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Systems Biology
Heralds of parallel MS: Data-independent acquisition surpassing sequential identification of data dependent acquisition in proteomics
Apr 21, 2017   Molecular & Cellular Proteomics : MCP
Bruderer R, Bernhardt OM, Gandhi T, Xuan Y, Sondermann J, Schmidt M, Gomez-Varela D, Reiter L
Heralds of parallel MS: Data-independent acquisition surpassing sequential identification of data dependent acquisition in proteomics
Apr 21, 2017
Molecular & Cellular Proteomics : MCP
Comprehensive, reproducible and precise analysis of large sample cohorts is one of the key objectives of quantitative proteomics. Here, we present an implementation of data-independent acquisition using its parallel acquisition nature that surpasses the serial limitation of data-dependent acquisition on a quadrupole ultra-high field Orbitrap mass spectrometer. In deep single shot data-independent acquisition, we quantified over 7,500 proteins of human cell lines and 9,000 proteins of mouse tissues, with fewer than 2.5% missing proteins and median coefficients of variation of down to 5% among replicates. In very complex mixtures, we could quantify more than 15,000 proteins, outperforming data-dependent acquisition methods by more than two-fold. Using this method, we investigated large-protein networks before and after the critical period for whisker experience-induced synaptic strength in the murine somatosensory cortex 1 barrel field. This work shows that parallel mass spectrometry enables proteome profiling for discovery with high coverage, reproducibility, precision and scalability. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Mapping Genes for Calcium Signaling and Their Associated Human Genetic Disorders
Apr 21, 2017   Bioinformatics (Oxford, England)
Hörtenhuber M, Toledo EM, Smedler E, Arenas E, Malmersjö S, Louhivuori L, Uhlén P
Mapping Genes for Calcium Signaling and Their Associated Human Genetic Disorders
Apr 21, 2017
Bioinformatics (Oxford, England)
Signal transduction via calcium ions (Ca 2+ ) represents a fundamental signaling pathway in all eukaryotic cells. A large portion of the human genome encodes proteins used to assemble signaling systems that can transduce signals with diverse spatial and temporal dynamics. Here, we provide a map of all of the genes involved in Ca 2+ signaling and link these genes to human genetic disorders. Using Gene Ontology terms and genome databases, 1,805 genes were identified as regulators or targets of intracellular Ca 2+ signals. Associating these 1,805 genes with human genetic disorders uncovered 1,470 diseases with mutated "Ca 2+ genes". A network with scale-free properties appeared when the Ca 2+ genes were mapped to their associated genetic disorders. The Ca 2+ genome database is freely available at http://cagedb.uhlenlab.org and will foster studies of gene functions and genetic disorders associated with Ca 2+ signaling. per.uhlen@ki.se. Supplementary data are available at Bioinformatics online.
Metabolomic and Proteomic Analysis of Maize Embryonic Callus induced from immature embryo
Apr 22, 2017   Scientific Reports
Ge F, Hu H, Huang X, Zhang Y, Wang Y, Li Z, Zou C, Peng H, Li L, Gao S, Pan G, Shen Y
Metabolomic and Proteomic Analysis of Maize Embryonic Callus induced from immature embryo
Apr 22, 2017
Scientific Reports
The low ratio of embryonic callus (EC) induction has inhibited the rapid development of maize genetic engineering. Still, little is known to explain the genotype-dependence of EC induction. Here, we performed a large-scale, quantitative analysis of the maize EC metabolome and proteome at three typical induction stages in two inbred lines with a range of EC induction capabilities. Comparison of the metabolomes and proteomes suggests that the differential molecular responses begin at an early stage of development and continue throughout the process of EC formation. The two inbred lines show different responses under various conditions, such as metal ion binding, cell enlargement, stem cell formation, meristematic activity maintenance, somatic embryogenesis, cell wall synthesis, and hormone signal transduction. Furthermore, the differences in hormone (auxin, cytokinin, gibberellin, salicylic acid, jasmonic acid, brassinosteroid and ethylene) synthesis and transduction ability could partially explain the higher EC induction ratio in the inbred line 18-599R. During EC formation, repression of the "histone deacetylase 2 and ERF transcription factors" complex in 18-599R activated the expression of downstream genes, which further promoted EC induction. Together, our data provide new insights into the molecular regulatory mechanism responsible for efficient EC induction in maize.
Systematic Synergy of Glucose and GLP-1 to Stimulate Insulin Secretion Revealed by Quantitative Phosphoproteomics
Apr 22, 2017   Scientific Reports
Tang JS, Li QR, Li JM, Wu JR, Zeng R
Systematic Synergy of Glucose and GLP-1 to Stimulate Insulin Secretion Revealed by Quantitative Phosphoproteomics
Apr 22, 2017
Scientific Reports
GLP-1 synergizes with glucose in regulating pancreatic β-cell function, including facilitating β-cell survival and insulin secretion. Though it has been widely accepted that phosphorylation is extremely important in regulating β-cell functions, our knowledge to the global mechanism is still limited. Here we performed a quantitative phosphoproteomics study to systematically present the synergistic regulation of INS-1E cell phosphoproteome mediated by glucose and GLP-1. We generated the largest pancreatic β-cell phosphoproteome by identifying 25,327 accurately localized phosphorylation sites on 5,389 proteins. Our results discovered several novel kinases regulated by glucose, GLP-1 or their synergism, and some of these kinases might act as downstream molecules of GLP-1 mediated PKA signaling cascade. A few phosphosites were regulated by both GLP-1 and glucose alone, and these target proteins were highly related to their biological function on pancreatic β-cells. Finally, we found glucose and GLP-1 executed their synergistic effect at multiple levels, especially at pathway level. Both GLP-1 and glucose participated in regulating every single step of the secretion pathway, and systematically synergized their effects in inducing insulin secretion.
Quantitative Imaging of Cerebral Thromboemboli In Vivo: The Effects of Tissue-Type Plasminogen Activator
Apr 22, 2017   Stroke
Kim DE, Kim JY, Schellingerhout D, Ryu JH, Lee SK,   . . . . . .   , Kim EJ, Kwon IC, Ahn CH, Nahrendorf M, Kim K
Quantitative Imaging of Cerebral Thromboemboli In Vivo: The Effects of Tissue-Type Plasminogen Activator
Apr 22, 2017
Stroke
Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan-coated gold nanoparticles and microcomputed tomography, with/without tPA therapy. We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan-coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment. Thrombus burden at baseline was 784×103±59×103 μm2 for the tPA group (n=42) and 655×103±103×103 μm2 for the saline group (n=8; P=0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm2/min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 μm2, equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm2; P
N-terminal proteomics assisted profiling of the unexplored translation initiation landscape in Arabidopsis thaliana
Apr 22, 2017   Molecular & Cellular Proteomics : MCP
Willems P, Ndah E, Jonckheere V, Stael S, Sticker A, Martens L, Van Breusegem F, Gevaert K, Van Damme P
N-terminal proteomics assisted profiling of the unexplored translation initiation landscape in Arabidopsis thaliana
Apr 22, 2017
Molecular & Cellular Proteomics : MCP
Proteogenomics is an emerging research field yet lacking a uniform method of analysis. Proteogenomic studies in which N-terminal proteomics and ribosome profiling are combined, suggest that a high number of protein start sites are currently missing in genome annotations. We constructed a proteogenomic pipeline specific for the analysis of N-terminal proteomics data, with the aim of discovering novel translational start sites outside annotated protein coding regions. In summary, unidentified MS/MS spectra were matched to a specific N-terminal peptide library encompassing protein N-termini encoded in the Arabidopsis thaliana genome. After a stringent false discovery rate filtering, 157 protein N-termini compliant with N-terminal methionine excision specificity and indicative of translation initiation were found. These include N-terminal protein extensions and translation from transposable elements and pseudogenes. Gene prediction provided supporting protein-coding models for approximately half of the protein N-termini. Besides the prediction of functional domains (partially) contained within the newly predicted ORFs, further supporting evidence of translation was found in the recently released Araport11 genome re-annotation of Arabidopsis and computational translations of sequences stored in public repositories. Most interestingly, complementary evidence by ribosome profiling was found for 23 protein N-termini. Finally, by analyzing protein N-terminal peptides, an in silico analysis demonstrates the applicability of our N-terminal proteogenomics strategy in revealing protein-coding potential in species with well- and poorly-annotated genomes. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry
Apr 21, 2017   Cell
Lim J, Giri PK, Kazadi D, Laffleur B, Zhang W,   . . . . . .   , Rothschild G, Cogné M, Pinaud E, Deng H, Basu U
Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry
Apr 21, 2017
Cell
The distribution of sense and antisense strand DNA mutations on transcribed duplex DNA contributes to the development of immune and neural systems along with the progression of cancer. Because developmentally matured B cells undergo biologically programmed strand-specific DNA mutagenesis at focal DNA/RNA hybrid structures, they make a convenient system to investigate strand-specific mutagenesis mechanisms. We demonstrate that the sense and antisense strand DNA mutagenesis at the immunoglobulin heavy chain locus and some other regions of the B cell genome depends upon localized RNA processing protein complex formation in the nucleus. Both the physical proximity and coupled activities of RNA helicase Mtr4 (and senataxin) with the noncoding RNA processing function of RNA exosome determine the strand-specific distribution of DNA mutations. Our study suggests that strand-specific DNA mutagenesis-associated mechanisms will play major roles in other undiscovered aspects of organismic development. Copyright © 2017 Elsevier Inc. All rights reserved.
Macrophages Facilitate Electrical Conduction in the Heart
Apr 21, 2017   Cell
Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR,   . . . . . .   , Kohl P, Vinegoni C, Milan DJ, Ellinor PT, Nahrendorf M
Macrophages Facilitate Electrical Conduction in the Heart
Apr 21, 2017
Cell
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction. Copyright © 2017 Elsevier Inc. All rights reserved.
The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover
Apr 21, 2017   Cell
Tawo R, Pokrzywa W, Kevei É, Akyuz ME, Balaji V, Adrian S, Höhfeld J, Hoppe T
The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover
Apr 21, 2017
Cell
Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Bacterial Metabolism Affects the C. elegans Response to Cancer Chemotherapeutics
Apr 21, 2017   Cell
García-González AP, Ritter AD, Shrestha S, Andersen EC, Yilmaz LS, Walhout AJM
Bacterial Metabolism Affects the C. elegans Response to Cancer Chemotherapeutics
Apr 21, 2017
Cell
The human microbiota greatly affects physiology and disease; however, the contribution of bacteria to the response to chemotherapeutic drugs remains poorly understood. Caenorhabditis elegans and its bacterial diet provide a powerful system to study host-bacteria interactions. Here, we use this system to study how bacteria affect the C. elegans response to chemotherapeutics. We find that different bacterial species can increase the response to one drug yet decrease the effect of another. We perform genetic screens in two bacterial species using three chemotherapeutic drugs: 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FUDR), and camptothecin (CPT). We find numerous bacterial nucleotide metabolism genes that affect drug efficacy in C. elegans. Surprisingly, we find that 5-FU and FUDR act through bacterial ribonucleotide metabolism to elicit their cytotoxic effects in C. elegans rather than by thymineless death or DNA damage. Our study provides a blueprint for characterizing the role of bacteria in the host response to chemotherapeutics. Copyright © 2017 Elsevier Inc. All rights reserved.
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Apr 21, 2017   ELife
Park HB, Perez CE, Barber KW, Rinehart J, Crawford JM
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Apr 21, 2017
ELife
Nonribosomal peptides represent a large class of metabolites with pharmaceutical relevance. Pteridines, such as pterins, folates, and flavins, are heterocyclic metabolites that often serve as redox-active cofactors. The biosynthetic machineries for construction of these distinct classes of small molecules operate independently in the cell. Here, we discovered an unprecedented nonribosomal peptide synthetase-like-pteridine synthase hybrid biosynthetic gene cluster in Photorhabdus luminescens using genome synteny analysis. P. luminescens is a Gammaproteobacterium that undergoes phenotypic variation and can have both pathogenic and mutualistic roles. Through extensive gene deletion, pathway-targeted molecular networking, quantitative proteomic analysis, and NMR, we show that the genetic locus affects the regulation of quorum sensing and secondary metabolic enzymes and encodes new pteridine metabolites functionalized with cis-amide acyl-side chains, termed pepteridine A (1) and B (2). The pepteridines are produced in the pathogenic phenotypic variant and represent the first reported metabolites to be synthesized by a hybrid NRPS-pteridine pathway. These studies expand our view of the combinatorial biosynthetic potential available in bacteria.
Disulfide bonds enable accelerated protein evolution
Apr 21, 2017   Molecular Biology And Evolution
Feyertag F, Alvarez-Ponce D
Disulfide bonds enable accelerated protein evolution
Apr 21, 2017
Molecular Biology And Evolution
The different proteins of any proteome evolve at enormously different rates. What factors contribute to this variability, and to what extent, is still a largely open question. We hypothesized that disulfide bonds, by increasing protein stability, should make proteins' structures relatively independent of their amino acid sequences, thus acting as buffers of deleterious mutations and enabling accelerated sequence evolution. In agreement with this hypothesis, we observed that membrane proteins with disulfide bonds evolved 88% faster than those without disulfide bonds, and that extracellular proteins with disulfide bonds evolved 49% faster than those without disulfide bonds. In addition, genes encoding proteins with disulfide bonds exhibit an increased likelihood of showing signatures of positive selection. Multivariate analyses indicate that the trend is independent of a number of potentially confounding factors. The effect, however, is not observed among the longest proteins, which can become stabilized by mechanisms other than disulfide bonds. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Switching of metabolic programs in response to light availability is an essential function of the cyanobacterial circadian output pathway
Apr 21, 2017   ELife
Puszynska AM, O'Shea EK
Switching of metabolic programs in response to light availability is an essential function of the cyanobacterial circadian output pathway
Apr 21, 2017
ELife
The transcription factor RpaA is the master regulator of circadian transcription in cyanobacteria, driving genome-wide oscillations in mRNA abundance. Deletion of rpaA has no effect on viability in constant light conditions, but renders cells inviable in cycling conditions when light and dark periods alternate. We investigated the mechanisms underlying this viability defect, and demonstrate that the rpaA- strain cannot maintain appropriate energy status at night, does not accumulate carbon reserves during the day, and is defective in transcription of genes crucial for utilization of carbohydrate stores at night. Reconstruction of carbon utilization pathways combined with provision of an external carbon source restores energy charge and viability of the rpaA- strain in light/dark cycling conditions. Our observations highlight how a circadian output pathway controls and temporally coordinates essential pathways in carbon metabolism to maximize fitness of cells facing periodic energy limitations.
Complete Genome Sequence of the Streptococcus gallolyticus subsp. gallolyticus Strain DSM 16831
Apr 21, 2017   Genome Announcements
Grimm I, Dumke J, Vollmer T, Hinse D, Rückert C, Kalinowski J, Knabbe C, Dreier J
Complete Genome Sequence of the Streptococcus gallolyticus subsp. gallolyticus Strain DSM 16831
Apr 21, 2017
Genome Announcements
Streptococcus gallolyticus subsp. gallolyticus DSM 16831 is an intriguing strain because of its low virulent phenotype compared to other isolates. We present here the complete genome sequence for this strain isolated from koala feces. Copyright © 2017 Grimm et al.
Comprehensive assessment showed no associations of variants at the SLC10A1 locus with susceptibility to persistent HBV infection among Southern Chinese
Apr 21, 2017   Scientific Reports
Zhang Y, Li Y, Wu M, Cao P, Liu X,   . . . . . .   , Shen H, Zeng YX, He F, Zhang H, Zhou G
Comprehensive assessment showed no associations of variants at the SLC10A1 locus with susceptibility to persistent HBV infection among Southern Chinese
Apr 21, 2017
Scientific Reports
The sodium taurocholate cotransporting polypeptide (NTCP) encoded by SLC10A1 was recently demonstrated to be a functional receptor for hepatitis B virus (HBV). The role of SLC10A1 polymorphisms, particularly the Ser267Phe variant (rs2296651) in exon 4, has been frequently investigated in regard to risk of persistent HBV infection. However, these investigations have generated conflicting results. To examine whether common genetic variation at the SLC10A1 locus is associated with risk of persistent HBV infection, haplotype-tagging and imputed single nucleotide polymorphisms (SNPs) were assessed in two case-control sample sets, totally including 2,550 cases (persistently HBV infected subjects, PIs) and 2,124 controls (spontaneously recovered subjects, SRs) of Southern Chinese ancestry. To test whether rare or subpolymorphic SLC10A1 variants are associated with disease risk, the gene's exons in 244 cases were sequenced. Overall, we found neither SNPs nor haplotypes of SLC10A1 showed significant association in the two sample sets. Furthermore, no significant associations of rare variants or copy number variation covering SLC10A1 were observed. Finally, expression quantitative trait locus analyses revealed that SNPs potentially affecting SLC10A1 expression also showed no significant associations. We conclude that genetic variation at the SLC10A1 locus is not likely a major risk factor of persistent HBV infection among Southern Chinese.
Novel SUMO-Protease SENP7S Regulates β-catenin Signaling and Mammary Epithelial Cell Transformation
Apr 21, 2017   Scientific Reports
Karami S, Lin FM, Kumar S, Bahnassy S, Thangavel H, Quttina M, Li Y, Ren J, Bawa-Khalfe T
Novel SUMO-Protease SENP7S Regulates β-catenin Signaling and Mammary Epithelial Cell Transformation
Apr 21, 2017
Scientific Reports
SUMO post-translational modification of proteins or SUMOylation ensures normal cell function. Disruption of SUMO dynamics prompts various pathophysiological conditions, including cancer. The burden of deSUMOylating the large SUMO-proteome rests on 6 full-length mammalian SUMO-proteases or SENP. While multiple SENP isoforms exist, the function of these isoforms remains undefined. We now delineate the biological role of a novel SENP7 isoform SENP7S in mammary epithelial cells. SENP7S is the predominant SENP transcript in human mammary epithelia but is significantly reduced in precancerous ductal carcinoma in situ and all breast cancer subtypes. Like other SENP family members, SENP7S has SUMO isopeptidase activity but unlike full-length SENP7L, SENP7S is localized in the cytosol. In vivo, SUMOylated β-catenin and Axin1 are both SENP7S-substrates. With knockdown of SENP7S in mammary epithelial cells, Axin1-β-catenin interaction is lost and β-catenin escapes ubiquitylation-dependent proteasomal degradation. SUMOylated β-catenin accumulates at the chromatin and activates multiple oncogenes. Hence, non-tumorigenic MCF10-2A cells with reduced SENP7S exhibit greater cell proliferation and anchorage-dependent growth. SENP7S depletion directly potentiates tumorigenic properties of MCF10-2A cells with induction of anchorage-independent growth and self-renewal in 3D-spheroid conditions. Collectively, the results identify SENP7S as a novel mediator of β-catenin signaling and normal mammary epithelial cell physiology.
A mouse tissue transcription factor atlas
Apr 21, 2017   Nature Communications
Zhou Q, Liu M, Xia X, Gong T, Feng J, Liu W, Liu Y, Zhen B, Wang Y, Ding C, Qin J
A mouse tissue transcription factor atlas
Apr 21, 2017
Nature Communications
Transcription factors (TFs) drive various biological processes ranging from embryonic development to carcinogenesis. Here, we employ a recently developed concatenated tandem array of consensus TF response elements (catTFRE) approach to profile the activated TFs in 24 adult and 8 fetal mouse tissues on proteome scale. A total of 941 TFs are quantitatively identified, representing over 60% of the TFs in the mouse genome. Using an integrated omics approach, we present a TF network in the major organs of the mouse, allowing data mining and generating knowledge to elucidate the roles of TFs in various biological processes, including tissue type maintenance and determining the general features of a physiological system. This study provides a landscape of TFs in mouse tissues that can be used to elucidate transcriptional regulatory specificity and programming and as a baseline that may facilitate understanding diseases that are regulated by TFs.
A computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue
Apr 21, 2017   Nature Communications
Talos F, Mitrofanova A, Bergren SK, Califano A, Shen MM
A computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue
Apr 21, 2017
Nature Communications
To date, reprogramming strategies for generating cell types of interest have been facilitated by detailed understanding of relevant developmental regulatory factors. However, identification of such regulatory drivers often represents a major challenge, as specific gene combinations may be required for reprogramming. Here we show that a computational systems approach can identify cell type specification genes (master regulators) that act synergistically, and demonstrate its application for reprogramming of fibroblasts to prostate tissue. We use three such master regulators (FOXA1, NKX3.1 and androgen receptor, AR) in a primed conversion strategy starting from mouse fibroblasts, resulting in prostate tissue grafts with appropriate histological and molecular properties that respond to androgen-deprivation. Moreover, generation of reprogrammed prostate does not require traversal of a pluripotent state. Thus, we describe a general strategy by which cell types and tissues can be generated even with limited knowledge of the developmental pathways required for their specification in vivo.
Separate neural systems for behavioral change and for emotional responses to failure during behavioral inhibition
Apr 21, 2017   Human Brain Mapping
Deng W, Rolls ET, Ji X, Robbins TW, Banaschewski T,   . . . . . .   , Smolka MN, Walter H, Whelan R, Schumann G, Feng J
Separate neural systems for behavioral change and for emotional responses to failure during behavioral inhibition
Apr 21, 2017
Human Brain Mapping
To analyze the involvement of different brain regions in behavioral inhibition and impulsiveness, differences in activation were investigated in fMRI data from a response inhibition task, the stop-signal task, in 1709 participants. First, areas activated more in stop-success (SS) than stop-failure (SF) included the lateral orbitofrontal cortex (OFC) extending into the inferior frontal gyrus (ventrolateral prefrontal cortex, BA 47/12), and the dorsolateral prefrontal cortex (DLPFC). Second, the anterior cingulate and anterior insula (AI) were activated more on failure trials, specifically in SF versus SS. The interaction between brain region and SS versus SF activations was significant (P = 5.6 * 10-8 ). The results provide new evidence from this "big data" investigation consistent with the hypotheses that the lateral OFC is involved in the stop-related processing that inhibits the action; that the DLPFC is involved in attentional processes that influence task performance; and that the AI and anterior cingulate are involved in emotional processes when failure occurs. The investigation thus emphasizes the role of the human lateral OFC BA 47/12 in changing behavior, and inhibiting behavior when necessary. A very similar area in BA47/12 is involved in changing behavior when an expected reward is not obtained, and has been shown to have high functional connectivity in depression. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium
Apr 21, 2017   Neurology. Genetics
Debette S, Saba Y, Vojinovic D, Jian X, Adams H,   . . . . . .   , Schmidt H, Longstreth WT, Fornage M, Seshadri S, neuro-CHARGE working group
19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium
Apr 21, 2017
Neurology. Genetics
The CHARGE consortium is an investigator-initiated collaboration to facilitate meta-analyses of genome-wide association studies (GWAS) and genomic analyses based on next generation sequencing (NGS), among multiple large and well-phenotyped population-based cohort studies around the world (http://www.chargeconsortium.com). Within the neuro-CHARGE working group, we are presenting an update of ongoing genomic studies on MRI-markers of cerebrovascular disease. Large population-based studies have shown that the burden of cerebrovascular disease extends far beyond that of clinical stroke. MRI-markers of cerebral small vessel disease, such as white matter hyperintensities (WMH), small subcortical brain infarcts, microbleeds, or dilated perivascular spaces, are particularly frequent in older community persons. These markers portend an increased risk of stroke, dementia, and premature death, and were shown to have a high heritability, especially WMH burden. Interestingly recent work has revealed genetic risk variants between WMH burden and stroke. To account for the major role of high blood pressure in the occurrence of WMH, we are performing a GWAS of WMH burden stratified on hypertension status, as well as a joint meta-analysis to account for gene-environment interaction with hypertension. Moreover, based on prior epidemiologic and histologic data suggesting that the pathogenesis of WMH may differ according to their location, we are running separate GWAS for periventricular and deep WMH burden. A GWAS of cerebral microbleeds is being finalized. We are also exploring the role of vascular risk factors in the occurrence of dementia by examining the relation of genetic risk scores for these factors with MRI-markers of brain aging and cerebrovascular disease. Finally, several NGS projects are being conducted to identify rare variants associated with WMH burden and lacunar brain infarcts. Additional projects are also currently being designed, including GWAS of novel MRI phenotypes, such as composite measures of cerebral small vessel disease, as well as lifetime, and epigenomic approaches.
Transgenerational transmission of environmental information in C. elegans
Apr 21, 2017   Science (New York, N.Y.)
Klosin A, Casas E, Hidalgo-Carcedo C, Vavouri T, Lehner B
Transgenerational transmission of environmental information in C. elegans
Apr 21, 2017
Science (New York, N.Y.)
The environment experienced by an animal can sometimes influence gene expression for one or a few subsequent generations. Here, we report the observation that a temperature-induced change in expression from a Caenorhabditis elegans heterochromatic gene array can endure for at least 14 generations. Inheritance is primarily in cis with the locus, occurs through both oocytes and sperm, and is associated with altered trimethylation of histone H3 lysine 9 (H3K9me3) before the onset of zygotic transcription. Expression profiling reveals that temperature-induced expression from endogenous repressed repeats can also be inherited for multiple generations. Long-lasting epigenetic memory of environmental change is therefore possible in this animal. Copyright © 2017, American Association for the Advancement of Science.
Biased partitioning of the multidrug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity
Apr 21, 2017   Science (New York, N.Y.)
Bergmiller T, Andersson AMC, Tomasek K, Balleza E, Kiviet DJ, Hauschild R, Tkačik G, Guet CC
Biased partitioning of the multidrug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity
Apr 21, 2017
Science (New York, N.Y.)
The molecular mechanisms underlying phenotypic variation in isogenic bacterial populations remain poorly understood. We report that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, exhibits a strong partitioning bias for old cell poles by a segregation mechanism that is mediated by ternary AcrAB-TolC complex formation. Mother cells inheriting old poles are phenotypically distinct and display increased drug efflux activity relative to daughters. Consequently, we find systematic and long-lived growth differences between mother and daughter cells in the presence of subinhibitory drug concentrations. A simple model for biased partitioning predicts a population structure of long-lived and highly heterogeneous phenotypes. This straightforward mechanism of generating sustained growth rate differences at subinhibitory antibiotic concentrations has implications for understanding the emergence of multidrug resistance in bacteria. Copyright © 2017, American Association for the Advancement of Science.
Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat
Apr 21, 2017   Science (New York, N.Y.)
Park TJ, Reznick J, Peterson BL, Blass G, Omerbašić D,   . . . . . .   , Smith ESJ, Larson J, Gotthardt M, Kempa S, Lewin GR
Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat
Apr 21, 2017
Science (New York, N.Y.)
The African naked mole-rat's (Heterocephalus glaber) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease. Copyright © 2017, American Association for the Advancement of Science.
Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors
Apr 21, 2017   Science (New York, N.Y.)
Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K,   . . . . . .   , Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N
Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors
Apr 21, 2017
Science (New York, N.Y.)
Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease. Copyright © 2017, American Association for the Advancement of Science.
Probing protein flexibility reveals a mechanism for selective promiscuity
Apr 22, 2017   ELife
Pabon NA, Camacho CJ
Probing protein flexibility reveals a mechanism for selective promiscuity
Apr 22, 2017
ELife
Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anti-cancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets.

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