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10.1242/dev.02263 | 100,780,785 | During vertebrate development, the endodermal germ layer becomes regionalized along its anteroposterior axis to give rise to a variety of organs, including the pancreas. Genetic studies in zebrafish and mice have established that the signaling molecule retinoic acid (RA) plays a crucial role in endoderm patterning and ... | 10.1038/nrg2318 | This paper describes an elegant study in zebrafish that makes use of genetics and chimeric embryos to demonstrate that the endoderm intrinsically responds to RA signalling to promote endocrine differentiation. |
10.1242/dev.001230 | 83,408,904 | The liver and pancreas are specified from the foregut endoderm through an interaction with the adjacent mesoderm. However, the earlier molecular mechanisms that establish the foregut precursors are largely unknown. In this study, we have identified a molecular pathway linking gastrula-stage endoderm patterning to organ... | 10.1038/nrg2318 | This paper is a superb and extensive study showing that suppression of Wnt signalling is needed for the earliest events in liver and pancreas induction, along with the discovery of a connected transcription factor network involving Hex and Vent2, both homeodomain proteins. |
10.1126/science.1113832 | 103,641,256 | Development of the animal body plan is controlled by large gene regulatory networks (GRNs), and hence evolution of body plans must depend upon change in the architecture of developmental GRNs. However, these networks are composed of diverse components that evolve at different rates and in different ways. Because of the... | 10.1038/nrg2318 | This paper presents a fascinating revelation about the extreme conservation of the regulatory network that specifies endoderm, and argues about how it has been so conserved, as well as elaborated upon, to generate different tissues. |
10.1101/gad.1575207 | 62,080,568 | PTF1a is an unusual basic helix–loop–helix (bHLH) transcription factor that is required for the development of the pancreas. We show that early in pancreatic development, active PTF1a requires interaction with RBPJ, the vertebrate Suppressor of Hairless, within a stable trimeric DNA-binding complex (PTF1). Later, as ac... | 10.1038/nrg2318 | This is a definitive study showing that the essential early pancreatic transcription factor Ptf1a uses different RPBJ subunits at different stages of pancreatic development, thereby changing the specificity and function of the transcription factor complex. |
10.1177/108705719900400206 | 83,393,225 | The ability to identify active compounds ("hits") from large chemical libraries accurately and rapidly has been the ultimate goal in developing high-throughput screening (HTS) assays. The ability to identify hits from a particular HTS assay depends largely on the suitability or quality of the assay used in the screenin... | 10.1038/nrd1063 | Describes a widely used metric for defining the quality of high-throughput screening assays. |
10.1126/science.285.5428.751 | 80,313,046 | A computational method is proposed for inferring protein interactions from genome sequences on the basis of the observation that some pairs of interacting proteins have homologs in another organism fused into a single protein chain. Searching sequences from many genomes revealed 6809 such putative protein-protein inter... | 10.1038/nrd1152 | Shows that products of genes that fuse in the course of evolution also tend to interact or participate in common pathways in species where they remain unfused. |
10.1126/science.1068996 | 41,459,632 | Although humans and their closest evolutionary relatives, the chimpanzees, are 98.7% identical in their genomic DNA sequences, they differ in many morphological, behavioral, and cognitive aspects. The underlying genetic basis of many of these differences may be altered gene expression. We have compared the transcriptom... | 10.1038/nrd1152 | Introduces the notion of phylogenetic analysis of overall gene expression patterns. |
10.1093/bioinformatics/18.3.440 | 122,525,150 | Abstract Motivation: Genomics and proteomics studies routinely depend on homology searches based on the strategy of finding short seed matches which are then extended. The exploding genomic data growth presents a dilemma for DNA homology search techniques: increasing seed size decreases sensitivity whereas decreasing s... | 10.1038/nmeth.1376 | PatternHunter was the first alignment program to implement the method of finding alignments by scanning with 'spaced seeds' that require exact matching positions to seed the alignments but do not require these seeds to be consecutive. This method is extremely effective for the mapping short sequencing reads and has bee... |
10.1126/science.1228186 | 104,284,404 | Whence Species Variation? Vertebrates have widely varying phenotypes that are at odds with their much more limited proteincoding genotypes and conserved messenger RNA expression patterns. Genes with multiple exons and introns can undergo alternative splicing, potentially resulting in multiple protein isoforms (see the ... | 10.1038/nrg.2017.19 | References 76 and 77 are the first systematic studies on alternative splicing evolution across vertebrates by RNA-seq. |
10.1126/science.1246426 | 125,208,390 | To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I–hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-r... | 10.1038/nrg.2017.19 | An analysis of open chromatin regions in 45 mouse cell and tissue types by DNase-seq, with a comparison to humans. |
10.1073/pnas.70.8.2281 | 60,620,511 | 18 Carcinogens, including aflatoxin B 1 , benzo(a)pyrene, acetylaminofluorene, benzidine, and dimethylamino- trans -stilbene, are shown to be activated by liver homogenates to form potent frameshift mutagens. We believe that these carcinogens have in common a ring system sufficiently planar for a stacking interaction w... | 10.1038/nrc1546 | Bruce Ames established the 'Ames Assay' for testing chemical-induced genotoxicity. |
10.1126/science.167.3915.184 | 36,535,717 | Injections of sulfate ion in rats given the carcinogen N -hydroxy-2-acetylaminofluorene increased (i) the formation of 1- and 3-(methion-S-yl)-2-acetylaminofluorene bound to protein in the liver, (ii) the formation of fluorenyl derivatives bound to total protein, ribosomal RNA, and DNA in the liver, and (iii) the toxic... | 10.1038/nrc1546 | First evidence that sulphate esters of N -hydroxyarylamines or -amides are the ultimate carcinogenic metabolites of the corresponding parent compounds formed in vivo |
10.1073/pnas.97.2.779 | 104,326,443 | The contribution of the aryl hydrocarbon receptor (AhR) in induction of a battery of xenobiotic-metabolizing enzymes has been studied extensively. However, no direct proof has been obtained that it plays a role in modulating carcinogenesis. To address the question of whether AhR is required for tumor induction, we have... | 10.1038/nrc1546 | Demonstrates that BP-mediated tumorigenesis in subcutaneous or epidermal mouse tissue requires the presence of a functional AhR. |
10.1126/science.274.5286.430 | 125,092,047 | Cigarette smoke carcinogens such as benzo[ a ]pyrene are implicated in the development of lung cancer. The distribution of benzo[ a ]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct f... | 10.1038/nrc1546 | Landmark paper in molecular epidemiology that provides an aetiological link between BP exposure and human lung cancer based on mutations at codons 157, 248 and 273 of cellular TP53 |
10.1002/bip.10239 | 124,030,191 | Abstract The function of the human nucleotide excision repair (NER) apparatus is to remove bulky adducts from damaged DNA. In an effort to gain insights into the molecular mechanisms involved in the recognition and excision of bulky lesions, we investigated a series of site specifically modified oligonucleotides contai... | 10.1038/nrc1546 | Demonstrates that the NER-catalysed excision of (+)- trans anti -BPDE-dG fails when its deoxycytosine base pair is deleted. This is known as the 'prototypic decoy adduct'. Bulky lesions opposite deoxycytosine deletion are also normally present in cells as an intermediate after replicative bypass of AAF or BP adducts. |
10.1091/mbc.e07-12-1248 | 120,017,162 | Activation of Rac1 GTPase signaling is stimulated by phosphorylation and release of RhoGDI by the effector p21-activated kinase 1 (PAK1), but it is unclear what initiates this potential feed-forward mechanism for regulation of Rac activity. Phosphatidic acid (PA), which is produced from the lipid second messenger diacy... | 10.1038/nrm3153 | Demonstrates that the phosphatidic acid produced by DGKζ initiates RHOGDI release and RAC1 activation through PAK1-mediated phosphorylation of RHOGDI. |
10.1083/jcb.200810179 | 39,180,742 | Fibroblast growth factor 2 (FGF2) is a major regulator of developmental, pathological, and therapeutic angiogenesis. Its activity is partially mediated by binding to syndecan 4 (S4), a proteoglycan receptor. Angiogenesis requires polarized activation of the small guanosine triphosphatase Rac1, which involves localized ... | 10.1038/nrm3153 | Shows that RHOG affinity for RHOGDI1 increases when RHOGDI forms a complex with syndecan 4 and its binding partner, synectin, and that, in response to FGF2 binding to syndecan 4, RHOG is released and activated as a result of phosphorylation by PKCα. |
10.1083/jcb.152.1.111 | 82,906,239 | Determinants of membrane targeting of Rho proteins were investigated in live cells with green fluorescent fusion proteins expressed with or without Rho-guanine nucleotide dissociation inhibitor (GDI)α. The hypervariable region determined to which membrane compartment each protein was targeted. Targeting was regulated b... | 10.1038/nrm3153 | A seminal paper analyzing the factors that affect the subcellular distribution of RHO GTPases. |
10.1083/jcb.201110067 | 123,010,849 | During muscle atrophy, myofibrillar proteins are degraded in an ordered process in which MuRF1 catalyzes ubiquitylation of thick filament components (Cohen et al. 2009. J. Cell Biol. http://dx.doi.org/10.1083/jcb.200901052). Here, we show that another ubiquitin ligase, Trim32, ubiquitylates thin filament (actin, tropom... | 10.1038/nrd4467 | References 13 and 14 describe the mechanism for myofibril disassembly during muscle atrophy. |
10.1152/ajpcell.00104.2009 | 38,890,121 | Loss of muscle mass occurs in a variety of diseases, including cancer, chronic heart failure, aquired immunodeficiency syndrome, diabetes, and renal failure, often aggravating pathological progression. Preventing muscle wasting by promoting muscle growth has been proposed as a possible therapeutic approach. Myostatin i... | 10.1038/nrd4467 | This study established the critical role of FOXO proteins in causing atrophy. |
10.1083/jcb.201001136 | 16,823,016 | The size of skeletal muscle cells is precisely regulated by intracellular signaling networks that determine the balance between overall rates of protein synthesis and degradation. Myofiber growth and protein synthesis are stimulated by the IGF-1/Akt/mammalian target of rapamycin (mTOR) pathway. In this study, we show t... | 10.1038/nrd4467 | This study demonstrates the crucial role of JUNB in maintaining muscle mass. |
10.1152/ajpregu.00121.2011 | 16,565,950 | Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-ol... | 10.1038/nrd4467 | References 109–111 describe several approaches to inhibit myostatin signalling and cachexia in tumour-bearing mice. |
10.1128/mcb.01036-12 | 20,315,421 | ABSTRACT Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21... | 10.1038/nrd4467 | This study identifies the transcriptional changes that occur during sarcopenia. |
10.2217/fon.09.106 | 37,085,341 | Cancer cachexia is a complex syndrome, affecting up to 60% of the approximately 1.4 million patients diagnosed with cancer each year in the USA. This condition is characterized by progressive deterioration of a patient’s nutritional status, weight loss, anorexia, diminished quality of life and increased mortality and m... | 10.1038/nrd4467 | References 242–244 describe the use of SARMs in pharmacological therapy of wasting in several diseases. |
10.1126/science.1241165 | 62,606,488 | Protecting the Guts Regulatory T cells (T regs ) in the gut are important sentinels in maintaining the peace between our gut and its trillions of resident bacteria and have been shown to be regulated by specific strains of bacteria in mouse models. Smith et al. (p. 569 , published online 4 July; see the Perspective by ... | 10.1038/nri.2016.42 | This paper illustrates that microbiota-derived SCFAs regulate T reg cell homeostasis in the colon and that SCFA-mediated effects on T reg cells are mediated in part by GPR43. |
10.1126/science.aaa4921 | 62,151,839 | Detecting Gramnegative bacteria Invariant molecules specific to different classes of microbes, but not expressed by eukaryotic cells, alert the immune system to a potential invader. Gaudet et al. identified one such molecule expressed by a variety of Gram-negative bacteria: the monosaccharide heptose-1,7-bisphosphate (... | 10.1038/nri.2016.42 | This work identifies a novel innate immune signalling axis that is initiated by a pro-inflammatory bacterial-derived metabolite, an intermediate in lipopolysaccharide biosynthesis of Gram-negative bacteria. |
10.1126/science.1178377 | 123,978,104 | Solving Pseudokinases Mutations of the protein kinase LKB1 are associated with cancer in humans. Many kinases are activated by phosphorylation, but LKB1 is activated by STRADα, a pseudokinase that is similar to protein kinases and binds ATP, but does not phosphorylate substrates. By solving the crystal structure of an ... | 10.1038/nrm3966 | This elegant structural study shows how conformational changes induced by protein–protein interactions within the LKB1–STRAD–MO25 scaffold lead to activation of the kinase LKB1. |
10.1073/pnas.1301985110 | 19,703,172 | Significance The role of catalytically inactive phosphatases (pseudophosphatases) remains enigmatic. Using a combination of experiments and modeling, we identified the pseudophosphatase serine/threonine/tyrosine-interacting protein (STYX) as a nuclear anchor and modulator of ERK signaling. Thereby, STYX regulates the m... | 10.1038/nrm3966 | This paper shows an example of STYX function in a well-defined cellular context. |
10.1523/jneurosci.3326-12.2012 | 20,704,035 | AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1–GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca 2+ influx. However, a small number of ... | 10.1038/nrm3966 | This paper provides compelling evidence that AKAP150-anchored PP2B is a dominant effectorin the modulation of synaptic transmission. |
10.1158/2159-8290.cd-rw2014-171 | 51,352,155 | Abstract L1 retrotransposition–mediated 3′ transductions occur in approximately 25% of cancer genomes. | 10.1038/nrc.2017.35 | Demonstration of a set of source elements responsible for LINE-1 retrotransposition with 3′ transduction in human cancers. |
10.1101/gr.201814.115 | 104,308,624 | Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether... | 10.1038/nrc.2017.35 | Description of a second somatically acquired LINE-1 insertion in the APC gene, which could be traced to a source element that escaped silencing in the normal colon. |
10.1073/pnas.0831042100 | 103,750,966 | Although LINE-1 (long interspersed nucleotide element-1, L1) retrotransposons comprise 17% of the human genome, an exhaustive search of the December 2001 “freeze” of the haploid human genome working draft sequence (95% complete) yielded only 90 L1s with intact ORFs. We demonstrate that 38 of 86 (44%) L1s are polymorphi... | 10.1038/nrc.2017.35 | Study that compared commonly occurring LINE-1 insertions for retrotransposition activity in vitro and established the term hot LINE-1. |
10.1126/science.1222077 | 20,844,906 | Movement in the Cancer Genome Transposable elements are genetic sequences that can replicate and move within the genome. The factors that make an element mobile are unknown but are generally considered rare in mammals. Lee et al. (p. 967 , published online 28 June) analyzed five cancer types occurring among several ind... | 10.1038/nrc.2017.35 | Demonstration of the different types of human cancer that support LINE-1 retrotransposition. |
10.1126/science.1091334 | 125,082,034 | The enormous number of commensal bacteria in the lower intestine of vertebrates share abundant molecular patterns used for innate immune recognition of pathogenic bacteria. We show that, even though commensals are rapidly killed by macrophages, intestinal dendritic cells (DCs) can retain small numbers of live commensal... | 10.1038/nrmicro1840 | Showed that the intragastric administration of GFP-expressing E. cloacae , a mouse commensal, results in the uptake of these bacteria by DCs in the Peyer's patches, and that these DCs traffic to the mesenteric lymph nodes. |
10.1128/iai.66.7.3183-3189.1998 | 103,460,017 | ABSTRACT Lactococcus lactis is a nonpathogenic and noncolonizing bacterium which is being developed as a vaccine delivery vehicle for immunization by mucosal routes. To determine whether lactococci can also deliver cytokines to the immune system, we have constructed novel constitutive expression strains of L. lactis wh... | 10.1038/nrmicro1840 | First demonstration that the secretion of cytokines in L. lactis together with the intracellular production of an antigen can enhance immune responses. |
10.4049/jimmunol.175.11.7297 | 20,466,635 | Abstract Current strategies to prevent or treat human papillomavirus type 16 (HPV-16) infection are promising, but remain costly. More economical but efficient vaccines are thus needed. In this study, we evaluated the protective effects of mucosally coadministered live Lactococcus lactis strains expressing cell wall-an... | 10.1038/nrmicro1840 | Demonstrated therapeutic immunization with a recombinant L. lactis cancer vaccine in a mouse model of human papillomavirus type 16-induced tumours. |
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/nrmicro1840 | Showed that IL-10-secreting lactococci can be used therapeutically in two models of murine colitis. |
10.1073/pnas.1934747100 | 18,555,226 | The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block... | 10.1038/nrmicro1840 | Demonstrated that LAB can produce a CD4 receptor that can bind HIV-1 in vitro |
10.1073/pnas.86.8.2863 | 18,146,308 | Three distinct human endothelin-related genes were cloned by screening a genomic DNA library under a low hybridization stringency with a synthetic oligonucleotide probe encoding a portion of the endothelin sequence. Genomic Southern blot analysis with the same oligonucleotide probe showed three corresponding chromosoma... | 10.1038/nrd962 | The authors report a pivotal observation of the existence of three components of the ET family discovered by screening a genomic DNA library with synthetic oligonucleotides encoding a portion of the ET sequence. |
10.1046/j.1440-1681.1999.03010.x | 80,643,251 | 1. Within the lung, endothelin (ET)‐1 is synthesized and released by airway epithelial and vascular endothelial cells, as well as by inflammatory cells, such as macrophages. Following release, ET‐1 can modulate the activities of a wide range of different cell types within the lung through the stimulation of specific en... | 10.1038/nrd962 | An overview of recent advances in our understanding of the distribution and function of ET receptors within the airway wall and peripheral lung. |
10.1073/pnas.0406698102 | 4,706,258 | The ability of the Ras oncogene to transform normal cells has been well established. One downstream effector of Ras is the lipid hydrolyzing enzyme phospholipase D. Recent evidence has emerged indicating a role for phospholipase D in cell proliferation, membrane trafficking, and migration. To study the potential import... | 10.1038/nrc3162 | Rat-2 fibroblasts transfected with HRAS-G12V formed colonies in agar and tumours in mice. However, HRAS-G12V-transfected Rat-2 cells with reduced PLD1 activity did not, thus showing the requirement for normal PLD1 activity during transformation. |
10.1126/science.1125951 | 61,098,598 | One of the most exciting developments in cancer research in recent years has been the clinical validation of molecularly targeted drugs that inhibit the action of pathogenic tyrosine kinases. Treatment of appropriately selected patients with these drugs can alter the natural history of their disease and improve surviva... | 10.1038/nrc1913 | This is a very recent review of tyrosine kinase inhibitors in cancer therapy, which includes their brief histories and current issues that will affect the future development of new molecularly targeted agents. |
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/nrc1913 | The above two reports (references 75 and 76) show the identification of somatic mutations in exons 18–21 of the EGFR gene in NSCLC. These results indicated these EGFR mutations as possible determinants of gefitinib sensitivity to NSCLC. |
10.1126/science.1101637 | 104,361,617 | Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively a... | 10.1038/nrc1913 | Describes the essential role of AKT and STAT signalling pathways in mutant EGFR-mediated cell survival, which provide a putative mechanism underlying the therapeutic effect of gefitinib in NSCLC. |
10.1098/rspa.1927.0118 | 20,818,866 | (1) One of the most striking features in the study of epidemics is the difficulty of finding a causal factor which appears to be adequate to account for the magnitude of the frequent epidemics of disease which visit almost every population. It was with a view to obtaining more insight regarding the effects of the vario... | 10.1038/nrmicro1845 | One of the earliest and fullest explorations of the mathematical representation of infectious disease transmission. |
10.1098/rspb.2006.3754 | 125,142,892 | Mathematical models of transmission have become invaluable management tools in planning for the control of emerging infectious diseases. A key variable in such models is the reproductive number R . For new emerging infectious diseases, the value of the reproductive number can only be inferred indirectly from the observ... | 10.1038/nrmicro1845 | A clear description of how the reproduction number can be estimated from early epidemic growth and the dependence of the estimate on the generation-time distribution. |
10.1073/pnas.0307506101 | 20,832,701 | The aim of this study is to identify general properties of emerging infectious agents that determine the likely success of two simple public health measures in controlling outbreaks, namely ( i ) isolating symptomatic individuals and ( ii ) tracing and quarantining their contacts. Because these measures depend on the r... | 10.1038/nrmicro1845 | An illustration of the power of simple mathematical approaches to answer important policy questions. This analysis made it clear why different micro-simulations of smallpox transmission and control provide different answers. |
10.1111/1467-9868.00177 | 82,670,127 | Summary Methods for the analysis of data on the incidence of an infectious disease are reviewed, with an emphasis on important objectives that such analyses should address and identifying areas where further work is required. Recent statistical work has adapted methods for constructing estimating functions from marting... | 10.1038/nrmicro1845 | An overview of the statistical challenges that are inherent to the analysis of infectious disease data. |
10.1126/science.1093857 | 125,149,857 | We have applied âwhole-genome shotgun sequencingâ to microbial populations collected en masse on tangential flow and impact filters from seawater samples collected from the Sargasso Sea near Bermuda. A total of 1.045 billion base pairs of nonredundant sequence was generated, annotated, and analyzed to elucidate the... | 10.1038/nrmicro1044 | Environmental sequencing of water samples from the Sargasso Sea reveals a predominance of α-proteobacterial species. |
10.1073/pnas.192319099 | 103,328,474 | The 3.31-Mb genome sequence of the intracellular pathogen and potential bioterrorism agent, Brucella suis , was determined. Comparison of B. suis with Brucella melitensis has defined a finite set of differences that could be responsible for the differences in virulence and host preference between these organisms, and i... | 10.1038/nrmicro1044 | Describes the Brucella suis genome and highlights similarities between the genomes of animal pathogens and plant symbionts. |
10.1126/science.1066804 | 38,893,468 | The 5.67-megabase genome of the plant pathogen Agrobacterium tumefaciens C58 consists of a circular chromosome, a linear chromosome, and two plasmids. Extensive orthology and nucleotide colinearity between the genomes of A. tumefaciens and the plant symbiont Sinorhizobium meliloti suggest a recent evolutionary divergen... | 10.1038/nrmicro1044 | References 10 and 11 present the genome sequence of the plant pathogen Agrobacterium tumefaciens |
10.1126/science.1060966 | 123,027,682 | The scarcity of usable nitrogen frequently limits plant growth. A tight metabolic association with rhizobial bacteria allows legumes to obtain nitrogen compounds by bacterial reduction of dinitrogen (N 2 ) to ammonium (NH 4 + ). We present here the annotated DNA sequence of the α-proteobacterium Sinorhizobium meliloti ... | 10.1038/nrmicro1044 | Presents a genomic analysis of the plant symbiont Sinorhizobium meliloti |
10.1073/pnas.0400975101 | 101,394,246 | The α-proteobacteria, from which mitochondria are thought to have originated, display a 10-fold genome size variation and provide an excellent model system for studies of genome size evolution in bacteria. Here, we use computational approaches to infer ancestral gene sets and to quantify the flux of genes along the bra... | 10.1038/nrmicro1044 | The first quantitative analysis of the flux of genes during the evolution of the α-proteobacterial genomes. |
10.1073/pnas.95.9.5145 | 19,771,810 | Nodulation and nitrogen fixation genes of Mesorhizobium loti are encoded on the chromosome of the bacterium. Nevertheless, there is strong evidence that these genes can be transferred from an inoculant strain to nonsymbiotic mesorhizobia in the field environment. Here we report that the chromosomal symbiotic element of... | 10.1038/nrmicro1044 | A landmark paper in the discovery of symbiotic islands in rhizobia. |
10.1242/jcs.110.18.2141 | 62,597,168 | Vascular colonisation by Bartonella henselae may cause vaso-proliferative tumour growth with clumps of bacteria found in close association with proliferating endothelial cells. By using B. henselae-infected human umbilical vein endothelial cells as an in vitro model for endothelial colonisation, we report here on a nov... | 10.1038/nrmicro1044 | Description of the 'invasome', a novel mechanism used by Bartonella to enter endothelial cells. |
10.1111/j.1365-2958.2003.03964.x | 26,841,983 | Summary Bartonella henselae is an arthropod‐borne zoonotic pathogen causing intraerythrocytic bacteraemia in the feline reservoir host and a broad range of clinical manifestations in incidentally infected humans. Remarkably, B. henselae can specifically colonize the human vascular endothelium, resulting in inflammation... | 10.1038/nrmicro1044 | Describes the multiple roles of the Bartonella VirB T4SS in the interaction with endothelial cells. |
10.1128/iai.67.8.4041-4047.1999 | 38,920,618 | ABSTRACT Brucella suis is a facultative intracellular pathogen of mammals, residing in macrophage vacuoles. In this work, we studied the phagosomal environment of these bacteria in order to better understand the mechanisms allowing survival and multiplication of B. suis . Intraphagosomal pH in murine J774 cells was det... | 10.1038/nrmicro1044 | Shows how phagosome acidification is essential for Brucella to survive in macrophages. |
10.1073/pnas.032514299 | 61,193,519 | A type IV secretion system similar to the VirB system of the phytopathogen Agrobacterium tumefaciens is essential for the intracellular survival and multiplication of the mammalian pathogen Brucella . Reverse transcriptase–PCR showed that the 12 genes encoding the Brucella suis VirB system form an operon. Semiquantitat... | 10.1038/nrmicro1044 | The B. suis VirB T4SS is one of the virulence factors induced by phagosome acidification. |
10.1104/pp.103.029223 | 38,844,478 | Abstract Agrobacterium tumefaciens uses a type IV secretion system to deliver a nucleoprotein complex and effector proteins directly into plant cells. The single-stranded DNA-binding protein VirE2, the F-box protein VirF and VirE3 are delivered into host cells via this VirB/D4 encoded translocation system. VirE1 functi... | 10.1038/nrmicro1044 | Use of the Cre recombinase as a reporter to demonstrate translocation of the Agrobacterium virulence proteins VirF and VirE2 through the VirB T4SS in the absence of T-DNA. |
10.1073/pnas.192439499 | 103,368,961 | A sensor protein ChvG is part of a chromosomally encoded two-component regulatory system ChvG/ChvI that is important for the virulence of Agrobacterium tumefaciens . However, it is not clear what genes ChvG regulates or what signal(s) it senses. In this communication, we demonstrate that ChvG is involved in the regulat... | 10.1038/nrmicro1044 | References 70 and 127 decribe how a conserved two-component regulatory system regulates the expression of virulence factors involved in the interaction with mammalian and plant hosts. |
10.1126/science.287.5462.2492 | 28,141,531 | Brucella abortus , a mammalian pathogen, and Rhizobium meliloti , a phylogenetically related plant symbiont, establish chronic infections in their respective hosts. Here a highly conserved B. abortus homolog of the R. meliloti bacA gene, which encodes a putative cytoplasmic membrane transport protein required for symbi... | 10.1038/nrmicro1044 | Shows that BacA is essential for both Brucella and Sinorhizobium maintenance in their host cells. Some of the clearest evidence for common symbiotic and pathogenic determinants. |
10.1073/pnas.0307137101 | 66,324,101 | Sinorhizobium meliloti , a legume symbiont, and Brucella abortus , a phylogenetically related mammalian pathogen, both require the bacterial-encoded BacA protein to establish chronic intracellular infections in their respective hosts. We found that the bacterial BacA proteins share sequence similarity with a family of ... | 10.1038/nrmicro1044 | Shows that the BacA protein is required for the incorperation of VLCFAs into the lipid A of Brucella and Sinorhizobium. |
10.1126/science.1107891 | 83,121,116 | Domestication promotes rapid phenotypic evolution through artificial selection. We investigated the genetic history by which the wild grass teosinte ( Zea mays ssp. parviglumis ) was domesticated into modern maize ( Z. mays ssp. mays ). Analysis of single-nucleotide polymorphisms in 774 genes indicates that 2 to 4% of ... | 10.1038/nrg3097 | This paper discusses a comparative resequencing study that used an original likelihood ratio test to model demography and selection. The paper was unique in providing an estimate of the proportion of loci in the genome involved in domestication and/or improvement. |
10.1126/science.1174276 | 104,220,601 | Codifying Maize Modifications Maize, one of our most important crop species, has been the target of genetic investigation and experimentation for more than 100 years. Crossing two inbred lines tends to result in “better” offspring, in a process known as heterosis. Attempts to map the genetic loci that control traits im... | 10.1038/nrg3097 | This study, using the NAM population, found that flowering time in maize provides a good fit to classic models of a quantitative trait and that a large number of loci contribute additively to the phenotype. |
10.1534/genetics.107.083873 | 40,110,989 | Abstract Recombinant inbred lines derived from an advanced intercross, in which multiple generations of mating have increased the density of recombination breakpoints, are powerful tools for mapping the loci underlying complex traits. We investigated the effects of intercross breeding designs on the utility of such lin... | 10.1038/nrg3097 | This study provides an examination of breeding designs that maximize genetic resolution in intercross populations. |
10.1534/genetics.106.069641 | 21,726,850 | Abstract We develop and implement a strategy to map QTL in two synthetic populations of Drosophila melanogaster each initiated with eight inbred founder strains. These recombinant populations allow simultaneous estimates of QTL location, effect, and frequency. Five X-linked QTL influencing bristle number were resolved ... | 10.1038/nrg3097 | The authors of this paper provide a strong rationale for the development of next-generation populations. The study design permits estimation of QTL location, effect and frequency. Comparison of effect size of alleles contributed by founders of the population is particularly compelling. |
10.1073/pnas.0905629106 | 15,974,563 | In contrast to most stimulated lymphocytes, B cells exposed to Toll-like receptor 9 ligands are nonself-adherent, allowing individual cells and families to be followed in vitro for up to 5 days. These B cells undergo phases typical of an adaptive response, dividing up to 6 times before losing the impetus for further gr... | 10.1038/nri2822 | This study uses long-term in vitro imaging to reveal that progeny of single founder B cells have markedly synchronized division properties. |
10.1084/jem.20091175 | 39,166,309 | The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcod... | 10.1038/nri2822 | This study develops barcode tagging of thymocytes and uses it to show that the progeny of single naive CD8 + T cells can take on multiple fates under various infectious challenges. |
10.1126/science.1175455 | 38,400,276 | Preparation for Cell Wars When T cells encounter an infection, they proliferate to create a larger army to fight the invader. The overall magnitude of the T cell response depends on the severity of infection and is determined by the number of T cells of a particular antigen specificity that are initially recruited, as ... | 10.1038/nri2822 | This paper uses cellular barcoding to show that the magnitude of CD8 + T cell responses is primarily determined by clonal burst size. |
10.1126/science.1166831 | 109,007,595 | Models of the differentiation of memory CD8 + T cells that replicate during secondary infections differ over whether such cells had acquired effector function during primary infections. We created a transgenic mouse line that permits mapping of the fate of granzyme B (gzmB)–expressing CD8 + T cells and their progeny by... | 10.1038/nri2822 | This paper uses a conditional granzyme B–YFP reporter mouse to show that granzyme B-expressing effector T cells can give rise to functional memory T cells. |
10.1073/pnas.0802278105 | 61,680,407 | Kaede is a photoconvertible fluorescence protein that changes from green to red upon exposure to violet light. The photoconversion of intracellular Kaede has no effect on cellular function. Using transgenic mice expressing the Kaede protein, we demonstrated that movement of cells with the photoconverted Kaede protein c... | 10.1038/nri2822 | In this paper, the Kaede transgenic mouse model is described, in which photoconversion of a fluorescent protein can be used to track cell migration. |
10.1073/pnas.0709610105 | 41,360,734 | An understanding of how allostery, the conformational coupling of distant functional sites, arises in highly evolvable systems is of considerable interest in areas ranging from cell biology to protein design and signaling networks. We reasoned that the rigidity and defined geometry of an α-helical domain linker would m... | 10.1038/nri2822 | This paper provides proof-of-concept for a light-activated transcription factor by fusing a photoactive LOV domain to the E. coli trp repressor and inducing DNA binding by blue light excitation. |
10.1182/blood-2007-01-068833 | 100,986,892 | Lenalidomide is approved for red blood cell (RBC) transfusion-dependent anemia due to low or intermediate-1 (int-1) risk myelodysplastic syndromes (MDSs) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We report results of a multicenter, phase 2 trial evaluating lenalidomi... | 10.1038/nrc3321 | This study shows that a percentage of patients with MDS without the del(5q) chromosomal deletion will respond to lenalidomide therapy. |
10.1128/jb.184.4.1140-1154.2002 | 83,553,832 | ABSTRACT Complementary approaches were employed to characterize transitional episodes in Pseudomonas aeruginosa biofilm development using direct observation and whole-cell protein analysis. Microscopy and in situ reporter gene analysis were used to directly observe changes in biofilm physiology and to act as signposts ... | 10.1038/nrmicro1838 | Demonstrated that P. aeruginosa undergoes a range of physiological changes during the initiation, development, maturation and dispersal of biofilms, and that each physiological state is accompanied by dramatic changes in the proteome profiles of the cells. |
10.1046/j.1365-2958.1998.00797.x | 62,584,155 | Populations of surface‐attached microorganisms comprising either single or multiple species are commonly referred to as biofilms. Using a simple assay for the initiation of biofilm formation (e.g. attachment to an abiotic surface) by Pseudomonas fluorescens strain WCS365, we have shown that: (i) P . fluorescens can for... | 10.1038/nrmicro1838 | Describes a microtitre dish screening assay that was used to identify transposon mutants that are unable to form biofilms, thereby linking distinct genetic loci to biofilm formation. |
10.1128/aem.59.11.3840-3849.1993 | 18,687,411 | The vertical distribution of sulfate-reducing bacteria (SRB) in photosynthetic biofilms from the trickling filter of a sewage treatment plant was investigated with oligonucleotide probes binding to 16S rRNA. To demonstrate the effect of daylight and photosynthesis and thereby of increased oxygen penetration, we incubat... | 10.1038/nrmicro1838 | Reports microelectrode measurements of concentration gradients in biofilms, and integrates these with ecological analysis by the use of FISH probes. |
10.1073/pnas.0407460101 | 62,084,337 | Diversity generally protects communities from unstable environmental conditions. This principle, known as the “insurance hypothesis,” has been tested in many different ecosystems. Here we show that the opportunistic pathogen Pseudomonas aeruginosa undergoes extensive genetic diversification during short-term growth in ... | 10.1038/nrmicro1838 | Demonstrated that P. aeruginosa undergoes genetic diversification during short-term biofilm growth, which might allow increased resistance of the population to environmental stresses. |
10.1111/j.1365-2958.2007.06040.x | 82,588,683 | Summary Biofilms of Bacillus subtilis consist of long chains of cells that are held together in bundles by an extracellular matrix of exopolysaccharide and the protein TasA. The exopolysaccharide is produced by enzymes encoded by the epsA‐O operon and the gene encoding TasA is located in the yqxM‐sipW‐tasA operon. Both... | 10.1038/nrmicro1838 | Demonstrated that matrix polymer production in B. subtilis is under the control of a bistable mechanism that involves the repressor SinR and its anti-repressor SinI. |
10.1073/pnas.191384198 | 125,166,784 | Spore formation by the bacterium Bacillus subtilis has long been studied as a model for cellular differentiation, but predominantly as a single cell. When analyzed within the context of highly structured, surface-associated communities (biofilms), spore formation was discovered to have heretofore unsuspected spatial or... | 10.1038/nrmicro1838 | Showed that, when cultured in biofilms, B. subtilis spore formation is spatially organized and occurs in structures that resemble fruiting bodies. |
10.1126/science.1099390 | 104,375,088 | A fraction of a genetically homogeneous microbial population may survive exposure to stress such as antibiotic treatment. Unlike resistant mutants, cells regrown from such persistent bacteria remain sensitive to the antibiotic. We investigated the persistence of single cells of Escherichia coli with the use of microflu... | 10.1038/nrmicro1838 | A microfluidics approach was used to investigate the pre-existing heterogeneity in growth rates of bacteria at the single-cell level. Cells that had reduced growth rates were linked with persistence to antibiotic challenge. |
10.1046/j.1365-2958.2003.03677.x | 27,905,824 | Summary Detailed knowledge of the developmental process from single cells scattered on a surface to complex multicellular biofilm structures is essential in order to create strategies to control biofilm development. In order to study bacterial migration patterns during Pseudomonas aeruginosa biofilm development, we hav... | 10.1038/nrmicro1838 | Used fluorescent-protein-labelled wild-type and motility-mutant strains of P. aeruginosa to show the role of cell migration and type IV pili in biofilm developmental processes. |
10.1073/pnas.94.26.14291 | 38,579,015 | F- and V-type ATPases are central enzymes in energy metabolism that couple synthesis or hydrolysis of ATP to the translocation of H + or Na + across biological membranes. They consist of a soluble headpiece that contains the catalytic sites and an integral membrane-bound part that conducts the ion flow. Energy coupling... | 10.1038/nrm729 | This provided the first evidence for multiple stalks that connect the V 1 and V 0 domains. |
10.1083/jcb.142.1.39 | 79,456,022 | Three previously identified genes from Saccharomyces cerevisiae, VMA12, VMA21, and VMA22, encode proteins localized to the endoplasmic reticulum (ER). These three proteins are required for the biogenesis of a functional vacuolar ATPase (V-ATPase), but are not part of the final enzyme complex. Subcellular fractionation ... | 10.1038/nrm729 | An important insight into the in vivo assembly pathway of the V-ATPase. |
10.1002/elps.200800126 | 18,202,924 | Abstract Multiplex ligation‐dependent probe amplification (MLPA) is a commonly used technique for determining relative DNA sequence dosage (or copy number) in a complex DNA sample. Originally MLPA was designed as a copy number analysis tool for detecting disease‐causing genomic mutations and has been successfully appli... | 10.1038/nrg3493 | This paper describes the MLPA technique and explores its utility in copy number variation diagnostics. |
10.1126/science.1215040 | 20,848,290 | Defective Gene Detective Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genet... | 10.1038/nrg3493 | This paper determined how many genetic variants predicted to cause loss of function of protein-coding genes humans carry. |
10.1073/pnas.1201904109 | 62,155,324 | Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project cho... | 10.1038/nrg3493 | The Genome–Environment–Trait Evidence (GET-Evidence) tool is introduced here; it is used for processing personal whole-genome data. |
10.1126/scitranslmed.3003651 | 38,295,252 | A targeted nanoparticle containing docetaxel displays antitumor activity in animals and differentiated pharmacological properties in patients with advanced solid tumors. | 10.1038/nnano.2012.168 | This article describes the translation of the first targeted polymeric nanoparticle for drug delivery from discovery to clinical trials |
10.1126/science.1188302 | 83,477,929 | Just Breathe Design of artificial systems that mimic in vivo organs could provide a better alternative for understanding mechanisms underlying physiological responses than current cell-based models or animal tests. Huh et al. (p. 1662 ) have created a tissue-tissue interface of human-cultured epithelial cells and endot... | 10.1038/nnano.2012.168 | This article describes the design and assembly of a microfluidic system that recreates the alveolar-endothelial interface in lungs |
10.7554/elife.02184 | 39,879,829 | The ESCRT machinery along with the AAA+ ATPase Vps4 drive membrane scission for trafficking into multivesicular bodies in the endocytic pathway and for the topologically related processes of viral budding and cytokinesis, but how they accomplish this remains unclear. Using deep-etch electron microscopy, we find that en... | 10.1038/nrm.2016.121 | Uses EM of ESCRT-III at HIV-1 Gag budding sites and reveals a funnel that nucleates at a narrow part of the membrane neck and widens as the funnel grows away from the bud. |
10.1126/science.aad8305 | 62,606,858 | ESCRTs work in two very different ways The so-called ESCRT proteins are involved in the budding of vesicles into the lumen of endosomes and in virus budding. These reactions involve the formation of a cytoplasm-filled neck that spirals of the ESCRTs help to seal. McCullough et al. now show that ESCRTs can also promote ... | 10.1038/nrm.2016.121 | Reveals that the atomic resolution structure of a CHMP1B–IST1 tube shows marked structural rearrangements in CHMP1B and that this particular combination of ESCRTs carries out normal-topology scission. |
10.1073/pnas.1518765113 | 40,269,352 | The endosomal sorting complexes required for transport (ESCRT) machinery functions in HIV-1 budding, cytokinesis, multivesicular body biogenesis, and other pathways, in the course of which it interacts with concave membrane necks and bud rims. To test the role of membrane shape in regulating ESCRT assembly, we nanofabr... | 10.1038/nrm.2016.121 | Uses real-time and super-resolution imaging of ESCRT-III polymerization on nanofabricated concave templates to show that ESCRT-III nucleation has a negative curvature preference. |
10.1038/ncomms9781 | 102,077,387 | Abstract The vacuolar protein sorting 4 AAA–ATPase (Vps4) recycles endosomal sorting complexes required for transport (ESCRT-III) polymers from cellular membranes. Here we present a 3.6-Å X-ray structure of ring-shaped Vps4 from Metallosphera sedula (MsVps4), seen as an asymmetric pseudohexamer. Conserved key interface... | 10.1038/nrm.2016.121 | Provides the first structure of the active hexameric form of Vps4. |
10.1073/pnas.84.8.2363 | 80,117,581 | Human genetic linkage maps are most accurately constructed by using information from many loci simultaneously. Traditional methods for such multilocus linkage analysis are computationally prohibitive in general, even with supercomputers. The problem has acquired practical importance because of the current international... | 10.1038/nrg2989 | This paper provides the theoretical foundation for peeling algorithms, which are used on family data in likelihood calculations involving large numbers of markers. |
10.1002/gepi.1370060124 | 60,000,613 | Abstract In the haplotype relative risk (HRR) statistic (Rubinstein et al.: Human Immunol 3:384 [abstract], 1981), a disease sample is constructed along with its own internal control by comparing those marker alleles passed from the parents to an affected child with the other parental marker alleles not transmitted. Ba... | 10.1038/nrg2989 | This study describes the statistical basis for the HRR approach that underlies development of the TDT. |
10.1159/000022846 | 38,581,258 | Single nucleotide polymorphisms (SNPs) are currently being developed for use in disequilibrium analyses. These SNPs consist of two alleles with varying degrees of polymorphism. A natural design for use with SNPs is the ‘haplotype relative risk’ sampling design in which a father, mother, and child are typed at an SNP lo... | 10.1038/nrg2989 | This provides the first evaluation of true and apparent error rates in trio families. |
10.1038/npg.els.0005429 | 65,026,425 | Abstract Genes that contribute to complex genetic diseases can sometimes be identified by studies that show genetic linkage, or association, with marker genes. The transmission/disequilibrium test is a procedure that tests for the simultaneous presence of these two genetic phenomena. | 10.1038/nrg2989 | This paper discusses the development of the TDT, the first method for carrying out family-based association mapping with multiple affected offspring. |
10.1159/000022918 | 38,548,459 | A general approach to family-based examinations of association between marker alleles and traits is proposed. The approach is based on computing p values by comparing test statistics for association to their conditional distributions given the minimal sufficient statistic under the null hypothesis for the genetic model... | 10.1038/nrg2989 | This study provides the initial theoretical foundation for the development of the FBAT approach. |
10.1038/npg.els.0005429 | 65,026,425 | Abstract Genes that contribute to complex genetic diseases can sometimes be identified by studies that show genetic linkage, or association, with marker genes. The transmission/disequilibrium test is a procedure that tests for the simultaneous presence of these two genetic phenomena. | 10.1038/nrg2989 | This paper describes the use of family-based tests that also account for association. |
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/nrc1739 | Evidence that subtle mutations in EGFR can affect the clinical response to gefitinib. |
10.1126/science.1112085 | 125,149,838 | The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose leve... | 10.1038/nrd2874 | This article showed that the CNS, specifically the mediobasal hypothalamus, responds to increased glucose availability to regulate hepatic glucose production. |
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