine receptor signaling, but the principal chemokine involved has not been defined. Here we show that the homing of CXCR4−/− B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice. We a... | 10.1038/nri1354 | This study delineates the importance of CCR7 and CXCR4 in transmitting integrin-activating signals to rolling T and B cells in HEVs. |
10.4049/jimmunol.171.2.553 | 123,816,434 | Abstract We previously reported that mac25/angiomodulin (AGM), a 30-kDa secretory protein, is abundantly expressed in high endothelial venules (HEVs), which play a crucial role in lymphocyte trafficking to the lymph nodes and Peyer’s patches. We report that mac25/AGM interacts preferentially with certain molecules that... | 10.1038/nri1354 | The first study to show that a component of the basal lamina of HEVs can bind lymphoid chemokines preferentially and present them to receptor-expressing cells. |
10.1084/jem.191.1.77 | 16,744,838 | Chemokines have been hypothesized to contribute to the selectivity of lymphocyte trafficking not only as chemoattractants, but also by triggering integrin-dependent sticking (arrest) of circulating lymphocytes at venular sites of extravasation. We show that T cells roll on most Peyer's patch high endothelial venules (P... | 10.1038/nri1354 | The authors use intravital microscopy to show the presence of T- and B-lymphotropic HEVs. This paper also shows that CCL21 expression by HEVs closely correlates with preferential T-cell adhesion to HEVs. |
10.1073/pnas.2628040100 | 101,179,152 | The recirculation of T cells between the blood and secondary lymphoid organs requires that T cells are motile and sensitive to tissue-specific signals. T cell motility has been studied in vitro , but the migratory behavior of individual T cells in vivo has remained enigmatic. Here, using intravital two-photon laser mic... | 10.1038/nri1354 | Together with reference 99, this paper shows that, after extravasation through HEVs, T cells move rapidly in the lymph-node parenchyma in a seemingly random manner. |
10.1084/jem.20022212 | 107,198,313 | Identification of cellular factors involved in HIV-1 entry and transmission at mucosal surfaces is critical for understanding viral pathogenesis and development of effective prevention strategies. Here we describe the evaluation of HIV-1 entry inhibitors for their ability to prevent infection of, and dissemination from... | 10.1038/nri2302 | This investigation clearly demonstrates that DCs migrating from HIV-1-exposed cervical tissue can efficiently transmit the virus. Inhibition of this pathway can occur only by simultaneous blockade of CD4 and mannose-binding C-type lectin receptors. |
10.1128/jvi.73.7.5833-5842.1999 | 105,368,841 | ABSTRACT Worldwide, human immunodeficiency virus (HIV) is transmitted predominantly by heterosexual contact. Here, we investigate for the first time, by examining mononuclear cells obtained from cervicovaginal tissue, the mechanisms whereby HIV type 1 (HIV-1) directly targets cells from the human genital tract. In cont... | 10.1038/nri2302 | This is the first reported observation that DCs isolated from the vaginal mucosa internalize HIV-1 into cytoplasmic endosomes and produce new virions that bud from the cell membrane. |
10.1084/jem.183.1.215 | 62,395,111 | We used the simian immunodeficiency virus (SIV)/rhesus macaque model to study events that underlie sexual transmission of human immunodeficiency virus type 1 (HIV-1). Four female rhesus macaques were inoculated intravaginally with SIVmac251, and then killed 2, 5, 7, and 9 d later. A technique that detected polymerase c... | 10.1038/nri2302 | In this study, intravaginal inoculation of macaques with SIV led to the infection of stromal DCs and cells in the draining lymph nodes within two days. |
10.1126/science.286.5443.1353 | 82,739,890 | In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus–type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4 + T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferati... | 10.1038/nri2302 | The authors identified CD4 + T cells in the macaque genital mucosa as the predominant targets for SIV infection, and they noted that both activated and resting T cells propagate virus. |
10.1126/science.1352913 | 41,121,863 | The paucity of virus-laden CD4 + cells in individuals infected with human immunodeficiency virus type-1 (HIV-1) contrasts with the greatly reduced numbers and function of these lymphocytes. A pathway is described whereby dendritic cells carry HIV-1 to uninfected T cells, amplifying the cytopathic effects of small amoun... | 10.1038/nri2302 | This is the first study demonstrating HIV-1 transmission from DCs to CD4 + T cells. |
10.1126/science.1084238 | 40,357,755 | Monocyte-derived dendritic cells (MDDCs) can efficiently bind and transfer HIV infectivity without themselves becoming infected. Using live-cell microscopy, we found that HIV was recruited to sites of cell contact in MDDCs. Analysis of conjugates between MDDCs and T cells revealed that, in the absence of antigen-specif... | 10.1038/nri2302 | The investigators introduce the concept of an infectious synapse between DCs and T cells to which HIV is recruited on the DC side and CD4 and CCR5 on the T-cell side, thus promoting efficient in trans infection. |
10.1084/jem.20021258 | 105,147,647 | Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. C... | 10.1038/nrc1252 | This study delineates a crucial role for microbial agents in the spontaneous development of lymphomas and solid tumors in Gm-csf Ifn-γ -deficient mice. |
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/nrc1252 | This study, together with reference 107, indicates that CTLA-4 antibody blockade can be combined with cancer vaccines to increase tumour immunity in patients, albeit with a risk of compromising tolerance to self-antigens. |
10.1200/jco.1995.13.6.1404 | 17,674,506 | PURPOSE Superficial bladder tumors (stage Ta, T1, and Tis) may progress to invade the bladder muscle and cause death from metastatic cancer. Transurethral tumor resection (TURB) is the standard therapy for such tumors, but surgery alone may not prevent tumor progression. Intravesical therapy is widely used as an adjunc... | 10.1038/nrc1252 | This study demonstrates that the therapeutic administration of a mycobacteria reduces morbidity and mortality of bladder carcinoma. |
10.1073/pnas.091000398 | 80,552,140 | A single retroviral protein, Gag, is sufficient for virus particle assembly. While Gag is capable of specifically packaging the genomic RNA into the particle, this RNA species is unnecessary for particle assembly in vivo . In vitro , nucleic acids profoundly enhance the efficiency of assembly by recombinant Gag protein... | 10.1038/nrmicro1210 | In addition to functioning as the genetic material for reverse transcription, the viral RNA has a structural role in mature retroviruses |
10.1128/jvi.69.10.6445-6456.1995 | 18,629,829 | The retroviral nucleocapsid (NC) protein is necessary for the specific encapsidation of the viral genomic RNA by the assembling virion. However, it is unclear whether NC contains the determinants for the specific recognition of the viral RNA or instead contributes nonspecific RNA contacts to strengthen a specific conta... | 10.1038/nrmicro1210 | The chimeric HIV-1 Gag polyprotein containing the MoMuLV NC domain can specifically package the MoMuLV genome |
10.1002/pro.5560010502 | 124,704,197 | Abstract All retroviral nucleocapsid (NC) proteins contain one or two copies of an invariant 3Cys‐1His array (CCHC = C‐X 2 ‐C‐X 4 ‐H‐X 4 ‐C; C = Cys, H = His, X = variable amino acid) that are essential for RNA genome packaging and infectivity and have been proposed to function as zinc‐binding domains. Although the arr... | 10.1038/nrmicro1210 | Direct detection of zinc and its coordination environment in intact retroviruses provided the first direct evidence that retroviral NC proteins contain zinc knuckles |
10.1128/jvi.54.2.401-407.1985 | 61,322,815 | By using a retroviral construct derived from Moloney murine leukemia virus and capable of expressing the dominant selectable neo gene, we measured the effects of moving or deleting a sequence (psi) known to be required in cis for the packaging of genomic RNA into virus particles. When psi was at its wild-type position ... | 10.1038/nrmicro1210 | The MoMuLV Ψ-site can direct packaging when relocated near the 3′ end of the genome, indicating that the residues function as an independent packaging domain |
10.1128/jvi.14.1.152-161.1974 | 123,538,620 | Production of particles with the ultrastructural appearance of C-type virions persisted for at least 6 h in actinomycin D-treated cells infected with murine leukemia virus. This phenomenon occurred despite severe inhibition of viral RNA synthesis. Virus particles present in a 6-h harvest sedimented in sucrose gradients... | 10.1038/nrmicro1210 | MoMuLV particles contain two genomic RNA molecules, even when produced under conditions that inhibit mRNA production |
10.1128/jvi.71.6.4544-4554.1997 | 102,720,214 | To determine whether there is a cis-acting effect of translational expression of gag on RNA encapsidation, we compared the encapsidation of wild-type RNA with that of a mutant in which the translation of gag was ablated. This comparison indicated that there is not such a cis effect. To determine what is necessary and s... | 10.1038/nrmicro1210 | The intact HIV-1 5′-UTR and residues of the gag open reading frame are capable of directing RNA packaging |
10.1073/pnas.062652199 | 60,378,559 | The retroviral Gag polyprotein directs budding from the plasma membrane of infected cells. Until now, it was believed that Gag proteins of type C retroviruses, including the prototypic oncoretrovirus Rous sarcoma virus, were synthesized on cytosolic ribosomes and targeted directly to the plasma membrane. Here we reveal... | 10.1038/nrmicro1210 | Mutations in RSV MA that inhibit nuclear export of Gag lead to accumulation of Gag and viral RNA in the nucleus and to the production of genome-deficient virus particles |
10.1002/jnr.23884 | 62,476,122 | A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male‐specific effects of the Y chromosome, including expression of th... | 10.1038/nrg.2017.60 | This paper presents a theory of sex differentiation that encompasses aspects of male and female development outside the gonads, sex ducts and external genitalia. |
10.1534/genetics.114.169284 | 61,484,410 | Abstract Sex determination can be robustly genetic, strongly environmental, or genetic subject to environmental perturbation. The genetic basis of sex determination is unknown for zebrafish (Danio rerio), a model for development and human health. We used RAD-tag population genomics to identify sex-linked polymorphisms.... | 10.1038/nrg.2017.60 | Here the authors show that the Y chromosome present in wild zebrafish was lost in laboratory strains and replaced by a new sex-determining system. |
10.1242/dev.076307 | 107,188,112 | The function of AMH (Anti-Müllerian hormone), a phylogenetically ancient member of the TGFβ family of proteins, in lower vertebrates is largely unknown. Previously, we have shown that the gene encoding the type II anti-Müllerian hormone receptor, amhrII, is responsible for excessive germ cell proliferation and male-to-... | 10.1038/nrg.2017.60 | References 159 and 160 were the first to show that germ cell number controls sexual fate in a fish. |
10.1084/jem.189.4.615 | 104,326,261 | Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinflammatory state in the infected host. Genetic regulation of this response has been localized to the Lps locus on mouse chromosome 4, through study of the C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr mice are homozygous f... | 10.1038/nrg1019 | References 34 and 35 describe the first indication of TLR4 function in vivo |
10.1126/science.289.5483.1352 | 39,291,514 | The cytokine interleukin-10 (IL-10) has shown promise in clinical trials for treatment of inflammatory bowel disease (IBD). Using two mouse models, we show that the therapeutic dose of IL-10 can be reduced by localized delivery of a bacterium genetically engineered to secrete the cytokine. Intragastric administration o... | 10.1038/nrg1019 | A paper that provides a new concept for mucosal immune modulation in mice by in situ delivery of cytokines using genetically engineered Lactococcus lactis |
10.1146/annurev.immunol.20.100301.064816 | 122,358,078 | In recent years the status of the inflammatory bowel diseases (IBDs) as canonical autoimmune diseases has risen steadily with the recognition that these diseases are, at their crux, abnormalities in mucosal responses to normally harmless antigens in the mucosal microflora and therefore responses to antigens that by the... | 10.1038/nrg1019 | A review that provides a broad overview of mucosal models of inflammation mainly in mice. |
10.4049/jimmunol.165.1.483 | 99,472,688 | Abstract Genetically susceptible, TNFRp55 gene-deficient (TNFRp55−/−) mice succumb to infection with Mycobacterium avium. Before their death, M. avium-infected TNFRp55−/− mice develop granulomatous lesions that, in contrast to granulomas in wild-type syngeneic mice, undergo acute disintegration. To determine the factor... | 10.1038/nrg1019 | Demonstration that lethal granuloma disintegration in mycobacteria-infected Tnfrp55 −/− mice is T cell and IL–12 dependent. |
10.1126/science.7660128 | 109,089,749 | In situ coating of the surface of endothelial cells in rat lung with cationic colloidal silica particles was used to separate caveolae from detergent-insoluble membranes rich in glycosyl phosphatidylinositol (GPI)-anchored proteins but devoid of caveolin. Immunogold electron microscopy showed that ganglioside G M1 -enr... | 10.1038/nrc1146 | This paper shows for the first time that caveolae and lipid rafts are biochemically distinct, based on their isolation from two different subcellular fractions derived from the same starting plasma membranes. The subfractionation technology described here makes possible the mapping of tumour-induced endothelial and cav... |
10.1126/science.274.5285.239 | 83,119,344 | Caveolae are specialized invaginated cell surface microdomains of undefined function. A cell-free system that reconstituted fission of caveolae from lung endothelial plasma membranes was developed. Addition of cytosol and the hydrolysis of guanosine triphosphate (GTP) induced caveolar fission. The budded caveolae were ... | 10.1038/nrc1146 | This paper, along with references 38 and 42, establishes that caveolae are not static 'little caves', but rather have the ability to bud from the plasma membrane through GTP hydrolysis mediated by the GTPase dynamin located at the neck of caveolae. |
10.1073/pnas.251662398 | 123,016,111 | Site-directed pharmacodelivery is a desirable but elusive goal. Endothelium and epithelium create formidable barriers to endogenous molecules as well as targeted therapies in vivo . Caveolae provide a possible, yet unproven, transcellular pathway to overcome such barriers. By using an antibody- and subfractionation-bas... | 10.1038/nrc1146 | This report is the first to show that molecular heterogeneity of the endothelium and its caveolae allows vascular targeting to achieve rapid tissue-specific delivery and bioefficacy and that caveolae, through transcytosis, might provide a tissue-specific pathway for overcoming key cell barriers to many drug and gene th... |
10.1073/pnas.041359198 | 100,426,694 | Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible... | 10.1038/nrc1146 | This study used eNos -null mice to show that eNos is involved in Vegf-induced angiogenesis and vascular permeability in vivo |
10.1242/dev.128.18.3623 | 20,853,916 | An organizer population has been identified in the anterior end of the primitive streak of the mid-streak stage embryo, by the expression of Hnf3β, GsclacZ and Chrd, and the ability of these cells to induce a second neural axis in the host embryo. This cell population can therefore be regarded as the mid-gastrula organ... | 10.1038/nrg1347 | Refutes the view that head-organizer activity in the mouse resides exclusively in the anterior visceral endoderm; shows that definitive anterior mesendoderm that is derived from the primitive streak harbours head-organizer activity. |
10.1101/gad.852400 | 82,117,971 | Spatial variations in the levels of bone morphogenetic protein (BMP) signaling are a critical determinant of dorsoanterior-ventroposterior pattern in vertebrate embryos. Whereas BMP overexpression abolishes both head and trunk development, known single and double loss-of-function mutations in BMP inhibitors have less d... | 10.1038/nrg1347 | Genetic evidence that bone morphogenetic protein antagonists function in the trunk organizer. bozozok chordino double mutants only form tails. |
10.1101/gad.1100503 | 107,312,284 | It is well known that cell fate decisions in the mouse organizer region during gastrulation ultimately govern gut formation and patterning, left–right axis determination, and development of the central nervous system. Previous studies suggest that signaling pathways activated by Nodal, bone morphogenetic protein (BMP),... | 10.1038/nrg1347 | Together with reference 82, this presents a rare case of a study on dose-dependent patterning effects by a growth factor in the mouse. |
10.1126/science.1083317 | 104,115,327 | The CD8 + cytotoxic T cell response to pathogens is thought to be CD4 + helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4 + T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However... | 10.1038/nri3152 | References 51 and 52 highlight the requirement for CD4 + T cell help during the priming of CD8 + T cells to generate functional memory cells. |
10.1084/jem.20101773 | 17,715,375 | CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associate... | 10.1038/nri3152 | This study shows that prolonged T cell receptor stimulation during chronic infection progressively redirects CD4 + T cell development towards a T follicular helper cell phenotype. |
10.1126/science.1151869 | 20,265,634 | Secondary lymphoid organs are dominant sites of T cell activation, although many T cells are subsequently retained within peripheral tissues. Currently, these nonlymphoid compartments are viewed as sites only of effector T cell function, without the involvement of renewed induction of immunity via the interactions with... | 10.1038/nri3152 | This study provides evidence that not only effector CD8 + T cell functions but initiation of CD8 + memory T cell responses can occur within extra-lymphoid tissues through interaction with CD4 + T cells and recently recruited DCs. |
10.1126/science.289.5481.920 | 20,795,104 | Using the atomic structures of the large ribosomal subunit from Haloarcula marismortui and its complexes with two substrate analogs, we establish that the ribosome is a ribozyme and address the catalytic properties of its all-RNA active site. Both substrate analogs are contacted exclusively by conserved ribosomal RNA (... | 10.1038/nrmicro1265 | The first structural data strongly indicating that peptide-bond formation is RNA-catalysed, and implicating 23S rRNA nucleotide A2451 in this process. |
10.1126/science.1060089 | 107,303,106 | We describe the crystal structure of the complete Thermus thermophilus 70 S ribosome containing bound messenger RNA and transfer RNAs (tRNAs) at 5.5 angstrom resolution. All of the 16 S , 23 S , and 5 S ribosomal RNA (rRNA) chains, the A-, P-, and E-site tRNAs, and most of the ribosomal proteins can be fitted to the el... | 10.1038/nrmicro1265 | Describes the crystal structures of both ribosomal subunits in functional complexes, and reveals essential details of tRNA interactions and how the ribosome works. |
10.1073/pnas.1133380100 | 123,920,685 | Protein biosynthesis on the ribosome requires accurate reading of the genetic code in mRNA. Two conformational rearrangements in the small ribosomal subunit, a closing of the head and body around the incoming tRNA and an RNA helical switch near the mRNA decoding site, have been proposed to select for complementary base... | 10.1038/nrmicro1265 | First structure of E. coli ribosomes, which had previously been thought to be refractory to crystallographic analysis. Presently at low resolution, but more highly resolved data are on the way. |
10.1126/science.285.5434.1722 | 60,789,821 | Translational fidelity is established by ribosomal recognition of the codon-anticodon interaction within the aminoacyl–transfer RNA (tRNA) site (A site) of the ribosome. Experiments are presented that reveal possible contacts between 16 S ribosomal RNA and the codon-anticodon complex. N1 methylation of adenine at posit... | 10.1038/nrmicro1265 | First conclusive experimental data that link the 16S rRNA bases A1492 and A1493 with the decoding process. |
10.1126/science.1060612 | 107,303,138 | Crystal structures of the 30 S ribosomal subunit in complex with messenger RNA and cognate transfer RNA in the A site, both in the presence and absence of the antibiotic paromomycin, have been solved at between 3.1 and 3.3 angstroms resolution. Cognate transfer RNA (tRNA) binding induces global domain movements of the ... | 10.1038/nrmicro1265 | Crystal study that confirms the involvement of A1492 and A1493 in the decoding process and links their movement with other conformational changes in the 30S ribosomal subunit. See also reference 67 for a review. |
10.1126/science.1167728 | 20,492,843 | Genome-wide association studies (GWASs) are regularly used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of 10 candidate genes in ... | 10.1038/nri2554 | This paper shows that re-sequencing studies can pinpoint disease-causing genes in genomic regions initially identified by genome-wide association studies. |
10.1126/science.1172747 | 60,070,567 | Commensal bacteria in the lower intestine of mammals are 10 times as numerous as the body’s cells. We investigated the relative importance of different immune mechanisms in limiting the spread of the intestinal microbiota. Here, we reveal a flexible continuum between innate and adaptive immune function in containing co... | 10.1038/nri3251 | An elegant study on the mutualism between the microbiota and the host with special reference to the role of TLR signalling. |
10.1002/eji.201041297 | 101,815,622 | Abstract Immunizations via the i.n. and intravaginal (ivag) routes effectively generate strong genital tract antibody‐mediated immunity. To what extent the same is true for T‐cell responses is incompletely known. Therefore, we set out to investigate optimal conditions for stimulation of genital tract CD4 + T‐cell respo... | 10.1038/nri3251 | The study shows that CTA1-DD cannot bind to the cells of the central nervous tissues following intranasal administration. |
10.4049/jimmunol.1003789 | 99,163,522 | Abstract Escherichia coli heat-labile enterotoxin (LT) is a powerful mucosal adjuvant; however, it is associated with toxic effects when delivered intranasally, and its mechanism of action is poorly understood. In this article, we demonstrate that LT acts as a highly effective adjuvant when administered parenterally, p... | 10.1038/nri3251 | Mechanistic studies of E. coli heat-labile enterotoxin and LTK63 and their role for augmenting T H 17 cell responses. |
10.1002/art.24566 | 61,502,335 | Abstract Objective To determine whether a cholera toxin–derived, novel immunomodulating fusion protein, CTA1R7K‐COL‐DD, carrying the class II major histocompatibility complex H‐2 q –restricted type II collagen peptide aa 259–274, can induce therapeutic tolerance and prevent collagen‐induced arthritis (CIA) when adminis... | 10.1038/nri3251 | The first demonstration that mutated CTA1-DD could work to tolerize CD4 + T cells in the context of autoimmune conditions. |
10.4049/jimmunol.1101107 | 36,172,836 | Abstract A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and... | 10.1038/nri3251 | This study demonstrates that adjuvants can bind to and activate follicular DCs. |
10.1038/ncomms11627 | 81,357,564 | Abstract IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T ce... | 10.1038/nri.2017.50 | This study identifies T-bet as an important regulator of the IL-23-driven pathogenicity of T H 17 cells. |
10.1101/gad.486808 | 109,005,427 | The conserved Polo kinase controls multiple events in mitosis and cytokinesis. Although Polo-like kinases are regulated by phosphorylation and proteolysis, control of subcellular localization plays a major role in coordinating their mitotic functions. This is achieved largely by the Polo-Box Domain, which binds prephos... | 10.1038/nrm3819 | Shows a phosphopriming-independent interaction of Polo with Map205, which inhibits Polo and sequesters it to the microtubules. This sequestration can be relieved by the activity of Cdk1 at the entry to mitosis. |
10.1083/jcb.200309035 | 20,166,341 | We have found that key mitotic regulators show distinct patterns of degradation during exit from mitosis in human cells. Using a live-cell assay for proteolysis, we show that two of these regulators, polo-like kinase 1 (Plk1) and Aurora A, are degraded at different times after the anaphase-promoting complex/cyclosome (... | 10.1038/nrm3819 | Identifies the D-box in PLK1 and shows that it is required for degradation through the APC/C of PLK1 in anaphase. |
10.1242/jcs.097105 | 38,523,938 | The correct segregation of DNA during cell division requires formation of a bipolar spindle, organized at each pole by a centrosome. The regulation of centrosome duplication such that each mitotic cell has exactly two centrosomes is therefore of central importance to cell division. Deregulation of centrosome duplicatio... | 10.1038/nrm3819 | Reports, together with references 22, 34 and 35, that PLK4 targets itself for degradation through the 26S proteosome via ubiquitylation mediated by the SCF components Slimb, βTrCP or LIN-23 in D. melanogaster , human cells and C. elegans , respectively. |
10.1126/science.1249749 | 103,889,229 | Problems making proteins kills nerve cells Neurodegeneration is associated with a variety of different diseases, but its cellular roots are often obscure. Ishimura et al. find that mutant mice whose brain cells start to die rapidly soon after birth have lost the function of two vital cellular components (see the Perspe... | 10.1038/nrg3861 | This study reports that a mutation in a nuclear-encoded tRNA gene, which is specifically expressed in the CNS, may itself be phenotypically silent but epistatically exacerbates the deleterious effect of the mutation in a partner of the ribosome recycling protein Pelota. |
10.15252/embj.201489282 | 20,780,837 | Abstract Mutations in the cytosine‐5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post‐transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine‐5 RNA methylomes in patient fibro... | 10.1038/nrg3861 | This paper shows that a mutation in a tRNA-modifying enzyme leads to mismodification of tRNAs and enhances their susceptibility to angiogenin-mediated cleavage with an enhanced effect in neuronal tissues. |
10.1126/science.1131262 | 107,326,362 | Catechol- O -methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous position, code for differences in COMT enzymatic activity and are associated with pain sensitivity. Haplo... | 10.1038/nrg3051 | The first study to elucidate a detailed molecular mechanism based on mRNA structure for how synonymous mutations can have physiological consequences. |
10.1126/science.1135308 | 18,212,386 | Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 ( MDR 1) gene, part of a haplotype previously linked to altered function... | 10.1038/nrg3051 | The first study to provide evidence that synonymous changes that do not affect mRNA levels have clinical consequences. |
10.1126/science.1170160 | 82,952,021 | Synonymous mutations do not alter the encoded protein, but they can influence gene expression. To investigate how, we engineered a synthetic library of 154 genes that varied randomly at synonymous sites, but all encoded the same green fluorescent protein (GFP). When expressed in Escherichia coli , GFP protein levels va... | 10.1038/nrg3051 | This important study, which was carried out using synthetic genes, shows the importance mRNA structure near the start codon and the consequenes of synonymous mutations in this region. |
10.1152/physrev.2001.81.1.239 | 123,244,981 | The cloning of a G protein-coupled extracellular Ca 2+ (Ca o 2+ )-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca o 2+ on tissues that maintain systemic Ca o 2+ homeostasis, especially parathyroid chief cells and several cells in the kidney. The availability... | 10.1038/nrc1144 | An excellent review of the calcium-sensing receptor (CaR) and extracellular calcium signalling in cells of different lineages. |
10.1002/ijc.22858 | 102,938,994 | Abstract An siRNA directed against the extracellular calcium‐sensing receptor (CaSR) was used to down‐regulate this protein in CBS colon carcinoma cells. In additional studies, we utilized a variant of the parental CBS line that demonstrates CaSR expression but does not upregulate this protein in response to extracellu... | 10.1038/nrc1144 | An interesting paper presenting evidence for the involvement of extracellular calcium and CaR in promoting the differentiation of colon cells and in suppressing β-catenin activation, which is a prominent signalling pathway involved in colon carcinogenesis. |
10.1126/science.283.5406.1317 | 122,101,669 | Cell proliferation and differentiation are regulated by growth regulatory factors such as transforming growth factor–β (TGF-β) and the liphophilic hormone vitamin D. TGF-β causes activation of SMAD proteins acting as coactivators or transcription factors in the nucleus. Vitamin D controls transcription of target genes ... | 10.1038/nrc1144 | An elegant paper showing the cross-talk between vitamin D and the TGF-β signalling pathway. |
10.1126/science.1070477 | 104,360,711 | The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive t... | 10.1038/nrc1144 | This work describes how the vitamin-D receptor 'senses' the presence of lithocholic acid, a potential pro-carcinogenic bile acid, and detoxifies it. |
10.1083/jcb.200102028 | 42,578,088 | The β-catenin signaling pathway is deregulated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1α,25-dehydroxyvitamin D3) analogues are candidate drugs to treat this neoplasia. We show that these compounds promote the differentiation of human colon carcinoma SW480 cells expressing vitamin D receptors (VDRs) (... | 10.1038/nrc1144 | Convincing data showing that the differentiation-inducing action of vitamin D depends, at least partly, on the inhibition of inappropriate β-catenin expression. |
10.1126/science.1083558 | 62,146,835 | Genome-wide DNA hypomethylation occurs in many human cancers, but whether this epigenetic change is a cause or consequence of tumorigenesis has been unclear. To explore this phenomenon, we generated mice carrying a hypomorphic DNA methyltransferase 1 ( Dnmt1 ) allele, which reduces Dnmt1 expression to 10% of wild-type ... | 10.1038/nrc1144 | References 112 and 113 provide solid evidence that DNA hypomethylation results in increased mutation rates, chromosome instability and neoplasia. |
10.4314/tjpr.v19i1.30 | 93,598,636 | Purpose: To investigate the toxicity of methylenetetrahydrofolate reductase (MTHFR) polymorphism in colorectal cancer patients treated with 5-fluorouracil (5-FU).Methods: A total of 105 patients with colorectal cancer who underwent 5-FU therapy were included in this study. MTHFR C677T polymorphisms were determined usin... | 10.1038/nrc1144 | The first paper to report that folate-replete individuals homozygous for a common polymorphic variant of MTHFR have half the risk of colon cancer compared with either the wild-type or heterozygous phenotypes. |
10.1126/science.1070710 | 122,517,241 | The abundance of individuals in microbial species is so large that dispersal is rarely (if ever) restricted by geographical barriers. This “ubiquitous” dispersal requires an alternative view of the scale and dynamics of biodiversity at the microbial level, wherein global species number is relatively low and local speci... | 10.1038/nrmicro1341 | A summary of the arguments for why microbial eukaryotes might not be restricted by geographic barriers. |
10.1128/aem.66.12.5448-5456.2000 | 123,948,946 | ABSTRACT Fluorescent Pseudomonas strains were isolated from 38 undisturbed pristine soil samples from 10 sites on four continents. A total of 248 isolates were confirmed as Pseudomonas sensu stricto by fluorescent pigment production and group-specific 16S ribosomal DNA (rDNA) primers. These isolates were analyzed by th... | 10.1038/nrmicro1341 | One of the first examples of relating the genetic similarity of a free-living bacterial assemblage with geographic distance, using fluorescent Pseudomonas isolates. |
10.1126/science.1086909 | 83,479,501 | Barriers to dispersal between populations allow them to diverge through local adaptation or random genetic drift. High-resolution multilocus sequence analysis revealed that, on a global scale, populations of hyperthermophilic microorganisms are isolated from one another by geographic barriers and have diverged over the... | 10.1038/nrmicro1341 | Already a classic microbial biogeography study, it considers both the effects of spatial isolation and contemporary environmental parameters on hotspring Sulfolobus assemblages within and across continents. |
10.1073/pnas.96.8.4285 | 83,341,445 | Determining protein functions from genomic sequences is a central goal of bioinformatics. We present a method based on the assumption that proteins that function together in a pathway or structural complex are likely to evolve in a correlated fashion. During evolution, all such functionally linked proteins tend to be e... | 10.1038/nrg1113 | This paper introduces the concept of phylogenetic profiles, and the idea that similar phylogenetic profiles indicate functional association between genes. |
10.1073/pnas.141236298 | 39,668,648 | Recent work in computational genomics has shown that a functional association between two genes can be derived from the existence of a fusion of the two as one continuous sequence in another genome. For each of 30 completely sequenced microbial genomes, we established all such fusion links among its genes and determine... | 10.1038/nrg1113 | This paper is a 'proof of principle' that gene-fusion events can be used to infer functional associations, as proposed in references 63 and 65. |
10.1128/mr.57.4.862-952.1993 | 125,242,422 | A list of currently identified gene products of Escherichia coli is given, together with a bibliography that provides pointers to the literature on each gene product. A scheme to categorize cellular functions is used to classify the gene products of E. coli so far identified. A count shows that the numbers of genes con... | 10.1038/nrg1113 | The original comprehensive functional-classification scheme, developed for the gene products of the E. coli genome. |
10.1155/2000/919260 | 27,917,251 | A set of seven structurally related Sm proteins forms the core of the snRNP particles containing the spliceosomal U1, U2, U4 and U5 snRNAs. A search of the genomic sequence of Saccharomyces cerevisiae has identified a number of open reading frames that potentially encode structurally similar proteins termed Lsm ( L ¯ i... | 10.1038/nrg1113 | This paper describes the first large-scale use of two-hybrid arrays to identify protein interactions in yeast. |
10.1101/gad.10.14.1796 | 81,504,594 | Transcriptional repression at the silent mating-type loci in yeast requires the targeting of silent information regulator (Sir) proteins through specific interactions formed at cis-acting silencer elements. We show here that a reporter gene flanked by two functional silencers is not repressed when integrated at >200... | 10.1038/nrg2122 | Telomere foci favour the repression of silencer-bound constructs by sequestering Sir proteins, which are shown to be limiting for repression. |
10.1126/science.1065366 | 104,285,103 | Little is known about the dynamics of chromosomes in interphase nuclei. By tagging four chromosomal regions with a green fluorescent protein fusion to lac repressor, we monitored the movement and subnuclear position of specific sites in the yeast genome, sampling at short time intervals. We found that early and late or... | 10.1038/nrg2122 | Silent telomeres and active non-telomeric loci are shown to have different amounts of spatial constraint in their random-walk movement in the yeast nucleus. This work coupled Nup49–GFP with LacO-tagged loci to measure the absolute movement of genes. |
10.1101/gad.1343105 | 38,589,795 | The mechanism through which gene expression originating from the single male or the two female X chromosomes in Drosophila is adjusted to autosomal gene expression has remained controversial. According to the prevalent model, transcription of the male X is increased twofold by the male-specific-lethal (MSL) complex. Ho... | 10.1038/nrg2122 | References 78 and 79 collectively show that transcription of MSL-bound X-linked genes is affected by depletion of MSL2 in D. melanogaster cells. |
10.1126/science.1174334 | 104,237,301 | A rare form of lung cancer in children is associated with mutational disruption of an enzyme that generates small noncoding RNAs. | 10.1038/nrc3932 | This study was the first to identify the germline mutations of DICER1 in patients with familial PPB. |
10.1182/blood-2004-07-2885 | 123,193,924 | Abstract Semaphorins, a large family of membrane-bound and secreted proteins, signal through their transmembrane receptors, the plexins. Semaphorins and plexins share structural homologies with scatter factor receptors, a family of tyrosine kinase receptors for which Met is the prototype. Semaphorins have been studied ... | 10.1038/nrm3012 | References 56–65 provide information on how MET-dependent signals can be tuned by the association of MET with surface transmembrane partners, including β4 integrin, CD44 and plexin B. |
10.1073/pnas.0702555104 | 100,977,982 | Gab1 is a multiadaptor protein that has been shown to be required for multiple processes in embryonic development and oncogenic transformation. Gab1 functions by amplifying signal transduction downstream of various receptor tyrosine kinases through recruitment of multiple signaling effectors, including phosphatidylinos... | 10.1038/nrm3012 | The authors show that the multi-adaptor GAB1 promotes different biological outcomes in vivo through the recruitment of distinct effectors. |
10.1073/pnas.0403412101 | 124,083,457 | Genetic analysis in mice has demonstrated a crucial role of the Met tyrosine kinase receptor and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), in development of the liver, muscle, and placenta. Here, we use conditional mutagenesis in mice to analyze the function of Met during liver regeneration, using t... | 10.1038/nrm3012 | References 125 and 126 describe the first genetic demonstrations that MET is essential in the regeneration of adult liver. |
10.1073/pnas.0707498104 | 40,379,014 | Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 cell lines derived from diverse epithelial cancers for sensitivity to 14 kinase inhibitors. Most inhibitors were... | 10.1038/nrm3012 | References 142 and 143 are the first demonstration that only cell lines with amplification of the Met gene respond to MET inhibition with substantial growth impairment. |
10.1126/scisignal.2000643 | 61,220,917 | Cells addicted to different oncogenic receptor tyrosine kinases develop common downstream mechanisms to sustain malignancy. | 10.1038/nrm3012 | References 144 and 145 are the first large-scale analyses of the signalling and transcriptional consequences of MET inhibition in drug-sensitive, MET-addicted cell lines. |
10.1126/science.1112014 | 125,082,116 | This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promo... | 10.1038/nrg2083 | This reference provides an unparalleled insight into the complexity of the mouse transcriptome on the basis of sequencing of full-length cDNAs and cDNA tags. |
10.1101/gr.4137606 | 109,172,691 | Transcription of a gene usually ends at a regulated termination point, preventing the RNA-polymerase from reading through the next gene. However, sporadic reports suggest that chimeric transcripts, formed by transcription of two consecutive genes into one RNA, can occur in human. The splicing and translation of such RN... | 10.1038/nrg2083 | References 14–18 were the first studies to detail developmental and tissue- or cell-type-specific regulatory regions that are distal from the genes they regulate, often utilizing promoters and exons from upstream genes to form chimeric versions of well annotated protein-coding transcripts. |
10.1073/pnas.2135255100 | 61,125,334 | We have mapped the chromosomal binding site distribution of a transcription factor in human cells. The NF-κB family of transcription factors plays an essential role in regulating the induction of genes involved in several physiological processes, including apoptosis, immunity, and inflammation. The binding sites of the... | 10.1038/nrg2083 | References 23 and 24 represent the first reports of the unbiased profiling of transcription factor binding sites and provide the first comprehensive evidence for the utilization of promoters in non-canonical genomic locations. |
10.1002/bies.10332 | 40,674,856 | Abstract The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from mi... | 10.1038/nrg2083 | References 38–41 review the concept of RNA as a carrier of information in the cell. |
10.1126/science.1115901 | 83,105,946 | Noncoding RNA molecules (ncRNAs) have been implicated in numerous biological processes including transcriptional regulation and the modulation of protein function. Yet, in spite of the apparent abundance of ncRNA, little is known about the biological role of the projected thousands of ncRNA genes present in the human g... | 10.1038/nrg2083 | An example of the use of high-throughput technologies to elucidate the function of human ncRNAs. |
10.1126/science.1068597 | 123,079,400 | The sequences of the human chromosomes 21 and 22 indicate that there are approximately 770 well-characterized and predicted genes. In this study, empirically derived maps identifying active areas of RNA transcription on these chromosomes have been constructed with the use of cytosolic polyadenylated RNA obtained from 1... | 10.1038/nrg2083 | The first unbiased high-resolution microarray-based study of the genomics era, showing that the transcriptional complexity of human cytosolic polyadenylated RNA is up to an order of magnitude more complex that can be explained by exons of known genes. |
10.1101/gad.866201 | 17,706,324 | To directly address the function of a putative auxin receptor designated ABP1, a reverse genetic approach was taken to identify and characterize ABP1 mutant alleles in Arabidopsis . A homozygous null mutation in ABP1 confers embryo lethality. Null mutant embryos develop normally until the early stages of the globular e... | 10.1038/nrm2020 | After many years of investigation, the importance of ABP1 for both cell elongation and cell division was clearly shown. Crucially, the loss-of-function abp1 mutant has an embryonic-lethal phenotype. |
10.1126/science.282.5397.2226 | 41,705,914 | Polar auxin transport controls multiple developmental processes in plants, including the formation of vascular tissue. Mutations affecting the PIN-FORMED (PIN1) gene diminish polar auxin transport in Arabidopsis thaliana inflorescence axes. The AtPIN1 gene was found to encode a 67-kilodalton protein with similarity to ... | 10.1038/nrm2020 | This paper shows that proteins can be localized polarly in plants. A correlation with the expected direction of auxin transport indicates that PIN is an auxin efflux carrier. |
10.1126/science.273.5277.948 | 104,328,031 | The plant hormone auxin regulates various developmental processes including root formation, vascular development, and gravitropism. Mutations within the AUX1 gene confer an auxin-resistant root growth phenotype and abolish root gravitropic curvature. Polypeptide sequence similarity to amino acid permeases suggests that... | 10.1038/nrm2020 | The authors present a detailed characterization of the auxin influx carrier and its function in the gravitropic response. |
10.1126/science.1100618 | 103,797,481 | Polar transport–dependent local accumulation of auxin provides positional cues for multiple plant patterning processes. This directional auxin flow depends on the polar subcellular localization of the PIN auxin efflux regulators. Overexpression of the PINOID protein kinase induces a basal-to-apical shift in PIN localiz... | 10.1038/nrm2020 | It was demonstrated that the kinase PINOID controls PIN polarity and is necessary for correct cellular patterning. |
10.1126/science.1214402 | 98,954,893 | Making the CoTC In eukaryotes, cotranscriptional cleavage (CoTC) of nascent RNA transcripts at the polyadenylation (polyA) site is involved in transcription termination of RNA polymerase II genes. The Dicer endoribonucleases, on the other hand, are generally associated with gene silencing through the generation of smal... | 10.1038/nrm3994 | This paper shows that a Dicer-like protein associates with the 3′ region of the FCA gene and promotes cleavage of the nascent transcript. |
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/nrc1997 | The first demonstration of a link between miRNA genes and cancer. |
10.1073/pnas.0509603102 | 38,240,893 | Apart from alterations in the RET/PTC-RAS-BRAF pathway, comparatively little is known about the genetics of papillary thyroid carcinoma (PTC). We show that numerous microRNAs (miRNAs) are transcriptionally up-regulated in PTC tumors compared with unaffected thyroid tissue. A set of five miRNAs, including the three most... | 10.1038/nrc1997 | The first report about germline alterations in miRNA-recognition sequences located in a messenger RNA. |
10.1073/pnas.0403293101 | 100,705,590 | MicroRNAs (miRNAs) are a class of small noncoding RNA genes recently found to be abnormally expressed in several types of cancer. Here, we describe a recently developed methodology for miRNA gene expression profiling based on the development of a microchip containing oligonucleotides corresponding to 245 miRNAs from hu... | 10.1038/nrc1997 | The first study to report on miRNA profiling using an oligonucleotide microchip. |
10.1073/pnas.0404432101 | 121,775,911 | Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673–676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253–25... | 10.1038/nrc1997 | The first paper to explore, by using genome-wide miRNA profiling by microarray, the potential importance of miRNAs in the diagnosis and prognosis of a human malignancy. |
10.1073/pnas.0602266103 | 107,273,305 | MicroRNAs (miRNAs) represent a newly discovered class of posttranscriptional regulatory noncoding small RNAs that bind to targeted mRNAs and either block their translation or initiate their degradation. miRNA profiling of hematopoietic lineages in humans and mice showed that some miRNAs are differentially expressed dur... | 10.1038/nrc1997 | The first paper to show that the deregulation of a single miRNA gene can lead to cancer. |
10.1073/pnas.0307323101 | 62,615,151 | A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a , located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investi... | 10.1038/nrc1997 | A genome-wide study proving that half of the annotated human miRNAs are located in genomic regions involved in cancer. |
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