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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
10.4049/jimmunol.178.2.817	81,538,269	Abstract Mutations in SH2D1A resulting in lack of SLAM-associated protein (SAP) expression cause the human genetic immunodeficiency X-linked lymphoproliferative disease. A severe block in germinal center development and lack of long-term humoral immunity is one of the most prominent phenotypes of SAP− mice. We show, in...	10.1038/nri2456	This paper, along with reference 25, provides the first evidence that germinal-centre defects that are associated with SAP deficiency result from a distinct signalling pathway that depends less on the ability of SAP to recruit molecules, including FYN, through its arginine 78 motif.
10.1126/scisignal.2001893	18,774,845	Signaling molecules downstream of the TCR are poised to rapidly respond to receptor activation.	10.1038/nri3403	This study shows that CSK and CD45 regulate the activity of LCK and influence feedback circuits that affect the threshold of activation in T cells.
10.1182/blood-2006-07-038752	105,393,504	Abstract In primary human T cells, anergy induction results in enhanced p59Fyn activity. Because Fyn is the kinase primarily responsible for the phosphorylation of PAG (the phosphoprotein associated with glycosphingolipid-enriched microdomains), which negatively regulates Src-kinase activity by recruiting Csk (the C-te...	10.1038/nri3403	The authors show that PAG interacts with negative regulators of T cell signalling, including CSK, in primary human T cells and that knocking down PAG with siRNA enhances SFK activity and RAS activation.
10.1126/scisignal.2000199	39,182,314	The timing and the distribution of signaling intermediates reflect the efficiency and nature of T cell receptor activation.	10.1038/nri3403	This paper follows the spatiotemporal patterning of 32 individual signalling components in primary mouse T cells stimulated by professional APCs and a variety of ligands of differing affinity. This systems level approach shows that patterning is highly diverse.
10.1126/scisignal.2003365	123,061,808	Loss of the phosphatase PTPN22 enhances the functions of both effector and regulatory T cells.	10.1038/nri3403	Mice that lack PTPN22 were shown to have increased numbers of T Reg cells with enhanced function, which were capable of restraining hyperactive Ptpn22 −/− T effector cells and maintaining T cell tolerance. The increased T Reg cell functionality could be explained at least in part by increased LFA1 adhesion (see also re...
10.1126/science.2821624	122,680,892	The role of guanine nucleotides in ras p21 function was determined by using the ability of p21 protein to induce maturation of Xenopus oocytes as a quantitative assay for biological activity. Two oncogenic mutant human N- ras p21 proteins, Asp12 and Val12, actively induced maturation, whereas normal Gly12 p21 was relat...	10.1038/nrm2438	References 41–46 established that oncogenic mutation of ras affects its nucleotide cycle.
10.1101/gad.10.19.2462	62,101,673	Metastasis of epithelial tumor cells can be associated with the acquisition of fibroblastoid features and the ability to invade stroma and blood vessels. Using matched in vivo and in vitro culture systems employing fully polarized, mammary epithelial cells, we report here that TGF-beta1 brings about these changes in Ra...	10.1038/nrc1208	One of the first demonstrations that TGF-β can cooperate with an activated RAS pathway in mammary tumour cells to induce an epithelial–mesenchymal transition, and enhance tumour-cell invasiveness.
10.1126/scitranslmed.aad5330	20,363,963	Disrupting the HNP1 and CCL5 heteromer between neutrophils and platelets blocks monocyte recruitment to inflammatory sites.	10.1038/nri.2017.10	References 40 and 41 provide novel mechanisms by which platelets and neutrophils work together to recruit inflammatory monocytes, and they establish therapeutic strategies for the inhibition of monocyte recruitment.
10.1161/circresaha.116.309492	81,526,578	Rationale: Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesi...	10.1038/nri.2017.10	This is the first study to show the therapeutic potential of pro-resolving lipid mediators during atheroprogression.
10.1126/scitranslmed.aab4109	82,544,875	In contrast to previous studies, targeting the mGluR pathway in fragile X syndrome patients did not improve behavior independent of FMR1 methylation.	10.1038/nrd.2017.221	This article presents the results of two of the largest randomized, placebo-controlled studies undertaken in adolescents and adults with FXS. These studies did not show efficacy of mavoglurant, but they have stimulated further study of mavoglurant in younger children with FXS.
10.1002/art.11303	61,558,473	Abstract Objective To evaluate the contribution of leptin (an adipose tissue–derived hormone) to the pathophysiology of osteoarthritis (OA), by determining the level of leptin in both synovial fluid (SF) and cartilage specimens obtained from human joints. We also investigated the effect of leptin on cartilage, using in...	10.1038/nrd1693	A recent perspective of leptin playing an important role in OA.
10.1242/jcs.080762	20,386,545	Increasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabol...	10.1038/nrcardio.2017.23	This paper shows that ER–mitochondria contact remodelling supports a metabolic adaptive response during cellular stress.
10.1126/scitranslmed.3002194	84,463,027	The endoplasmic reticulum stress protein Nogo is a culprit in the mitochondrial defects that characterize pulmonary hypertension, pointing to therapeutic drug targets.	10.1038/nrcardio.2017.23	This paper shows the participation of dysfunctional SR–mitochondria communication in the pathogenesis of PAH mediated by ER stress and upregulation of the ER-remodelling protein NOGO B.
10.1073/pnas.1210718109	122,299,128	Mitochondrial ability of shaping Ca 2+ signals has been demonstrated in a large number of cell types, but it is still debated in heart cells. Here, we take advantage of the molecular identification of the mitochondrial Ca 2+ uniporter (MCU) and of unique targeted Ca 2+ probes to directly address this issue. We demonstr...	10.1038/nrcardio.2017.23	This paper shows that modulation of mitochondrial Ca 2+ uptake capacity shapes cytosolic Ca 2+ kinetics during cardiomyocyte beating.
10.1073/pnas.1513047112	39,413,144	Calcium (Ca 2+ ) released from the sarcoplasmic reticulum (SR) is crucial for excitation–contraction (E–C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca 2+ is essential for optimal function of these organelles. ...	10.1038/nrcardio.2017.23	This paper reveals considerable participation of leaky RYR2 channels in mitochondrial Ca 2+ overload and dysfunction in HF.
10.1242/jcs.139394	125,301,355	Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, whose morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy...	10.1038/nrcardio.2017.23	This paper shows that mitochondrial fission is sufficient to induce hypertrophy in cultured cardiomyocytes.
10.1073/pnas.70.8.2276	122,681,240	Various species of Streptomyces possess aminoglycoside-modifying enzymes. Streptomyces kanamyceticus contains an enzyme that acetylates the 6′-amino group of kanamycin A and B, gentamicin C 1a , and neomycin. Streptomyces spectabilis produces an enzyme that acetylates the 2′-amino group of the hexose ring of gentamicin...	10.1038/nrmicro2312	Antibiotic-resistant pathogens can arise rapidly in response to treatment with antibiotics, but the origin of the resistance is often unknown. This is one of the first reports of an origin for some resistance genes: the producers of the antibiotic.
10.1126/science.1120800	62,159,235	Microbial resistance to antibiotics currently spans all known classes of natural and synthetic compounds. It has not only hindered our treatment of infections but also dramatically reshaped drug discovery, yet its origins have not been systematically studied. Soil-dwelling bacteria produce and encounter a myriad of ant...	10.1038/nrmicro2312	A selection for an antibiotic-resistant Streptomyces sp. from soil reveals diverse and novel resistance mechanisms.
10.1111/j.1462-2920.2004.00664.x	82,376,159	Summary Antibiotic resistance genes are typically isolated by cloning from cultured bacteria or by polymerase chain reaction (PCR) amplification from environmental samples. These methods do not access the potential reservoir of undiscovered antibiotic resistance genes harboured by soil bacteria because most soil bacter...	10.1038/nrmicro2312	This article describes the use of functional metagenomics to discover aminoglycoside antibiotic resistance genes in a soil microbial community.
10.1002/ijc.26219	100,359,420	Abstract Our study investigated the immunomodulatory effects of sunitinib to rationally design combinational platforms with immunotherapies for the treatment of solid tumors. Using a mouse model, we studied the effects of sunitinib given for 4 weeks at concentrations comparable to 37.5–50 mg/day in humans, followed by ...	10.1038/nrc3237	This paper details how alterations in the scheduling of the targeted therapy sunitinib significantly alter T Reg cell populations, and that pretreating with sunitinib improves vaccine efficacy in animal models; whereas, co-administration had no effect on vaccine efficacy.
10.1158/0008-5472.can-05-0529	40,571,314	Abstract Abnormal dendritic cell differentiation and accumulation of immunosuppressive myeloid cells in cancer is one of the major factors of tumor nonresponsiveness. We have previously shown that hyperactivation of the Janus-activated kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) induced b...	10.1038/nrc3237	This paper discusses the use of a JAK2 inhibitor to improve the maturation of DCs, showing that animals treated with JAK2 inhibitors have increased numbers of mature DCs, increased T cell priming by DCs and have increased surival when the inhibitor was combined with a DC vaccine.
10.1073/pnas.1016569108	62,042,077	Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2/ErbB-2), has become the mainstay of treatment for HER2-positive breast cancer. Nevertheless, its exact mechanism of action has not been fully elucidated. Although several studies suggest that Fc receptor-expressing immune cells ...	10.1038/nrc3237	This paper demonstrates how targeted monoclonal antibody therapies, such as HER2 antibodies, require immune-mediated tumour destruction for clinical responses and synergize with both co-stimulatory 4-1BB agonistic antibodies, as well as blockade of an inhibitory signal through a PD1 antibody.
10.1084/jem.20101123	109,216,372	The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molec...	10.1038/nrc3237	This paper shows that IAP inhibitors increase T cell responses to multiple different immune stimuli in vitro and that combining IAP inhibitors with tumour vaccination decreases tumour growth kinetics.
10.1158/0008-5472.can-10-0118	61,469,312	Abstract Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose comb...	10.1038/nrc3237	This paper shows how targeted inhibition of mutant BRAF augments expression of tumour antigens on the tumour cell surface, increasing T cell responses against tumour cells while showing no deleterious effect on T cell proliferation or function.
10.1158/0008-5472.can-08-4709	100,360,767	Abstract In tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) play important roles in immune suppression, the reversal of which is vitally important for the success of immune therapy. We have shown that ckit ligand is required for MDSC accumulation and Treg development. We hypot...	10.1038/nrc3237	This paper demonstrates how a targeted therapy, sunitinib, is able to decrease both the number and function of suppressive cells (T Reg cells and MDSCs) in tumour-infiltrating lymphocytes in an in vivo mouse model of colon cancer, and that combining sunitinib with agonistic 4-1BB antibodies and IL-12 improved responses...
10.1158/0008-5472.can-08-3807	98,294,765	Abstract Clinical outcomes of gastrointestinal stromal tumor (GIST)–bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activi...	10.1038/nrc3237	This paper demonstrates that the presence of NK cells in patients with gastrointestinal stromal tumour treated with imatinib serves as an independent prognostic factor of clinical response, suggesting that off-target effects of imatinib that stimulate NK cells may partially account for its therapeutic success.
10.1126/science.1098650	123,203,571	We describe a new genus, Osedax , and two new species of annelids with females that consume the bones of dead whales via ramifying roots. Molecular and morphological evidence revealed that Osedax belongs to the Siboglinidae, which includes pogonophoran and vestimentiferan worms from deep-sea vents, seeps, and anoxic ba...	10.1038/nrmicro1992	The first paper to describe the gutless siboglinid worms that colonize whale bones.
10.1111/j.1439-0485.1993.tb00001.x	83,435,719	Abstract. In April 1990 a new species of mytilid containing bacterial endosymbionts was discovered at a deep‐water seep site within Alaminos Canyon in the Gulf of Mexico. Activities of ribulose bisphosphate carboxylase/oxygenase and ATP sulfurylase, as well as the presence of substantial levels of elemental sulfur in t...	10.1038/nrmicro1992	The first detailed description of a dual symbiosis in a chemosynthetic host.
10.1073/pnas.92.21.9598	62,247,229	The coexistence of two phylogenetically distinct symbiont species within a single cell, a condition not previously known in any metazoan, is demonstrated in the gills of a Mid-Atlantic Ridge hydrothermal vent mussel (family Mytilidae). Large and small symbiont morphotypes within the gill bacteriocytes are shown to be s...	10.1038/nrmicro1992	The first study to show that two bacterial symbionts can coexist within the same metazoan host cell.
10.1126/science.1132913	46,786,021	The bacterial endosymbiont of the deep-sea tube worm Riftia pachyptila has never been successfully cultivated outside its host. In the absence of cultivation data, we have taken a proteomic approach based on the metagenome sequence to study the metabolism of this peculiar microorganism in detail. As one result, we foun...	10.1038/nrmicro1992	This paper provides the first evidence that a chemoautotrophic symbiont uses two different pathways to fix inorganic carbon depending on its energy store.
10.1101/gad.1824809	123,004,958	Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism ...	10.1038/nrc3055	This is the first preclinical evidence that blocking TGFβ signalling decreases the development and progression of breast cancer bone metastases.
10.1158/0008-5472.can-09-3194	79,793,576	Abstract Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between...	10.1038/nrc3055	Vitamin D deficiency working at least in part via alterations in the bone microenvironment promotes the growth of human breast cancer cells in bone.
10.1182/blood-2005-04-1730	16,674,637	One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B p...	10.1038/nrc3055	This paper describes a spontaneous animal model of hypercalcaemia and tumour-associated osteolysis and demonstrates that the viral oncogene Tax is responsible for cellular transformation and induces the expression of osteoclast-activating factors resulting in bone loss and hypercalcaemia.
10.1073/pnas.1830978100	16,755,139	Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates ...	10.1038/nrc3055	This is the first preclinical evidence that endothelin receptor blockade reduces the development and progression of osteoblastic bone metastases.
10.1093/bioinformatics/18.3.405	123,748,584	Abstract Motivation: The existence of several technologies for measuring gene expression makes the question of cross-technology agreement of measurements an important issue. Cross-platform utilization of data from different technologies has the potential to reduce the need to duplicate experiments but requires correspo...	10.1038/nrd961	One of the first studies to compare published measurements of, in theory, the same cancer cell lines on cDNA and oligonucleotide microarrays. Shows that these measurements are not directly comparable.
10.1126/science.286.5439.531	82,952,752	Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarray...	10.1038/nrd961	One of the first publications to show how microarrays can assist in difficult clinical diagnosis; in this case, determining acute lymphocytic leukaemia from acute myelogenous leukaemia using a nearest-neighbour approach.
10.1073/pnas.95.1.334	20,407,358	We used reverse transcription–coupled PCR to produce a high-resolution temporal map of fluctuations in mRNA expression of 112 genes during rat central nervous system development, focusing on the cervical spinal cord. The data provide a temporal gene expression “fingerprint” of spinal cord development based on major fam...	10.1038/nrd961	One of the first large microarray publications, with 112 genes measured in 9 conditions, analysed using dendograms created using Euclidean distance.
10.1073/pnas.96.6.2907	40,779,263	Array technologies have made it straightforward to monitor simultaneously the expression pattern of thousands of genes. The challenge now is to interpret such massive data sets. The first step is to extract the fundamental patterns of gene expression inherent in the data. This paper describes the application of self-or...	10.1038/nrd961	Tamayo and colleagues were the first to use self-organizing maps to show clusters of genes measured across time from differentiating hematopoetic cells.
10.1091/mbc.9.12.3273	45,488,808	We sought to create a comprehensive catalog of yeast genes whose transcript levels vary periodically within the cell cycle. To this end, we used DNA microarrays and samples from yeast cultures synchronized by three independent methods: α factor arrest, elutriation, and arrest of a cdc15 temperature-sensitive mutant. Us...	10.1038/nrd961	The first publication to merge several microarray experiments, to show clusters using dendrograms constructed using correlation coefficients, and to analyse the time-series pattern of genes using Fourier analysis.
10.1126/science.1099314	41,637,132	Receptor tyrosine kinase genes were sequenced in non–small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Ir...	10.1038/nrc3775	In this study, the clinical observation that only some lung cancers responded well to the EGFR inhibitor gefitinib was linked to the presence of EGFR-activating mutations in the responding tumours. This finding revolutionized the stratification of patients that receive EGFR inhibitor treatment and furthered our underst...
10.1073/pnas.1112499109	18,937,396	Identifying the cells of origin of lung cancer may lead to new therapeutic strategies. Previous work has focused upon the putative bronchoalveolar stem cell at the bronchioalveolar duct junction as a cancer cell of origin when a codon 12 K-Ras mutant is induced via adenoviral Cre inhalation. In the present study, we us...	10.1038/nrc3775	This study expanded our understanding of cells of origin in GEMMs of lung ADC by using cell-type specific promoters to drive Cre-Lox Kras activation. In contrast to previous theories, the authors find that AT2 cells, rather than BASCs or club cells, are the most likely cells of origin for KRAS-driven tumours.
10.1073/pnas.0906850106	83,509,303	The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 ( p63 ) and cytokeratins 5 ( Krt5 ) and Krt14 . Using a KRT5-CreER T2 transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth an...	10.1038/nrc3775	In this study, the KRT5 + and p63 + basal cells of the trachea were shown to be true stem or progenitor cells through lineage tracing experiments during development and tracheal epithelial repair. The authors isolated similar cells from human tracheas and showed that both murine and human cells can be cultured as trach...
10.1101/gad.943001	62,147,000	Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras . Here we show that the use of ...	10.1038/nrc3775	GEMMs of lung cancer have been developed largely based on this prototypical study, in which the Cre-Lox system was used to induce oncogenic Kras expression specifically in the lung through Adeno-Cre intranasal instillation.
10.1126/science.279.5349.349	62,182,498	Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment ep...	10.1038/nrm.2016.171	Establishes a causal relationship between telomere shortening and cellular senescence.
10.1126/science.1229259	20,742,948	Promoter Mutations and Cancer Cancer genome sequencing projects have highlighted the pathogenic role of recurrent mutations within the protein-coding regions of genes. Now, two studies suggest that the scope of mutations in human tumors extends to gene regulatory regions. In a study of 70 melanomas, Huang et al. (p. 95...	10.1038/nrm.2016.171	Uses whole-genome sequencing in melanomas to identify activating mutations in the TERT promoter.
10.1126/science.1230062	125,072,654	Promoter Mutations and Cancer Cancer genome sequencing projects have highlighted the pathogenic role of recurrent mutations within the protein-coding regions of genes. Now, two studies suggest that the scope of mutations in human tumors extends to gene regulatory regions. In a study of 70 melanomas, Huang et al. (p. 95...	10.1038/nrm.2016.171	Identifies activating mutations in the TERT promoter through an analysis of melanoma-prone families.
10.1002/ijc.29393	82,070,094	Recent evidence from several relatively small nested case‐control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of sev...	10.1038/nrm.2016.171	Assesses telomere length using telomere length-associated single-nucleotide polymorphisms and finds that longer telomere length is associated with increased risk of non-Hodgkin lymphoma.
10.1182/blood-2010-02-272104	102,220,502	Abstract We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue, reinforcing the concept that there is significant cell division in CLL. Furthermore,...	10.1038/nrm.2016.171	Shows that telomere shortening and fusions in CLL increase with advanced disease and correlate with large-scale genome rearrangements.
10.1101/gr.200840.115	61,714,608	Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combinati...	10.1038/nrm.2016.171	Uses single molecule analysis to demonstrate that a single dysfunctional telomere can fuse with diverse non-telomeric loci.
10.1126/scitranslmed.3003045	107,388,612	Vitamin D is required for both innate and adaptive immunity to tuberculosis.	10.1038/nri3532	This is a translationally important study showing that vitamin D has a key cooperative role with IFNγ in inducing antimicrobial autophagy in human cells, whereas vitamin D metabolites are diminished in tuberculosis and HIV.
10.1073/pnas.0704014104	60,944,767	Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5–Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibrobl...	10.1038/nri3532	This is a key study that led to the appreciation of the interference between autophagy and type I IFN signalling.
10.1083/jcb.200507002	41,664,928	Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytoso...	10.1038/nri3532	This is a seminal study that led to the identification of autophagic receptors and mechanisms of selective autophagy in mammalian cells.
10.1073/pnas.1210500109	19,670,560	Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against Mycobacterium tuberculosis , but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. M . tuberculosis infecti...	10.1038/nri3532	This paper is an in vivo demonstration of the role of autophagy in controlling both inflammation and bacteria during infection.
10.1126/science.1227026	82,817,874	Axing Autophagy When intracellular pathogens like Legionella pneumophila take up residence in mammalian host cells, they must combat the efforts of the host cell to attack them. Autophagy is a process by which cells digest their own constituents, often involved in response to starvation or pathogen attack. Choy et al. ...	10.1038/nri3532	This is an elegant recent example of how bacteria defend themselves against autophagy by preventing LC3 lipidation, which thus stalls the autophagic response.
10.1126/science.272.5260.408	125,150,432	Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity. Both proteins were identified by peptide microseq...	10.1038/nrg3413	The authors describe the first evidence that epigenetic modifications are reversible by enzymes that remove or erase the modification. This paper describes the discovery of HDAC and initiated the idea that epigenetic modification was a dynamic state rather than an irreversible process.
10.1073/pnas.0506383102	63,110,711	Archaea and their viruses are poorly understood when compared with the Eukarya and Bacteria domains of life. We report here the crystal structure of the major capsid protein (MCP) of the Sulfolobus turreted icosahedral virus, an archaeal virus isolated from an acidic hot spring (pH 2–4, 72–92°C) in Yellowstone National...	10.1038/nrmicro1527	Shows that the major capsid protein of STIV is highly similar in structure to capsid proteins of some bacterial and eukaryal viruses.
10.1083/jcb.113.1.123	18,528,693	Antibodies specific for the insulin-regulatable glucose transporter (GLUT 4) were used to immunolocalize this protein in brown adipose tissue from basal- and insulin-treated rats. Cryosections of fixed tissue were incubated with antibodies, which were subsequently labeled with Protein A/gold and examined by EM. Antibod...	10.1038/nrm3351	The first to examine the localization of GLUT4 in intact adipocytes by immunostaining, showing that the transporter is distributed between the TGN, endosomes and small tubulo-vesicular compartments.
10.1128/mcb.24.14.6456-6466.2004	101,578,039	ABSTRACT The insulin-responsive glucose transporter GLUT4 plays an essential role in glucose homeostasis. A novel assay was used to study GLUT4 trafficking in 3T3-L1 fibroblasts/preadipocytes and adipocytes. Whereas insulin stimulated GLUT4 translocation to the plasma membrane in both cell types, in nonstimulated fibro...	10.1038/nrm3351	The authors show that adipocytes contain a recycling pool of GLUT4 and a pool of GLUT4 that is sequestered in GSVs, which are mobilized to the plasma membrane only after stimulation with insulin.
10.1042/bj3150487	40,421,412	The translocation of a unique facilitative glucose transporter isoform (GLUT4) from an intracellular site to the plasma membrane accounts for the large insulin-dependent increase in glucose transport observed in muscle and adipose tissue. The intracellular location of GLUT4 in the basal state and the pathway by which i...	10.1038/nrm3351	By chemically ablating compartments that contain TfR, this study demonstrates that a large portion of cellular GLUT4 is found in a vesicle population that is distinct from endosomes.
10.1083/jcb.201008135	102,209,344	Insulin stimulates translocation of GLUT4 storage vesicles (GSVs) to the surface of adipocytes, but precisely where insulin acts is controversial. Here we quantify the size, dynamics, and frequency of single vesicle exocytosis in 3T3-L1 adipocytes. We use a new GSV reporter, VAMP2-pHluorin, and bypass insulin signaling...	10.1038/nrm3351	The authors use a novel TIRFM approach to distinguish vesicles by size and show that immediately after insulin stimulation GLUT4 is mainly exocytosed from GSVs, but after prolonged insulin treatment GLUT4 arrives at the plasma membrane in endosomes.
10.1091/mbc.e03-07-0517	28,234,698	The intracellularly stored GLUT4 glucose transporter is rapidly translocated to the cell surface upon insulin stimulation. Regulation of GLUT4 distribution is key for the maintenance of whole body glucose homeostasis. We find that GLUT4 is excluded from the plasma membrane of adipocytes by a dynamic retention/retrieval...	10.1038/nrm3351	Demonstrates that futile cycling between GLUT4 vesicles and endosomes is part of a mechanism that retains GLUT4 within non-stimulated cells.
10.1042/bj20050887	83,373,936	Recently, we described a 160 kDa protein (designated AS160, for Akt substrate of 160 kDa) with a predicted Rab GAP (GTPase-activating protein) domain that is phosphorylated on multiple sites by the protein kinase Akt. Phosphorylation of AS160 in adipocytes is required for insulin-stimulated translocation of the glucose...	10.1038/nrm3351	Biochemical characterization of the AS160 RAB GAP activity identifies RAB8, RAB10 and RAB14 as targets of AS160.
10.1073/pnas.90.4.1526	83,355,452	Cultured pigment epithelial cells of the fetal human retina secrete a protein, pigment epithelium-derived factor (PEDF), that induces a neuronal phenotype in cultured human retinoblastoma cells. Morphological changes include the induction of an extensive neurite meshwork and the establishment of corona-like cellular ag...	10.1038/nrc3484	The first article to report the complete sequence of the human PEDF mRNA and protein, and its identification as a member of the serpin gene family with neurotrophic activity on retinoblastoma tumour cells.
10.1126/science.285.5425.245	20,729,299	In the absence of disease, the vasculature of the mammalian eye is quiescent, in part because of the action of angiogenic inhibitors that prevent vessels from invading the cornea and vitreous. Here, an inhibitor responsible for the avascularity of these ocular compartments is identified as pigment epithelium–derived fa...	10.1038/nrc3484	The first report on the potent anti-angiogenic activity of PEDF in the cornea and vitreous humour and on how hypoxia regulates PEDF.
10.1073/pnas.211268598	103,375,086	Pigment epithelium-derived factor (PEDF), a noninhibitory member of the serpin superfamily, is the most potent inhibitor of angiogenesis in the mammalian ocular compartment. It also has neurotrophic activity, both in the retina and in the central nervous system, and is highly up-regulated in young versus senescent fibr...	10.1038/nrc3484	The crystal structure of glycosylated human PEDF was solved to 2.85 ansgstroms resolution, which revealed its serpin structure homology and possible receptor- and heparin-binding sites.
10.1126/science.1065810	82,755,186	In Saccharomyces cerevisiae , more than 80% of the ∼6200 predicted genes are nonessential, implying that the genome is buffered from the phenotypic consequences of genetic perturbation. To evaluate function, we developed a method for systematic construction of double mutants, termed synthetic genetic array (SGA) analys...	10.1038/nrg1248	Describes the first use of the synthetic genetic array strategy, in which a mutant of interest is crossed with all yeast deletion strains, allowing a genetic network to be constructed.
10.1126/science.1081403	105,350,397	Classical genetic screens can be limited by the selectivity of mutational targeting, the complexities of anatomically based phenotypic analysis, or difficulties in subsequent gene identification. Focusing on signaling response to the secreted morphogen Hedgehog (Hh), we used RNA interference (RNAi) and a quantitative c...	10.1038/nrg1248	Reports the screening by dsRNA against ∼ 43% of the Drosophila genome using a reporter assay.
10.1126/science.1086391	83,406,628	Over 225,000 independent Agrobacterium transferred DNA (T-DNA) insertion events in the genome of the reference plant Arabidopsis thaliana have been created that represent near saturation of the gene space. The precise locations were determined for more than 88,000 T-DNA insertions, which resulted in the identification ...	10.1038/nrg1248	Insertional mutants in ∼ 75% of Arabidopsis genes were made, although the entire set was not screened.
10.1017/s0021900200034446	82,014,966	A new Markov chain is introduced which can be used to describe the family relationships among n individuals drawn from a particular generation of a large haploid population. The properties of this process can be studied, simultaneously for all n, by coupling techniques. Recent results in neutral mutation theory are see...	10.1038/nrg1961	19A Introduces the coalescent as a way of exploiting ancestry in population genetics models.
10.1093/genetics/165.4.2213	41,625,870	Abstract We introduce a new statistical model for patterns of linkage disequilibrium (LD) among multiple SNPs in a population sample. The model overcomes limitations of existing approaches to understanding, summarizing, and interpreting LD by (i) relating patterns of LD directly to the underlying recombination process;...	10.1038/nrg1961	An early application of the ABC idea; it is used here to construct tractable approximations to more complex evolutionary models.
10.1093/genetics/162.4.2025	41,759,250	Abstract We propose a new method for approximate Bayesian statistical inference on the basis of summary statistics. The method is suited to complex problems that arise in population genetics, extending ideas developed in this setting by earlier authors. Properties of the posterior distribution of a parameter, such as i...	10.1038/nrg1961	Coins the term approximate Bayesian computation, and applies it to microsatellite data.
10.1093/genetics/151.3.1217	103,431,398	Abstract In this article we discuss the ancestry of sequences sampled from the coalescent with recombination with constant population size 2N. We have studied a number of variables based on simulations of sample histories, and some analytical results are derived. Consider the leftmost nucleotide in the sequences. We sh...	10.1038/nrg1961	References 73 and 74 present an elegant construction of the coalescent in the presence of recombination.
10.1101/gr.3709305	101,038,496	Population genetic models play an important role in human genetic research, connecting empirical observations about sequence variation with hypotheses about underlying historical and biological causes. More specifically, models are used to compare empirical measures of sequence variation, linkage disequilibrium (LD), a...	10.1038/nrg1961	A comprehensive study that shows that the coalescent is a good model for complex evolutionary data.
10.1073/pnas.0902882106	83,052,608	Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans . We observed the age-dependent misfol...	10.1038/nrd3453	This study describes a widespread failure in protein folding that occurs in early adulthood and coincides with reduced activation of HSF1 and chaperone protein expression in C. elegans
10.1073/pnas.100107297	122,817,061	Expansion of polyglutamine repeats in several unrelated proteins causes neurodegenerative diseases with distinct but related pathologies. To provide a model system for investigating common pathogenic features, we have examined the behavior of polyglutamine expansions expressed in Caenorhabditis elegans . The expression...	10.1038/nrd3453	This study shows that the expression of polyQ proteins in C. elegans disrupts general protein folding, causes aggregation of otherwise soluble proteins and constitutively promotes the activation of HSF1 and chaperone proteins.
10.1126/science.1165946	20,432,519	Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of th...	10.1038/nrd3453	This study demonstrated that the DNA binding activity of HSF1 is inhibited by acetylation within the DNA binding domain, and HSF1 is maintained in a deacetylated state via SIRT1.
10.1073/pnas.0500055102	17,580,645	We explore the hypothesis that pathology of Huntington's disease involves multiple cellular mechanisms whose contributions to disease are incrementally additive or synergistic. We provide evidence that the photoreceptor neuron degeneration seen in flies expressing mutant human huntingtin correlates with widespread dege...	10.1038/nrd3453	This study demonstrated that the HSP90 inhibitor geldanamycin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid have combinatorial efficacy in ameliorating cytotoxicity in a fruitfly model of neurodegenerative disease.
10.1073/pnas.0506249102	40,659,441	Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene ( AR ). The pathogenic, polyglutamine-expanded AR protein accumulates in the cell nucleus in a ligand-de...	10.1038/nrd3453	This work demonstrated that pharmacological activation of HSF1 via geranylgeranylacetone promotes the activation of chaperone protein expression and ameliorates cytotoxicity in a mouse model of spinal and bulbar muscular atrophy.
10.1002/pro.363	80,792,775	Abstract The formation of amyloid, a cross‐β‐sheet fibrillar aggregate, is associated with a variety of aging‐associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell l...	10.1038/nrd3453	This work describes the discovery of a mammalian disaggregase with the ability to disaggregate β-amyloid aggregates.
10.1073/pnas.0600645103	102,649,511	Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumor-suppr...	10.1038/nrm2161	Recent evidence that epigenetic silencing of WRN expression confers cellular phenotypes similar to WRN mutations, and that WRN silencing in colon cancers might have prognostic significances.
10.1126/science.1127168	20,707,967	Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defect...	10.1038/nrm2161	Evidence that the mechanisms that underlie HGPS might also have a role in normal human ageing.
10.1073/pnas.0504641102	83,068,114	Hutchinson–Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a “ CAAX protein” that is farnesylated and then processed further to generate mature ...	10.1038/nrm2161	Reference 73, as well as 87 and 88, describe the three mouse models of HGPS that have been generated by mutating or altering Lmna expression.
10.1126/science.1124875	38,294,519	Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of f...	10.1038/nrm2161	References 72 and 74 demonstrate that FTIs markedly reduce the disease phenotypes in mouse models of HGPS.
10.1126/science.2570460	125,121,557	Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to...	10.1038/nrg3849	References 3–5 are landmark papers from 25 years ago reporting the discovery of the CFTR gene.
10.1073/pnas.0800254105	59,361,910	Deletion of phenylalanine-508 (Phe-508) from the N-terminal nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette (ABC) transporter family, disrupts both its folding and function and causes most cystic fibrosis. Most mutant nascent chain...	10.1038/nrg3849	References 25–27 provide a foundation for the three-dimensional modelling of CFTR.
10.1126/science.1163600	20,851,834	Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characterist...	10.1038/nrg3849	References 40 and 41 are the first reports to describe the phenotypes of ferrets and pigs caused by loss of CFTR function.
10.1073/pnas.0904709106	125,319,199	Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number ...	10.1038/nrg3849	This is the first report that ivacaftor potentiates the function of CFTR bearing the G551D mutation.
10.1126/science.1059108	125,115,620	Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a “BH3-domain–only” BCL-2 family member, triggers the homooligomerization of “multidomain” conserved proapoptotic family members B...	10.1038/nrm2952	Describes the effect of knocking out both BAX and BAK in mice and reveals an absolute requirement for BAX and BAK in MOMP.
10.1083/jcb.144.5.883	20,716,368	During apoptosis induced by various stimuli, cytochrome c is released from mitochondria into the cytosol where it participates in caspase activation. This process has been proposed to be an irreversible consequence of mitochondrial permeability transition pore opening, which leads to mitochondrial swelling and rupture ...	10.1038/nrm2952	References 117 and 118 were the first to show that MOMP does not necessarily commit a cell to death.
10.1182/blood-2010-12-323154	57,473,365	Abstract Viral persistence during chronic viral infections is associated with a progressive loss of T-cell effector function called functional exhaustion. There is therefore a need to develop immunotherapies to remediate the functional deficits of T cells during these infections. We investigated the immunotherapeutic e...	10.1038/nri2970	References 90 and 91 were the first descriptions of the postive effect of IL-7 on T cell-dependent immunity and viral clearance in chronic infection models.
10.4049/jimmunol.0903151	82,828,754	Abstract Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, reco...	10.1038/nri2970	This study describes the potential for a positive effect of IL-7 therapy in bacterial infection.
10.1084/jem.20071681	61,689,700	Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL...	10.1038/nri2970	The first complete description of the immunological effects of rhIL-7 therapy in humans, including the important observation that TCR repertoire diversification occurs, at least in part, through the preferential expansion of RTEs and naive T cell populations.
10.1182/blood-2008-11-191288	36,448,243	Abstract Interleukin-7 (IL-7), the principal cytokine implicated in thymopoiesis and peripheral T-cell homeostasis, is presently under evaluation in human diseases characterized by persistent lymphopenia. Unexpectedly, before the eventual IL-7–driven T-cell expansion, all treated patients showed a profound T-cell deple...	10.1038/nri2970	This study shows that glycosylation of IL-7 can decrease its immunogenicity.
10.1182/blood-2008-10-186601	107,200,787	Abstract Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-...	10.1038/nri2970	The first report of IL-7 therapy in HIV-infected individuals. In this study, patients were administered a single dose of IL-7, thereby allowing a definitive description of the length of biological effect of IL-7 in humans.
10.1126/science.281.5380.1191	29,119,706	In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell–induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), ...	10.1038/nri1457	This report shows that IDO activity inhibits a T-cell-mediated process in mice; in this case maternal T-cell immunity to fetal alloantigens during pregnancy.
10.1002/ijc.10645	124,034,016	Abstract The priming of an appropriate anti‐tumor T cell response rarely results in the rejection of established tumors. The characteristics of tumors that allow them to evade a T cell‐mediated rejection are unknown for many tumors. We report on evidence that the expression of the immunosuppressive enzyme, indoleamine ...	10.1038/nri1457	References 18 and 19 show that IDO activity can suppress antitumour immunity, challenging previous notions that IDO activity is exclusively an innate host defence mechanism against tumours.
10.1084/jem.189.9.1363	20,783,585	We have recently shown that expression of the enzyme indoleamine 2,3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here ...	10.1038/nri1457	This report identifies tryptophan depletion due to IDO upregulation in human macrophages as a mechanism to inhibit T cell proliferation.
10.4049/jimmunol.164.7.3596	104,438,296	Abstract Dendritic cells (DCs) play a key role in the activation and regulation of B and T lymphocytes. Production of indoleamine 2,3-dioxygenase (IDO) by macrophages has recently been described to result in inhibition of T cell proliferation through tryptophan degradation. Since DCs can be derived from monocytes, we s...	10.1038/nri1457	These authors show that human DCs also mediate IDO-dependent T-cell suppression.
10.4049/jimmunol.171.4.1652	17,588,938	Abstract In mice, immunoregulatory APCs express the dendritic cell (DC) marker CD11c, and one or more distinctive markers (CD8α, B220, DX5). In this study, we show that expression of the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase (IDO) is selectively induced in specific splenic DC subsets when mice were ex...	10.1038/nri1457	This paper shows that specific DC subsets in mouse spleens mediate dominant IDO-dependent T-cell suppression in vivo following ligation of CD80/CD86.
10.4049/jimmunol.165.3.1357	41,632,570	Abstract Using an in vivo model of tumor/self peptide presentation for induction of class I-restricted skin test reactivity, we have previously shown that a minority population of CD8+ dendritic cells (DC) negatively regulates the induction of T cell reactivity by peptide-loaded CD8− DC in DBA/2 mice. However, the CD8−...	10.1038/nri1457	This report identifies IDO as a mechanism used by mouse regulatory DCs.

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