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Computational Biology
PGBD5 promotes site-specific oncogenic mutations in human tumors
May 15, 2017   Nature Genetics Add nature.com free-link Cancel
Henssen AG, Koche R, Zhuang J, Jiang E, Reed C,   . . . . . .   , Jackson SP, Torrents D, Weng Z, Armstrong SA, Kentsis A
PGBD5 promotes site-specific oncogenic mutations in human tumors
May 15, 2017
Nature Genetics
Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.
Whole brain volume changes and its correlation with clinical symptom severity in patients with schizophrenia: A DARTEL-based VBM study
May 18, 2017   PloS One
Kim GW, Kim YH, Jeong GW
Whole brain volume changes and its correlation with clinical symptom severity in patients with schizophrenia: A DARTEL-based VBM study
May 18, 2017
PloS One
The purpose of this study was to evaluate gray matter (GM) and white matter (WM) volume alterations in whole-brain structures in patients with schizophrenia and healthy controls using voxel-based morphometry (VBM), and further to assess the correlation between GM and WM volume variations and symptom severity in schizophrenia. A total of 22 patients with schizophrenia and 22 age-matched healthy controls participated. Magnetic resonance image data were processed using SPM8 software with diffeomorphic anatomical registration via an exponentiated Lie algebra (DARTEL) algorithm. Patients with schizophrenia exhibited significantly decreased GM volumes of the insula, superior temporal gyrus (STG), gyrus rectus, and anterior cingulate cortex (ACC) compared with healthy controls. The GM volumes of the STG and gyrus rectus were negatively correlated with the positive scales on the Positive and Negative Syndrome Scale (PANSS) and those of the STG and ACC were negatively correlated with the negative scales. The durations of illness in schizophrenia were negatively correlated with the GM volumes of the insula, STG, and ACC. Patients with schizophrenia exhibited significantly decreased WM volumes of the superior frontal gyrus, inferior temporal gyrus, and STG. The WM volumes of the STG were negatively correlated with the duration of illness. Our findings suggest that GM and WM volume abnormalities in the STG are associated with the psychopathology of schizophrenia.
Perfusion MR imaging detection of carcinoma arising from preexisting salivary gland pleomorphic adenoma by computer-assisted analysis of time-signal intensity maps
May 22, 2017   PloS One
Katayama I, Eida S, Fujita S, Hotokezaka Y, Sumi M, Nakamura T
Perfusion MR imaging detection of carcinoma arising from preexisting salivary gland pleomorphic adenoma by computer-assisted analysis of time-signal intensity maps
May 22, 2017
PloS One
Tumor perfusion can be evaluated by analyzing the time-signal intensity curve (TIC) after dynamic contrast-enhanced (DCE) MR imaging. Accordingly, TIC profiles are characteristic of some benign and malignant salivary gland tumors. A carcinoma ex pleomorphic adenoma (CXPA) arises from a long-standing pleomorphic adenoma (PA) and has a distinctive prognostic risk depending on the tumor growth potential such as invasion beyond the preexisting capsule. Differentiating CXPA from PA can be very challenging. In this study, we have attempted to discriminate CXPA from PA based on a two-dimensional TIC mapping algorithm. TIC mapping analysis was performed on 8 patients with CXPA and 20 patients with PA after dynamic contrast-enhanced (DCE) MR imaging using a 1.5-T MR system. The TIC profiles obtained were automatically categorized into 5 types based on the enhancement ratio, maximum time, and washout ratio (Type 1 TIC with flat profile, Type 2 TIC with slow uptake, Type 3 TIC with rapid uptake and a low washout ratio, Type 4 TIC with rapid uptake and a high washout ratio, and Type 5 TIC not otherwise specific). The percentage tumor areas with each of the 5 TIC types were compared between CXPAs and PAs. Stepwise differentiation and cluster analysis using multiple TIC cut-off thresholds distinguished CXPAs from PAs with 75% sensitivity, 95% specificity, 86% accuracy, and 86% positive and 90% negative predictive values, when tumors with ≤1.1% Type 1 and ≥15% Type 4, or those with ≤1.1% Type 1, ≥78.1% Type 2, ≥16.1% Type 3, and 1.1% Type 1, ≥78.1% Type 2, and ≥16.1% Type 3 areas were diagnosed as CXPAs. The overall TIC profiles predicted some aggressive CXPA growth patterns. These results suggest that stepwise differentiation based on TIC mapping is helpful in differentiating CXPAs from PAs.
Genome Partitioner: A web tool for multi-level partitioning of large-scale DNA constructs for synthetic biology applications
May 22, 2017   PloS One
Christen M, Del Medico L, Christen H, Christen B
Genome Partitioner: A web tool for multi-level partitioning of large-scale DNA constructs for synthetic biology applications
May 22, 2017
PloS One
Recent advances in lower-cost DNA synthesis techniques have enabled new innovations in the field of synthetic biology. Still, efficient design and higher-order assembly of genome-scale DNA constructs remains a labor-intensive process. Given the complexity, computer assisted design tools that fragment large DNA sequences into fabricable DNA blocks are needed to pave the way towards streamlined assembly of biological systems. Here, we present the Genome Partitioner software implemented as a web-based interface that permits multi-level partitioning of genome-scale DNA designs. Without the need for specialized computing skills, biologists can submit their DNA designs to a fully automated pipeline that generates the optimal retrosynthetic route for higher-order DNA assembly. To test the algorithm, we partitioned a 783 kb Caulobacter crescentus genome design. We validated the partitioning strategy by assembling a 20 kb test segment encompassing a difficult to synthesize DNA sequence. Successful assembly from 1 kb subblocks into the 20 kb segment highlights the effectiveness of the Genome Partitioner for reducing synthesis costs and timelines for higher-order DNA assembly. The Genome Partitioner is broadly applicable to translate DNA designs into ready to order sequences that can be assembled with standardized protocols, thus offering new opportunities to harness the diversity of microbial genomes for synthetic biology applications. The Genome Partitioner web tool can be accessed at https://christenlab.ethz.ch/GenomePartitioner.
Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug
May 22, 2017   Nature Medicine Add nature.com free-link Cancel
Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R,   . . . . . .   , Burcelin R, Ricart W, Perkins R, Fernàndez-Real JM, Bäckhed F
Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug
May 22, 2017
Nature Medicine
Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.
Reevaluation of SNP heritability in complex human traits
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Speed D, Cai N, UCLEB Consortium, Johnson MR, Nejentsev S, Balding DJ
Reevaluation of SNP heritability in complex human traits
May 22, 2017
Nature Genetics
SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but current assumptions have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency (MAF), linkage disequilibrium (LD) and genotype certainty. Across 19 traits, our improved model leads to estimates of common SNP heritability on average 43% (s.d. 3%) higher than those obtained from the widely used software GCTA and 25% (s.d. 2%) higher than those from the recently proposed extension GCTA-LDMS. Previously, DNase I hypersensitivity sites were reported to explain 79% of SNP heritability; using our improved heritability model, their estimated contribution is only 24%.
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Howson JMM, Zhao W, Barnes DR, Ho WK, Young R,   . . . . . .   , Nordestgaard BG, Assimes TL, Danesh J, Butterworth AS, Saleheen D
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
May 22, 2017
Nature Genetics
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.
Church attendance, allostatic load and mortality in middle aged adults
May 18, 2017   PloS One
Bruce MA, Martins D, Duru K, Beech BM, Sims M, Harawa N, Vargas R, Kermah D, Nicholas SB, Brown A, Norris KC
Church attendance, allostatic load and mortality in middle aged adults
May 18, 2017
PloS One
Religiosity has been associated with positive health outcomes. Hypothesized pathways for this association include religious practices, such as church attendance, that result in reduced stress. The objective of this study was to examine the relationship between religiosity (church attendance), allostatic load (AL) (a physiologic measure of stress) and all-cause mortality in middle-aged adults. Data for this study are from NHANES III (1988-1994). The analytic sample (n = 5449) was restricted to adult participants, who were between 40-65 years of age at the time of interview, had values for at least 9 out of 10 clinical/biologic markers used to derive AL, and had complete information on church attendance. The primary outcomes were AL and mortality. AL was derived from values for metabolic, cardiovascular, and nutritional/inflammatory clinical/biologic markers. Mortality was derived from a probabilistic algorithm matching the NHANES III Linked Mortality File to the National Death Index through December 31, 2006, providing up to 18 years follow-up. The primary predictor variable was baseline report of church attendance over the past 12 months. Cox proportional hazard logistic regression models contained key covariates including socioeconomic status, self-rated health, co-morbid medical conditions, social support, healthy eating, physical activity, and alcohol intake. Churchgoers (at least once a year) comprised 64.0% of the study cohort (n = 3782). Non-churchgoers had significantly higher overall mean AL scores and higher prevalence of high-risk values for 3 of the 10 markers of AL than did churchgoers. In bivariate analyses non-churchgoers, compared to churchgoers, had higher odds of an AL score 2-3 (OR 1.24; 95% CI 1.01, 1.50) or ≥4 (OR 1.38; 95% CI 1.11, 1.71) compared to AL score of 0-1. More frequent churchgoers (more than once a week) had a 55% reduction of all-cause mortality risk compared with non-churchgoers. (HR 0.45, CI 0.24-0.85) in the fully adjusted model that included AL. We found a significant association between church attendance and mortality among middle-aged adults after full adjustments. AL, a measure of stress, only partially explained differences in mortality between church and non-church attendees. These findings suggest a potential independent effect of church attendance on mortality.
Network based stratification of major cancers by integrating somatic mutation and gene expression data
May 18, 2017   PloS One
He Z, Zhang J, Yuan X, Liu Z, Liu B, Tuo S, Liu Y
Network based stratification of major cancers by integrating somatic mutation and gene expression data
May 18, 2017
PloS One
The stratification of cancer into subtypes that are significantly associated with clinical outcomes is beneficial for targeted prognosis and treatment. In this study, we integrated somatic mutation and gene expression data to identify clusters of patients. In contrast to previous studies, we constructed cancer-type-specific significant co-expression networks (SCNs) rather than using a fixed gene network across all cancers, such as the network-based stratification (NBS) method, which ignores cancer heterogeneity. For each type of cancer, the gene expression data were used to construct the SCN network, while the gene somatic mutation data were mapped onto the network, propagated, and used for further clustering. For the clustering, we adopted an improved network-regularized non-negative matrix factorization (netNMF) (netNMF_HC) for a more precise classification. We applied our method to various datasets, including ovarian cancer (OV), lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC) cohorts derived from the TCGA (The Cancer Genome Atlas) project. Based on the results, we evaluated the performance of our method to identify survival-relevant subtypes and further compared it to the NBS method, which adopts priori networks and netNMF algorithm. The proposed algorithm outperformed the NBS method in identifying informative cancer subtypes that were significantly associated with clinical outcomes in most cancer types we studied. In particular, our method identified survival-associated UCEC subtypes that were not identified by the NBS method. Our analysis indicated valid subtyping of patient could be applied by mutation data with cancer-type-specific SCNs and netNMF_HC for individual cancers because of specific cancer co-expression patterns and more precise clustering.
An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice
May 18, 2017   PloS One
Ghosh S, Forney LA, Wanders D, Stone KP, Gettys TW
An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice
May 18, 2017
PloS One
Dietary methionine restriction (MR) produces a coordinated series of transcriptional responses in peripheral tissues that limit fat accretion, remodel lipid metabolism in liver and adipose tissue, and improve overall insulin sensitivity. Hepatic sensing of reduced methionine leads to induction and release of fibroblast growth factor 21 (FGF21), which acts centrally to increase sympathetic tone and activate thermogenesis in adipose tissue. FGF21 also has direct effects in adipose to enhance glucose uptake and oxidation. However, an understanding of how the liver senses and translates reduced dietary methionine into these transcriptional programs remains elusive. A comprehensive systems biology approach integrating transcriptomic and metabolomic readouts in MR-treated mice confirmed that three interconnected mechanisms (fatty acid transport and oxidation, tricarboxylic acid cycle, and oxidative phosphorylation) were activated in MR-treated inguinal adipose tissue. In contrast, the effects of MR in liver involved up-regulation of anti-oxidant responses driven by the nuclear factor, erythroid 2 like 2 transcription factor, NFE2L2. Metabolomic analysis provided evidence for redox imbalance, stemming from large reductions in the master anti-oxidant molecule glutathione coupled with disproportionate increases in ophthalmate and its precursors, glutamate and 2-aminobutyrate. Thus, cysteine and its downstream product, glutathione, emerge as key early hepatic signaling molecules linking dietary MR to its metabolic phenotype.
Genome-wide gene expression array identifies novel genes related to disease severity and excessive daytime sleepiness in patients with obstructive sleep apnea
May 18, 2017   PloS One
Chen YC, Chen KD, Su MC, Chin CH, Chen CJ,   . . . . . .   , Chang JC, Lin YY, Zheng YX, Lin MC, Hsiao CC
Genome-wide gene expression array identifies novel genes related to disease severity and excessive daytime sleepiness in patients with obstructive sleep apnea
May 18, 2017
PloS One
We aimed to identify novel molecular associations between chronic intermittent hypoxia with re-oxygenation and adverse consequences in obstructive sleep apnea (OSA). We analyzed gene expression profiles of peripheral blood mononuclear cells from 48 patients with sleep-disordered breathing stratified into four groups: primary snoring (PS), moderate to severe OSA (MSO), very severe OSA (VSO), and very severe OSA patients on long-term continuous positive airway pressure treatment (VSOC). Comparisons of the microarray gene expression data identified eight genes up-regulated with OSA and down-regulated with CPAP treatment, and five genes down-regulated with OSA and up-regulated with CPAP treatment. Protein expression levels of two genes related to endothelial tight junction (AMOT P130, and PLEKHH3), and three genes related to anti-or pro-apoptosis (BIRC3, ADAR1 P150, and LGALS3) were all increased in the VSO group, while AMOT P130 was further increased, and PLEKHH3, BIRC3, and ADAR1 P150 were all decreased in the VSOC group. Subgroup analyses revealed that AMOT P130 protein expression was increased in OSA patients with excessive daytime sleepiness, BIRC3 protein expression was decreased in OSA patients with hypertension, and LGALS3 protein expression was increased in OSA patients with chronic kidney disease. In vitro short-term intermittent hypoxia with re-oxygenation experiment showed immediate over-expression of ADAR1 P150. In conclusion, we identified a novel association between AMOT/PLEKHH3/BIRC3/ADAR1/LGALS3 over-expressions and high severity index in OSA patients. AMOT and GALIG may constitute an important determinant for the development of hypersomnia and kidney injury, respectively, while BIRC3 may play a protective role in the development of hypertension.
An index-based algorithm for fast on-line query processing of latent semantic analysis
May 18, 2017   PloS One
Zhang M, Li P, Wang W
An index-based algorithm for fast on-line query processing of latent semantic analysis
May 18, 2017
PloS One
Latent Semantic Analysis (LSA) is widely used for finding the documents whose semantic is similar to the query of keywords. Although LSA yield promising similar results, the existing LSA algorithms involve lots of unnecessary operations in similarity computation and candidate check during on-line query processing, which is expensive in terms of time cost and cannot efficiently response the query request especially when the dataset becomes large. In this paper, we study the efficiency problem of on-line query processing for LSA towards efficiently searching the similar documents to a given query. We rewrite the similarity equation of LSA combined with an intermediate value called partial similarity that is stored in a designed index called partial index. For reducing the searching space, we give an approximate form of similarity equation, and then develop an efficient algorithm for building partial index, which skips the partial similarities lower than a given threshold θ. Based on partial index, we develop an efficient algorithm called ILSA for supporting fast on-line query processing. The given query is transformed into a pseudo document vector, and the similarities between query and candidate documents are computed by accumulating the partial similarities obtained from the index nodes corresponds to non-zero entries in the pseudo document vector. Compared to the LSA algorithm, ILSA reduces the time cost of on-line query processing by pruning the candidate documents that are not promising and skipping the operations that make little contribution to similarity scores. Extensive experiments through comparison with LSA have been done, which demonstrate the efficiency and effectiveness of our proposed algorithm.
On the slope of the regression between stem cell divisions and cancer risk, and the lack of correlation between stem cell divisions and environmental factors-associated cancer risk
May 18, 2017   PloS One
Tomasetti C, Vogelstein B
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
May 15, 2017   Nature Genetics Add nature.com free-link Cancel
Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA,   . . . . . .   , Mortensen PB, Børglum AD, Smith GD, Daly MJ, Robinson EB
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
May 15, 2017
Nature Genetics
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Prognostic significance of TCF21 mRNA expression in patients with lung adenocarcinoma
May 18, 2017   Scientific Reports
Xiao J, Liu A, Lu X, Chen X, Li W, He S, He B, Chen Q
Prognostic significance of TCF21 mRNA expression in patients with lung adenocarcinoma
May 18, 2017
Scientific Reports
Several prognostic indicators have shown inconsistencies in patients of different genders with lung adenocarcinoma, indicating that these variations may be due to the different genetic background of males and females with lung adenocarcinoma. In this study, we first used the Gene-Cloud of Biotechnology Information (GCBI) bioinformatics platform to identify differentially expressed genes (DEGs) that eliminated gender differences between lung adenocarcinoma and normal lung tissues. Then, we screened out that transcription factor 21 (TCF21) is a hub gene among these DEGs by creating a gene co-expression network on the GCBI platform. Furthermore, we used the comprehensive survival analysis platforms Kaplan-Meier plotter and PrognoScan to assess the prognostic value of TCF21 expression in lung adenocarcinoma patients. Finally, we concluded that decreased mRNA expression of TCF21 is a predictor for poor prognosis in patients with lung adenocarcinoma.
Chromatin states define tumour-specific T cell dysfunction and reprogramming
May 17, 2017   Nature Add nature.com free-link Cancel
Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, Scott AC, Viale A, Lauer P, Merghoub T, Hellmann MD, Wolchok JD, Leslie CS, Schietinger A
Chromatin states define tumour-specific T cell dysfunction and reprogramming
May 17, 2017
Nature
Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.
Structure of the full-length glucagon class B G-protein-coupled receptor
May 17, 2017   Nature Add nature.com free-link Cancel
Zhang H, Qiao A, Yang D, Yang L, Dai A,   . . . . . .   , Stevens RC, Zhao Q, Jiang H, Wang MW, Wu B
Structure of the full-length glucagon class B G-protein-coupled receptor
May 17, 2017
Nature
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.
Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
May 17, 2017   Nature Add nature.com free-link Cancel
Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, Tayyari F, McSkimming D, Kannan N, Tojo A, Edison AS, Ito T
Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
May 17, 2017
Nature
Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.
Tree-based approach for exploring marine spatial patterns with raster datasets
May 16, 2017   PloS One
Liao X, Xue C, Su F
Tree-based approach for exploring marine spatial patterns with raster datasets
May 16, 2017
PloS One
From multiple raster datasets to spatial association patterns, the data-mining technique is divided into three subtasks, i.e., raster dataset pretreatment, mining algorithm design, and spatial pattern exploration from the mining results. Comparison with the former two subtasks reveals that the latter remains unresolved. Confronted with the interrelated marine environmental parameters, we propose a Tree-based Approach for eXploring Marine Spatial Patterns with multiple raster datasets called TAXMarSP, which includes two models. One is the Tree-based Cascading Organization Model (TCOM), and the other is the Spatial Neighborhood-based CAlculation Model (SNCAM). TCOM designs the "Spatial node→Pattern node" from top to bottom layers to store the table-formatted frequent patterns. Together with TCOM, SNCAM considers the spatial neighborhood contributions to calculate the pattern-matching degree between the specified marine parameters and the table-formatted frequent patterns and then explores the marine spatial patterns. Using the prevalent quantification Apriori algorithm and a real remote sensing dataset from January 1998 to December 2014, a successful application of TAXMarSP to marine spatial patterns in the Pacific Ocean is described, and the obtained marine spatial patterns present not only the well-known but also new patterns to Earth scientists.
Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors
May 15, 2017   PloS One
Di Pietro O, Juárez-Jiménez J, Muñoz-Torrero D, Laughton CA, Luque FJ
Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors
May 15, 2017
PloS One
The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer's disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challenging. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments-huprine and rhein-that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8-14, 154-169 and 307-318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable "floppy" pocket would enable the binding of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligomethylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications introduced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors.
Using NextRAD sequencing to infer movement of herbivores among host plants
May 15, 2017   PloS One
Fu Z, Epstein B, Kelley JL, Zheng Q, Bergland AO, Castillo Carrillo CI, Jensen AS, Dahan J, Karasev AV, Snyder WE
Using NextRAD sequencing to infer movement of herbivores among host plants
May 15, 2017
PloS One
Herbivores often move among spatially interspersed host plants, tracking high-quality resources through space and time. This dispersal is of particular interest for vectors of plant pathogens. Existing molecular tools to track such movement have yielded important insights, but often provide insufficient genetic resolution to infer spread at finer spatiotemporal scales. Here, we explore the use of Nextera-tagmented reductively-amplified DNA (NextRAD) sequencing to infer movement of a highly-mobile winged insect, the potato psyllid (Bactericera cockerelli), among host plants. The psyllid vectors the pathogen that causes zebra chip disease in potato (Solanum tuberosum), but understanding and managing the spread of this pathogen is limited by uncertainty about the insect's host plant(s) outside of the growing season. We identified 1,978 polymorphic loci among psyllids separated spatiotemporally on potato or in patches of bittersweet nightshade (S. dulcumara), a weedy plant proposed to be the source of potato-colonizing psyllids. A subset of the psyllids on potato exhibited genetic similarity to insects on nightshade, consistent with regular movement between these two host plants. However, a second subset of potato-collected psyllids was genetically distinct from those collected on bittersweet nightshade; this suggests that a currently unrecognized source, i.e., other nightshade patches or a third host-plant species, could be contributing to psyllid populations in potato. Oftentimes, dispersal of vectors of pathogens must be tracked at a fine scale in order to understand, predict, and manage disease spread. We demonstrate that emerging sequencing technologies that detect genome-wide SNPs of a vector can be used to infer such localized movement.
Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan
May 15, 2017   PloS One
Koga T, Okada A, Fukuda T, Hidaka T, Ishii T,   . . . . . .   , Nakamura H, Aoyagi K, Eguchi K, Kawakami A, Japanese RA Patients with RRP Study Group
Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan
May 15, 2017
PloS One
To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) achieving remission or low disease activity (LDA) in clinical practice. Using data from a nationwide, multicenter, prospective study in Japan, we evaluated 198 biological disease-modifying antirheumatic drug (bDMARD)-naïve RA patients who were in remission or had LDA at study entry after being treated with conventional synthetic DMARDs (csDMARDs). CRRP was defined as the yearly progression of modified total Sharp score (mTSS) >3.0 U. We performed a multiple logistic regression analysis to explore the factors to predict CRRP at 1 year. We used receiver operating characteristic (ROC) curve to estimate the performance of relevant variables for predicting CRRP. The mean Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) was 2.32 ± 0.58 at study entry. During the 1-year observation, remission or LDA persisted in 72% of the patients. CRRP was observed in 7.6% of the patients. The multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: anti-citrullinated peptide antibodies (ACPA) positivity at baseline (OR = 15.2, 95%CI 2.64-299), time-integrated DAS28-ESR during the 1 year post-baseline (7.85-unit increase, OR = 1.83, 95%CI 1.03-3.45), and the mTSS at baseline (13-unit increase, OR = 1.22, 95%CI 1.06-1.42). ACPA positivity was the strongest independent predictor of CRRP in patients with RA in remission or LDA. Physicians should recognize ACPA as a poor-prognosis factor regarding the radiographic outcome of RA, even among patients showing a clinically favorable response to DMARDs.
Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation
May 15, 2017   Nature Cell Biology Add nature.com free-link Cancel
Liu X, Zhang Y, Ni M, Cao H, Signer RAJ,   . . . . . .   , Chandel NS, DeBerardinis RJ, Zhou F, Shao Z, Xu J
Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation
May 15, 2017
Nature Cell Biology
Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signalling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to haematologic defects associated with mitochondrial diseases and ageing.
The mitochondrial respiratory chain is essential for haematopoietic stem cell function
May 15, 2017   Nature Cell Biology Add nature.com free-link Cancel
Ansó E, Weinberg SE, Diebold LP, Thompson BJ, Malinge S, Schumacker PT, Liu X, Zhang Y, Shao Z, Steadman M, Marsh KM, Xu J, Crispino JD, Chandel NS
The mitochondrial respiratory chain is essential for haematopoietic stem cell function
May 15, 2017
Nature Cell Biology
Adult and fetal haematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron-sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anaemia and prenatal death. RISP-null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP-null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation associated with increases in 2-hydroxyglutarate (2HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence concomitant with severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.
Sex-specific metabolic profiles of androgens and its main binding protein SHBG in a middle aged population without diabetes
May 23, 2017   Scientific Reports
Piontek U, Wallaschofski H, Kastenmüller G, Suhre K, Völzke H, Do KT, Artati A, Nauck M, Adamski J, Friedrich N, Pietzner M
Sex-specific metabolic profiles of androgens and its main binding protein SHBG in a middle aged population without diabetes
May 23, 2017
Scientific Reports
The role of androgens in metabolism with respect to sex-specific disease associations is poorly understood. Therefore, we aimed to provide molecular signatures in plasma and urine of androgen action in a sex-specific manner using state-of-the-art metabolomics techniques. Our study population consisted of 430 men and 343 women, aged 20-80 years, who were recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP-TREND), Germany. We used linear regression models to identify associations between testosterone, androstenedione and dehydroepiandrosterone-sulfate (DHEAS) as well as sex hormone-binding globulin and plasma or urine metabolites measured by mass spectrometry. The analyses revealed major sex-specific differences in androgen-associated metabolites, particularly for levels of urate, lipids and metabolic surrogates of lifestyle factors, like cotinine or piperine. In women, in particular in the postmenopausal state, androgens showed a greater impact on the metabolome than in men (especially DHEAS and lipids were highly related in women). We observed a novel association of androstenedione on the metabolism of biogenic amines and only a small sex-overlap of associations within steroid metabolism. The present study yields new insights in the interaction between androgens and metabolism, especially about their implication in female metabolism.

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