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  1. Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

    Science.gov (United States)

    Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

    2016-07-01

    Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

  2. Large scale fusion of gray matter and resting-state functional MRI reveals common and shared biological markers across the psychosis spectrum in the B-SNIP cohort

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    Zheng eWang

    2015-12-01

    Full Text Available To investigate whether aberrant interactions between brain structure and function present similarly or differently across probands with psychotic illnesses (schizophrenia (SZ, schizoaffective disorder (SAD, and bipolar I disorder with psychosis (BP and whether these deficits are shared with their first-degree non-psychotic relatives. A total of 1199 subjects were assessed, including 220 SZ, 147 SAD, 180 psychotic BP, 150 first-degree relatives of SZ, 126 SAD relatives, 134 BP relatives and 242 healthy controls. All subjects underwent structural MRI (sMRI and resting-state functional MRI (rs-fMRI scanning. Joint independent analysis (jICA was used to fuse sMRI gray matter (GM and rs-fMRI amplitude of low frequency fluctuations (ALFF data to identify the relationship between the two modalities. Joint ICA revealed two significantly fused components. The association between functional brain alteration in a prefrontal-striatal-thalamic-cerebellar network and structural abnormalities in the default mode network (DMN was found to be common across psychotic diagnoses and correlated with cognitive function, social function and Schizo-Bipolar Scale (SBS scores. The fused alteration in the temporal lobe was unique to SZ and SAD. The above effects were not seen in any relative group (including those with cluster-A personality. Using a multivariate fused approach involving two widely used imaging markers we demonstrate both shared and distinct biological traits across the psychosis spectrum. Further, our results suggest that the above traits are psychosis biomarkers rather than endophenotypes.

  3. Audits reveal ten common environmental problems

    International Nuclear Information System (INIS)

    Buys, M.W.

    1992-01-01

    The old saying that open-quotes an ounce of prevention is worth a pound of cureclose quotes rings particularly true in environmental matters in the 1990s. Environmental problems can potentially lead to expensive fines, costly cleanups, negative public relations, and even criminal sanctions against members of the corporation. A recurring pattern of problems has been noted during the performance of environmental disposition, acquisition, and compliance assessments of many different operators in most of the producing states. The ten most common problems found in oilfield audits are discussed here in an effort to enhance the awareness of operators

  4. Four not six: Revealing culturally common facial expressions of emotion.

    Science.gov (United States)

    Jack, Rachael E; Sun, Wei; Delis, Ioannis; Garrod, Oliver G B; Schyns, Philippe G

    2016-06-01

    As a highly social species, humans generate complex facial expressions to communicate a diverse range of emotions. Since Darwin's work, identifying among these complex patterns which are common across cultures and which are culture-specific has remained a central question in psychology, anthropology, philosophy, and more recently machine vision and social robotics. Classic approaches to addressing this question typically tested the cross-cultural recognition of theoretically motivated facial expressions representing 6 emotions, and reported universality. Yet, variable recognition accuracy across cultures suggests a narrower cross-cultural communication supported by sets of simpler expressive patterns embedded in more complex facial expressions. We explore this hypothesis by modeling the facial expressions of over 60 emotions across 2 cultures, and segregating out the latent expressive patterns. Using a multidisciplinary approach, we first map the conceptual organization of a broad spectrum of emotion words by building semantic networks in 2 cultures. For each emotion word in each culture, we then model and validate its corresponding dynamic facial expression, producing over 60 culturally valid facial expression models. We then apply to the pooled models a multivariate data reduction technique, revealing 4 latent and culturally common facial expression patterns that each communicates specific combinations of valence, arousal, and dominance. We then reveal the face movements that accentuate each latent expressive pattern to create complex facial expressions. Our data questions the widely held view that 6 facial expression patterns are universal, instead suggesting 4 latent expressive patterns with direct implications for emotion communication, social psychology, cognitive neuroscience, and social robotics. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  5. Exploring Function Transformations Using the Common Core

    Science.gov (United States)

    Hall, Becky; Giacin, Rich

    2013-01-01

    When examining transformations of the plane in geometry, teachers typically have students experiment with transformations of polygons. Students are usually quick to notice patterns with ordered pairs. The Common Core State Standard, Geometry, Congruence 2 (G-CO.2), requires students to describe transformations as functions that take points in the…

  6. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism.

    Science.gov (United States)

    Schuijers, Jurian; Manteiga, John Colonnese; Weintraub, Abraham Selby; Day, Daniel Sindt; Zamudio, Alicia Viridiana; Hnisz, Denes; Lee, Tong Ihn; Young, Richard Allen

    2018-04-10

    Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism

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    Jurian Schuijers

    2018-04-01

    Full Text Available Summary: Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. : Schuijers et al. show that a conserved CTCF site at the promoter of the MYC oncogene plays an important role in enhancer-promoter looping with tumor-specific super-enhancers. Perturbation of this site provides a potential therapeutic vulnerability. Keywords: gene regulation, super-enhancers, chromosome structure, enhancer docking

  8. Transcriptome profiling in engrailed-2 mutant mice reveals common molecular pathways associated with autism spectrum disorders.

    Science.gov (United States)

    Sgadò, Paola; Provenzano, Giovanni; Dassi, Erik; Adami, Valentina; Zunino, Giulia; Genovesi, Sacha; Casarosa, Simona; Bozzi, Yuri

    2013-12-19

    Transcriptome analysis has been used in autism spectrum disorder (ASD) to unravel common pathogenic pathways based on the assumption that distinct rare genetic variants or epigenetic modifications affect common biological pathways. To unravel recurrent ASD-related neuropathological mechanisms, we took advantage of the En2-/- mouse model and performed transcriptome profiling on cerebellar and hippocampal adult tissues. Cerebellar and hippocampal tissue samples from three En2-/- and wild type (WT) littermate mice were assessed for differential gene expression using microarray hybridization followed by RankProd analysis. To identify functional categories overrepresented in the differentially expressed genes, we used integrated gene-network analysis, gene ontology enrichment and mouse phenotype ontology analysis. Furthermore, we performed direct enrichment analysis of ASD-associated genes from the SFARI repository in our differentially expressed genes. Given the limited number of animals used in the study, we used permissive criteria and identified 842 differentially expressed genes in En2-/- cerebellum and 862 in the En2-/- hippocampus. Our functional analysis revealed that the molecular signature of En2-/- cerebellum and hippocampus shares convergent pathological pathways with ASD, including abnormal synaptic transmission, altered developmental processes and increased immune response. Furthermore, when directly compared to the repository of the SFARI database, our differentially expressed genes in the hippocampus showed enrichment of ASD-associated genes significantly higher than previously reported. qPCR was performed for representative genes to confirm relative transcript levels compared to those detected in microarrays. Despite the limited number of animals used in the study, our bioinformatic analysis indicates the En2-/- mouse is a valuable tool for investigating molecular alterations related to ASD.

  9. Identifying and annotating human bifunctional RNAs reveals their versatile functions.

    Science.gov (United States)

    Chen, Geng; Yang, Juan; Chen, Jiwei; Song, Yunjie; Cao, Ruifang; Shi, Tieliu; Shi, Leming

    2016-10-01

    Bifunctional RNAs that possess both protein-coding and noncoding functional properties were less explored and poorly understood. Here we systematically explored the characteristics and functions of such human bifunctional RNAs by integrating tandem mass spectrometry and RNA-seq data. We first constructed a pipeline to identify and annotate bifunctional RNAs, leading to the characterization of 132 high-confidence bifunctional RNAs. Our analyses indicate that bifunctional RNAs may be involved in human embryonic development and can be functional in diverse tissues. Moreover, bifunctional RNAs could interact with multiple miRNAs and RNA-binding proteins to exert their corresponding roles. Bifunctional RNAs may also function as competing endogenous RNAs to regulate the expression of many genes by competing for common targeting miRNAs. Finally, somatic mutations of diverse carcinomas may generate harmful effect on corresponding bifunctional RNAs. Collectively, our study not only provides the pipeline for identifying and annotating bifunctional RNAs but also reveals their important gene-regulatory functions.

  10. Common brain regions underlying different arithmetic operations as revealed by conjunct fMRI-BOLD activation.

    Science.gov (United States)

    Fehr, Thorsten; Code, Chris; Herrmann, Manfred

    2007-10-03

    The issue of how and where arithmetic operations are represented in the brain has been addressed in numerous studies. Lesion studies suggest that a network of different brain areas are involved in mental calculation. Neuroimaging studies have reported inferior parietal and lateral frontal activations during mental arithmetic using tasks of different complexities and using different operators (addition, subtraction, etc.). Indeed, it has been difficult to compare brain activation across studies because of the variety of different operators and different presentation modalities used. The present experiment examined fMRI-BOLD activity in participants during calculation tasks entailing different arithmetic operations -- addition, subtraction, multiplication and division -- of different complexities. Functional imaging data revealed a common activation pattern comprising right precuneus, left and right middle and superior frontal regions during all arithmetic operations. All other regional activations were operation specific and distributed in prominently frontal, parietal and central regions when contrasting complex and simple calculation tasks. The present results largely confirm former studies suggesting that activation patterns due to mental arithmetic appear to reflect a basic anatomical substrate of working memory, numerical knowledge and processing based on finger counting, and derived from a network originally related to finger movement. We emphasize that in mental arithmetic research different arithmetic operations should always be examined and discussed independently of each other in order to avoid invalid generalizations on arithmetics and involved brain areas.

  11. Comparative mapping reveals similar linkage of functional genes to ...

    Indian Academy of Sciences (India)

    genes between O. sativa and B. napus may have consistent function and control similar traits, which may be ..... acea chromosomes reveals islands of conserved organization. ... 1998 Conserved structure and function of the Arabidopsis flow-.

  12. Population structure analysis using rare and common functional variants

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    Ding Lili

    2011-11-01

    Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

  13. Transcriptome analysis reveals the time of the fourth round of genome duplication in common carp (Cyprinus carpio)

    Science.gov (United States)

    2012-01-01

    Background Common carp (Cyprinus carpio) is thought to have undergone one extra round of genome duplication compared to zebrafish. Transcriptome analysis has been used to study the existence and timing of genome duplication in species for which genome sequences are incomplete. Large-scale transcriptome data for the common carp genome should help reveal the timing of the additional duplication event. Results We have sequenced the transcriptome of common carp using 454 pyrosequencing. After assembling the 454 contigs and the published common carp sequences together, we obtained 49,669 contigs and identified genes using homology searches and an ab initio method. We identified 4,651 orthologous pairs between common carp and zebrafish and found 129,984 paralogous pairs within the common carp. An estimation of the synonymous substitution rate in the orthologous pairs indicated that common carp and zebrafish diverged 120 million years ago (MYA). We identified one round of genome duplication in common carp and estimated that it had occurred 5.6 to 11.3 MYA. In zebrafish, no genome duplication event after speciation was observed, suggesting that, compared to zebrafish, common carp had undergone an additional genome duplication event. We annotated the common carp contigs with Gene Ontology terms and KEGG pathways. Compared with zebrafish gene annotations, we found that a set of biological processes and pathways were enriched in common carp. Conclusions The assembled contigs helped us to estimate the time of the fourth-round of genome duplication in common carp. The resource that we have built as part of this study will help advance functional genomics and genome annotation studies in the future. PMID:22424280

  14. Burden of common mental disorders in patients with Functional Dyspepsia

    International Nuclear Information System (INIS)

    Sattar, A.; Salih, M.; Jafri, W.

    2010-01-01

    Objective: To assess the frequency of common mental disorders among diagnosed functional dyspepsia patients. Methods: A case-control study with 150 cases of functional dyspepsia (FD) and 150 healthy controls were recruited from Gastroenterology Clinic at the Aga Khan University Hospital Karachi from 1, March 2009 through 31, August 2009. Urdu version of WHO-developed Self-Reporting Questionnaire (SRQ) was administered to diagnose patients of FD and healthy controls. A cut off score of 8 on SRQ was used to confirm cases of Common mental disorders (CMD). Data was entered and analyzed by SPSS version 16.0. Result: There was significant difference in CMD i.e. 107 (71.33%) versus 23 (15.33%) in cases and controls respectively (p- <0.001). Among cases CMD was more common in females i.e. in 57 (80.3%) as compared 50 (63.3%) in males (p- 0.022). Conclusion: There is high prevalence of Common mental disorders among patients with functional dyspepsia and this needs to be addressed while treating patients. (author)

  15. Comparative transcriptome analysis reveals the genetic basis of skin color variation in common carp.

    Directory of Open Access Journals (Sweden)

    Yanliang Jiang

    Full Text Available The common carp is an important aquaculture species that is widely distributed across the world. During the long history of carp domestication, numerous carp strains with diverse skin colors have been established. Skin color is used as a visual criterion to determine the market value of carp. However, the genetic basis of common carp skin color has not been extensively studied.In this study, we performed Illumina sequencing on two common carp strains: the reddish Xingguo red carp and the brownish-black Yellow River carp. A total of 435,348,868 reads were generated, resulting in 198,781 assembled contigs that were used as reference sequences. Comparisons of skin transcriptome files revealed 2,012 unigenes with significantly different expression in the two common carp strains, including 874 genes that were up-regulated in Xingguo red carp and 1,138 genes that were up-regulated in Yellow River carp. The expression patterns of 20 randomly selected differentially expressed genes were validated using quantitative RT-PCR. Gene pathway analysis of the differentially expressed genes indicated that melanin biosynthesis, along with the Wnt and MAPK signaling pathways, is highly likely to affect the skin pigmentation process. Several key genes involved in the skin pigmentation process, including TYRP1, SILV, ASIP and xCT, showed significant differences in their expression patterns between the two strains.In this study, we conducted a comparative transcriptome analysis of Xingguo red carp and Yellow River carp skins, and we detected key genes involved in the common carp skin pigmentation process. We propose that common carp skin pigmentation depends upon at least three pathways. Understanding fish skin color genetics will facilitate future molecular selection of the fish skin colors with high market values.

  16. Comparative transcriptome analysis reveals the genetic basis of skin color variation in common carp.

    Science.gov (United States)

    Jiang, Yanliang; Zhang, Songhao; Xu, Jian; Feng, Jianxin; Mahboob, Shahid; Al-Ghanim, Khalid A; Sun, Xiaowen; Xu, Peng

    2014-01-01

    The common carp is an important aquaculture species that is widely distributed across the world. During the long history of carp domestication, numerous carp strains with diverse skin colors have been established. Skin color is used as a visual criterion to determine the market value of carp. However, the genetic basis of common carp skin color has not been extensively studied. In this study, we performed Illumina sequencing on two common carp strains: the reddish Xingguo red carp and the brownish-black Yellow River carp. A total of 435,348,868 reads were generated, resulting in 198,781 assembled contigs that were used as reference sequences. Comparisons of skin transcriptome files revealed 2,012 unigenes with significantly different expression in the two common carp strains, including 874 genes that were up-regulated in Xingguo red carp and 1,138 genes that were up-regulated in Yellow River carp. The expression patterns of 20 randomly selected differentially expressed genes were validated using quantitative RT-PCR. Gene pathway analysis of the differentially expressed genes indicated that melanin biosynthesis, along with the Wnt and MAPK signaling pathways, is highly likely to affect the skin pigmentation process. Several key genes involved in the skin pigmentation process, including TYRP1, SILV, ASIP and xCT, showed significant differences in their expression patterns between the two strains. In this study, we conducted a comparative transcriptome analysis of Xingguo red carp and Yellow River carp skins, and we detected key genes involved in the common carp skin pigmentation process. We propose that common carp skin pigmentation depends upon at least three pathways. Understanding fish skin color genetics will facilitate future molecular selection of the fish skin colors with high market values.

  17. A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases.

    Science.gov (United States)

    Ruiz, Patricia; Perlina, Ally; Mumtaz, Moiz; Fowler, Bruce A

    2016-07-01

    A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published. We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases. For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes. Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies. Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ

  18. Commonly Used Dietary Supplements on Coagulation Function during Surgery

    Directory of Open Access Journals (Sweden)

    Chong-Zhi Wang

    2015-07-01

    Full Text Available Background: Patients who undergo surgery appear to use dietary supplements significantly more frequently than the general population. Because they contain pharmacologically active compounds, dietary supplements may affect coagulation and platelet function during the perioperative period through direct effects, pharmacodynamic interactions, and pharmacokinetic interactions. However, in this regard, limited studies have been conducted that address the pharmacological interactions of dietary supplements. To avoid possible bleeding risks during surgery, information about the potential complications of dietary supplements during perioperative management is important for physicians. Methods: Through a systematic database search of all available years, articles were identified in this review if they included dietary supplements and coagulation/platelet function, while special attention was paid to studies published after 1990. Results: Safety concerns are reported in commercially available dietary supplements. Effects of the most commonly used natural products on blood coagulation and platelet function are systematically reviewed, including 11 herbal medicines (echinacea, ephedra, garlic, ginger, ginkgo, ginseng, green tea, kava, saw palmetto, St John’s wort, and valerian and four other dietary supplements (coenzyme Q10, glucosamine and chondroitin sulfate, fish oil, and vitamins. Bleeding risks of garlic, ginkgo, ginseng, green tea, saw palmetto, St John’s wort, and fish oil are reported. Cardiovascular instability was observed with ephedra, ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary supplements and drugs used in the perioperative period are discussed. Conclusions: To prevent potential problems associated with the use of dietary supplements, physicians should be familiar with the perioperative effects of commonly used dietary supplements. Since the effects of dietary supplements on coagulation and platelet

  19. Commonly Used Dietary Supplements on Coagulation Function during Surgery

    Science.gov (United States)

    Wang, Chong-Zhi; Moss, Jonathan; Yuan, Chun-Su

    2015-01-01

    Abstract Background Patients who undergo surgery appear to use dietary supplements significantly more frequently than the general population. Because they contain pharmacologically active compounds, dietary supplements may affect coagulation and platelet function during the perioperative period through direct effects, pharmacodynamic interactions, and pharmacokinetic interactions. However, in this regard, limited studies have been conducted that address the pharmacological interactions of dietary supplements. To avoid possible bleeding risks during surgery, information about the potential complications of dietary supplements during perioperative management is important for physicians. Methods Through a systematic database search of all available years, articles were identified in this review if they included dietary supplements and coagulation/platelet function, while special attention was paid to studies published after 1990. Results Safety concerns are reported in commercially available dietary supplements. Effects of the most commonly used natural products on blood coagulation and platelet function are systematically reviewed, including 11 herbal medicines (echinacea, ephedra, garlic, ginger, ginkgo, ginseng, green tea, kava, saw palmetto, St John’s wort, and valerian) and four other dietary supplements (coenzyme Q10, glucosamine and chondroitin sulfate, fish oil, and vitamins). Bleeding risks of garlic, ginkgo, ginseng, green tea, saw palmetto, St John’s wort, and fish oil are reported. Cardiovascular instability was observed with ephedra, ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary supplements and drugs used in the perioperative period are discussed. Conclusions To prevent potential problems associated with the use of dietary supplements, physicians should be familiar with the perioperative effects of commonly used dietary supplements. Since the effects of dietary supplements on coagulation and platelet function are

  20. Commonly Used Dietary Supplements on Coagulation Function during Surgery.

    Science.gov (United States)

    Wang, Chong-Zhi; Moss, Jonathan; Yuan, Chun-Su

    2015-09-01

    Patients who undergo surgery appear to use dietary supplements significantly more frequently than the general population. Because they contain pharmacologically active compounds, dietary supplements may affect coagulation and platelet function during the perioperative period through direct effects, pharmacodynamic interactions, and pharmacokinetic interactions. However, in this regard, limited studies have been conducted that address the pharmacological interactions of dietary supplements. To avoid possible bleeding risks during surgery, information of potential complications of dietary supplements during perioperative management is important for physicians. Through a systematic database search of all available years, articles were identified in this review if they included dietary supplements and coagulation/platelet function, while special attention was paid to studies published after 1990. Safety concerns are reported in commercially available dietary supplements. Effects of the most commonly used natural products on blood coagulation and platelet function are systematically reviewed, including 11 herbal medicines (echinacea, ephedra, garlic, ginger, ginkgo, ginseng, green tea, kava, saw palmetto, St John's wort, and valerian) and 4 other dietary supplements (coenzyme Q 10 , glucosamine and chondroitin sulfate, fish oil, and vitamins). Bleeding risks of garlic, ginkgo, ginseng, green tea, saw palmetto, St John's wort, and fish oil are reported. Cardiovascular instability was observed with ephedra, ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary supplements and drugs used in the perioperative period are discussed. To prevent potential problems associated with the use of dietary supplements, physicians should be familiar with the perioperative effects of commonly used dietary supplements. Since the effects of dietary supplements on coagulation and platelet function are difficult to predict, it is prudent to advise their

  1. Common Functional Gastroenterologic Disorders Associated With Abdominal Pain

    Science.gov (United States)

    Bharucha, Adil E.; Chakraborty, Subhankar; Sletten, Christopher D.

    2016-01-01

    Although abdominal pain is a symptom of several structural gastrointestinal disorders (eg, peptic ulcer disease), this comprehensive review will focus on the 4 most common nonstructural, or functional, disorders associated with abdominal pain: functional dyspepsia, constipation-predominant and diarrhea-predominant irritable bowel syndrome, and functional abdominal pain syndrome. Together, these conditions affect approximately 1 in 4 people in the United States. They are associated with comorbid conditions (eg, fibromyalgia, depression), impaired quality of life, and increased health care utilization. Symptoms are explained by disordered gastrointestinal motility and sensation, which are implicated in a variety of peripheral (eg, postinfectious inflammation, luminal irritants) and/or central (eg, stress and anxiety) factors. These disorders are defined and can generally be diagnosed by symptoms alone. Often prompted by alarm features, selected testing is useful to exclude structural disease. Identifying the specific diagnosis (eg, differentiating between functional abdominal pain and irritable bowel syndrome) and establishing an effective patient-physician relationship are the cornerstones of therapy. Many patients with mild symptoms can be effectively managed with limited tests, sensible dietary modifications, and over-the-counter medications tailored to symptoms. If these measures are not sufficient, pharmacotherapy should be considered for bowel symptoms (constipation or diarrhea) and/or abdominal pain; opioids should not be used. Behavioral and psychological approaches (eg, cognitive behavioral therapy) can be very helpful, particularly in patients with chronic abdominal pain who require a multidisciplinary pain management program without opioids. PMID:27492916

  2. Herbarium specimens reveal a historical shift in phylogeographic structure of common ragweed during native range disturbance.

    Science.gov (United States)

    Martin, Michael D; Zimmer, Elizabeth A; Olsen, Morten T; Foote, Andrew D; Gilbert, M Thomas P; Brush, Grace S

    2014-04-01

    Invasive plants provide ample opportunity to study evolutionary shifts that occur after introduction to novel environments. However, although genetic characters pre-dating introduction can be important determinants of later success, large-scale investigations of historical genetic structure have not been feasible. Common ragweed (Ambrosia artemisiifolia L.) is an invasive weed native to North America that is known for its allergenic pollen. Palynological records from sediment cores indicate that this species was uncommon before European colonization of North America, and ragweed populations expanded rapidly as settlers deforested the landscape on a massive scale, later becoming an aggressive invasive with populations established globally. Towards a direct comparison of genetic structure now and during intense anthropogenic disturbance of the late 19th century, we sampled 45 natural populations of common ragweed across its native range as well as historical herbarium specimens collected up to 140 years ago. Bayesian clustering analyses of 453 modern and 473 historical samples genotyped at three chloroplast spacer regions and six nuclear microsatellite loci reveal that historical ragweed's spatial genetic structure mirrors both the palaeo-record of Ambrosia pollen deposition and the historical pattern of agricultural density across the landscape. Furthermore, for unknown reasons, this spatial genetic pattern has changed substantially in the intervening years. Following on previous work relating morphology and genetic expression between plants collected from eastern North America and Western Europe, we speculate that the cluster associated with humans' rapid transformation of the landscape is a likely source of these aggressive invasive populations. © 2014 John Wiley & Sons Ltd.

  3. Neuter is not common in Dutch: eye movements reveal asymmetrical gender processing.

    Science.gov (United States)

    Loerts, Hanneke; Wieling, Martijn; Schmid, Monika S

    2013-12-01

    Native speakers of languages with transparent gender systems can use gender cues to anticipate upcoming words. To examine whether this also holds true for a non-transparent two-way gender system, i.e. Dutch, eye movements were monitored as participants followed spoken instructions to click on one of four displayed items on a screen (e.g., Klik op [Formula: see text] rode appel [Formula: see text], 'Click on the[Formula: see text] red apple[Formula: see text]'). The items contained the target, a colour- and/or gender-matching competitor, and two unrelated distractors. A mixed-effects regression analysis revealed that the presence of a colour-matching and/or gender-matching competitor significantly slowed the process of finding the target. The gender effect, however, was only observed for common nouns, reflecting the fact that neuter gender-marking cannot disambiguate as all Dutch nouns become neuter when used as diminutives. The gender effect for common nouns occurred before noun onset, suggesting that gender information is, at least partially, activated automatically before encountering the noun.

  4. Common Functional Gastroenterological Disorders Associated With Abdominal Pain.

    Science.gov (United States)

    Bharucha, Adil E; Chakraborty, Subhankar; Sletten, Christopher D

    2016-08-01

    Although abdominal pain is a symptom of several structural gastrointestinal disorders (eg, peptic ulcer disease), this comprehensive review will focus on the 4 most common nonstructural, or functional, disorders associated with abdominal pain: functional dyspepsia, constipation-predominant and diarrhea-predominant irritable bowel syndrome, and functional abdominal pain syndrome. Together, these conditions affect approximately 1 in 4 people in the United States. They are associated with comorbid conditions (eg, fibromyalgia and depression), impaired quality of life, and increased health care utilization. Symptoms are explained by disordered gastrointestinal motility and sensation, which are implicated in various peripheral (eg, postinfectious inflammation and luminal irritants) and/or central (eg, stress and anxiety) factors. These disorders are defined and can generally be diagnosed by symptoms alone. Often prompted by alarm features, selected testing is useful to exclude structural disease. Identifying the specific diagnosis (eg, differentiating between functional abdominal pain and irritable bowel syndrome) and establishing an effective patient-physician relationship are the cornerstones of therapy. Many patients with mild symptoms can be effectively managed with limited tests, sensible dietary modifications, and over-the-counter medications tailored to symptoms. If these measures are not sufficient, pharmacotherapy should be considered for bowel symptoms (constipation or diarrhea) and/or abdominal pain; opioids should not be used. Behavioral and psychological approaches (eg, cognitive behavioral therapy) can be helpful, particularly in patients with chronic abdominal pain who require a multidisciplinary pain management program without opioids. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  5. Joint Service Common Operating Environment (COE) Common Geographic Information System functional requirements

    Energy Technology Data Exchange (ETDEWEB)

    Meitzler, W.D.

    1992-06-01

    In the context of this document and COE, the Geographic Information Systems (GIS) are decision support systems involving the integration of spatially referenced data in a problem solving environment. They are digital computer systems for capturing, processing, managing, displaying, modeling, and analyzing geographically referenced spatial data which are described by attribute data and location. The ability to perform spatial analysis and the ability to combine two or more data sets to create new spatial information differentiates a GIS from other computer mapping systems. While the CCGIS allows for data editing and input, its primary purpose is not to prepare data, but rather to manipulate, analyte, and clarify it. The CCGIS defined herein provides GIS services and resources including the spatial and map related functionality common to all subsystems contained within the COE suite of C4I systems. The CCGIS, which is an integral component of the COE concept, relies on the other COE standard components to provide the definition for other support computing services required.

  6. Confirmatory factor analysis reveals a latent cognitive structure common to bipolar disorder, schizophrenia, and normal controls.

    Science.gov (United States)

    Schretlen, David J; Peña, Javier; Aretouli, Eleni; Orue, Izaskun; Cascella, Nicola G; Pearlson, Godfrey D; Ojeda, Natalia

    2013-06-01

    We sought to determine whether a single hypothesized latent factor structure would characterize cognitive functioning in three distinct groups. We assessed 576 adults (340 community controls, 126 adults with bipolar disorder, and 110 adults with schizophrenia) using 15 measures derived from nine cognitive tests. Confirmatory factor analysis (CFA) was conducted to examine the fit of a hypothesized six-factor model. The hypothesized factors included attention, psychomotor speed, verbal memory, visual memory, ideational fluency, and executive functioning. The six-factor model provided an excellent fit for all three groups [for community controls, root mean square error of approximation (RMSEA) schizophrenia, RMSEA = 0.06 and CFI = 0.98]. Alternate models that combined fluency with processing speed or verbal and visual memory reduced the goodness of fit. Multi-group CFA results supported factor invariance across the three groups. Confirmatory factor analysis supported a single six-factor structure of cognitive functioning among patients with schizophrenia or bipolar disorder and community controls. While the three groups clearly differ in level of performance, they share a common underlying architecture of information processing abilities. These cognitive factors could provide useful targets for clinical trials of treatments that aim to enhance information processing in persons with neurological and neuropsychiatric disorders. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations?

    Directory of Open Access Journals (Sweden)

    Yan-Feng Zhang

    2017-10-01

    Full Text Available Striatal cholinergic interneurons, the so-called tonically active neurons (TANs, pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses.

  8. Comparative analyses reveal discrepancies among results of commonly used methods for Anopheles gambiaemolecular form identification

    Directory of Open Access Journals (Sweden)

    Pinto João

    2011-08-01

    Full Text Available Abstract Background Anopheles gambiae M and S molecular forms, the major malaria vectors in the Afro-tropical region, are ongoing a process of ecological diversification and adaptive lineage splitting, which is affecting malaria transmission and vector control strategies in West Africa. These two incipient species are defined on the basis of single nucleotide differences in the IGS and ITS regions of multicopy rDNA located on the X-chromosome. A number of PCR and PCR-RFLP approaches based on form-specific SNPs in the IGS region are used for M and S identification. Moreover, a PCR-method to detect the M-specific insertion of a short interspersed transposable element (SINE200 has recently been introduced as an alternative identification approach. However, a large-scale comparative analysis of four widely used PCR or PCR-RFLP genotyping methods for M and S identification was never carried out to evaluate whether they could be used interchangeably, as commonly assumed. Results The genotyping of more than 400 A. gambiae specimens from nine African countries, and the sequencing of the IGS-amplicon of 115 of them, highlighted discrepancies among results obtained by the different approaches due to different kinds of biases, which may result in an overestimation of MS putative hybrids, as follows: i incorrect match of M and S specific primers used in the allele specific-PCR approach; ii presence of polymorphisms in the recognition sequence of restriction enzymes used in the PCR-RFLP approaches; iii incomplete cleavage during the restriction reactions; iv presence of different copy numbers of M and S-specific IGS-arrays in single individuals in areas of secondary contact between the two forms. Conclusions The results reveal that the PCR and PCR-RFLP approaches most commonly utilized to identify A. gambiae M and S forms are not fully interchangeable as usually assumed, and highlight limits of the actual definition of the two molecular forms, which might

  9. Metabolite analysis of Mycobacterium species under aerobic and hypoxic conditions reveals common metabolic traits.

    Science.gov (United States)

    Drapal, Margit; Wheeler, Paul R; Fraser, Paul D

    2016-08-01

    A metabolite profiling approach has been implemented to elucidate metabolic adaptation at set culture conditions in five Mycobacterium species (two fast- and three slow-growing) with the potential to act as model organisms for Mycobacterium tuberculosis (Mtb). Analysis has been performed over designated growth phases and under representative environments (nutrient and oxygen depletion) experienced by Mtb during infection. The procedure was useful in determining a range of metabolites (60-120 compounds) covering nucleotides, amino acids, organic acids, saccharides, fatty acids, glycerols, -esters, -phosphates and isoprenoids. Among these classes of compounds, key biomarker metabolites, which can act as indicators of pathway/process activity, were identified. In numerous cases, common metabolite traits were observed for all five species across the experimental conditions (e.g. uracil indicating DNA repair). Amino acid content, especially glutamic acid, highlighted the different properties between the fast- and slow-growing mycobacteria studied (e.g. nitrogen assimilation). The greatest similarities in metabolite composition between fast- and slow-growing mycobacteria were apparent under hypoxic conditions. A comparison to previously reported transcriptomic data revealed a strong correlation between changes in transcription and metabolite content. Collectively, these data validate the changes in the transcription at the metabolite level, suggesting transcription exists as one of the predominant modes of cellular regulation in Mycobacterium. Sectors with restricted correlation between metabolites and transcription (e.g. hypoxic cultivation) warrant further study to elucidate and exploit post-transcriptional modes of regulation. The strong correlation between the laboratory conditions used and data derived from in vivo conditions, indicate that the approach applied is a valuable addition to our understanding of cell regulation in these Mycobacterium species.

  10. Seahorse Brood Pouch Transcriptome Reveals Common Genes Associated with Vertebrate Pregnancy.

    Science.gov (United States)

    Whittington, Camilla M; Griffith, Oliver W; Qi, Weihong; Thompson, Michael B; Wilson, Anthony B

    2015-12-01

    Viviparity (live birth) has evolved more than 150 times in vertebrates, and represents an excellent model system for studying the evolution of complex traits. There are at least 23 independent origins of viviparity in fishes, with syngnathid fishes (seahorses and pipefish) unique in exhibiting male pregnancy. Male seahorses and pipefish have evolved specialized brooding pouches that provide protection, gas exchange, osmoregulation, and limited nutrient provisioning to developing embryos. Pouch structures differ widely across the Syngnathidae, offering an ideal opportunity to study the evolution of reproductive complexity. However, the physiological and genetic changes facilitating male pregnancy are largely unknown. We used transcriptome profiling to examine pouch gene expression at successive gestational stages in a syngnathid with the most complex brood pouch morphology, the seahorse Hippocampus abdominalis. Using a unique time-calibrated RNA-seq data set including brood pouch at key stages of embryonic development, we identified transcriptional changes associated with brood pouch remodeling, nutrient and waste transport, gas exchange, osmoregulation, and immunological protection of developing embryos at conception, development and parturition. Key seahorse transcripts share homology with genes of reproductive function in pregnant mammals, reptiles, and other live-bearing fish, suggesting a common toolkit of genes regulating pregnancy in divergent evolutionary lineages. © The Author 2015. 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.

  11. Memory functions reveal structural properties of gene regulatory networks

    Science.gov (United States)

    Perez-Carrasco, Ruben

    2018-01-01

    Gene regulatory networks (GRNs) control cellular function and decision making during tissue development and homeostasis. Mathematical tools based on dynamical systems theory are often used to model these networks, but the size and complexity of these models mean that their behaviour is not always intuitive and the underlying mechanisms can be difficult to decipher. For this reason, methods that simplify and aid exploration of complex networks are necessary. To this end we develop a broadly applicable form of the Zwanzig-Mori projection. By first converting a thermodynamic state ensemble model of gene regulation into mass action reactions we derive a general method that produces a set of time evolution equations for a subset of components of a network. The influence of the rest of the network, the bulk, is captured by memory functions that describe how the subnetwork reacts to its own past state via components in the bulk. These memory functions provide probes of near-steady state dynamics, revealing information not easily accessible otherwise. We illustrate the method on a simple cross-repressive transcriptional motif to show that memory functions not only simplify the analysis of the subnetwork but also have a natural interpretation. We then apply the approach to a GRN from the vertebrate neural tube, a well characterised developmental transcriptional network composed of four interacting transcription factors. The memory functions reveal the function of specific links within the neural tube network and identify features of the regulatory structure that specifically increase the robustness of the network to initial conditions. Taken together, the study provides evidence that Zwanzig-Mori projections offer powerful and effective tools for simplifying and exploring the behaviour of GRNs. PMID:29470492

  12. The science commons in health research: structure, function, and value.

    Science.gov (United States)

    Cook-Deegan, Robert

    The "science commons," knowledge that is widely accessible at low or no cost, is a uniquely important input to scientific advance and cumulative technological innovation. It is primarily, although not exclusively, funded by government and nonprofit sources. Much of it is produced at academic research centers, although some academic science is proprietary and some privately funded R&D enters the science commons. Science in general aspires to Mertonian norms of openness, universality, objectivity, and critical inquiry. The science commons diverges from proprietary science primarily in being open and being very broadly available. These features make the science commons particularly valuable for advancing knowledge, for training innovators who will ultimately work in both public and private sectors, and in providing a common stock of knowledge upon which all players-both public and private-can draw readily. Open science plays two important roles that proprietary R&D cannot: it enables practical benefits even in the absence of profitable markets for goods and services, and its lays a shared foundation for subsequent private R&D. The history of genomics in the period 1992-2004, covering two periods when genomic startup firms attracted significant private R&D investment, illustrates these features of how a science commons contributes value. Commercial interest in genomics was intense during this period. Fierce competition between private sector and public sector genomics programs was highly visible. Seemingly anomalous behavior, such as private firms funding "open science," can be explained by unusual business dynamics between established firms wanting to preserve a robust science commons to prevent startup firms from limiting established firms' freedom to operate. Deliberate policies to create and protect a large science commons were pursued by nonprofit and government funders of genomics research, such as the Wellcome Trust and National Institutes of Health. These

  13. Differential proteomics reveals the hallmarks of seed development in common bean (Phaseolus vulgaris L.)

    NARCIS (Netherlands)

    Parreira, J R; Bouraada, J; Fitzpatrick, M A; Silvestre, S; Bernardes da Silva, A; Marques da Silva, J; Almeida, A M; Fevereiro, P; Altelaar, A F M; Araújo, S S

    2016-01-01

    Common bean (Phaseolus vulgaris L.) is one of the most consumed staple foods worldwide. Little is known about the molecular mechanisms controlling seed development. This study aims to comprehensively describe proteome dynamics during seed development of common bean. A high-throughput gel-free

  14. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

    NARCIS (Netherlands)

    Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan; Johnson, Toby; Shen, Haiqing; Nelson, Christopher P.; Klopp, Norman; Baumert, Jens; Padmanabhan, Sandosh; Pankratz, Nathan; Pankow, James S.; Shah, Sonia; Taylor, Kira; Barnard, John; Peters, Bas J.; Maloney, Cliona M.; Lobmeyer, Maximilian T.; Stanton, Alice; Zafarmand, M. Hadi; Romaine, Simon P. R.; Mehta, Amar; van Iperen, Erik P. A.; Gong, Yan; Price, Tom S.; Smith, Erin N.; Kim, Cecilia E.; Li, Yun R.; Asselbergs, Folkert W.; Atwood, Larry D.; Bailey, Kristian M.; Bhatt, Deepak; Bauer, Florianne; Behr, Elijah R.; Bhangale, Tushar; Boer, Jolanda M. A.; Boehm, Bernhard O.; Bradfield, Jonathan P.; Brown, Morris; Braund, Peter S.; Burton, Paul R.; Carty, Cara; Chandrupatla, Hareesh R.; Chen, Wei; Connell, John; Dalgeorgou, Chrysoula; de Boer, Anthonius; Drenos, Fotios; Elbers, Clara C.; Fang, James C.; Fox, Caroline S.; Frackelton, Edward C.; Fuchs, Barry; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Goel, Anuj; Grobbee, Diederik E.; Hastie, Claire; Howard, Philip J.; Huang, Guan-Hua; Johnson, W. Craig; Li, Qing; Kleber, Marcus E.; Klein, Barbara E. K.; Klein, Ronald; Kooperberg, Charles; Ky, Bonnie; LaCroix, Andrea; Lanken, Paul; Lathrop, Mark; Li, Mingyao; Marshall, Vanessa; Melander, Olle; Mentch, Frank D.; Meyer, Nuala J.; Monda, Keri L.; Montpetit, Alexandre; Murugesan, Gurunathan; Nakayama, Karen; Nondahl, Dave; Onipinla, Abiodun; Rafelt, Suzanne; Newhouse, Stephen J.; Otieno, F. George; Patel, Sanjey R.; Putt, Mary E.; Rodriguez, Santiago; Safa, Radwan N.; Sawyer, Douglas B.; Schreiner, Pamela J.; Simpson, Claire; Sivapalaratnam, Suthesh; Srinivasan, Sathanur R.; Suver, Christine; Swergold, Gary; Sweitzer, Nancy K.; Thomas, Kelly A.; Thorand, Barbara; Timpson, Nicholas J.; Tischfield, Sam; Tobin, Martin; Tomaszewski, Maciej; Tomaszweski, Maciej; Verschuren, W. M. Monique; Wallace, Chris; Winkelmann, Bernhard; Zhang, Haitao; Zheng, Dongling; Zhang, Li; Zmuda, Joseph M.; Clarke, Robert; Balmforth, Anthony J.; Danesh, John; Day, Ian N.; Schork, Nicholas J.; de Bakker, Paul I. W.; Delles, Christian; Duggan, David; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofker, Marten H.; Humphries, Steve E.; Kivimaki, Mika; Lawlor, Debbie A.; Kottke-Marchant, Kandice; Mega, Jessica L.; Mitchell, Braxton D.; Morrow, David A.; Palmen, Jutta; Redline, Susan; Shields, Denis C.; Shuldiner, Alan R.; Sleiman, Patrick M.; Smith, George Davey; Farrall, Martin; Jamshidi, Yalda; Christiani, David C.; Casas, Juan P.; Hall, Alistair S.; Doevendans, Pieter A.; Christie, Jason D.; Berenson, Gerald S.; Murray, Sarah S.; Illig, Thomas; Dorn, Gerald W.; Cappola, Thomas P.; Boerwinkle, Eric; Sever, Peter; Rader, Daniel J.; Reilly, Muredach P.; Caulfield, Mark; Talmud, Philippa J.; Topol, Eric; Engert, James C.; Wang, Kai; Dominiczak, Anna; Hamsten, Anders; Curtis, Sean P.; Silverstein, Roy L.; Lange, Leslie A.; Sabatine, Marc S.; Trip, Mieke; Saleheen, Danish; Peden, John F.; Cruickshanks, Karen J.; März, Winfried; O'Connell, Jeffrey R.; Klungel, Olaf H.; Wijmenga, Cisca; Maitland-van der Zee, Anke Hilse; Schadt, Eric E.; Johnson, Julie A.; Jarvik, Gail P.; Papanicolaou, George J.; Grant, Struan F. A.; Munroe, Patricia B.; North, Kari E.; Samani, Nilesh J.; Koenig, Wolfgang; Gaunt, Tom R.; Anand, Sonia S.; van der Schouw, Yvonne T.; Soranzo, Nicole; FitzGerald, Garret A.; Reiner, Alex; Hegele, Robert A.; Hakonarson, Hakon; Keating, Brendan J.

    2011-01-01

    Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and

  15. Common carp disrupt ecosystem structure and function through middle-out effects

    Science.gov (United States)

    Kaemingk, Mark A.; Jolley, Jeffrey C.; Paukert, Craig P.; Willis, David W.; Henderson, Kjetil R.; Holland, Richard S.; Wanner, Greg A.; Lindvall, Mark L.

    2016-01-01

    Middle-out effects or a combination of top-down and bottom-up processes create many theoretical and empirical challenges in the realm of trophic ecology. We propose using specific autecology or species trait (i.e. behavioural) information to help explain and understand trophic dynamics that may involve complicated and non-unidirectional trophic interactions. The common carp (Cyprinus carpio) served as our model species for whole-lake observational and experimental studies; four trophic levels were measured to assess common carp-mediated middle-out effects across multiple lakes. We hypothesised that common carp could influence aquatic ecosystems through multiple pathways (i.e. abiotic and biotic foraging, early life feeding, nutrient). Both studies revealed most trophic levels were affected by common carp, highlighting strong middle-out effects likely caused by common carp foraging activities and abiotic influence (i.e. sediment resuspension). The loss of water transparency, submersed vegetation and a shift in zooplankton dynamics were the strongest effects. Trophic levels furthest from direct pathway effects were also affected (fish life history traits). The present study demonstrates that common carp can exert substantial effects on ecosystem structure and function. Species capable of middle-out effects can greatly modify communities through a variety of available pathways and are not confined to traditional top-down or bottom-up processes.

  16. Statistical universals reveal the structures and functions of human music.

    Science.gov (United States)

    Savage, Patrick E; Brown, Steven; Sakai, Emi; Currie, Thomas E

    2015-07-21

    Music has been called "the universal language of mankind." Although contemporary theories of music evolution often invoke various musical universals, the existence of such universals has been disputed for decades and has never been empirically demonstrated. Here we combine a music-classification scheme with statistical analyses, including phylogenetic comparative methods, to examine a well-sampled global set of 304 music recordings. Our analyses reveal no absolute universals but strong support for many statistical universals that are consistent across all nine geographic regions sampled. These universals include 18 musical features that are common individually as well as a network of 10 features that are commonly associated with one another. They span not only features related to pitch and rhythm that are often cited as putative universals but also rarely cited domains including performance style and social context. These cross-cultural structural regularities of human music may relate to roles in facilitating group coordination and cohesion, as exemplified by the universal tendency to sing, play percussion instruments, and dance to simple, repetitive music in groups. Our findings highlight the need for scientists studying music evolution to expand the range of musical cultures and musical features under consideration. The statistical universals we identified represent important candidates for future investigation.

  17. Reveal genes functionally associated with ACADS by a network study.

    Science.gov (United States)

    Chen, Yulong; Su, Zhiguang

    2015-09-15

    Establishing a systematic network is aimed at finding essential human gene-gene/gene-disease pathway by means of network inter-connecting patterns and functional annotation analysis. In the present study, we have analyzed functional gene interactions of short-chain acyl-coenzyme A dehydrogenase gene (ACADS). ACADS plays a vital role in free fatty acid β-oxidation and regulates energy homeostasis. Modules of highly inter-connected genes in disease-specific ACADS network are derived by integrating gene function and protein interaction data. Among the 8 genes in ACADS web retrieved from both STRING and GeneMANIA, ACADS is effectively conjoined with 4 genes including HAHDA, HADHB, ECHS1 and ACAT1. The functional analysis is done via ontological briefing and candidate disease identification. We observed that the highly efficient-interlinked genes connected with ACADS are HAHDA, HADHB, ECHS1 and ACAT1. Interestingly, the ontological aspect of genes in the ACADS network reveals that ACADS, HAHDA and HADHB play equally vital roles in fatty acid metabolism. The gene ACAT1 together with ACADS indulges in ketone metabolism. Our computational gene web analysis also predicts potential candidate disease recognition, thus indicating the involvement of ACADS, HAHDA, HADHB, ECHS1 and ACAT1 not only with lipid metabolism but also with infant death syndrome, skeletal myopathy, acute hepatic encephalopathy, Reye-like syndrome, episodic ketosis, and metabolic acidosis. The current study presents a comprehensible layout of ACADS network, its functional strategies and candidate disease approach associated with ACADS network. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Functional metabolomics reveals novel active products in the DHA metabolome

    Directory of Open Access Journals (Sweden)

    Masakazu eShinohara

    2012-04-01

    Full Text Available Endogenous mechanisms for successful resolution of an acute inflammatory response and the local return to homeostasis are of interest because excessive inflammation underlies many human diseases. In this review, we provide an update and overview of functional metabolomics that identified a new bioactive metabolome of docosahexaenoic acid (DHA. Systematic studies revealed that DHA was converted to DHEA-derived novel bioactive products as well as aspirin-triggered (AT forms of protectins. The new oxygenated DHEA derived products blocked PMN chemotaxis, reduced P-selectin expression and platelet-leukocyte adhesion, and showed organ protection in ischemia/reperfusion injury. These products activated cannabinoid receptor (CB2 receptor and not CB1 receptors. The AT-PD1 reduced neutrophil (PMN recruitment in murine peritonitis. With human cells, AT-PD1 decreased transendothelial PMN migration as well as enhanced efferocytosis of apoptotic human PMN by macrophages. The recent findings reviewed here indicate that DHEA oxidative metabolism and aspirin-triggered conversion of DHA produce potent novel molecules with anti-inflammatory and organ-protective properties, opening the DHA metabolome functional roles.

  19. Aging in cats: Common physical and functional changes.

    Science.gov (United States)

    Bellows, Jan; Center, Sharon; Daristotle, Leighann; Estrada, Amara H; Flickinger, Elizabeth A; Horwitz, Debra F; Lascelles, B Duncan X; Lepine, Allan; Perea, Sally; Scherk, Margie; Shoveller, Anna K

    2016-07-01

    Aged pets comprise a significant proportion of the small animal veterinarian's patient population; in the USA, for example, it was estimated that over 20% of pet cats were 11 years of age or older in 2011. Certain changes associated with aging are neither positive nor negative, but others are less desirable, associated with illness, changes in mobility or the development of unwanted behaviors. These changes can greatly affect the health and wellbeing of the cat and have a tremendous impact on the owner. Regular veterinary examinations are essential for evaluating the health of older patients and for providing owners with guidance regarding optimal care. With the exception of overt disease, however, it is difficult to definitively determine if a cat is displaying changes that are appropriate for age or if they reflect an abnormal process or condition. This is the first of two review articles in a Special Issue devoted to feline healthy aging. The goals of the project culminating in these publications included developing a working definition for healthy aging in feline patients and identifying clinical methods that can be used to accurately classify healthy aged cats. This first review provides a thorough, systems-based overview of common health-related changes observed in cats as they age. There is a paucity of research in feline aging. The authors have drawn on expert opinion and available data in both the cat and other species. © The Author(s) 2016.

  20. Network Analysis Reveals a Common Host–Pathogen Interaction Pattern in Arabidopsis Immune Responses

    Directory of Open Access Journals (Sweden)

    Hong Li

    2017-05-01

    Full Text Available Many plant pathogens secrete virulence effectors into host cells to target important proteins in host cellular network. However, the dynamic interactions between effectors and host cellular network have not been fully understood. Here, an integrative network analysis was conducted by combining Arabidopsis thaliana protein–protein interaction network, known targets of Pseudomonas syringae and Hyaloperonospora arabidopsidis effectors, and gene expression profiles in the immune response. In particular, we focused on the characteristic network topology of the effector targets and differentially expressed genes (DEGs. We found that effectors tended to manipulate key network positions with higher betweenness centrality. The effector targets, especially those that are common targets of an individual effector, tended to be clustered together in the network. Moreover, the distances between the effector targets and DEGs increased over time during infection. In line with this observation, pathogen-susceptible mutants tended to have more DEGs surrounding the effector targets compared with resistant mutants. Our results suggest a common plant–pathogen interaction pattern at the cellular network level, where pathogens employ potent local impact mode to interfere with key positions in the host network, and plant organizes an in-depth defense by sequentially activating genes distal to the effector targets.

  1. Decreased shoulder function and pain common in recreational badminton players.

    Science.gov (United States)

    Fahlström, M; Söderman, K

    2007-06-01

    The aim of this study was to describe the prevalence and consequences of painful conditions in the shoulder region in recreational badminton players. A questionnaire study was performed on 99 players, of whom 57 were also assessed with Constant score. Previous or present pain in the dominant shoulder was reported by 52% of the players. Sixteen percent of the players had on-going shoulder pain associated with badminton play. A majority of these players reported that their training habits were affected by the pain. Total Constant score was lower in the painful shoulders. Furthermore, range of active pain-free shoulder abduction was decreased. However, isometric shoulder strength test showed no differences when compared with pain-free shoulders. Even though the pain caused functional problems, the players were still playing with on-going symptoms. The diagnoses were mostly unknown, although history and clinical tests indicate problems resembling subacromial impingement.

  2. Spores of most common airborne fungi reveal no ice nucleation activity

    Science.gov (United States)

    Pummer, B. G.; Atanasova, L.; Bauer, H.; Bernardi, J.; Druzhinina, I. S.; Grothe, H.

    2013-06-01

    Fungal spores are ubiquitous biological aerosols, which are considered to show ice nucleation (IN) activity. In this study the respective IN activity was tested in oil emulsion in the immersion freezing mode. The focus was laid on species of economical, ecological or sanitary significance. For the first time, not only common moulds, but also edible mushrooms (Basidiomycota, Agaricomycetes) were investigated, as they contribute massively to the total amount of fungal spores in the atmosphere. Only Fusarium avenaceum showed freezing events at low subzero-temperatures, while the other investigated fungal spores showed no significant IN activity. Furthermore, we selected a set of fungal strains from different sites and exposed them to occasional freezing stress during cultivation. Although the total protein expression was altered by this treatment, it had no significant impact on the IN activity.

  3. An economic experiment reveals that humans prefer pool punishment to maintain the commons

    Science.gov (United States)

    Traulsen, Arne; Röhl, Torsten; Milinski, Manfred

    2012-01-01

    Punishment can stabilize costly cooperation and ensure the success of a common project that is threatened by free-riders. Punishment mechanisms can be classified into pool punishment, where the punishment act is carried out by a paid third party, (e.g. a police system or a sheriff), and peer punishment, where the punishment act is carried out by peers. Which punishment mechanism is preferred when both are concurrently available within a society? In an economic experiment, we show that the majority of subjects choose pool punishment, despite being costly even in the absence of defectors, when second-order free-riders, cooperators that do not punish, are also punished. Pool punishers are mutually enforcing their support for the punishment organization, stably trapping each other. Our experimental results show how organized punishment could have displaced individual punishment in human societies. PMID:22764167

  4. Spores of many common airborne fungi reveal no ice nucleation activity in oil immersion freezing experiments

    Science.gov (United States)

    Pummer, B. G.; Atanasova, L.; Bauer, H.; Bernardi, J.; Druzhinina, I. S.; Fröhlich-Nowoisky, J.; Grothe, H.

    2013-12-01

    Fungal spores are ubiquitous biological aerosols, which are considered to act as ice nuclei. In this study the ice nucleation (IN) activity of spores harvested from 29 fungal strains belonging to 21 different species was tested in the immersion freezing mode by microscopic observation of water-in-oil emulsions. Spores of 8 of these strains were also investigated in a microdroplet freezing array instrument. The focus was laid on species of economical, ecological or sanitary significance. Besides common molds (Ascomycota), some representatives of the widespread group of mushrooms (Basidiomycota) were also investigated. Fusarium avenaceum was the only sample showing IN activity at relatively high temperatures (about 264 K), while the other investigated fungal spores showed no freezing above 248 K. Many of the samples indeed froze at homogeneous ice nucleation temperatures (about 237 K). In combination with other studies, this suggests that only a limited number of species may act as atmospheric ice nuclei. This would be analogous to what is already known for the bacterial ice nuclei. Apart from that, we selected a set of fungal strains from different sites and exposed them to occasional freezing stress during their cultivation. This was in order to test if the exposure to a cold environment encourages the expression of ice nuclei during growth as a way of adaptation. Although the total protein expression was altered by this treatment, it had no significant impact on the IN activity.

  5. Revealing strong bias in common measures of galaxy properties using new inclination-independent structures

    Science.gov (United States)

    Devour, Brian M.; Bell, Eric F.

    2017-06-01

    Accurate measurement of galaxy structures is a prerequisite for quantitative investigation of galaxy properties or evolution. Yet, the impact of galaxy inclination and dust on commonly used metrics of galaxy structure is poorly quantified. We use infrared data sets to select inclination-independent samples of disc and flattened elliptical galaxies. These samples show strong variation in Sérsic index, concentration and half-light radii with inclination. We develop novel inclination-independent galaxy structures by collapsing the light distribution in the near-infrared on to the major axis, yielding inclination-independent 'linear' measures of size and concentration. With these new metrics we select a sample of Milky Way analogue galaxies with similar stellar masses, star formation rates, sizes and concentrations. Optical luminosities, light distributions and spectral properties are all found to vary strongly with inclination: When inclining to edge-on, r-band luminosities dim by >1 magnitude, sizes decrease by a factor of 2, 'dust-corrected' estimates of star formation rate drop threefold, metallicities decrease by 0.1 dex and edge-on galaxies are half as likely to be classified as star forming. These systematic effects should be accounted for in analyses of galaxy properties.

  6. Logical and physical resource management in the common node of a distributed function laboratory computer network

    International Nuclear Information System (INIS)

    Stubblefield, F.W.

    1976-01-01

    A scheme for managing resources required for transaction processing in the common node of a distributed function computer system has been given. The scheme has been found to be satisfactory for all common node services provided so far

  7. Patterns of hypothalamic regionalization in amphibians and reptiles: common traits revealed by a genoarchitectonic approach

    Directory of Open Access Journals (Sweden)

    Laura eDominguez

    2015-02-01

    Full Text Available Most studies in mammals and birds have demonstrated common patterns of hypothalamic development highlighted by the combination of developmental regulatory genes (genoarchitecture, supporting the notion of the hypothalamus as a component of the secondary prosencephalon, topologically rostral to the diencephalon. In our comparative analysis we have summarized the data on the expression patterns of different transcription factors and neuroactive substances, used as anatomical markers, in the developing hypothalamus of the amphibian Xenopus laevis and the juvenile turtle Pseudemys scripta. This analysis served to highlight the organization of the hypothalamus in the anamniote/amniotic transition. We have identified supraoptoparaventricular and the suprachiasmatic regions in the alar part of the hypothalamus, and tuberal and mammillary regions in the basal hypothalamus. Shared features in the two species are: 1 The supraoptoparaventricular region is defined by the expression of Otp and the lack of Nkx2.1/Isl1. It is subdivided into rostral, rich in Otp and Nkx2.2, and caudal, only Otp-positive, portions. 2 The suprachiasmatic area contains catecholaminergic cell groups and lacks Otp, and can be further divided into rostral (rich in Nkx2.1 and Nkx2.2 and a caudal (rich in Isl1 and devoid of Nkx2.1 portions. 3 Expression of Nkx2.1 and Isl1 define the tuberal hypothalamus and only the rostral portion expresses Otp. 4 Its caudal boundary is evident by the lack of Isl1 in the adjacent mammillary region, which expresses Nkx2.1 and Otp. Differences in the anamnio-amniote transition were noted since in the turtle, like in other amniotes, the boundary between the alar hypothalamus and the telencephalic preoptic area shows distinct Nkx2.2 and Otp expressions but not in the amphibian (anamniote, and the alar supraoptoparaventricular region is defined by the expression of Otp/Pax6, whereas in Xenopus only Otp is expressed.

  8. Intravarietal polymorphisms reveal possible common ancestor of native Schinus terebinthifolius Raddi populations in Brazil.

    Science.gov (United States)

    Pinto, J V C; Crispim, B A; Vasconcelos, A A; Geelen, D; Grisolia, A B; Vieira, M C

    2016-01-08

    Schinus terebinthifolius Raddi is a perennial native from Atlantic forest. It is of high ecological plasticity and is used in traditional medicine. Based on promising reports concerning its bioactivity, it was included as a species of great interest for distribution through the National Health System. A number of agronomic studies to guide its crop production are therefore underway. This study examined diversity and phylogenetic relationships among native S. terebinthifolius populations from different Brazilian ecosystems: Cerrado; sandbanks; dense rainforest; and deciduous forest. The intergenic regions rpl20-5'rps12, trnH-psbA, and trnS-trnG were sequenced from cpDNA and aligned using BLASTn. There were few fragments for comparison in GenBank and so only region trnS-trnG was informative. There were variations among and within populations with intravarietal polymorphisms and three distinct haplotypes (HpSM, HpDDO, HpNE), once populations from NE (sandbanks and rainforest) clustered together. Sequences from HpSM, HpNE, and HpDDO returned greater similarity to haplotypes A (AY928398.1), B (AY928399.1), and C (AY928400.1), respectively. A network, built by median-joining among native haplotypes and 10 available on GenBank, revealed HpSM as the origin of all other haplogroups. HpDDO showed the most mutations and was closely related to haplogroups from Argentina. While this could indicate hybridization, we believe that the polymorphisms resulted from adaptation to events such as deforestation, fire, rising temperature, and seasonal drought during the transition from Atlantic forest to Cerrado. While more detailed phylogeographical studies are needed, these results indicate eligible groups for distinct climates as an important step for pre-breeding programs before field propagation.

  9. The Chlamydomonas Genome Reveals the Evolution of Key Animal and Plant Functions

    Energy Technology Data Exchange (ETDEWEB)

    Merchant, Sabeeha S

    2007-04-09

    Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the 120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella.

  10. Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes.

    Science.gov (United States)

    Liu, Chunyu; Fetterman, Jessica L; Liu, Poching; Luo, Yan; Larson, Martin G; Vasan, Ramachandran S; Zhu, Jun; Levy, Daniel

    2018-03-01

    Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic-the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age-related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2. We discovered 11 heteroplasmic "hot" spots [NADH dehydrogenase (ND) subunit 1, 4, 5 and 6 genes, n = 7; cytochrome c oxidase I (COI), n = 2; 16S rRNA, n = 1; D-loop, n = 1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction p < 0.001). Four of these heteroplasmic mutations in ND and COI genes were predicted to be deleterious nonsynonymous mutations which may have direct impact on ATP production. We confirmed previous findings that healthy individuals carry many low-frequency heteroplasmy mutations with potentially deleterious effects. We hypothesize that the effect of a single deleterious heteroplasmy may be minimal due to a low mutant-to-wildtype allele ratio, whereas the aggregate effects of many deleterious mutations may cause changes in mitochondrial function and contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step to understand the genetic architecture of age-related diseases and may uncover novel therapeutic targets for such diseases.

  11. Heterogeneity in Neutrophil Microparticles Reveals Distinct Proteome and Functional Properties*

    Science.gov (United States)

    Dalli, Jesmond; Montero-Melendez, Trinidad; Norling, Lucy V; Yin, Xiaoke; Hinds, Charles; Haskard, Dorian; Mayr, Manuel; Perretti, Mauro

    2013-01-01

    Altered plasma neutrophil microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Herein, we investigate the proteome of neutrophil microparticles in order to shed light on their biological actions. Stimulation of human neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >400 distinct proteins with only 223 being shared by the two subsets. For instance, postadherent microparticles were enriched in alpha-2 macroglobulin and ceruloplasmin, whereas microparticles produced by neutrophils in suspension were abundant in heat shock 70 kDa protein 1. Annexin A1 and lactotransferrin were expressed in both microparticle subsets. We next determined relative abundance of these proteins in three types of human microparticle samples: healthy volunteer plasma, plasma of septic patients and skin blister exudates finding that these proteins were differentially expressed on neutrophil microparticles from these samples reflecting in part the expression profiles we found in vitro. Functional assessment of the neutrophil microparticles subsets demonstrated that in response to direct stimulation neutrophil microparticles produced reactive oxygen species and leukotriene B4 as well as locomoted toward a chemotactic gradient. Finally, we investigated the actions of the two neutrophil microparticles subsets described herein on target cell responses. Microarray analysis with human primary endothelial cells incubated with either microparticle subset revealed a discrete modulation of endothelial cell gene expression profile. These findings demonstrate that neutrophil microparticles are heterogenous and can deliver packaged information propagating the activation status of the parent cell, potentially exerting novel and fundamental roles both under homeostatic and disease conditions. PMID:23660474

  12. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

  13. MDEP Common Position CP-DICWG-07. Common position on selection and use of industrial digital devices of limited functionality

    International Nuclear Information System (INIS)

    2014-01-01

    The nuclear power industry is increasingly interested in using industrial digital devices of limited functionality in systems important to safety, but that have not been developed specifically for use in nuclear power applications. These devices should meet certain specific requirements in order to be selected and used in systems important to safety at nuclear power plants. Typically, some of these devices are found embedded in plant components and actuating devices, e.g. sensing instrumentation, motors, pumps, actuators, breakers. The Digital Instrumentation and Controls Working Group (DICWG) has agreed that a common position on this topic is warranted given the increase of use of Digital I and C in new reactor designs, its safety implications, and the need to develop a common understanding from the perspectives of regulatory authorities. This action follows the DICWG examination of the regulatory requirements of the participating members and of relevant industry standards and IAEA documents. The DICWG proposes a common position based on its recent experience with the new reactor application reviews and operating plant issues

  14. Impaired work functioning due to common mental disorders in nurses and allied health professionals: the Nurses Work Functioning Questionnaire

    NARCIS (Netherlands)

    Gärtner, F. R.; Nieuwenhuijsen, K.; van Dijk, F. J. H.; Sluiter, J. K.

    2012-01-01

    Common mental disorders (CMD) negatively affect work functioning. In the health service sector not only the prevalence of CMDs is high, but work functioning problems are associated with a risk of serious consequences for patients and healthcare providers. If work functioning problems due to CMDs are

  15. A common functional neural network for overt production of speech and gesture.

    Science.gov (United States)

    Marstaller, L; Burianová, H

    2015-01-22

    The perception of co-speech gestures, i.e., hand movements that co-occur with speech, has been investigated by several studies. The results show that the perception of co-speech gestures engages a core set of frontal, temporal, and parietal areas. However, no study has yet investigated the neural processes underlying the production of co-speech gestures. Specifically, it remains an open question whether Broca's area is central to the coordination of speech and gestures as has been suggested previously. The objective of this study was to use functional magnetic resonance imaging to (i) investigate the regional activations underlying overt production of speech, gestures, and co-speech gestures, and (ii) examine functional connectivity with Broca's area. We hypothesized that co-speech gesture production would activate frontal, temporal, and parietal regions that are similar to areas previously found during co-speech gesture perception and that both speech and gesture as well as co-speech gesture production would engage a neural network connected to Broca's area. Whole-brain analysis confirmed our hypothesis and showed that co-speech gesturing did engage brain areas that form part of networks known to subserve language and gesture. Functional connectivity analysis further revealed a functional network connected to Broca's area that is common to speech, gesture, and co-speech gesture production. This network consists of brain areas that play essential roles in motor control, suggesting that the coordination of speech and gesture is mediated by a shared motor control network. Our findings thus lend support to the idea that speech can influence co-speech gesture production on a motoric level. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Functions of two distinct prolactin-releasing peptides evolved from a common ancestral gene

    Directory of Open Access Journals (Sweden)

    Tetsuya eTachibana

    2014-11-01

    Full Text Available Prolactin-releasing peptide (PrRP is one of the RF-amide peptides and was originally identified in the bovine hypothalamus as a stimulator of prolactin (PRL release. Independently, another RF-amide peptide was found in Japanese crucian carp and named Carassius RFa (C-RFa, which shows high homology to PrRP and stimulates PRL secretion in teleost fish. Therefore, C-RFa has been recognized as fish PrRP. However, recent work has revealed that PrRP and C-RFa in non-mammalian vertebrates are encoded by separate genes originated through duplication of an ancestral gene. Indeed, both PrRP and C-RFa are suggested to exist in teleost, amphibian, reptile, and avian species. Therefore, we propose that non-mammalian PrRP (C-RFa be renamed PrRP2. Despite a common evolutionary origin, PrRP2 appears to be a physiological regulator of PRL, whereas this is not a consistent role for PrRP itself. Further work revealed that the biological functions of PrRP and PrRP2 are not limited solely to PRL release, because they are also neuromodulators of several hypothalamus-pituitary axes and are involved in some brain circuits related to the regulation of food intake, stress, and cardiovascular functions. However, these actions appear to be different among vertebrates. For example, central injection of PrRP inhibits feeding behavior in rodents and teleosts while it stimulates it in chicks. Therefore, both PrRP and PrRP2 have acquired diverse actions through evolution. In this review, we integrate the burgeoning information of structures, expression profiles, and multiple biological actions of PrRP in higher vertebrates, as well as those of PrRP2 in non-mammals.

  17. Metatranscriptomic analysis of diverse microbial communities reveals core metabolic pathways and microbiome-specific functionality.

    Science.gov (United States)

    Jiang, Yue; Xiong, Xuejian; Danska, Jayne; Parkinson, John

    2016-01-12

    Metatranscriptomics is emerging as a powerful technology for the functional characterization of complex microbial communities (microbiomes). Use of unbiased RNA-sequencing can reveal both the taxonomic composition and active biochemical functions of a complex microbial community. However, the lack of established reference genomes, computational tools and pipelines make analysis and interpretation of these datasets challenging. Systematic studies that compare data across microbiomes are needed to demonstrate the ability of such pipelines to deliver biologically meaningful insights on microbiome function. Here, we apply a standardized analytical pipeline to perform a comparative analysis of metatranscriptomic data from diverse microbial communities derived from mouse large intestine, cow rumen, kimchi culture, deep-sea thermal vent and permafrost. Sequence similarity searches allowed annotation of 19 to 76% of putative messenger RNA (mRNA) reads, with the highest frequency in the kimchi dataset due to its relatively low complexity and availability of closely related reference genomes. Metatranscriptomic datasets exhibited distinct taxonomic and functional signatures. From a metabolic perspective, we identified a common core of enzymes involved in amino acid, energy and nucleotide metabolism and also identified microbiome-specific pathways such as phosphonate metabolism (deep sea) and glycan degradation pathways (cow rumen). Integrating taxonomic and functional annotations within a novel visualization framework revealed the contribution of different taxa to metabolic pathways, allowing the identification of taxa that contribute unique functions. The application of a single, standard pipeline confirms that the rich taxonomic and functional diversity observed across microbiomes is not simply an artefact of different analysis pipelines but instead reflects distinct environmental influences. At the same time, our findings show how microbiome complexity and availability of

  18. Revealing topological organization of human brain functional networks with resting-state functional near infrared spectroscopy.

    Science.gov (United States)

    Niu, Haijing; Wang, Jinhui; Zhao, Tengda; Shu, Ni; He, Yong

    2012-01-01

    The human brain is a highly complex system that can be represented as a structurally interconnected and functionally synchronized network, which assures both the segregation and integration of information processing. Recent studies have demonstrated that a variety of neuroimaging and neurophysiological techniques such as functional magnetic resonance imaging (MRI), diffusion MRI and electroencephalography/magnetoencephalography can be employed to explore the topological organization of human brain networks. However, little is known about whether functional near infrared spectroscopy (fNIRS), a relatively new optical imaging technology, can be used to map functional connectome of the human brain and reveal meaningful and reproducible topological characteristics. We utilized resting-state fNIRS (R-fNIRS) to investigate the topological organization of human brain functional networks in 15 healthy adults. Brain networks were constructed by thresholding the temporal correlation matrices of 46 channels and analyzed using graph-theory approaches. We found that the functional brain network derived from R-fNIRS data had efficient small-world properties, significant hierarchical modular structure and highly connected hubs. These results were highly reproducible both across participants and over time and were consistent with previous findings based on other functional imaging techniques. Our results confirmed the feasibility and validity of using graph-theory approaches in conjunction with optical imaging techniques to explore the topological organization of human brain networks. These results may expand a methodological framework for utilizing fNIRS to study functional network changes that occur in association with development, aging and neurological and psychiatric disorders.

  19. Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

    Science.gov (United States)

    Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; O'Seaghdha, Conall M.; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V.; O'Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D.; Gierman, Hinco J.; Feitosa, Mary; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Chouraki, Vincent; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B.; Launer, Lenore J.; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D.; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank B.; Demirkan, Ayse; Oostra, Ben A.; de Andrade, Mariza; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H.-Erich; Kolcic, Ivana; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E.; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H.; Wright, Alan F.; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Endlich, Karlhans; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K.; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Giulianini, Franco; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Metzger, Marie; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K.; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J. Wouter; Probst-Hensch, Nicole M.; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R.; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S.; van Duijn, Cornelia M.; Borecki, Ingrid; Kardia, Sharon L. R.; Liu, Yongmei; Curhan, Gary C.; Rudan, Igor; Gyllensten, Ulf; Wilson, James F.; Franke, Andre; Pramstaller, Peter P.; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline C. M.; Hayward, Caroline; Ridker, Paul; Parsa, Afshin; Bochud, Murielle; Heid, Iris M.; Goessling, Wolfram; Chasman, Daniel I.; Kao, W. H. Linda; Fox, Caroline S.

    2012-01-01

    Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. PMID:22479191

  20. Genome-wide association and functional follow-up reveals new loci for kidney function.

    Science.gov (United States)

    Pattaro, Cristian; Köttgen, Anna; Teumer, Alexander; Garnaas, Maija; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C; O'Seaghdha, Conall M; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V; O'Connell, Jeffrey R; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D; Gierman, Hinco J; Feitosa, Mary; Hwang, Shih-Jen; Atkinson, Elizabeth J; Lohman, Kurt; Cornelis, Marilyn C; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Chouraki, Vincent; Holliday, Elizabeth G; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B; Launer, Lenore J; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank B; Demirkan, Ayse; Oostra, Ben A; de Andrade, Mariza; Turner, Stephen T; Ding, Jingzhong; Andrews, Jeanette S; Freedman, Barry I; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H-Erich; Kolcic, Ivana; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H; Wright, Alan F; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Endlich, Karlhans; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G; Rivadeneira, Fernando; Aulchenko, Yurii S; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Giulianini, Franco; Krämer, Bernhard K; Portas, Laura; Ford, Ian; Buckley, Brendan M; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Metzger, Marie; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J Wouter; Probst-Hensch, Nicole M; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S; van Duijn, Cornelia M; Borecki, Ingrid; Kardia, Sharon L R; Liu, Yongmei; Curhan, Gary C; Rudan, Igor; Gyllensten, Ulf; Wilson, James F; Franke, Andre; Pramstaller, Peter P; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline C M; Hayward, Caroline; Ridker, Paul; Parsa, Afshin; Bochud, Murielle; Heid, Iris M; Goessling, Wolfram; Chasman, Daniel I; Kao, W H Linda; Fox, Caroline S

    2012-01-01

    Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

  1. Genome-wide association and functional follow-up reveals new loci for kidney function.

    Directory of Open Access Journals (Sweden)

    Cristian Pattaro

    Full Text Available Chronic kidney disease (CKD is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR, the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

  2. Standardized reporting of functioning information on ICF-based common metrics.

    Science.gov (United States)

    Prodinger, Birgit; Tennant, Alan; Stucki, Gerold

    2018-02-01

    In clinical practice and research a variety of clinical data collection tools are used to collect information on people's functioning for clinical practice and research and national health information systems. Reporting on ICF-based common metrics enables standardized documentation of functioning information in national health information systems. The objective of this methodological note on applying the ICF in rehabilitation is to demonstrate how to report functioning information collected with a data collection tool on ICF-based common metrics. We first specify the requirements for the standardized reporting of functioning information. Secondly, we introduce the methods needed for transforming functioning data to ICF-based common metrics. Finally, we provide an example. The requirements for standardized reporting are as follows: 1) having a common conceptual framework to enable content comparability between any health information; and 2) a measurement framework so that scores between two or more clinical data collection tools can be directly compared. The methods needed to achieve these requirements are the ICF Linking Rules and the Rasch measurement model. Using data collected incorporating the 36-item Short Form Health Survey (SF-36), the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), and the Stroke Impact Scale 3.0 (SIS 3.0), the application of the standardized reporting based on common metrics is demonstrated. A subset of items from the three tools linked to common chapters of the ICF (d4 Mobility, d5 Self-care and d6 Domestic life), were entered as "super items" into the Rasch model. Good fit was achieved with no residual local dependency and a unidimensional metric. A transformation table allows for comparison between scales, and between a scale and the reporting common metric. Being able to report functioning information collected with commonly used clinical data collection tools with ICF-based common metrics enables clinicians

  3. Functional imaging reveals movement preparatory activity in the vegetative state

    Directory of Open Access Journals (Sweden)

    Tristan A Bekinschtein

    2011-01-01

    Full Text Available The Vegetative State (VS is characterized by the absence of awareness of self or the environment and preserved autonomic functions. The diagnosis relies critically on the lack of consistent signs of purposeful behavior in response to external stimulation. Yet, given that patients with disorders of consciousness often exhibit fragmented movement patterns, voluntary actions may go unnoticed. Here we designed a simple motor paradigm that could potentially detect residual conscious awareness in VS patients with mild to severe brain damage by examining the neural correlates of motor preparation in response to verbal commands. Twenty-four patients who met the diagnostic criteria for VS were recruited for this study. Eleven of these patients showing preserved auditory evoked potentials underwent functional magnetic resonance imaging (fMRI to test for basic speech processing. Five of these patients, who showed word related activity, were included in a second fMRI study aimed at detecting functional changes in premotor cortex elicited by specific verbal instructions to move either their left or their right hand. Despite the lack of overt muscle activity, two patients out of five activated the dorsal premotor cortex contralateral to the instructed hand, consistent with movement preparation. Given that movement preparation in response to a motor command is a sign of purposeful behavior, our results are consistent with residual conscious awareness in these patients. We believe that the identification of positive results with fMRI using this simple task, may complement the clinical assessment by helping attain a more precise diagnosis in patients with disorders of consciousness.

  4. Remote synchronization reveals network symmetries and functional modules.

    Science.gov (United States)

    Nicosia, Vincenzo; Valencia, Miguel; Chavez, Mario; Díaz-Guilera, Albert; Latora, Vito

    2013-04-26

    We study a Kuramoto model in which the oscillators are associated with the nodes of a complex network and the interactions include a phase frustration, thus preventing full synchronization. The system organizes into a regime of remote synchronization where pairs of nodes with the same network symmetry are fully synchronized, despite their distance on the graph. We provide analytical arguments to explain this result, and we show how the frustration parameter affects the distribution of phases. An application to brain networks suggests that anatomical symmetry plays a role in neural synchronization by determining correlated functional modules across distant locations.

  5. Comparative genomics of Geobacter chemotaxis genes reveals diverse signaling function

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    Antommattei Frances M

    2008-10-01

    Full Text Available Abstract Background Geobacter species are δ-Proteobacteria and are often the predominant species in a variety of sedimentary environments where Fe(III reduction is important. Their ability to remediate contaminated environments and produce electricity makes them attractive for further study. Cell motility, biofilm formation, and type IV pili all appear important for the growth of Geobacter in changing environments and for electricity production. Recent studies in other bacteria have demonstrated that signaling pathways homologous to the paradigm established for Escherichia coli chemotaxis can regulate type IV pili-dependent motility, the synthesis of flagella and type IV pili, the production of extracellular matrix material, and biofilm formation. The classification of these pathways by comparative genomics improves the ability to understand how Geobacter thrives in natural environments and better their use in microbial fuel cells. Results The genomes of G. sulfurreducens, G. metallireducens, and G. uraniireducens contain multiple (~70 homologs of chemotaxis genes arranged in several major clusters (six, seven, and seven, respectively. Unlike the single gene cluster of E. coli, the Geobacter clusters are not all located near the flagellar genes. The probable functions of some Geobacter clusters are assignable by homology to known pathways; others appear to be unique to the Geobacter sp. and contain genes of unknown function. We identified large numbers of methyl-accepting chemotaxis protein (MCP homologs that have diverse sensing domain architectures and generate a potential for sensing a great variety of environmental signals. We discuss mechanisms for class-specific segregation of the MCPs in the cell membrane, which serve to maintain pathway specificity and diminish crosstalk. Finally, the regulation of gene expression in Geobacter differs from E. coli. The sequences of predicted promoter elements suggest that the alternative sigma factors

  6. Teaching assistants’ performance at identifying common introductory student difficulties in mechanics revealed by the Force Concept Inventory

    Directory of Open Access Journals (Sweden)

    Alexandru Maries

    2016-05-01

    Full Text Available The Force Concept Inventory (FCI has been widely used to assess student understanding of introductory mechanics concepts by a variety of educators and physics education researchers. One reason for this extensive use is that many of the items on the FCI have strong distractor choices which correspond to students’ alternate conceptions in mechanics. Instruction is unlikely to be effective if instructors do not know the common alternate conceptions of introductory physics students and explicitly take into account students’ initial knowledge states in their instructional design. Here, we discuss research involving the FCI to evaluate one aspect of the pedagogical content knowledge of teaching assistants (TAs: knowledge of introductory student alternate conceptions in mechanics as revealed by the FCI. For each item on the FCI, the TAs were asked to identify the most common incorrect answer choice of introductory physics students. This exercise was followed by a class discussion with the TAs related to this task, including the importance of knowing student difficulties in teaching and learning. Then, we used FCI pretest and post-test data from a large population (∼900 of introductory physics students to assess the extent to which TAs were able to identify alternate conceptions of introductory students related to force and motion. In addition, we carried out think-aloud interviews with graduate students who had more than two semesters of teaching experience in recitations to examine how they reason about the task. We find that while the TAs, on average, performed better than random guessing at identifying introductory students’ difficulties with FCI content, they did not identify many common difficulties that introductory physics students have after traditional instruction. We discuss specific alternate conceptions, the extent to which TAs are able to identify them, and results from the think-aloud interviews that provided valuable information

  7. Serial functional imaging poststroke reveals visual cortex reorganization.

    Science.gov (United States)

    Brodtmann, Amy; Puce, Aina; Darby, David; Donnan, Geoffrey

    2009-02-01

    Visual cortical reorganization following injury remains poorly understood. The authors performed serial functional magnetic resonance imaging (fMRI) on patients with visual cortex infarction to evaluate early and late striate, ventral, and dorsal extrastriate cortical activation. Patients were studied with fMRI within 10 days and at 6 months. The authors used a high-level visual activation task designed to activate the ventral extrastriate cortex. These data were compared to those of age-appropriate healthy control participants. The results from 24 healthy control individuals (mean age 65.7 +/- SE 3.6 years, range 32-89) were compared to those from 5 stroke patients (mean age 73.8 +/- SE 7 years, range 49-86). Patients had infarcts involving the striate and ventral extrastriate cortex. Patient activation patterns were markedly different to controls. Bilateral striate and ventral extrastriate activation was reduced at both sessions, but dorsal extrastriate activated voxel counts remained comparable to controls. Conversely, mean percent magnetic resonance signal change increased in dorsal sites. These data provide strong evidence of bilateral poststroke functional depression of striate and ventral extrastriate cortices. Possible utilization or surrogacy of the dorsal visual system was demonstrated following stroke. This activity could provide a target for novel visual rehabilitation therapies.

  8. PET imaging reveals brain functional changes in internet gaming disorder

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Mei; Zhang, Ying; Du, Fenglei; Hou, Haifeng; Chao, Fangfang; Zhang, Hong [The Second Hospital of Zhejiang University School of Medicine, Department of Nuclear Medicine, Hangzhou, Zhejiang (China); Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou (China); Chen, Qiaozhen [The Second Hospital of Zhejiang University School of Medicine, Department of Nuclear Medicine, Hangzhou, Zhejiang (China); The Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Psychiatry, Hangzhou (China)

    2014-07-15

    Internet gaming disorder is an increasing problem worldwide, resulting in critical academic, social, and occupational impairment. However, the neurobiological mechanism of internet gaming disorder remains unknown. The aim of this study is to assess brain dopamine D{sub 2} (D{sub 2})/Serotonin 2A (5-HT{sub 2A}) receptor function and glucose metabolism in the same subjects by positron emission tomography (PET) imaging approach, and investigate whether the correlation exists between D{sub 2} receptor and glucose metabolism. Twelve drug-naive adult males who met criteria for internet gaming disorder and 14 matched controls were studied with PET and {sup 11}C-N-methylspiperone ({sup 11}C-NMSP) to assess the availability of D{sub 2}/5-HT{sub 2A} receptors and with {sup 18}F-fluoro-D-glucose ({sup 18}F-FDG) to assess regional brain glucose metabolism, a marker of brain function. {sup 11}C-NMSP and {sup 18}F-FDG PET imaging data were acquired in the same individuals under both resting and internet gaming task states. In internet gaming disorder subjects, a significant decrease in glucose metabolism was observed in the prefrontal, temporal, and limbic systems. Dysregulation of D{sub 2} receptors was observed in the striatum, and was correlated to years of overuse. A low level of D{sub 2} receptors in the striatum was significantly associated with decreased glucose metabolism in the orbitofrontal cortex. For the first time, we report the evidence that D{sub 2} receptor level is significantly associated with glucose metabolism in the same individuals with internet gaming disorder, which indicates that D{sub 2}/5-HT{sub 2A} receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects. (orig.)

  9. PET imaging reveals brain functional changes in internet gaming disorder

    International Nuclear Information System (INIS)

    Tian, Mei; Zhang, Ying; Du, Fenglei; Hou, Haifeng; Chao, Fangfang; Zhang, Hong; Chen, Qiaozhen

    2014-01-01

    Internet gaming disorder is an increasing problem worldwide, resulting in critical academic, social, and occupational impairment. However, the neurobiological mechanism of internet gaming disorder remains unknown. The aim of this study is to assess brain dopamine D 2 (D 2 )/Serotonin 2A (5-HT 2A ) receptor function and glucose metabolism in the same subjects by positron emission tomography (PET) imaging approach, and investigate whether the correlation exists between D 2 receptor and glucose metabolism. Twelve drug-naive adult males who met criteria for internet gaming disorder and 14 matched controls were studied with PET and 11 C-N-methylspiperone ( 11 C-NMSP) to assess the availability of D 2 /5-HT 2A receptors and with 18 F-fluoro-D-glucose ( 18 F-FDG) to assess regional brain glucose metabolism, a marker of brain function. 11 C-NMSP and 18 F-FDG PET imaging data were acquired in the same individuals under both resting and internet gaming task states. In internet gaming disorder subjects, a significant decrease in glucose metabolism was observed in the prefrontal, temporal, and limbic systems. Dysregulation of D 2 receptors was observed in the striatum, and was correlated to years of overuse. A low level of D 2 receptors in the striatum was significantly associated with decreased glucose metabolism in the orbitofrontal cortex. For the first time, we report the evidence that D 2 receptor level is significantly associated with glucose metabolism in the same individuals with internet gaming disorder, which indicates that D 2 /5-HT 2A receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects. (orig.)

  10. Coherence and Coupling Functions Reveal Microvascular Impairment in Treated Hypertension

    Directory of Open Access Journals (Sweden)

    Valentina Ticcinelli

    2017-10-01

    Full Text Available The complex interactions that give rise to heart rate variability (HRV involve coupled physiological oscillators operating over a wide range of different frequencies and length-scales. Based on the premise that interactions are key to the functioning of complex systems, the time-dependent deterministic coupling parameters underlying cardiac, respiratory and vascular regulation have been investigated at both the central and microvascular levels. Hypertension was considered as an example of a globally altered state of the complex dynamics of the cardiovascular system. Its effects were established through analysis of simultaneous recordings of the electrocardiogram (ECG, respiratory effort, and microvascular blood flow [by laser Doppler flowmetry (LDF]. The signals were analyzed by methods developed to capture time-dependent dynamics, including the wavelet transform, wavelet-based phase coherence, non-linear mode decomposition, and dynamical Bayesian inference, all of which can encompass the inherent frequency and coupling variability of living systems. Phases of oscillatory modes corresponding to the cardiac (around 1.0 Hz, respiratory (around 0.25 Hz, and vascular myogenic activities (around 0.1 Hz were extracted and combined into two coupled networks describing the central and peripheral systems, respectively. The corresponding spectral powers and coupling functions were computed. The same measurements and analyses were performed for three groups of subjects: healthy young (Y group, 24.4 ± 3.4 y, healthy aged (A group, 71.1 ± 6.6 y, and aged treated hypertensive patients (ATH group, 70.3 ± 6.7 y. It was established that the degree of coherence between low-frequency oscillations near 0.1 Hz in blood flow and in HRV time series differs markedly between the groups, declining with age and nearly disappearing in treated hypertension. Comparing the two healthy groups it was found that the couplings to the cardiac rhythm from both respiration and

  11. Quantitative protein localization signatures reveal an association between spatial and functional divergences of proteins.

    Science.gov (United States)

    Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling

    2014-03-01

    Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein

  12. Live cell imaging reveals different modes of cytotoxic action of extracts derived from commonly used luting cements.

    Science.gov (United States)

    Trumpaitė-Vanagienė, Rita; Čebatariūnienė, Alina; Tunaitis, Virginijus; Pūrienė, Alina; Pivoriūnas, Augustas

    2018-02-01

    To compare cytotoxicity of extracts derived from commonly used luting cements: Hoffmann's Zinc Phosphate (ZPC), GC Fuji Plus Resin Modified Glass Ionomer (RMGIC) and 3M ESPE RelyX Unicem Resin Cement (RC) on primary human gingival fibroblasts (HGFs). HGFs were exposed to different concentrations of the ZPC, RMGIC and RC extracts. The cytotoxicity was assessed with the PrestoBlue Cell Viability Reagent and viable cells were counted by a haemocytometer using the trypan blue exclusion test. In order to determine the primary mechanism of the cell death induced by extracts from different luting cements, the real-time monitoring of caspase-3/-7 activity and membrane integrity of cells was employed. The extracts from the RMGIC and ZPC decreased the metabolic activity and numbers of viable cells. Unexpectedly, the extracts from the RC evoked only small effects on the metabolic activity of HGFs with a decreasing number of viable cells in a dose-and time-dependent manner. The live cell imaging revealed that the apoptosis was the primary mechanism of a cell death induced by the extracts derived from the RMGIC, whereas the extracts from the RC and ZPC induced a cell death through a necrotic and caspase-independent pathway. The apoptosis was the primary mechanism of the cell death induced by the extracts derived from the RMGIC, whereas the extracts from the RC and ZPC induced a cell death via a necrotic pathway. We suggest that metabolic assays commonly used to assess the cytotoxicity of luting cements should be validated by alternative methods. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Meta-analysis reveals association between most common class II haplotype in full-heritage Native Americans and rheumatoid arthritis.

    Science.gov (United States)

    Williams, R C; Jacobsson, L T; Knowler, W C; del Puente, A; Kostyu, D; McAuley, J E; Bennett, P H; Pettitt, D J

    1995-01-01

    The association of RA with the alleles at the HLA system was tested among Pima and Tohono O'odham Indians (Pimans) of the Gila River Indian Community of Arizona. Serologic class I (HLA-A, -B, and -C) alleles were typed in 51 individuals with RA and in 302 without RA. Serologic class II (HLA-DR, DQ; DR52 DR53) alleles were typed in a subset of 47 with RA and 147 without RA. Molecular subtypes of DR3X6, DRB1*1402, and *1406 were determined in 29 individuals, 16 with RA and 13 without RA. Among the cases with RA, 46 of 47 had the serologic antigen HLA-DR3X6, as did 140 of 147 of those without the disease. However, this association was not statistically significant because of the high prevalence of the antigen in the controls. Data from Pimans were analyzed with similar results from the Tlingit and Yakima Indians. A meta-analysis employing the Mantel-Haenszel procedure, stratified by tribe, revealed a statistically significant association between the most common haplotype, DRB1*1402 DQA1*0501 DQB1*0301 DRB3*0101, and RA (summary odds ratio = 2.63, 95% confidence interval = 1.08, 6.46). There was also a statistically significant difference in the genotype distributions of one class I locus, HLA-C, between those with and without RA (chi 2 = 12.4, 5 df; p = 0.03). It is concluded that the association with the most common class II haplotype in full-heritage Native Americans might help explain their high prevalence of RA.

  14. Phylogenetic Analysis Reveals Common Antimicrobial Resistant Campylobacter coli Population in Antimicrobial-Free (ABF) and Commercial Swine Systems

    Science.gov (United States)

    Quintana-Hayashi, Macarena P.; Thakur, Siddhartha

    2012-01-01

    The objective of this study was to compare the population biology of antimicrobial resistant (AR) Campylobacter coli isolated from swine reared in the conventional and antimicrobial-free (ABF) swine production systems at farm, slaughter and environment. A total of 200 C. coli isolates selected from fecal, environmental, and carcass samples of ABF (n = 100) and conventional (n = 100) swine production systems were typed by multilocus sequence typing (MLST). Sequence data from seven housekeeping genes was analyzed for the identification of allelic profiles, sequence types (STs) and clonal complex determination. Phylogenetic trees were generated to establish the relationships between the genotyped isolates. A total of 51 STs were detected including two novel alleles (glnA 424 and glyA 464) and 14 novel STs reported for the first time. The majority of the C. coli isolates belonged to ST-854 (ABF: 31, conventional: 17), and were grouped in clonal complex ST-828 (ABF: 68%, conventional: 66%). The mean genetic diversity (H) for the ABF (0.3963+/−0.0806) and conventional (0.4655+/−0.0714) systems were similar. The index of association () for the ABF ( = 0.1513) and conventional ( = 0.0991) C. coli populations were close to linkage equilibrium, indicative of a freely recombining population. Identical STs were detected between the pigs and their environment both at farm and slaughter. A minimum spanning tree revealed the close clustering of C. coli STs that originated from swine and carcass with those from the environment. In conclusion, our study reveals a genotypic diverse C. coli population that shares a common ancestry in the conventional and ABF swine production systems. This could potentially explain the high prevalence of antimicrobial resistant C. coli in the ABF system in the absence of antimicrobial selection pressure. PMID:22984540

  15. Analysis of the cartilage proteome from three different mouse models of genetic skeletal diseases reveals common and discrete disease signatures

    Directory of Open Access Journals (Sweden)

    Peter A. Bell

    2013-06-01

    Pseudoachondroplasia and multiple epiphyseal dysplasia are genetic skeletal diseases resulting from mutations in cartilage structural proteins. Electron microscopy and immunohistochemistry previously showed that the appearance of the cartilage extracellular matrix (ECM in targeted mouse models of these diseases is disrupted; however, the precise changes in ECM organization and the pathological consequences remain unknown. Our aim was to determine the effects of matrilin-3 and COMP mutations on the composition and extractability of ECM components to inform how these detrimental changes might influence cartilage organization and degeneration. Cartilage was sequentially extracted using increasing denaturants and the extraction profiles of specific proteins determined using SDS-PAGE/Western blotting. Furthermore, the relative composition of protein pools was determined using mass spectrometry for a non-biased semi-quantitative analysis. Western blotting revealed changes in the extraction of matrilins, COMP and collagen IX in mutant cartilage. Mass spectrometry confirmed quantitative changes in the extraction of structural and non-structural ECM proteins, including proteins with roles in cellular processes such as protein folding and trafficking. In particular, genotype-specific differences in the extraction of collagens XII and XIV and tenascins C and X were identified; interestingly, increased expression of several of these genes has recently been implicated in susceptibility and/or progression of murine osteoarthritis. We demonstrated that mutation of matrilin-3 and COMP caused changes in the extractability of other cartilage proteins and that proteomic analyses of Matn3 V194D, Comp T585M and Comp DelD469 mouse models revealed both common and discrete disease signatures that provide novel insight into skeletal disease mechanisms and cartilage degradation.

  16. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease

    Science.gov (United States)

    Savarino, E; Pohl, D; Zentilin, P; Dulbecco, P; Sammito, G; Sconfienza, L; Vigneri, S; Camerini, G; Tutuian, R; Savarino, V

    2009-01-01

    Introduction: Functional dyspepsia and non-erosive reflux disease (NERD) are prevalent gastrointestinal conditions with accumulating evidence regarding an overlap between the two. Still, patients with NERD represent a very heterogeneous group and limited data on dyspeptic symptoms in various subgroups of NERD are available. Aim: To evaluate the prevalence of dyspeptic symptoms in patients with NERD subclassified by using 24 h impedance-pH monitoring (MII-pH). Methods: Patients with typical reflux symptoms and normal endoscopy underwent impedance-pH monitoring off proton pump inhibitor treatment. Oesophageal acid exposure time (AET), type of acid and non-acid reflux episodes, and symptom association probability (SAP) were calculated. A validated dyspepsia questionnaire was used to quantify dyspeptic symptoms prior to reflux monitoring. Results: Of 200 patients with NERD (105 female; median age, 48 years), 81 (41%) had an abnormal oesophageal AET (NERD pH-POS), 65 (32%) had normal oesophageal AET and positive SAP for acid and/or non-acid reflux (hypersensitive oesophagus), and 54 (27%) had normal oesophageal AET and negative SAP (functional heartburn). Patients with functional heartburn had more frequent (pheartburn reinforces the concept that functional gastrointestinal disorders extend beyond the boundaries suggested by the anatomical location of symptoms. This should be regarded as a further argument to test patients with symptoms of gastro-oesophageal reflux disease in order to separate patients with functional heartburn from patients with NERD in whom symptoms are associated with gastro-oesophageal reflux. PMID:19460766

  17. A strategy for minimizing common mode human error in executing critical functions and tasks

    International Nuclear Information System (INIS)

    Beltracchi, L.; Lindsay, R.W.

    1992-01-01

    Human error in execution of critical functions and tasks can be costly. The Three Mile Island and the Chernobyl Accidents are examples of results from human error in the nuclear industry. There are similar errors that could no doubt be cited from other industries. This paper discusses a strategy to minimize common mode human error in the execution of critical functions and tasks. The strategy consists of the use of human redundancy, and also diversity in human cognitive behavior: skill-, rule-, and knowledge-based behavior. The authors contend that the use of diversity in human cognitive behavior is possible, and it minimizes common mode error

  18. Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules.

    Science.gov (United States)

    Tikka, Saara; Monogioudi, Evanthia; Gotsopoulos, Athanasios; Soliymani, Rabah; Pezzini, Francesco; Scifo, Enzo; Uusi-Rauva, Kristiina; Tyynelä, Jaana; Baumann, Marc; Jalanko, Anu; Simonati, Alessandro; Lalowski, Maciej

    2016-03-01

    Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood

  19. Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate

    Science.gov (United States)

    Mangold, Elisabeth; Böhmer, Anne C.; Ishorst, Nina; Hoebel, Ann-Kathrin; Gültepe, Pinar; Schuenke, Hannah; Klamt, Johanna; Hofmann, Andrea; Gölz, Lina; Raff, Ruth; Tessmann, Peter; Nowak, Stefanie; Reutter, Heiko; Hemprich, Alexander; Kreusch, Thomas; Kramer, Franz-Josef; Braumann, Bert; Reich, Rudolf; Schmidt, Gül; Jäger, Andreas; Reiter, Rudolf; Brosch, Sibylle; Stavusis, Janis; Ishida, Miho; Seselgyte, Rimante; Moore, Gudrun E.; Nöthen, Markus M.; Borck, Guntram; Aldhorae, Khalid A.; Lace, Baiba; Stanier, Philip; Knapp, Michael; Ludwig, Kerstin U.

    2016-01-01

    Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10−2). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10−5; ORallelic = 2.46 [95% CI 1.6–3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10−9). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO. PMID:27018475

  20. Common variants in Mendelian kidney disease genes and their association with renal function.

    Science.gov (United States)

    Parsa, Afshin; Fuchsberger, Christian; Köttgen, Anna; O'Seaghdha, Conall M; Pattaro, Cristian; de Andrade, Mariza; Chasman, Daniel I; Teumer, Alexander; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Kim, Young J; Taliun, Daniel; Li, Man; Feitosa, Mary; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C; Glazer, Nicole; Isaacs, Aaron; Rao, Madhumathi; Smith, Albert V; O'Connell, Jeffrey R; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Hwang, Shih-Jen; Atkinson, Elizabeth J; Lohman, Kurt; Cornelis, Marilyn C; Johansson, Asa; Tönjes, Anke; Dehghan, Abbas; Couraki, Vincent; Holliday, Elizabeth G; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B; Launer, Lenore J; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D; Boerwinkle, Eric; Schmidt, Helena; Hofer, Edith; Hu, Frank; Demirkan, Ayse; Oostra, Ben A; Turner, Stephen T; Ding, Jingzhong; Andrews, Jeanette S; Freedman, Barry I; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H-Erich; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H; Wright, Alan F; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G; Rivadeneira, Fernando; Aulchenko, Yurii S; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K; Portas, Laura; Ford, Ian; Buckley, Brendan M; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J Wouter; Probst-Hensch, Nicole M; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; van Duijn, Cornelia M; Borecki, Ingrid; Kardia, Sharon L R; Liu, Yongmei; Curhan, Gary C; Rudan, Igor; Gyllensten, Ulf; Wilson, James F; Franke, Andre; Pramstaller, Peter P; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M; Bochud, Murielle; Heid, Iris M; Siscovick, David S; Fox, Caroline S; Kao, W Linda; Böger, Carsten A

    2013-12-01

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

  1. Biospectroscopy reveals the effect of varying water quality on tadpole tissues of the common frog (Rana temporaria).

    Science.gov (United States)

    Strong, Rebecca J; Halsall, Crispin J; Ferenčík, Martin; Jones, Kevin C; Shore, Richard F; Martin, Francis L

    2016-06-01

    Amphibians are undergoing large population declines in many regions around the world. As environmental pollution from both agricultural and urban sources has been implicated in such declines, there is a need for a biomonitoring approach to study potential impacts on this vulnerable class of organism. This study assessed the use of infrared (IR) spectroscopy as a tool to detect changes in several tissues (liver, muscle, kidney, heart and skin) of late-stage common frog (Rana temporaria) tadpoles collected from ponds with differing water quality. Small differences in spectral signatures were revealed between a rural agricultural pond and an urban pond receiving wastewater and landfill run-off; these were limited to the liver and heart, although large differences in body size were apparent, surprisingly with tadpoles from the urban site larger than those from the rural site. Large differences in liver spectra were found between tadpoles from the pesticide and nutrient impacted pond compared to the rural agricultural pond, particularly in regions associated with lipids. Liver mass and hepatosomatic indices were found to be significantly increased in tadpoles from the site impacted by pesticides and trace organic chemicals, suggestive of exposure to environmental contamination. Significant alterations were also found in muscle tissue between tadpoles from these two ponds in regions associated with glycogen, potentially indicative of a stress response. This study highlights the use of IR spectroscopy, a low-cost, rapid and reagent-free technique in the biomonitoring of a class of organisms susceptible to environmental degradation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Computational study of the fibril organization of polyglutamine repeats reveals a common motif identified in beta-helices.

    Science.gov (United States)

    Zanuy, David; Gunasekaran, Kannan; Lesk, Arthur M; Nussinov, Ruth

    2006-04-21

    The formation of fibril aggregates by long polyglutamine sequences is assumed to play a major role in neurodegenerative diseases such as Huntington. Here, we model peptides rich in glutamine, through a series of molecular dynamics simulations. Starting from a rigid nanotube-like conformation, we have obtained a new conformational template that shares structural features of a tubular helix and of a beta-helix conformational organization. Our new model can be described as a super-helical arrangement of flat beta-sheet segments linked by planar turns or bends. Interestingly, our comprehensive analysis of the Protein Data Bank reveals that this is a common motif in beta-helices (termed beta-bend), although it has not been identified so far. The motif is based on the alternation of beta-sheet and helical conformation as the protein sequence is followed from the N to the C termini (beta-alpha(R)-beta-polyPro-beta). We further identify this motif in the ssNMR structure of the protofibril of the amyloidogenic peptide Abeta(1-40). The recurrence of the beta-bend suggests a general mode of connecting long parallel beta-sheet segments that would allow the growth of partially ordered fibril structures. The design allows the peptide backbone to change direction with a minimal loss of main chain hydrogen bonds. The identification of a coherent organization beyond that of the beta-sheet segments in different folds rich in parallel beta-sheets suggests a higher degree of ordered structure in protein fibrils, in agreement with their low solubility and dense molecular packing.

  3. 28 CFR 0.135 - Functions common to heads of organizational units.

    Science.gov (United States)

    2010-07-01

    ... organizational unit authority and responsibility for the reallotment of such funds and control of obligations and... organizational units. 0.135 Section 0.135 Judicial Administration DEPARTMENT OF JUSTICE ORGANIZATION OF THE... Disqualification to Act § 0.135 Functions common to heads of organizational units. Subject to the general...

  4. Loss of Retinal Function and Pigment Epithelium Changes in a Patient with Common Variable Immunodeficiency

    Directory of Open Access Journals (Sweden)

    Jakob Halborg

    2012-01-01

    Full Text Available Common variable immunodeficiency (CVID has only scarcely been associated with ocular symptoms and rarely with retinal disease. In this case we describe a patient with distinct morphological and functional alterations in the retina. The patient presents with characteristic changes in retinal pigment epithelium, autofluorescence, and electrophysiology.

  5. Revealing the functions of the transketolase enzyme isoforms in Rhodopseudomonas palustris using a systems biology approach.

    Directory of Open Access Journals (Sweden)

    Chia-Wei Hu

    Full Text Available BACKGROUND: Rhodopseudomonas palustris (R. palustris is a purple non-sulfur anoxygenic phototrophic bacterium that belongs to the class of proteobacteria. It is capable of absorbing atmospheric carbon dioxide and converting it to biomass via the process of photosynthesis and the Calvin-Benson-Bassham (CBB cycle. Transketolase is a key enzyme involved in the CBB cycle. Here, we reveal the functions of transketolase isoforms I and II in R. palustris using a systems biology approach. METHODOLOGY/PRINCIPAL FINDINGS: By measuring growth ability, we found that transketolase could enhance the autotrophic growth and biomass production of R. palustris. Microarray and real-time quantitative PCR revealed that transketolase isoforms I and II were involved in different carbon metabolic pathways. In addition, immunogold staining demonstrated that the two transketolase isoforms had different spatial localizations: transketolase I was primarily associated with the intracytoplasmic membrane (ICM but transketolase II was mostly distributed in the cytoplasm. Comparative proteomic analysis and network construction of transketolase over-expression and negative control (NC strains revealed that protein folding, transcriptional regulation, amino acid transport and CBB cycle-associated carbon metabolism were enriched in the transketolase I over-expressed strain. In contrast, ATP synthesis, carbohydrate transport, glycolysis-associated carbon metabolism and CBB cycle-associated carbon metabolism were enriched in the transketolase II over-expressed strain. Furthermore, ATP synthesis assays showed a significant increase in ATP synthesis in the transketolase II over-expressed strain. A PEPCK activity assay showed that PEPCK activity was higher in transketolase over-expressed strains than in the negative control strain. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that the two isoforms of transketolase in R. palustris could affect photoautotrophic growth

  6. Comparative Evaluation of Functional Properties of Some Commonly Used Cereal and Legume Flours and Their Blends

    Directory of Open Access Journals (Sweden)

    Haq Nawaz

    2015-12-01

    Full Text Available Functional properties such as protein solubility, swelling capacity, water holding capacity, gelling ability, bulk density and foaming capacity of flours of some commonly used cereals and legume (wheat, refined wheat, maize and chickpea and their blends were studied. Blends of flours were prepared by mixing equal proportions of selected floors. Statistically significant difference  in studied functional properties except bulk density was observed among cereal flours and their blends. Chickpea flour was found to possess comparatively high water holding capacity, protein solubility index and swelling capacity. The functional properties of maize and wheat flours were found to be improved when blended with chickpea. Chickpea flour and its blends with cereal flours were found to possess good functional score and suggested as favorable candidates for use in the preparation of viscous foods and bakery products. The data provide guidelines regarding the improvement in functional properties of economically favorable cereal flours.

  7. Inter-species activity correlations reveal functional correspondences between monkey and human brain areas

    Science.gov (United States)

    Mantini, Dante; Hasson, Uri; Betti, Viviana; Perrucci, Mauro G.; Romani, Gian Luca; Corbetta, Maurizio; Orban, Guy A.; Vanduffel, Wim

    2012-01-01

    Evolution-driven functional changes in the primate brain are typically assessed by aligning monkey and human activation maps using cortical surface expansion models. These models use putative homologous areas as registration landmarks, assuming they are functionally correspondent. In cases where functional changes have occurred in an area, this assumption prohibits to reveal whether other areas may have assumed lost functions. Here we describe a method to examine functional correspondences across species. Without making spatial assumptions, we assess similarities in sensory-driven functional magnetic resonance imaging responses between monkey (Macaca mulatta) and human brain areas by means of temporal correlation. Using natural vision data, we reveal regions for which functional processing has shifted to topologically divergent locations during evolution. We conclude that substantial evolution-driven functional reorganizations have occurred, not always consistent with cortical expansion processes. This novel framework for evaluating changes in functional architecture is crucial to building more accurate evolutionary models. PMID:22306809

  8. Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels.

    Science.gov (United States)

    Shaya, David; Findeisen, Felix; Abderemane-Ali, Fayal; Arrigoni, Cristina; Wong, Stephanie; Nurva, Shailika Reddy; Loussouarn, Gildas; Minor, Daniel L

    2014-01-23

    Voltage-gated sodium channels (NaVs) are central elements of cellular excitation. Notwithstanding advances from recent bacterial NaV (BacNaV) structures, key questions about gating and ion selectivity remain. Here, we present a closed conformation of NaVAe1p, a pore-only BacNaV derived from NaVAe1, a BacNaV from the arsenite oxidizer Alkalilimnicola ehrlichei found in Mono Lake, California, that provides insight into both fundamental properties. The structure reveals a pore domain in which the pore-lining S6 helix connects to a helical cytoplasmic tail. Electrophysiological studies of full-length BacNaVs show that two elements defined by the NaVAe1p structure, an S6 activation gate position and the cytoplasmic tail "neck", are central to BacNaV gating. The structure also reveals the selectivity filter ion entry site, termed the "outer ion" site. Comparison with mammalian voltage-gated calcium channel (CaV) selectivity filters, together with functional studies, shows that this site forms a previously unknown determinant of CaV high-affinity calcium binding. Our findings underscore commonalities between BacNaVs and eukaryotic voltage-gated channels and provide a framework for understanding gating and ion permeation in this superfamily. © 2013. Published by Elsevier Ltd. All rights reserved.

  9. Commonalities in Development of Pure Breeds and Population Isolates Revealed in the Genome of the Sardinian Fonni's Dog

    Science.gov (United States)

    Dreger, Dayna L.; Davis, Brian W.; Cocco, Raffaella; Sechi, Sara; Di Cerbo, Alessandro; Parker, Heidi G.; Polli, Michele; Marelli, Stefano P.; Crepaldi, Paola; Ostrander, Elaine A.

    2016-01-01

    The island inhabitants of Sardinia have long been a focus for studies of complex human traits due to their unique ancestral background and population isolation reflecting geographic and cultural restriction. Population isolates share decreased genomic diversity, increased linkage disequilibrium, and increased inbreeding coefficients. In many regions, dogs and humans have been exposed to the same natural and artificial forces of environment, growth, and migration. Distinct dog breeds have arisen through human-driven selection of characteristics to meet an ideal standard of appearance and function. The Fonni’s Dog, an endemic dog population on Sardinia, has not been subjected to an intensive system of artificial selection, but rather has developed alongside the human population of Sardinia, influenced by geographic isolation and unregulated selection based on its environmental adaptation and aptitude for owner-desired behaviors. Through analysis of 28 dog breeds, represented with whole-genome sequences from 13 dogs and ∼170,000 genome-wide single nucleotide variants from 155 dogs, we have produced a genomic illustration of the Fonni’s Dog. Genomic patterns confirm within-breed similarity, while population and demographic analyses provide spatial identity of Fonni’s Dog to other Mediterranean breeds. Investigation of admixture and fixation indices reveals insights into the involvement of Fonni’s Dogs in breed development throughout the Mediterranean. We describe how characteristics of population isolates are reflected in dog breeds that have undergone artificial selection, and are mirrored in the Fonni’s Dog through traditional isolating factors that affect human populations. Lastly, we show that the genetic history of Fonni’s Dog parallels demographic events in local human populations. PMID:27519604

  10. A preliminary investigation of sleep quality in functional neurological disorders: Poor sleep appears common, and is associated with functional impairment.

    Science.gov (United States)

    Graham, Christopher D; Kyle, Simon D

    2017-07-15

    Functional neurological disorders (FND) are disabling conditions for which there are few empirically-supported treatments. Disturbed sleep appears to be part of the FND context; however, the clinical importance of sleep disturbance (extent, characteristics and impact) remains largely unknown. We described sleep quality in two samples, and investigated the relationship between sleep and FND-related functional impairment. We included a sample recruited online via patient charities (N=205) and a consecutive clinical sample (N=20). Participants completed validated measures of sleep quality and sleep characteristics (e.g. total sleep time, sleep efficiency), mood, and FND-related functional impairment. Poor sleep was common in both samples (89% in the clinical range), which was characterised by low sleep efficiency (M=65.40%) and low total sleep time (M=6.05h). In regression analysis, sleep quality was negatively associated with FND-related functional impairment, accounting for 16% of the variance and remaining significant after the introduction of mood variables. These preliminary analyses suggest that subjective sleep disturbance (low efficiency, short sleep) is common in FND. Sleep quality was negatively associated with the functional impairment attributed to FND, independent of depression. Therefore, sleep disturbance may be a clinically important feature of FND. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. The Effect of Endovascular Revascularization of Common Iliac Artery Occlusions on Erectile Function

    International Nuclear Information System (INIS)

    Gur, Serkan; Ozkan, Uğur; Onder, Hakan; Tekbas, Güven; Oguzkurt, Levent

    2013-01-01

    To determine the incidence of erectile dysfunction in patients with common iliac artery (CIA) occlusive disease and the effect of revascularization on erectile function using the sexual health inventory for males (SHIM) questionnaire. All patients (35 men; mean age 57 ± 5 years; range 42–67 years) were asked to recall their sexual function before and 1 month after iliac recanalization. Univariate and multivariate analyses were performed to determine variables effecting improvement of impotence. The incidence of impotence in patients with CIA occlusion was 74% (26 of 35) preoperatively. Overall 16 (46%) of 35 patients reported improved erectile function after iliac recanalization. The rate of improvement of impotence was 61.5% (16 of 26 impotent patients). Sixteen patients (46%), including seven with normal erectile function before the procedure, had no change. Three patients (8%) reported deterioration of their sexual function, two of whom (6%) had normal erectile function before the procedure. The median SHIM score increased from 14 (range 4–25) before the procedure to 20 (range 1–25) after the procedure (P = 0.005). The type of recanalization, the age of the patients, and the length of occlusion were related to erectile function improvement in univariate analysis. However, these factors were not independent factors for improvement of erectile dysfunction in multivariate analysis (P > 0.05). Endovascular recanalization of CIA occlusions clearly improves sexual function. More than half of the patients with erectile dysfunction who underwent endovascular recanalization of the CIA experienced improvement.

  12. The Effect of Endovascular Revascularization of Common Iliac Artery Occlusions on Erectile Function

    Energy Technology Data Exchange (ETDEWEB)

    Gur, Serkan, E-mail: mserkangur@yahoo.com [Sifa Hospital, Department of Radiology (Turkey); Ozkan, Ugur [Baskent University, Department of Radiology, Faculty of Medicine (Turkey); Onder, Hakan; Tekbas, Gueven [Dicle University, Department of Radiology, Faculty of Medicine (Turkey); Oguzkurt, Levent [Baskent University, Department of Radiology, Faculty of Medicine (Turkey)

    2013-02-15

    To determine the incidence of erectile dysfunction in patients with common iliac artery (CIA) occlusive disease and the effect of revascularization on erectile function using the sexual health inventory for males (SHIM) questionnaire. All patients (35 men; mean age 57 {+-} 5 years; range 42-67 years) were asked to recall their sexual function before and 1 month after iliac recanalization. Univariate and multivariate analyses were performed to determine variables effecting improvement of impotence. The incidence of impotence in patients with CIA occlusion was 74% (26 of 35) preoperatively. Overall 16 (46%) of 35 patients reported improved erectile function after iliac recanalization. The rate of improvement of impotence was 61.5% (16 of 26 impotent patients). Sixteen patients (46%), including seven with normal erectile function before the procedure, had no change. Three patients (8%) reported deterioration of their sexual function, two of whom (6%) had normal erectile function before the procedure. The median SHIM score increased from 14 (range 4-25) before the procedure to 20 (range 1-25) after the procedure (P = 0.005). The type of recanalization, the age of the patients, and the length of occlusion were related to erectile function improvement in univariate analysis. However, these factors were not independent factors for improvement of erectile dysfunction in multivariate analysis (P > 0.05). Endovascular recanalization of CIA occlusions clearly improves sexual function. More than half of the patients with erectile dysfunction who underwent endovascular recanalization of the CIA experienced improvement.

  13. Overview of Four Functional Classification Systems Commonly Used in Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Andrea Paulson

    2017-04-01

    Full Text Available Cerebral palsy (CP is the most common physical disability in childhood. CP comprises a heterogeneous group of disorders that can result in spasticity, dystonia, muscle contractures, weakness and coordination difficulty that ultimately affects the ability to control movements. Traditionally, CP has been classified using a combination of the motor type and the topographical distribution, as well as subjective severity level. Imprecise terms such as these tell very little about what a person is able to do functionally and can impair clear communication between providers. More recently, classification systems have been created employing a simple ordinal grading system of functional performance. These systems allow a more precise discussion between providers, as well as better subject stratification for research. The goal of this review is to describe four common functional classification systems for cerebral palsy: the Gross Motor Function Classification System (GMFCS, the Manual Ability Classification System (MACS, the Communication Function Classification System (CFCS, and the Eating and Drinking Ability Classification System (EDACS. These measures are all standardized, reliable, and complementary to one another.

  14. Chronic Exposure to Tributyltin Induces Brain Functional Damage in Juvenile Common Carp (Cyprinus carpio)

    OpenAIRE

    Li, Zhi-Hua; Li, Ping; Shi, Ze-Chao

    2015-01-01

    The aim of the present study was to investigate the effect of Tributyltin (TBT) on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase), Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide) in the brain of common carp were evaluated. Fish we...

  15. A hierarchical analysis of transcriptome alterations in intrauterine growth restriction (IUGR) reveals common pathophysiological pathways in mammals.

    Science.gov (United States)

    Buffat, C; Mondon, F; Rigourd, V; Boubred, F; Bessières, B; Fayol, L; Feuerstein, J-M; Gamerre, M; Jammes, H; Rebourcet, R; Miralles, F; Courbières, B; Basire, A; Dignat-Georges, F; Carbonne, B; Simeoni, U; Vaiman, D

    2007-11-01

    Intra-uterine growth restriction (IUGR) is a frequent disease, affecting up to 10% of human pregnancies and responsible for increased perinatal morbidity and mortality. Moreover, low birth weight is an important cause of the metabolic syndrome in the adult. Protein depletion during the gestation of rat females has been widely used as a model for human IUGR. By transcriptome analysis of control and protein-deprived rat placentas, we were able to identify 2543 transcripts modified more than 2.5 fold (1347 induced and 1196 repressed). Automatic functional classification enabled us to identify clusters of induced genes affecting chromosome structure, transcription, intracellular transport, protein modifications and apoptosis. In particular, we suggest the existence of a complex balance regulating apoptosis. Among repressed genes, we noted several groups of genes involved in immunity, signalling and degradation of noxious chemicals. These observations suggest that IUGR placentas have a decreased resistance to external aggression. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites. There was an over-representation of Zn finger (ZNF) proteins and Pdx1 (pancreatic and duodenal homeobox protein 1) putative binding sites. Consistently, Pdx1 and a high proportion of ZNF genes were induced at the transcriptional level. A similar analysis of ZNF promoters showed an increased presence of putative binding sites for the Tata box binding protein (Tbp). Consistently again, we showed that the Tbp and TBP-associated factors (Tafs) were up-regulated in IUGR placentas. Also, samples of human IUGR and control placentas showed that human orthologous ZNFs and PDX1 were transcriptionally induced, especially in non-vascular IUGR. Immunohistochemistry revealed increased expression of PDX1 in IUGR human placentas. In conclusion, our approach permitted the proposition of hypotheses on a hierarchy of

  16. Effects of common mental disorders and physical conditions on role functioning in Spain.

    Science.gov (United States)

    Barbaglia, Gabriela; Duran, Núria; Vilagut, Gemma; Forero, Carlos García; Haro, Josep Maria; Alonso, Jordi

    2013-01-01

    To examine the effects of common mental disorders and physical conditions on role functioning in Spain. Cross-sectional study of the general adult population of Spain (n = 2,121). Non-psychotic mental disorders were assessed with the Composite International Diagnostic Interview (CIDI 3.0) and physical conditions with a checklist. The role functioning dimension of the WHO-Disability Assessment Schedule (WHODAS) was used to asses the number of days in the past month in which respondents were fully or partially limited to perform daily activities. Generalized linear models were used to estimate individual-level associations of specific conditions and role functioning, controlling for co-morbidity. Societal level estimates were calculated using population attributable risk proportions (PARP). Mental disorders and physical conditions showed similar number of days with full role limitation (about 20 days per year); in contrast mental disorders were responsible for twice as many days with partial role limitation than physical conditions (42 vs 21 days, respectively). If the population were entirely unexposed to mental and physical conditions, days with full limitation would be reduced by 73% and days with partial limitation by 41%. Common health conditions in Spain are associated with considerably more days with role limitation than other Western countries. There is need of mainstreaming disability in the Spanish public health agenda in order to reduce role limitation among individuals with common conditions. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

  17. Impaired work functioning due to common mental disorders in nurses and allied health professionals: the Nurses Work Functioning Questionnaire.

    Science.gov (United States)

    Gärtner, F R; Nieuwenhuijsen, K; van Dijk, F J H; Sluiter, J K

    2012-02-01

    Common mental disorders (CMD) negatively affect work functioning. In the health service sector not only the prevalence of CMDs is high, but work functioning problems are associated with a risk of serious consequences for patients and healthcare providers. If work functioning problems due to CMDs are detected early, timely help can be provided. Therefore, the aim of this study is to develop a detection questionnaire for impaired work functioning due to CMDs in nurses and allied health professionals working in hospitals. First, an item pool was developed by a systematic literature study and five focus group interviews with employees and experts. To evaluate the content validity, additional interviews were held. Second, a cross-sectional assessment of the item pool in 314 nurses and allied health professionals was used for item selection and for identification and corroboration of subscales by explorative and confirmatory factor analysis. The study results in the Nurses Work Functioning Questionnaire (NWFQ), a 50-item self-report questionnaire consisting of seven subscales: cognitive aspects of task execution, impaired decision making, causing incidents at work, avoidance behavior, conflicts and irritations with colleagues, impaired contact with patients and their family, and lack of energy and motivation. The questionnaire has a proven high content validity. All subscales have good or acceptable internal consistency. The Nurses Work Functioning Questionnaire gives insight into precise and concrete aspects of impaired work functioning of nurses and allied health professionals. The scores can be used as a starting point for purposeful interventions.

  18. Configuration space analysis of common cost functions in radiotherapy beam-weight optimization algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Rowbottom, Carl Graham [Joint Department of Physics, Institute of Cancer Research and the Royal Marsden NHS Trust, Sutton, Surrey (United Kingdom); Webb, Steve [Joint Department of Physics, Institute of Cancer Research and the Royal Marsden NHS Trust, Sutton, Surrey (United Kingdom)

    2002-01-07

    The successful implementation of downhill search engines in radiotherapy optimization algorithms depends on the absence of local minima in the search space. Such techniques are much faster than stochastic optimization methods but may become trapped in local minima if they exist. A technique known as 'configuration space analysis' was applied to examine the search space of cost functions used in radiotherapy beam-weight optimization algorithms. A downhill-simplex beam-weight optimization algorithm was run repeatedly to produce a frequency distribution of final cost values. By plotting the frequency distribution as a function of final cost, the existence of local minima can be determined. Common cost functions such as the quadratic deviation of dose to the planning target volume (PTV), integral dose to organs-at-risk (OARs), dose-threshold and dose-volume constraints for OARs were studied. Combinations of the cost functions were also considered. The simple cost function terms such as the quadratic PTV dose and integral dose to OAR cost function terms are not susceptible to local minima. In contrast, dose-threshold and dose-volume OAR constraint cost function terms are able to produce local minima in the example case studied. (author)

  19. Functional fixedness and functional reduction as common sense reasonings in chemical equilibrium and in geometry and polarity of molecules

    Science.gov (United States)

    Furió, C.; Calatayud, M. L.; Bárcenas, S. L.; Padilla, O. M.

    2000-09-01

    Many of the learning difficulties in the specific domain of chemistry are found not only in the ideas already possessed by students but in the strategic and procedural knowledge that is characteristic of everyday thinking. These defects in procedural knowledge have been described as functional fixedness and functional reduction. This article assesses the procedural difficulties of students (grade 12 and first and third year of university) based on common sense reasoning in two areas of chemistry: chemical equilibrium and geometry and polarity of molecules. In the first area, the theme of external factors affecting equilibria (temperature and concentration change) was selected because the explanations given by the students could be analyzed easily. The existence of a functional fixedness where Le Chatelier's principle was almost exclusively applied by rote could be observed, with this being the cause of the incorrect responses given to the proposed items. Functional fixedness of the Lewis structure also led to an incorrect prediction of molecular geometry. When molecular geometry was correctly determined by the students, it seemed that other methodological or procedural difficulties appeared when the task was to determine molecular polarity. The students showed a tendency, in many cases, to reduce the factors affecting molecular polarity in two possible ways: (a) assuming that polarity depends only on shape (geometric functional reduction) or (b) assuming that molecular polarity depends only on the polarity of bonds (bonding functional reduction).

  20. Commonly Employed African Neonatal Skin Care Products Compromise Epidermal Function in Mice.

    Science.gov (United States)

    Man, Mao-Qiang; Sun, Richard; Man, George; Lee, Dale; Hill, Zelee; Elias, Peter M

    2016-09-01

    Neonatal mortality is much higher in the developing world than in developed countries. Infections are a major cause of neonatal death, particularly in preterm infants, in whom defective epidermal permeability barrier function facilitates transcutaneous pathogen invasion. The objective was to determine whether neonatal skin care products commonly used in Africa benefit or compromise epidermal functions in murine skin. After twice-daily treatment of 6- to 8-week-old hairless mice with each skin care product for 3 days, epidermal permeability barrier function, skin surface pH, stratum corneum hydration, and barrier recovery were measured using a multiprobe adapter system physiology monitor. For products showing some benefits in these initial tests, the epidermal permeability barrier homeostasis was assessed 1 and 5 hours after a single application to acutely disrupted skin. All of the skin care products compromised basal permeability barrier function and barrier repair kinetics. Moreover, after 3 days of treatment, most of the products also reduced stratum corneum hydration while elevating skin surface pH to abnormal levels. Some neonatal skin care products that are widely used in Africa perturb important epidermal functions, including permeability barrier homeostasis in mice. Should these products have similar effects on newborn human skin, they could cause a defective epidermal permeability barrier, which can increase body fluid loss, impair thermoregulation, and contribute to the high rates of neonatal morbidity and mortality seen in Africa. Accordingly, alternative products that enhance permeability barrier function should be identified, particularly for use in preterm infants. © 2016 Wiley Periodicals, Inc.

  1. Ultrasound versus liver function tests for diagnosis of common bile duct stones.

    Science.gov (United States)

    Gurusamy, Kurinchi Selvan; Giljaca, Vanja; Takwoingi, Yemisi; Higgie, David; Poropat, Goran; Štimac, Davor; Davidson, Brian R

    2015-02-26

    Ultrasound and liver function tests (serum bilirubin and serum alkaline phosphatase) are used as screening tests for the diagnosis of common bile duct stones in people suspected of having common bile duct stones. There has been no systematic review of the diagnostic accuracy of ultrasound and liver function tests. To determine and compare the accuracy of ultrasound versus liver function tests for the diagnosis of common bile duct stones. We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov to September 2012. We searched the references of included studies to identify further studies and systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects, Health Technology Assessment, Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. We included studies that provided the number of true positives, false positives, false negatives, and true negatives for ultrasound, serum bilirubin, or serum alkaline phosphatase. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test result, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct, or symptom-free follow-up for at least six months for a negative test result as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones, with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors screened abstracts and selected studies for inclusion independently. Two authors independently collected data from

  2. Evaluation of common mode failure of safety functions for limiting fault events

    International Nuclear Information System (INIS)

    Rezendes, J.P.; Hyde, A.W.

    2004-01-01

    The draft U.S. Nuclear Regulatory Commission (NRC) policy on digital protection system software requires all Advanced Light Water Reactors (ALWRs) to be evaluated assuming a hypothetical common mode failure (CMF) which incapacitates the normal automatic initiation of safety functions. The System 80 + ALWR has been evaluated for such hypothetical conditions. The results show that the diverse automatic and manual protective systems in System 80 + provide ample safety performance margins relative to core coolability, offsite radiological releases. Reactor Coolant System (RCS) pressurization and containment integrity. This deterministic evaluation served to quantify the significant inherent safety margins in the System 80 + Standard Plant design even in the event of this extremely low probability scenario of a common mode failure. (author)

  3. Functional proteomic analyses of Bothrops atrox venom reveals phenotypes associated with habitat variation in the Amazon.

    Science.gov (United States)

    Sousa, Leijiane F; Portes-Junior, José A; Nicolau, Carolina A; Bernardoni, Juliana L; Nishiyama, Milton Y; Amazonas, Diana R; Freitas-de-Sousa, Luciana A; Mourão, Rosa Hv; Chalkidis, Hipócrates M; Valente, Richard H; Moura-da-Silva, Ana M

    2017-04-21

    Venom variability is commonly reported for venomous snakes including Bothrops atrox. Here, we compared the composition of venoms from B. atrox snakes collected at Amazonian conserved habitats (terra-firme upland forest and várzea) and human modified areas (pasture and degraded areas). Venom samples were submitted to shotgun proteomic analysis as a whole or compared after fractionation by reversed-phase chromatography. Whole venom proteomes revealed a similar composition among the venoms with predominance of SVMPs, CTLs, and SVSPs and intermediate amounts of PLA 2 s and LAAOs. However, when distribution of particular isoforms was analyzed by either method, the venom from várzea snakes showed a decrease in hemorrhagic SVMPs and an increase in SVSPs, and procoagulant SVMPs and PLA 2 s. These differences were validated by experimental approaches including both enzymatic and in vivo assays, and indicated restrictions in respect to antivenom efficacy to variable components. Thus, proteomic analysis at the isoform level combined to in silico prediction of functional properties may indicate venom biological activity. These results also suggest that the prevalence of functionally distinct isoforms contributes to the variability of the venoms and could reflect the adaptation of B. atrox to distinct prey communities in different Amazon habitats. In this report, we compared isoforms present in venoms from snakes collected at different Amazonian habitats. By means of a species venom gland transcriptome and the in silico functional prediction of each isoform, we were able to predict the principal venom activities in vitro and in animal models. We also showed remarkable differences in the venom pools from snakes collected at the floodplain (várzea habitat) compared to other habitats. Not only was this venom less hemorrhagic and more procoagulant, when compared to the venom pools from the other three habitats studied, but also this enhanced procoagulant activity was not

  4. Phylogeny and phylogeography of functional genes shared among seven terrestrial subsurface metagenomes reveal N-cycling and microbial evolutionary relationships

    Directory of Open Access Journals (Sweden)

    Maggie CY Lau

    2014-10-01

    Full Text Available Comparative studies on community phylogenetics and phylogeography of microorganisms living in extreme environments are rare. Terrestrial subsurface habitats are valuable for studying microbial biogeographical patterns due to their isolation and the restricted dispersal mechanisms. Since the taxonomic identity of a microorganism does not always correspond well with its functional role in a particular community, the use of taxonomic assignments or patterns may give limited inference on how microbial functions are affected by historical, geographical and environmental factors. With seven metagenomic libraries generated from fracture water samples collected from five South African mines, this study was carried out to (1 screen for ubiquitous functions or pathways of biogeochemical cycling of CH4, S and N; (2 to characterize the biodiversity represented by the common functional genes; (3 to investigate the subsurface biogeography as revealed by this subset of genes; and (4 to explore the possibility of using metagenomic data for evolutionary study. The ubiquitous functional genes are NarV, NPD, PAP reductase, NifH, NifD, NifK, NifE and NifN genes. Although these 8 common functional genes were taxonomically and phylogenetically diverse and distinct from each other, the dissimilarity between samples did not correlate strongly with either geographical, environmental or residence time of the water. Por genes homologous to those of Thermodesulfovibrio yellowstonii detected in all metagenomes were deep lineages of Nitrospirae, suggesting that subsurface habitats have preserved ancestral genetic signatures that inform the study of the origin and evolution of prokaryotes.

  5. A novel fragile X syndrome mutation reveals a conserved role for the carboxy-terminus in FMRP localization and function.

    Science.gov (United States)

    Okray, Zeynep; de Esch, Celine E F; Van Esch, Hilde; Devriendt, Koen; Claeys, Annelies; Yan, Jiekun; Verbeeck, Jelle; Froyen, Guy; Willemsen, Rob; de Vrij, Femke M S; Hassan, Bassem A

    2015-04-01

    Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5' untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR1 mutation and reveal an unexpected nuclear export function for the C-terminus of FMRP. We screened a cohort of patients with typical FXS symptoms who tested negative for CGG repeat expansion in the FMR1 locus. In one patient, we identified a guanine insertion in FMR1 exon 15. This mutation alters the open reading frame creating a short novel C-terminal sequence, followed by a stop codon. We find that this novel peptide encodes a functional nuclear localization signal (NLS) targeting the patient FMRP to the nucleolus in human cells. We also reveal an evolutionarily conserved nuclear export function associated with the endogenous C-terminus of FMRP. In vivo analyses in Drosophila demonstrate that a patient-mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  6. Biospectroscopy reveals the effect of varying water quality on tadpole tissues of the common frog (Rana temporaria)

    OpenAIRE

    Strong, Becky; Halsall, Crispin James; Ferenčík, Martin; Jones, Kevin Christopher; Shore, Richard Francis; Martin, Francis Luke

    2016-01-01

    Amphibians are undergoing large population declines in many regions around the world. As environmental pollution from both agricultural and urban sources has been implicated in such declines, there is a need for a biomonitoring approach to study potential impacts on this vulnerable class of organism. This study assessed the use of infrared (IR) spectroscopy as a tool to detect changes in several tissues (liver, muscle, kidney, heart and skin) of late-stage common frog (Rana temporaria) tadpol...

  7. The CRINE initiative -- Producing the engineering tools (functional specifications and common working practices)

    International Nuclear Information System (INIS)

    Tuft, V.

    1995-01-01

    Alongside culture change, CRINE's other challenge is producing the right tools for the North Sea industry to change its traditional method of operation. CRINE, an acronym for Cost Reduction Initiative for the New Era, is an industry-wide program now underway in the UK Continental Shelf whose main objective is to achieve thirty percent or more savings in capital costs and to half operating costs over the next few years. These tools cover functional specifications, common working practices and quality. Turning these tools into deliverables, and on time, was a mixture of painstaking work and willingness by people to adapt to the needs of the task

  8. Role of Placental VDR Expression and Function in Common Late Pregnancy Disorders

    Directory of Open Access Journals (Sweden)

    Julia Knabl

    2017-11-01

    Full Text Available Vitamin D, besides its classical role in bone metabolism, plays a distinct role in multiple pathways of the feto-maternal unit. Calcitriol is the major active ligand of the nuclear vitamin D receptor (VDR. The vitamin D receptor (VDR is expressed in different uteroplacental parts and exerts a variety of functions in physiologic pregnancy. It regulates decidualisation and implantation, influences hormone secretion and placental immune modulations. This review highlights the role of the vitamin D receptor in physiologic and disturbed pregnancy, as preeclampsia, fetal growth restriction, gestational diabetes and preterm birth. We discuss the existing literature regarding common VDR polymorphisms in these pregnancy disorders.

  9. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb.

    Science.gov (United States)

    Sahay, Amar; Wilson, Donald A; Hen, René

    2011-05-26

    While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, "Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Comparative mRNA and microRNA expression profiling of three genitourinary cancers reveals common hallmarks and cancer-specific molecular events.

    Directory of Open Access Journals (Sweden)

    Xianxin Li

    Full Text Available Genome-wide gene expression profile using deep sequencing technologies can drive the discovery of cancer biomarkers and therapeutic targets. Such efforts are often limited to profiling the expression signature of either mRNA or microRNA (miRNA in a single type of cancer.Here we provided an integrated analysis of the genome-wide mRNA and miRNA expression profiles of three different genitourinary cancers: carcinomas of the bladder, kidney and testis.Our results highlight the general or cancer-specific roles of several genes and miRNAs that may serve as candidate oncogenes or suppressors of tumor development. Further comparative analyses at the systems level revealed that significant aberrations of the cell adhesion process, p53 signaling, calcium signaling, the ECM-receptor and cell cycle pathways, the DNA repair and replication processes and the immune and inflammatory response processes were the common hallmarks of human cancers. Gene sets showing testicular cancer-specific deregulation patterns were mainly implicated in processes related to male reproductive function, and general disruptions of multiple metabolic pathways and processes related to cell migration were the characteristic molecular events for renal and bladder cancer, respectively. Furthermore, we also demonstrated that tumors with the same histological origins and genes with similar functions tended to group together in a clustering analysis. By assessing the correlation between the expression of each miRNA and its targets, we determined that deregulation of 'key' miRNAs may result in the global aberration of one or more pathways or processes as a whole.This systematic analysis deciphered the molecular phenotypes of three genitourinary cancers and investigated their variations at the miRNA level simultaneously. Our results provided a valuable source for future studies and highlighted some promising genes, miRNAs, pathways and processes that may be useful for diagnostic or

  11. Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms.

    Directory of Open Access Journals (Sweden)

    Jonna Jalanka-Tuovinen

    Full Text Available While our knowledge of the intestinal microbiota during disease is accumulating, basic information of the microbiota in healthy subjects is still scarce. The aim of this study was to characterize the intestinal microbiota of healthy adults and specifically address its temporal stability, core microbiota and relation with intestinal symptoms. We carried out a longitudinal study by following a set of 15 healthy Finnish subjects for seven weeks and regularly assessed their intestinal bacteria and archaea with the Human Intestinal Tract (HIT Chip, a phylogenetic microarray, in conjunction with qPCR analyses. The health perception and occurrence of intestinal symptoms was recorded by questionnaire at each sampling point.A high overall temporal stability of the microbiota was observed. Five subjects showed transient microbiota destabilization, which correlated not only with the intake of antibiotics but also with overseas travelling and temporary illness, expanding the hitherto known factors affecting the intestinal microbiota. We identified significant correlations between the microbiota and common intestinal symptoms, including abdominal pain and bloating. The most striking finding was the inverse correlation between Bifidobacteria and abdominal pain: subjects who experienced pain had over five-fold less Bifidobacteria compared to those without pain. Finally, a novel computational approach was used to define the common core microbiota, highlighting the role of the analysis depth in finding the phylogenetic core and estimating its size. The in-depth analysis suggested that we share a substantial number of our intestinal phylotypes but as they represent highly variable proportions of the total community, many of them often remain undetected.A global and high-resolution microbiota analysis was carried out to determine the temporal stability, the associations with intestinal symptoms, and the individual and common core microbiota in healthy adults. The

  12. GWAS signals across the HLA regions: revealing a clue for common etiology underlying infectious tumors and other immunity diseases

    Institute of Scientific and Technical Information of China (English)

    Yin Yao Shugart; Ying Wang; Wei-Hua Jia; Yi-Xin Zeng

    2011-01-01

    Increasing evidence suggests that multiple genes in the human leukocyte antigen (HLA) regions play an important role in development of cancers and immunity disorders. However, the biological mechanisms of the HLA associations are not well understood. We recently conducted a survey of all genome-wide association studies (GWAS) with significant findings in the HLA regions and concluded that diseases such as cancer and immune disorders are more likely to be associated with genetic variants located in the HLA regions than other diseases. This finding is suggestive for testing a hypothesis of a common etiology of infectious tumors and other immunity diseases.

  13. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage.

    Science.gov (United States)

    Bachmann, Rosilla F; Wang, Yun; Yuan, Peixiong; Zhou, Rulun; Li, Xiaoxia; Alesci, Salvatore; Du, Jing; Manji, Husseini K

    2009-07-01

    Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.

  14. Molecular markers reveal spatially segregated cryptic species in a critically endangered fish, the common skate (Dipturus batis).

    Science.gov (United States)

    Griffiths, Andrew M; Sims, David W; Cotterell, Stephen P; El Nagar, Aliya; Ellis, Jim R; Lynghammar, Arve; McHugh, Matthew; Neat, Francis C; Pade, Nicolas G; Queiroz, Nuno; Serra-Pereira, Bárbara; Rapp, Toby; Wearmouth, Victoria J; Genner, Martin J

    2010-05-22

    Many sharks and skates are particularly vulnerable to overfishing because of their large size, slow growth, late maturity and low fecundity. In Europe dramatic population declines have taken place in common skate (Dipturus batis L.), one of the largest demersal fish in regional shelf seas, leading to extirpations from substantial parts of its former range. Here we report the discovery of cryptic species in common skate collected from the northeast Atlantic continental shelf. Data from nuclear microsatellite markers indicated two clearly distinct clades and phylogenetic analysis of mitochondrial DNA sequences demonstrated monophyly of each one of them. Capture locations showed evidence of strong spatial segregation, with one taxon occurring mainly in waters off the southern British Isles and around Rockall, while the other was restricted to more northerly shelf waters. These apparently cryptic species showed overlapping substrate and depth preferences, but distributional limits were closely related to temperature gradients, potentially indicating thermal limits to their distributions. This discovery of hidden diversity within a large, critically endangered marine vertebrate demonstrates how marine biodiversity can be underestimated, even in such a relatively well-studied and heavily exploited region.

  15. Molecular markers reveal spatially segregated cryptic species in a critically endangered fish, the common skate (Dipturus batis)

    Science.gov (United States)

    Griffiths, Andrew M.; Sims, David W.; Cotterell, Stephen P.; El Nagar, Aliya; Ellis, Jim R.; Lynghammar, Arve; McHugh, Matthew; Neat, Francis C.; Pade, Nicolas G.; Queiroz, Nuno; Serra-Pereira, Bárbara; Rapp, Toby; Wearmouth, Victoria J.; Genner, Martin J.

    2010-01-01

    Many sharks and skates are particularly vulnerable to overfishing because of their large size, slow growth, late maturity and low fecundity. In Europe dramatic population declines have taken place in common skate (Dipturus batis L.), one of the largest demersal fish in regional shelf seas, leading to extirpations from substantial parts of its former range. Here we report the discovery of cryptic species in common skate collected from the northeast Atlantic continental shelf. Data from nuclear microsatellite markers indicated two clearly distinct clades and phylogenetic analysis of mitochondrial DNA sequences demonstrated monophyly of each one of them. Capture locations showed evidence of strong spatial segregation, with one taxon occurring mainly in waters off the southern British Isles and around Rockall, while the other was restricted to more northerly shelf waters. These apparently cryptic species showed overlapping substrate and depth preferences, but distributional limits were closely related to temperature gradients, potentially indicating thermal limits to their distributions. This discovery of hidden diversity within a large, critically endangered marine vertebrate demonstrates how marine biodiversity can be underestimated, even in such a relatively well-studied and heavily exploited region. PMID:20106849

  16. Functional interactome of Aquaporin 1 sub-family reveals new physiological functions in Arabidopsis Thaliana

    Directory of Open Access Journals (Sweden)

    Mohamed Ragab Abdel Gawwad

    2013-09-01

    Full Text Available Aquaporins are channel proteins found in plasma membranes and intercellular membranes of different cellular compartments, facilitate the water flux, solutes and gases across the cellular plasma membranes. The present study highlights the sub-family plasma membrane intrinsic protein (PIP predicting the 3-D structure and analyzing the functional interactome of it homologs. PIP1 homologs integrate with many proteins with different plant physiological roles in Arabidopsis thaliana including; PIP1A and PIP1B: facilitate the transport of water, diffusion of amino acids and/or peptides from the vacuolar compartment to the cytoplasm, play a role in the control of cell turgor and cell expansion and involved in root water uptake respectively. In addition we found that PIP1B plays a defensive role against Pseudomonas syringae infection through the interaction with the plasma membrane Rps2 protein. Another substantial function of PIP1C via the interaction with PIP2E is the response to nematode infection. Generally, PIP1 sub-family interactome controlling many physiological processes in plant cell like; osmoregulation in plants under high osmotic stress such as under a high salt, response to nematode, facilitate the transport of water across cell membrane and regulation of floral initiation in Arabidopsis thaliana.

  17. A Process to Establish the Common Functions Performed by a Multi-Role Vessel

    Science.gov (United States)

    2010-09-01

    25 5.9 EPF – Environmental Protection Functions...Functions WFO Offshore Warfighting Functions EPF Environmental Protection Functions EPF .1 Waste Treatment Functions DSTO-TR-2473 16 HSF...Mission Command Function CFV Vessel Command Function EPF Environmental Protection Functions HSF Hotel Services Functions HVAC HVAC Functions

  18. Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway.

    Science.gov (United States)

    Medhurst, A L; Huber, P A; Waisfisz, Q; de Winter , J P; Mathew, C G

    2001-02-15

    Fanconi anaemia (FA) is an autosomal recessive inherited disorder associated with a progressive aplastic anaemia, diverse congenital abnormalities and cancer. The condition is genetically heterogeneous, with at least seven complementation groups (A-G) described. Cells from individuals who are homozygous for mutations in FA genes are characterized by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents. These features suggest a possible role for the encoded proteins in the recognition or repair of these lesions, but neither their function nor whether they operate in a concerted or discrete functional pathways is known. The recent cloning of the FANCF and FANCE genes has allowed us to investigate the interaction of the proteins encoded by five of the seven complementation groups of FA. We used the yeast two-hybrid system and co-immunoprecipitation analysis to test the 10 possible pairs of proteins for direct interaction. In addition to the previously described binding of FANCA to FANCG, we now demonstrate direct interaction of FANCF with FANCG, of FANCC with FANCE and a weaker interaction of FANCE with both FANCA and FANCG. These findings show that the newly identified FANCE protein is an integral part of the FA pathway, and support the concept of a functional link between all known proteins encoded by the genes that are mutated in this disorder. These proteins may act either as a multimeric complex or by sequential recruitment of subsets of the proteins in a common pathway that protects the genomic integrity of mammalian cells.

  19. Migration routes and strategies in a highly aerial migrant, the common swift Apus apus, revealed by light-level geolocators.

    Directory of Open Access Journals (Sweden)

    Susanne Åkesson

    Full Text Available The tracking of small avian migrants has only recently become possible by the use of small light-level geolocators, allowing the reconstruction of whole migration routes, as well as timing and speed of migration and identification of wintering areas. Such information is crucial for evaluating theories about migration strategies and pinpointing critical areas for migrants of potential conservation value. Here we report data about migration in the common swift, a highly aerial and long-distance migrating species for which only limited information based on ringing recoveries about migration routes and wintering areas is available. Six individuals were successfully tracked throughout a complete migration cycle from Sweden to Africa and back. The autumn migration followed a similar route in all individuals, with an initial southward movement through Europe followed by a more southwest-bound course through Western Sahara to Sub-Saharan stopovers, before a south-eastward approach to the final wintering areas in the Congo basin. After approximately six months at wintering sites, which shifted in three of the individuals, spring migration commenced in late April towards a restricted stopover area in West Africa in all but one individual that migrated directly towards north from the wintering area. The first part of spring migration involved a crossing of the Gulf of Guinea in those individuals that visited West Africa. Spring migration was generally wind assisted within Africa, while through Europe variable or head winds were encountered. The average detour at about 50% could be explained by the existence of key feeding sites and wind patterns. The common swift adopts a mixed fly-and-forage strategy, facilitated by its favourable aerodynamic design allowing for efficient use of fuel. This strategy allowed swifts to reach average migration speeds well above 300 km/day in spring, which is higher than possible for similar sized passerines. This study

  20. Single-Cell Analysis of Growth in Budding Yeast and Bacteria Reveals a Common Size Regulation Strategy.

    Science.gov (United States)

    Soifer, Ilya; Robert, Lydia; Amir, Ariel

    2016-02-08

    To maintain a constant cell size, dividing cells have to coordinate cell-cycle events with cell growth. This coordination has long been supposed to rely on the existence of size thresholds determining cell-cycle progression [1]. In budding yeast, size is controlled at the G1/S transition [2]. In agreement with this hypothesis, the size at birth influences the time spent in G1: smaller cells have a longer G1 period [3]. Nevertheless, even though cells born smaller have a longer G1, the compensation is imperfect and they still bud at smaller cell sizes. In bacteria, several recent studies have shown that the incremental model of size control, in which size is controlled by addition of a constant volume (in contrast to a size threshold), is able to quantitatively explain the experimental data on four different bacterial species [4-7]. Here, we report on experimental results for the budding yeast Saccharomyces cerevisiae, finding, surprisingly, that cell size control in this organism is very well described by the incremental model, suggesting a common strategy for cell size control with bacteria. Additionally, we argue that for S. cerevisiae the "volume increment" is not added from birth to division, but rather between two budding events. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Narrow-front loop migration in a population of the common cuckoo Cuculus canorus, as revealed by satellite telemetry.

    Directory of Open Access Journals (Sweden)

    Mikkel Willemoes

    Full Text Available Narrow migration corridors known in diurnal, social migrants such as raptors, storks and geese are thought to be caused by topographical leading line effects in combination with learning detailed routes across generations. Here, we document narrow-front migration in a nocturnal, solitary migrant, the common cuckoo Cuculus canorus, using satellite telemetry. We tracked the migration of adult cuckoos from the breeding grounds in southern Scandinavia (n = 8, to wintering sites in south-western Central Africa (n = 6 and back to the breeding grounds (n = 3. Migration patterns were very complex; in addition to the breeding and wintering sites, six different stopover sites were identified during the 16,000 km annual route that formed a large-scale clockwise loop. Despite this complexity, individuals showed surprisingly similar migration patterns, with very little variation between routes. We compared observed tracks with simulated routes based on vector orientation (with and without effects of barriers on orientation and survival. Observed distances between routes were often significantly smaller than expected if the routes were established on the basis of an innate vector orientation programme. Average distance between individuals in eastern Sahel after having migrated more than 5,000 km for example, was merely 164 km. This implies that more sophisticated inherent guiding mechanisms, possibly involving elements of intermediate goal area navigation or more elaborate external cues, are necessary to explain the complex narrow-front migration pattern observed for the cuckoos in this study.

  2. Bacterial communities of two ubiquitous Great Barrier Reef corals reveals both site- and species-specificity of common bacterial associates.

    Directory of Open Access Journals (Sweden)

    E Charlotte E Kvennefors

    Full Text Available BACKGROUND: Coral-associated bacteria are increasingly considered to be important in coral health, and altered bacterial community structures have been linked to both coral disease and bleaching. Despite this, assessments of bacterial communities on corals rarely apply sufficient replication to adequately describe the natural variability. Replicated data such as these are crucial in determining potential roles of bacteria on coral. METHODOLOGY/PRINCIPAL FINDINGS: Denaturing Gradient Gel Electrophoresis (DGGE of the V3 region of the 16S ribosomal DNA was used in a highly replicated approach to analyse bacterial communities on both healthy and diseased corals. Although site-specific variations in the bacterial communities of healthy corals were present, host species-specific bacterial associates within a distinct cluster of gamma-proteobacteria could be identified, which are potentially linked to coral health. Corals affected by "White Syndrome" (WS underwent pronounced changes in their bacterial communities in comparison to healthy colonies. However, the community structure and bacterial ribotypes identified in diseased corals did not support the previously suggested theory of a bacterial pathogen as the causative agent of the syndrome. CONCLUSIONS/SIGNIFICANCE: This is the first study to employ large numbers of replicated samples to assess the bacterial communities of healthy and diseased corals, and the first culture-independent assessment of bacterial communities on WS affected Acroporid corals on the GBR. Results indicate that a minimum of 6 replicate samples are required in order to draw inferences on species, spatial or health-related changes in community composition, as a set of clearly distinct bacterial community profiles exist in healthy corals. Coral bacterial communities may be both site and species specific. Furthermore, a cluster of gamma-proteobacterial ribotypes may represent a group of specific common coral and marine

  3. The elastic network model reveals a consistent picture on intrinsic functional dynamics of type II restriction endonucleases

    International Nuclear Information System (INIS)

    Uyar, A; Kurkcuoglu, O; Doruker, P; Nilsson, L

    2011-01-01

    The vibrational dynamics of various type II restriction endonucleases, in complex with cognate/non-cognate DNA and in the apo form, are investigated with the elastic network model in order to reveal common functional mechanisms in this enzyme family. Scissor-like and tong-like motions observed in the slowest modes of all enzymes and their complexes point to common DNA recognition and cleavage mechanisms. Normal mode analysis further points out that the scissor-like motion has an important role in differentiating between cognate and non-cognate sequences at the recognition site, thus implying its catalytic relevance. Flexible regions observed around the DNA-binding site of the enzyme usually concentrate on the highly conserved β-strands, especially after DNA binding. These β-strands may have a structurally stabilizing role in functional dynamics for target site recognition and cleavage. In addition, hot spot residues based on high-frequency modes reveal possible communication pathways between the two distant cleavage sites in the enzyme family. Some of these hot spots also exist on the shortest path between the catalytic sites and are highly conserved

  4. Functional analysis of rice HOMEOBOX4 (Oshox4) gene reveals a negative function in gibberellin responses.

    Science.gov (United States)

    Dai, Mingqiu; Hu, Yongfeng; Ma, Qian; Zhao, Yu; Zhou, Dao-Xiu

    2008-02-01

    The homeodomain-leucine zipper (HD-Zip) putative transcription factor genes are divided into 4 families. In this work, we studied the function of a rice HD-Zip I gene, H OME O BO X4 (Oshox4). Oshox4 transcripts were detected in leaf and floral organ primordia but excluded from the shoot apical meristem and the protein was nuclear localized. Over-expression of Oshox4 in rice induced a semi-dwarf phenotype that could not be complemented by applied GA3. The over-expression plants accumulated elevated levels of bioactive GA, while the GA catabolic gene GA2ox3 was upregulated in the transgenic plants. In addition, over-expression of Oshox4 blocked GA-dependent alpha-amylase production. However, down-regulation of Oshox4 in RNAi transgenic plants induced no phenotypic alteration. Interestingly, the expression of YAB1 that is involved in the negative feedback regulation of the GA biosynthesis was upregulated in the Oshox4 over-expressing plants. One-hybrid assays showed that Oshox4 could interact with YAB1 promoter in yeast. In addition, Oshox4 expression was upregulated by GA. These data together suggest that Oshox4 may be involved in the negative regulation of GA signalling and may play a role to fine tune GA responses in rice.

  5. Effects of methylmercury exposure on the immune function of juvenile common loons (Gavia immer)

    Science.gov (United States)

    Kenow, K.P.; Grasman, K.A.; Hines, R.K.; Meyer, M.W.; Gendron-Fitzpatrick, A.; Spalding, M.G.; Gray, B.R.

    2007-01-01

    We conducted a dose-response laboratory study to quantify the level of exposure to dietary Hg, delivered as methylmercury chloride (CH3HgCl), that is associated with suppressed immune function in captive-reared common loon (Gavia immer) chicks. We used the phytohemagglutinin (PHA) skin test to assess T-lymphocyte function and the sheep red blood cell (SRBC) hemagglutination test to measure antibody-mediated immunity. The PHA stimulation index among chicks receiving dietary Hg treatment did not differ significantly from those of chicks on the control diet (p = 0.15). Total antibody (immunoglobulin [Ig] M [primary antibody] + IgG [secondary response]) production to the SRBC antigen in chicks treated with dietary methylmercury (MeHg), however, was suppressed (p = 0.04) relative to chicks on control diets. Analysis indicated suppression of total Ig production (p = 0.025 with comparisonwise ?? level = 0.017) between control and 0.4 ??g Hg/g wet food intake treatment groups. Furthermore, the control group exhibited a higher degree of variability in antibody response compared to the Hg groups, suggesting that in addition to reducing the mean response, Hg treatment reduced the normal variation attributable to other biological factors. We observed bursal lymphoid depletion in chicks receiving the 1.2 ??g Hg/g treatment (p = 0.017) and a marginally significant effect (p = 0.025) in chicks receiving the 0.4 ??g Hg/g diet. These findings suggest that common loon chick immune systems may be compromised at an ecologically relevant dietary exposure concentration (0.4 ??g Hg/g wet wt food intake). We also found that chicks hatched from eggs collected from low-pH lakes exhibited higher levels of lymphoid depletion in bursa tissue relative to chicks hatched from eggs collected from neutral-pH lakes. ?? 2007 SETAC.

  6. The radioimmunoassay in revealing preclinical disorders of the pituitary-thyroid system functioning

    International Nuclear Information System (INIS)

    Piven', N.V.; Pilatova, N.L.; Lukhverchik, L.N.; Kuz'menkova, E.I.; Solovej, V.V.; Mokhort, T.V.

    2001-01-01

    The main purpose of this research was to study the value of radioimmunoassay (RIA) for assessing the pituitary - thyroid function in healthy persons (aged 18-45). Quantitative criteria have been worked put for estimation of thyroid gland function for the population of Belarus in accordance with regional ecological situation. On this basis, concentrations of thyrotropin, thyroxine, triiodothyronine, thyroglobulin, thyroxine binding globulin were determined by RIA in blood samples. The analysis of the data obtained revealed latent forms of hyperthyroidism (42%) and hypothyroidism (21%), regarded by the authors as late medical consequences of Chernobyl accident. Subclinical stages were diagnosed in most cases. Thus RIA has proved useful for studying the functional state of the regulatory 'pituitary-thyroid gland' system and revealing prenosological disorders in it

  7. Systematic analysis of phloem-feeding insect-induced transcriptional reprogramming in Arabidopsis highlights common features and reveals distinct responses to specialist and generalist insects.

    Science.gov (United States)

    Foyer, Christine H; Verrall, Susan R; Hancock, Robert D

    2015-02-01

    Phloem-feeding insects (PFIs), of which aphids are the largest group, are major agricultural pests causing extensive damage to crop plants. In contrast to chewing insects, the nature of the plant response to PFIs remains poorly characterized. Scrutiny of the literature concerning transcriptional responses of model and crop plant species to PFIs reveals surprisingly little consensus with respect to the transcripts showing altered abundance following infestation. Nevertheless, core features of the transcriptional response to PFIs can be defined in Arabidopsis thaliana. This comparison of the PFI-associated transcriptional response observed in A. thaliana infested by the generalists Myzus persicae and Bemisia tabaci with the specialist Brevicoryne brassicae highlights the importance of calcium-dependent and receptor kinase-associated signalling. We discuss these findings within the context of the complex cross-talk between the different hormones regulating basal immune response mechanisms in plants. We identify PFI-responsive genes, highlighting the importance of cell wall-associated kinases in plant-PFI interactions, as well as the significant role of kinases containing the domain of unknown function 26. A common feature of plant-PFI interaction is enhanced abundance of transcripts encoding WRKY transcription factors. However, significant divergence was observed with respect to secondary metabolism dependent upon the insect attacker. Transcripts encoding enzymes and proteins associated with glucosinolate metabolism were decreased following attack by the generalist M. persicae but not by the specialist B. brassicae. This analysis provides a comprehensive overview of the molecular patterns associated with the plant response to PFIs and suggests that plants recognize and respond to perturbations in the cell wall occurring during PFI infestation. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights

  8. Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development

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    Kyle J. Beauchemin

    2016-08-01

    Full Text Available To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ. Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS. Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO archive (GSE74243. Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org.

  9. Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development.

    Science.gov (United States)

    Beauchemin, Kyle J; Wells, Julie M; Kho, Alvin T; Philip, Vivek M; Kamir, Daniela; Kohane, Isaac S; Graber, Joel H; Bult, Carol J

    2016-01-01

    To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ). Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS). Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular) defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO) archive (GSE74243). Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org).

  10. A meta-analysis reveals the commonalities and differences in Arabidopsis thaliana response to different viral pathogens.

    Directory of Open Access Journals (Sweden)

    Guillermo Rodrigo

    Full Text Available Understanding the mechanisms by which plants trigger host defenses in response to viruses has been a challenging problem owing to the multiplicity of factors and complexity of interactions involved. The advent of genomic techniques, however, has opened the possibility to grasp a global picture of the interaction. Here, we used Arabidopsis thaliana to identify and compare genes that are differentially regulated upon infection with seven distinct (+ssRNA and one ssDNA plant viruses. In the first approach, we established lists of genes differentially affected by each virus and compared their involvement in biological functions and metabolic processes. We found that phylogenetically related viruses significantly alter the expression of similar genes and that viruses naturally infecting Brassicaceae display a greater overlap in the plant response. In the second approach, virus-regulated genes were contextualized using models of transcriptional and protein-protein interaction networks of A. thaliana. Our results confirm that host cells undergo significant reprogramming of their transcriptome during infection, which is possibly a central requirement for the mounting of host defenses. We uncovered a general mode of action in which perturbations preferentially affect genes that are highly connected, central and organized in modules.

  11. The structures of cytosolic and plastid-located glutamine synthetases from Medicago truncatula reveal a common and dynamic architecture

    International Nuclear Information System (INIS)

    Torreira, Eva; Seabra, Ana Rita; Marriott, Hazel; Zhou, Min; Llorca, Óscar; Robinson, Carol V.; Carvalho, Helena G.; Fernández-Tornero, Carlos; Pereira, Pedro José Barbosa

    2014-01-01

    The experimental models of dicotyledonous cytoplasmic and plastid-located glutamine synthetases unveil a conserved eukaryotic-type decameric architecture, with subtle structural differences in M. truncatula isoenzymes that account for their distinct herbicide resistance. The first step of nitrogen assimilation in higher plants, the energy-driven incorporation of ammonia into glutamate, is catalyzed by glutamine synthetase. This central process yields the readily metabolizable glutamine, which in turn is at the basis of all subsequent biosynthesis of nitrogenous compounds. The essential role performed by glutamine synthetase makes it a prime target for herbicidal compounds, but also a suitable intervention point for the improvement of crop yields. Although the majority of crop plants are dicotyledonous, little is known about the structural organization of glutamine synthetase in these organisms and about the functional differences between the different isoforms. Here, the structural characterization of two glutamine synthetase isoforms from the model legume Medicago truncatula is reported: the crystallographic structure of cytoplasmic GSII-1a and an electron cryomicroscopy reconstruction of plastid-located GSII-2a. Together, these structural models unveil a decameric organization of dicotyledonous glutamine synthetase, with two pentameric rings weakly connected by inter-ring loops. Moreover, rearrangement of these dynamic loops changes the relative orientation of the rings, suggesting a zipper-like mechanism for their assembly into a decameric enzyme. Finally, the atomic structure of M. truncatula GSII-1a provides important insights into the structural determinants of herbicide resistance in this family of enzymes, opening new avenues for the development of herbicide-resistant plants

  12. The structures of cytosolic and plastid-located glutamine synthetases from Medicago truncatula reveal a common and dynamic architecture

    Energy Technology Data Exchange (ETDEWEB)

    Torreira, Eva [Centro de Investigaciones Biológicas – CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain); Seabra, Ana Rita [IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto (Portugal); Marriott, Hazel; Zhou, Min [University of Oxford, South Parks Road, Oxford OX1 3QZ (United Kingdom); Llorca, Óscar [Centro de Investigaciones Biológicas – CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain); Robinson, Carol V. [University of Oxford, South Parks Road, Oxford OX1 3QZ (United Kingdom); Carvalho, Helena G. [IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto (Portugal); Fernández-Tornero, Carlos, E-mail: cftornero@cib.csic.es [Centro de Investigaciones Biológicas – CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain); Pereira, Pedro José Barbosa, E-mail: cftornero@cib.csic.es [IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto (Portugal); Centro de Investigaciones Biológicas – CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain)

    2014-04-01

    The experimental models of dicotyledonous cytoplasmic and plastid-located glutamine synthetases unveil a conserved eukaryotic-type decameric architecture, with subtle structural differences in M. truncatula isoenzymes that account for their distinct herbicide resistance. The first step of nitrogen assimilation in higher plants, the energy-driven incorporation of ammonia into glutamate, is catalyzed by glutamine synthetase. This central process yields the readily metabolizable glutamine, which in turn is at the basis of all subsequent biosynthesis of nitrogenous compounds. The essential role performed by glutamine synthetase makes it a prime target for herbicidal compounds, but also a suitable intervention point for the improvement of crop yields. Although the majority of crop plants are dicotyledonous, little is known about the structural organization of glutamine synthetase in these organisms and about the functional differences between the different isoforms. Here, the structural characterization of two glutamine synthetase isoforms from the model legume Medicago truncatula is reported: the crystallographic structure of cytoplasmic GSII-1a and an electron cryomicroscopy reconstruction of plastid-located GSII-2a. Together, these structural models unveil a decameric organization of dicotyledonous glutamine synthetase, with two pentameric rings weakly connected by inter-ring loops. Moreover, rearrangement of these dynamic loops changes the relative orientation of the rings, suggesting a zipper-like mechanism for their assembly into a decameric enzyme. Finally, the atomic structure of M. truncatula GSII-1a provides important insights into the structural determinants of herbicide resistance in this family of enzymes, opening new avenues for the development of herbicide-resistant plants.

  13. Transverse grooved artefacts from southwestern Asia and northern Eurasia: Common traits and the reconstruction of function

    Directory of Open Access Journals (Sweden)

    Irina Usacheva

    2016-10-01

    Full Text Available Transverse grooved artefacts (TGA appeared as a new cultural element in Mesolithic-Proto-Neolithic sites in southwestern Asia. We know of similar artefacts from northern Africa. Hundreds of TGA have also been found in northern Eurasia. Some common traits were found in specimens from far apart territories, such as the non-abrasive heat-resistant nature of the raw materials, specificity of fragmentation without any signs of physical impact, the standard size of the grooves, association with a specific type of landscape, the similar economic level of the societies with which the items are associated, and use-wear marks in the grooves. Based on these regularities we can speak of a single main function for these artefacts which support the earlier reconstruction of R.L. and R.S. Solecki, suggesting that grooved stones were used for straightening cane and reed shafts under heating. Other evidence and traces that have been identified on the surface of TGA outside the groove could be associated with a variety of additional functions.

  14. Morphologic, cytometric and functional characterization of the common octopus (Octopus vulgaris) hemocytes.

    Science.gov (United States)

    Castellanos-Martínez, S; Prado-Alvarez, M; Lobo-da-Cunha, A; Azevedo, C; Gestal, C

    2014-05-01

    The hemocytes of Octopus vulgaris were morphologically and functionally characterized. Light and electron microscopy (TEM and SEM), and flow cytometry analyses revealed the existence of two hemocyte populations. Large granulocytes showed U-shaped nucleus, a mean of 11.6 μm±1.2 in diameter with basophilic granules, polysaccharide and lysosomic deposits in the cytoplasm. Small granulocytes measured a mean of 8.1 μm±0.7 in diameter, and have a round nucleus occupying almost the entire cell and few or not granules in the cytoplasm. Flow cytometry analysis showed that large granulocytes are the principal cells that develop phagocytosis of latex beads (rising up to 56%) and ROS after zymosan stimulation. Zymosan induced the highest production of both ROS and NO. This study is the first tread towards understanding the O. vulgaris immune system by applying new tools to provide a most comprehensive morpho-functional study of their hemocytes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Evaluation of functional potentiality of selected commonly consumed foods of Bangladesh

    Directory of Open Access Journals (Sweden)

    Nazma Shaheen

    2016-11-01

    Full Text Available Background: Rising tide of chronic nutrition related non-communicable diseases yoked with extant under nutrition problems makes it imperative to carry out scientific research towards the discovery of functional foods. Although the emergence of these diseases are believed to be related to a constellation of dietary, socio-economic and lifestyle related risk factors, central to the pathogenesis of these diseases (or disease states are free radicals, oxidative stress, and inflammatory processes typically accompanied by pain. Therefore, functional whole foods with physiologically active antioxidants, anti-inflammatory, and analgesic compounds seem to be the most promising option to deal with the pathogenesis of existing and emerging chronic diseases burden of Bangladesh. Methods: Edible portions of 70 commonly consumed Bangladeshi foods – including one cereal, five legumes, fourteen vegetables, four tea varieties, five oil seeds, twenty spices, and twenty one fruits – were evaluated for total phenol content (TPC by Folin-Ciocalteau assay. To evaluate functional potentiality, in vitro antioxidant capacity (AC of selected food items were evaluated by DPPH (2,2-diphenyl- 1-picrylhydrazyl radical scavenging assays, in vitro anti-inflammatory potential by observing the production of pro-inflammatory cytokine TNF-α using J774A.1 cells stimulated with lipopolysaccharide (LPS, in vivo anti-inflammatory potential by measuring carrageenan induced rat paw edema reduction, and in vivo analgesic potential by acetic acid induced writhing test in mice. Results: Spices, oilseeds, and teas showed high concentration of TPC among the analyzed foods, while spices and teas exhibited notable AC. Green tea showed highest concentrations of TPC (2349 mg Gallic Acid Equivalent / g and AC (2432 µmole Trolox Equivalent/g. Fourteen food items showed potential in vitro anti-inflammatory activity with confirmatory dose response effect shown by 8 items. In vivo, black sesame

  16. Functional redundancy patterns reveal non-random assembly rules in a species-rich marine assemblage.

    Directory of Open Access Journals (Sweden)

    Nicolas Guillemot

    Full Text Available The relationship between species and the functional diversity of assemblages is fundamental in ecology because it contains key information on functional redundancy, and functionally redundant ecosystems are thought to be more resilient, resistant and stable. However, this relationship is poorly understood and undocumented for species-rich coastal marine ecosystems. Here, we used underwater visual censuses to examine the patterns of functional redundancy for one of the most diverse vertebrate assemblages, the coral reef fishes of New Caledonia, South Pacific. First, we found that the relationship between functional and species diversity displayed a non-asymptotic power-shaped curve, implying that rare functions and species mainly occur in highly diverse assemblages. Second, we showed that the distribution of species amongst possible functions was significantly different from a random distribution up to a threshold of ∼90 species/transect. Redundancy patterns for each function further revealed that some functions displayed fast rates of increase in redundancy at low species diversity, whereas others were only becoming redundant past a certain threshold. This suggested non-random assembly rules and the existence of some primordial functions that would need to be fulfilled in priority so that coral reef fish assemblages can gain a basic ecological structure. Last, we found little effect of habitat on the shape of the functional-species diversity relationship and on the redundancy of functions, although habitat is known to largely determine assemblage characteristics such as species composition, biomass, and abundance. Our study shows that low functional redundancy is characteristic of this highly diverse fish assemblage, and, therefore, that even species-rich ecosystems such as coral reefs may be vulnerable to the removal of a few keystone species.

  17. Integrative Analysis of Subcellular Quantitative Proteomics Studies Reveals Functional Cytoskeleton Membrane-Lipid Raft Interactions in Cancer.

    Science.gov (United States)

    Shah, Anup D; Inder, Kerry L; Shah, Alok K; Cristino, Alexandre S; McKie, Arthur B; Gabra, Hani; Davis, Melissa J; Hill, Michelle M

    2016-10-07

    Lipid rafts are dynamic membrane microdomains that orchestrate molecular interactions and are implicated in cancer development. To understand the functions of lipid rafts in cancer, we performed an integrated analysis of quantitative lipid raft proteomics data sets modeling progression in breast cancer, melanoma, and renal cell carcinoma. This analysis revealed that cancer development is associated with increased membrane raft-cytoskeleton interactions, with ∼40% of elevated lipid raft proteins being cytoskeletal components. Previous studies suggest a potential functional role for the raft-cytoskeleton in the action of the putative tumor suppressors PTRF/Cavin-1 and Merlin. To extend the observation, we examined lipid raft proteome modulation by an unrelated tumor suppressor opioid binding protein cell-adhesion molecule (OPCML) in ovarian cancer SKOV3 cells. In agreement with the other model systems, quantitative proteomics revealed that 39% of OPCML-depleted lipid raft proteins are cytoskeletal components, with microfilaments and intermediate filaments specifically down-regulated. Furthermore, protein-protein interaction network and simulation analysis showed significantly higher interactions among cancer raft proteins compared with general human raft proteins. Collectively, these results suggest increased cytoskeleton-mediated stabilization of lipid raft domains with greater molecular interactions as a common, functional, and reversible feature of cancer cells.

  18. Genetic Interaction Maps in Escherichia coli Reveal Functional Crosstalk among Cell Envelope Biogenesis Pathways

    Science.gov (United States)

    Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J.; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F.; Emili, Andrew

    2011-01-01

    As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among >235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target. PMID:22125496

  19. Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways.

    Directory of Open Access Journals (Sweden)

    Mohan Babu

    2011-11-01

    Full Text Available As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium and prototrophic (minimal medium culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens and an important target.

  20. Finding an acceleration function for calculating the reliability of redundant systems - Application to common mode failures

    International Nuclear Information System (INIS)

    Gonnot, R.

    1975-01-01

    While it may be reasonable to assume that the reliability of a system - the design of which is perfectly known - can be evaluated, it seems less easy to be sure that overall reliability is correctly estimated in the case of multiple redundancies arranged in sequence. Framatome is trying to develop a method of evaluating overall reliability correctly for its installations. For example, the protection systems in its power stations considered as a whole are such that several scram signals may be relayed in sequence when an incident occurs. These signals all involve the same components for a given type of action, but the components themselves are in fact subject to different stresses and constraints, which tend to reduce their reliability. Whatever the sequence in which these signals are transmitted (in a fast-developing accident, for example), it is possible to evaluate the actual reliability of a given system (or component) for different constraints, as the latter are generally obtained via the transient codes. By applying the so-called ''equal probability'' hypothesis one can estimate a reliability acceleration function taking into account the constraints imposed. This function is linear for the principal failure probability distribution laws. By generalizing such a method one can: (1) Perform failure calculations for redundant systems (or components) in a more general way than is possible with event trees, since one of the main parameters is the constraint exercised on that system (or component); (2) Determine failure rates of components on the basis of accelerated tests (up to complete failure of the component) which are quicker than the normal long-term tests (statistical results of operation); (3) Evaluate the multiplication factor for the reliability of a system or component in the case of common mode failures. The author presents the mathematical tools required for such a method and described their application in the cases mentioned above

  1. Chronic exposure to Tributyltin induces brain functional damage in juvenile common carp (Cyprinus carpio.

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    Zhi-Hua Li

    Full Text Available The aim of the present study was to investigate the effect of Tributyltin (TBT on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase, Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters. The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity.

  2. Chronic Exposure to Tributyltin Induces Brain Functional Damage in Juvenile Common Carp (Cyprinus carpio)

    Science.gov (United States)

    Li, Zhi-Hua; Li, Ping; Shi, Ze-Chao

    2015-01-01

    The aim of the present study was to investigate the effect of Tributyltin (TBT) on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase), Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide) in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L) for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days) to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters). The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity. PMID:25879203

  3. Chronic exposure to Tributyltin induces brain functional damage in juvenile common carp (Cyprinus carpio).

    Science.gov (United States)

    Li, Zhi-Hua; Li, Ping; Shi, Ze-Chao

    2015-01-01

    The aim of the present study was to investigate the effect of Tributyltin (TBT) on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase), Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide) in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L) for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days) to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters). The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity.

  4. Chitin's Functionality as a Novel Disintegrant: Benchmarking Against Commonly Used Disintegrants in Different Physicochemical Environments.

    Science.gov (United States)

    Chaheen, Mohammad; Soulairol, Ian; Bataille, Bernard; Yassine, Ahmad; Belamie, Emmanuel; Sharkawi, Tahmer

    2017-07-01

    Disintegrants are used as excipients to ensure rapid disintegration of pharmaceutical tablets and further ensure proper dissolution of the active pharmaceutical ingredient. This study investigates disintegration mechanisms of chitin and common disintegrants. Swelling assessment (swelling force and swelling ratio) in different media, and compaction behavior (pure or mixed with other excipients) tabletability, deformation (Heckel modeling), and compact disintegration times were investigated on the tested disintegrants (alginic acid calcium salt, crospovidone, sodium starch glycolate, croscarmellose sodium, and chitin). Results show that the physicochemical properties of the disintegration medium such as pH and ionic strength, as well as other formulation ingredients, affect the disintegrant functionalities. Heckel analysis using the mean yield pressure "Py" shows that alginic acid calcium salt is the most brittle among the studied disintegrants, while crospovidone has the most plastic deformation mechanism, followed by chitin. Chitin showed good tabletability and disintegration properties that were not influenced by the physicochemical formulation environment. Chitin is largely available and easily modifiable and thus a promising material that could be used as a multifunctional excipient in tablet formulation. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  5. Chemical and functional properties of different common Brazilian bean (Phaseolus vulgaris L. cultivars

    Directory of Open Access Journals (Sweden)

    Milene Marquezi

    2017-06-01

    Full Text Available Abstract Six different common bean cultivars (BRS Embaixador, BRS Pitanga, BRS Estilo, Pérola, BRS Campeiro and BRS Esplendor were characterized aiming to determine possible uses for them in various food products. The samples were analysed to determine their chemical composition, weight per hundred beans, pH, water and oil absorption capacities (WAC and OAC, respectively, foaming at pH 2.5, 5.6 and 8.0 and emulsifying properties. The relationship between the physicochemical and functional properties was described using the Principal Component Analysis (PCA. The results of the chemical composition, weight per hundred beans, WAC and OAC showed differences even between cultivars of the same commercial group. Foaming also varied between the cultivars and foaming capacity and stability were greatest at pH 5.6 and 8.0. The emulsifying capacity proved quite high for all cultivars, as well as the stability of the emulsion. According to these properties, with the contribution of the PCA, each different bean cultivar can be destined to specific applications according to its physicochemical properties.

  6. Abnormal functional brain asymmetry in depression: evidence of biologic commonality between major depression and dysthymia.

    Science.gov (United States)

    Bruder, Gerard E; Stewart, Jonathan W; Hellerstein, David; Alvarenga, Jorge E; Alschuler, Daniel; McGrath, Patrick J

    2012-04-30

    Prior studies have found abnormalities of functional brain asymmetry in patients having a major depressive disorder (MDD). This study aimed to replicate findings of reduced right hemisphere advantage for perceiving dichotic complex tones in depressed patients, and to determine whether patients having "pure" dysthymia show the same abnormality of perceptual asymmetry as MDD. It also examined gender differences in lateralization, and the extent to which abnormalities of perceptual asymmetry in depressed patients are dependent on gender. Unmedicated patients having either a MDD (n=96) or "pure" dysthymic disorder (n=42) and healthy controls (n=114) were tested on dichotic fused-words and complex-tone tests. Patient and control groups differed in right hemisphere advantage for complex tones, but not left hemisphere advantage for words. Reduced right hemisphere advantage for tones was equally present in MDD and dysthymia, but was more evident among depressed men than depressed women. Also, healthy men had greater hemispheric asymmetry than healthy women for both words and tones, whereas this gender difference was not seen for depressed patients. Dysthymia and MDD share a common abnormality of hemispheric asymmetry for dichotic listening. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  7. A common neonicotinoid pesticide, thiamethoxam, alters honey bee activity, motor functions, and movement to light.

    Science.gov (United States)

    Tosi, S; Nieh, J C

    2017-11-09

    Honey bees provide key ecosystem services. To pollinate and to sustain the colony, workers must walk, climb, and use phototaxis as they move inside and outside the nest. Phototaxis, orientation to light, is linked to sucrose responsiveness and the transition of work from inside to outside the nest, and is also a key component of division of labour. However, the sublethal effects of pesticides on locomotion and movement to light are relatively poorly understood. Thiamethoxam (TMX) is a common neonicotinoid pesticide that bees can consume in nectar and pollen. We used a vertical arena illuminated from the top to test the effects of acute and chronic sublethal exposures to TMX. Acute consumption (1.34 ng/bee) impaired locomotion, caused hyperactivity (velocity: +109%; time moving: +44%) shortly after exposure (30 min), and impaired motor functions (falls: +83%; time top: -43%; time bottom: +93%; abnormal behaviours: +138%; inability to ascend: +280%) over a longer period (60 min). A 2-day chronic exposure (field-relevant daily intakes of 1.42-3.48 ng/bee/day) impaired bee ability to ascend. TMX increased movement to light after acute and chronic exposure. Thus, TMX could reduce colony health by harming worker locomotion and, potentially, alter division of labour if bees move outside or remain outdoors.

  8. Sparse coding reveals greater functional connectivity in female brains during naturalistic emotional experience.

    Directory of Open Access Journals (Sweden)

    Yudan Ren

    Full Text Available Functional neuroimaging is widely used to examine changes in brain function associated with age, gender or neuropsychiatric conditions. FMRI (functional magnetic resonance imaging studies employ either laboratory-designed tasks that engage the brain with abstracted and repeated stimuli, or resting state paradigms with little behavioral constraint. Recently, novel neuroimaging paradigms using naturalistic stimuli are gaining increasing attraction, as they offer an ecologically-valid condition to approximate brain function in real life. Wider application of naturalistic paradigms in exploring individual differences in brain function, however, awaits further advances in statistical methods for modeling dynamic and complex dataset. Here, we developed a novel data-driven strategy that employs group sparse representation to assess gender differences in brain responses during naturalistic emotional experience. Comparing to independent component analysis (ICA, sparse coding algorithm considers the intrinsic sparsity of neural coding and thus could be more suitable in modeling dynamic whole-brain fMRI signals. An online dictionary learning and sparse coding algorithm was applied to the aggregated fMRI signals from both groups, which was subsequently factorized into a common time series signal dictionary matrix and the associated weight coefficient matrix. Our results demonstrate that group sparse representation can effectively identify gender differences in functional brain network during natural viewing, with improved sensitivity and reliability over ICA-based method. Group sparse representation hence offers a superior data-driven strategy for examining brain function during naturalistic conditions, with great potential for clinical application in neuropsychiatric disorders.

  9. An atlas of the thioredoxin fold class reveals the complexity of function-enabling adaptations.

    Science.gov (United States)

    Atkinson, Holly J; Babbitt, Patricia C

    2009-10-01

    The group of proteins that contain a thioredoxin (Trx) fold is huge and diverse. Assessment of the variation in catalytic machinery of Trx fold proteins is essential in providing a foundation for understanding their functional diversity and predicting the function of the many uncharacterized members of the class. The proteins of the Trx fold class retain common features-including variations on a dithiol CxxC active site motif-that lead to delivery of function. We use protein similarity networks to guide an analysis of how structural and sequence motifs track with catalytic function and taxonomic categories for 4,082 representative sequences spanning the known superfamilies of the Trx fold. Domain structure in the fold class is varied and modular, with 2.8% of sequences containing more than one Trx fold domain. Most member proteins are bacterial. The fold class exhibits many modifications to the CxxC active site motif-only 56.8% of proteins have both cysteines, and no functional groupings have absolute conservation of the expected catalytic motif. Only a small fraction of Trx fold sequences have been functionally characterized. This work provides a global view of the complex distribution of domains and catalytic machinery throughout the fold class, showing that each superfamily contains remnants of the CxxC active site. The unifying context provided by this work can guide the comparison of members of different Trx fold superfamilies to gain insight about their structure-function relationships, illustrated here with the thioredoxins and peroxiredoxins.

  10. Core microbial functional activities in ocean environments revealed by global metagenomic profiling analyses.

    Directory of Open Access Journals (Sweden)

    Ari J S Ferreira

    Full Text Available Metagenomics-based functional profiling analysis is an effective means of gaining deeper insight into the composition of marine microbial populations and developing a better understanding of the interplay between the functional genome content of microbial communities and abiotic factors. Here we present a comprehensive analysis of 24 datasets covering surface and depth-related environments at 11 sites around the world's oceans. The complete datasets comprises approximately 12 million sequences, totaling 5,358 Mb. Based on profiling patterns of Clusters of Orthologous Groups (COGs of proteins, a core set of reference photic and aphotic depth-related COGs, and a collection of COGs that are associated with extreme oxygen limitation were defined. Their inferred functions were utilized as indicators to characterize the distribution of light- and oxygen-related biological activities in marine environments. The results reveal that, while light level in the water column is a major determinant of phenotypic adaptation in marine microorganisms, oxygen concentration in the aphotic zone has a significant impact only in extremely hypoxic waters. Phylogenetic profiling of the reference photic/aphotic gene sets revealed a greater variety of source organisms in the aphotic zone, although the majority of individual photic and aphotic depth-related COGs are assigned to the same taxa across the different sites. This increase in phylogenetic and functional diversity of the core aphotic related COGs most probably reflects selection for the utilization of a broad range of alternate energy sources in the absence of light.

  11. Core microbial functional activities in ocean environments revealed by global metagenomic profiling analyses.

    KAUST Repository

    Ferreira, Ari J S

    2014-06-12

    Metagenomics-based functional profiling analysis is an effective means of gaining deeper insight into the composition of marine microbial populations and developing a better understanding of the interplay between the functional genome content of microbial communities and abiotic factors. Here we present a comprehensive analysis of 24 datasets covering surface and depth-related environments at 11 sites around the world\\'s oceans. The complete datasets comprises approximately 12 million sequences, totaling 5,358 Mb. Based on profiling patterns of Clusters of Orthologous Groups (COGs) of proteins, a core set of reference photic and aphotic depth-related COGs, and a collection of COGs that are associated with extreme oxygen limitation were defined. Their inferred functions were utilized as indicators to characterize the distribution of light- and oxygen-related biological activities in marine environments. The results reveal that, while light level in the water column is a major determinant of phenotypic adaptation in marine microorganisms, oxygen concentration in the aphotic zone has a significant impact only in extremely hypoxic waters. Phylogenetic profiling of the reference photic/aphotic gene sets revealed a greater variety of source organisms in the aphotic zone, although the majority of individual photic and aphotic depth-related COGs are assigned to the same taxa across the different sites. This increase in phylogenetic and functional diversity of the core aphotic related COGs most probably reflects selection for the utilization of a broad range of alternate energy sources in the absence of light.

  12. Core microbial functional activities in ocean environments revealed by global metagenomic profiling analyses.

    KAUST Repository

    Ferreira, Ari J S; Siam, Rania; Setubal, Joã o C; Moustafa, Ahmed; Sayed, Ahmed; Chambergo, Felipe S; Dawe, Adam S; Ghazy, Mohamed A; Sharaf, Hazem; Ouf, Amged; Alam, Intikhab; Abdel-Haleem, Alyaa M; Lehvä slaiho, Heikki; Ramadan, Eman; Antunes, André ; Stingl, Ulrich; Archer, John A.C.; Jankovic, Boris R; Sogin, Mitchell; Bajic, Vladimir B.; El-Dorry, Hamza

    2014-01-01

    Metagenomics-based functional profiling analysis is an effective means of gaining deeper insight into the composition of marine microbial populations and developing a better understanding of the interplay between the functional genome content of microbial communities and abiotic factors. Here we present a comprehensive analysis of 24 datasets covering surface and depth-related environments at 11 sites around the world's oceans. The complete datasets comprises approximately 12 million sequences, totaling 5,358 Mb. Based on profiling patterns of Clusters of Orthologous Groups (COGs) of proteins, a core set of reference photic and aphotic depth-related COGs, and a collection of COGs that are associated with extreme oxygen limitation were defined. Their inferred functions were utilized as indicators to characterize the distribution of light- and oxygen-related biological activities in marine environments. The results reveal that, while light level in the water column is a major determinant of phenotypic adaptation in marine microorganisms, oxygen concentration in the aphotic zone has a significant impact only in extremely hypoxic waters. Phylogenetic profiling of the reference photic/aphotic gene sets revealed a greater variety of source organisms in the aphotic zone, although the majority of individual photic and aphotic depth-related COGs are assigned to the same taxa across the different sites. This increase in phylogenetic and functional diversity of the core aphotic related COGs most probably reflects selection for the utilization of a broad range of alternate energy sources in the absence of light.

  13. Modular organization of the white spruce (Picea glauca) transcriptome reveals functional organization and evolutionary signatures.

    Science.gov (United States)

    Raherison, Elie S M; Giguère, Isabelle; Caron, Sébastien; Lamara, Mebarek; MacKay, John J

    2015-07-01

    Transcript profiling has shown the molecular bases of several biological processes in plants but few studies have developed an understanding of overall transcriptome variation. We investigated transcriptome structure in white spruce (Picea glauca), aiming to delineate its modular organization and associated functional and evolutionary attributes. Microarray analyses were used to: identify and functionally characterize groups of co-expressed genes; investigate expressional and functional diversity of vascular tissue preferential genes which were conserved among Picea species, and identify expression networks underlying wood formation. We classified 22 857 genes as variable (79%; 22 coexpression groups) or invariant (21%) by profiling across several vegetative tissues. Modular organization and complex transcriptome restructuring among vascular tissue preferential genes was revealed by their assignment to coexpression groups with partially overlapping profiles and partially distinct functions. Integrated analyses of tissue-based and temporally variable profiles identified secondary xylem gene networks, showed their remodelling over a growing season and identified PgNAC-7 (no apical meristerm (NAM), Arabidopsis transcription activation factor (ATAF) and cup-shaped cotyledon (CUC) transcription factor 007 in Picea glauca) as a major hub gene specific to earlywood formation. Reference profiling identified comprehensive, statistically robust coexpressed groups, revealing that modular organization underpins the evolutionary conservation of the transcriptome structure. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  14. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.; Cruchaga, Carlos; Colonna, Marco; Holtzman, Michael J.; Brett, Thomas J. (WU-MED)

    2016-12-20

    Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.

  15. Prokaryotic regulatory systems biology: Common principles governing the functional architectures of Bacillus subtilis and Escherichia coli unveiled by the natural decomposition approach.

    Science.gov (United States)

    Freyre-González, Julio A; Treviño-Quintanilla, Luis G; Valtierra-Gutiérrez, Ilse A; Gutiérrez-Ríos, Rosa María; Alonso-Pavón, José A

    2012-10-31

    Escherichia coli and Bacillus subtilis are two of the best-studied prokaryotic model organisms. Previous analyses of their transcriptional regulatory networks have shown that they exhibit high plasticity during evolution and suggested that both converge to scale-free-like structures. Nevertheless, beyond this suggestion, no analyses have been carried out to identify the common systems-level components and principles governing these organisms. Here we show that these two phylogenetically distant organisms follow a set of common novel biologically consistent systems principles revealed by the mathematically and biologically founded natural decomposition approach. The discovered common functional architecture is a diamond-shaped, matryoshka-like, three-layer (coordination, processing, and integration) hierarchy exhibiting feedback, which is shaped by four systems-level components: global transcription factors (global TFs), locally autonomous modules, basal machinery and intermodular genes. The first mathematical criterion to identify global TFs, the κ-value, was reassessed on B. subtilis and confirmed its high predictive power by identifying all the previously reported, plus three potential, master regulators and eight sigma factors. The functionally conserved cores of modules, basal cell machinery, and a set of non-orthologous common physiological global responses were identified via both orthologous genes and non-orthologous conserved functions. This study reveals novel common systems principles maintained between two phylogenetically distant organisms and provides a comparison of their lifestyle adaptations. Our results shed new light on the systems-level principles and the fundamental functions required by bacteria to sustain life. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Fluorescence In Situ Hybridization (FISH-Based Karyotyping Reveals Rapid Evolution of Centromeric and Subtelomeric Repeats in Common Bean (Phaseolus vulgaris and Relatives

    Directory of Open Access Journals (Sweden)

    Aiko Iwata-Otsubo

    2016-04-01

    Full Text Available Fluorescence in situ hybridization (FISH-based karyotyping is a powerful cytogenetics tool to study chromosome organization, behavior, and chromosome evolution. Here, we developed a FISH-based karyotyping system using a probe mixture comprised of centromeric and subtelomeric satellite repeats, 5S rDNA, and chromosome-specific BAC clones in common bean, which enables one to unambiguously distinguish all 11 chromosome pairs. Furthermore, we applied the karyotyping system to several wild relatives and landraces of common bean from two distinct gene pools, as well as other related Phaseolus species, to investigate repeat evolution in the genus Phaseolus. Comparison of karyotype maps within common bean indicates that chromosomal distribution of the centromeric and subtelomeric satellite repeats is stable, whereas the copy number of the repeats was variable, indicating rapid amplification/reduction of the repeats in specific genomic regions. In Phaseolus species that diverged approximately 2–4 million yr ago, copy numbers of centromeric repeats were largely reduced or diverged, and chromosomal distributions have changed, suggesting rapid evolution of centromeric repeats. We also detected variation in the distribution pattern of subtelomeric repeats in Phaseolus species. The FISH-based karyotyping system revealed that satellite repeats are actively and rapidly evolving, forming genomic features unique to individual common bean accessions and Phaseolus species.

  17. Transaction processing in the common node of a distributed function laboratory computer system

    International Nuclear Information System (INIS)

    Stubblefield, F.W.; Dimmler, D.G.

    1975-01-01

    A computer network architecture consisting of a common node processor for managing peripherals and files and a number of private node processors for laboratory experiment control is briefly reviewed. Central to the problem of private node-common node communication is the concept of a transaction. The collection of procedures and the data structure associated with a transaction are described. The common node properties assigned to a transaction and procedures required for its complete processing are discussed. (U.S.)

  18. Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia

    Directory of Open Access Journals (Sweden)

    E. Damaraju

    2014-01-01

    Full Text Available Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length, and a dynamic sense, computed using sliding windows (44 s in length and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual, as well as reduced connectivity (hypoconnectivity between sensory networks from all modalities. Dynamic analysis suggests that (1, on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2, that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical–subcortical antagonism (anti-correlations and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity

  19. Individual-based analyses reveal limited functional overlap in a coral reef fish community.

    Science.gov (United States)

    Brandl, Simon J; Bellwood, David R

    2014-05-01

    Detailed knowledge of a species' functional niche is crucial for the study of ecological communities and processes. The extent of niche overlap, functional redundancy and functional complementarity is of particular importance if we are to understand ecosystem processes and their vulnerability to disturbances. Coral reefs are among the most threatened marine systems, and anthropogenic activity is changing the functional composition of reefs. The loss of herbivorous fishes is particularly concerning as the removal of algae is crucial for the growth and survival of corals. Yet, the foraging patterns of the various herbivorous fish species are poorly understood. Using a multidimensional framework, we present novel individual-based analyses of species' realized functional niches, which we apply to a herbivorous coral reef fish community. In calculating niche volumes for 21 species, based on their microhabitat utilization patterns during foraging, and computing functional overlaps, we provide a measurement of functional redundancy or complementarity. Complementarity is the inverse of redundancy and is defined as less than 50% overlap in niche volumes. The analyses reveal extensive complementarity with an average functional overlap of just 15.2%. Furthermore, the analyses divide herbivorous reef fishes into two broad groups. The first group (predominantly surgeonfishes and parrotfishes) comprises species feeding on exposed surfaces and predominantly open reef matrix or sandy substrata, resulting in small niche volumes and extensive complementarity. In contrast, the second group consists of species (predominantly rabbitfishes) that feed over a wider range of microhabitats, penetrating the reef matrix to exploit concealed surfaces of various substratum types. These species show high variation among individuals, leading to large niche volumes, more overlap and less complementarity. These results may have crucial consequences for our understanding of herbivorous processes on

  20. A functional genomics screen in planarians reveals regulators of whole-brain regeneration

    Science.gov (United States)

    Roberts-Galbraith, Rachel H; Brubacher, John L; Newmark, Phillip A

    2016-01-01

    Planarians regenerate all body parts after injury, including the central nervous system (CNS). We capitalized on this distinctive trait and completed a gene expression-guided functional screen to identify factors that regulate diverse aspects of neural regeneration in Schmidtea mediterranea. Our screen revealed molecules that influence neural cell fates, support the formation of a major connective hub, and promote reestablishment of chemosensory behavior. We also identified genes that encode signaling molecules with roles in head regeneration, including some that are produced in a previously uncharacterized parenchymal population of cells. Finally, we explored genes downregulated during planarian regeneration and characterized, for the first time, glial cells in the planarian CNS that respond to injury by repressing several transcripts. Collectively, our studies revealed diverse molecules and cell types that underlie an animal’s ability to regenerate its brain. DOI: http://dx.doi.org/10.7554/eLife.17002.001 PMID:27612384

  1. Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development.

    Directory of Open Access Journals (Sweden)

    Anita M Quintana

    Full Text Available There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf, but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.

  2. Common variants in mendelian kidney disease genes and their association with renal function

    NARCIS (Netherlands)

    A. Parsa (Afshin); C. Fuchsberger (Christian); A. Köttgen (Anna); C.M. O'Seaghdha (Conall); C. Pattaro (Cristian); M. de Andrade (Mariza); D.I. Chasman (Daniel); A. Teumer (Alexander); K. Endlich (Karlhans); M. Olden (Matthias); M-H. Chen (Ming-Huei); A. Tin (Adrienne); Y-J. Kim (Yong-Jin); D. Taliun (Daniel); M. Li (Man); M.F. Feitosa (Mary Furlan); M. Gorski (Mathias); Q. Yang (Qiong); C. Hundertmark (Claudia); M.C. Foster (Michael); N. Glazer (Nicole); A.J. Isaacs (Aaron); M. Rao (Madhumathi); G.D. Smith; J.R. O´Connell; M.V. Struchalin (Maksim); T. Tanaka (Toshiko); G. Li (Guo); S.J. Hwang; E.J. Atkinson (Elizabeth); K. Lohman (Kurt); M. Cornelis (Marilyn); A. Johansson (Åsa); A. Tönjes (Anke); A. Dehghan (Abbas); V. Couraki (Vincent); E.G. Holliday (Elizabeth); R. Sorice; Z. Kutalik (Zoltán); T. Lehtimäki (Terho); T. Esko (Tõnu); H. Deshmukh (Harshal); S. Ulivi (Shelia); A.Y. Chu (Audrey); D. Murgia (Daniela); S. Trompet (Stella); M. Imboden (Medea); B. Kollerits (Barbara); G. Pistis (Giorgio); T.B. Harris (Tamara); L.J. Launer (Lenore); T. Aspelund (Thor); G. Eiriksdottir (Gudny); B.D. Mitchell (Braxton); E.A. Boerwinkle (Eric); H. Schmidt (Helena); E. Hofer (Edith); F.B. Hu (Frank); A. Demirkan (Ayşe); B.A. Oostra (Ben); S.T. Turner (Stephen); J. Ding (Jingzhong); J.S. Andrews (Jeanette); B.I. Freedman (Barry); F. Giulianini (Franco); W. Koenig (Wolfgang); T. Illig (Thomas); A. Döring (Angela); H.E. Wichmann (Heinz Erich); L. Zgaga (Lina); T. Zemunik (Tatijana); M. Boban (Mladen); C. Minelli (Cosetta); H.E. Wheeler (Heather); W. Igl (Wilmar); G. Zaboli (Ghazal); S.H. Wild (Sarah); A.F. Wright (Alan); H. Campbell (Harry); D. Ellinghaus (David); U. Nöthlings (Ute); G. Jacobs (Gunnar); R. Biffar (Reiner); F.D.J. Ernst (Florian); G. Homuth (Georg); H.K. Kroemer (Heyo); M. Nauck (Matthias); S. Stracke (Sylvia); U. Vol̈ker (Uwe); H. Völzke (Henry); P. Kovacs (Peter); M. Stumvoll (Michael); R. Mägi (Reedik); A. Hofman (Albert); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); Y.S. Aulchenko (Yurii); O. Polasek (Ozren); N. Hastie (Nick); V. Vitart (Veronique); C. Helmer (Catherine); J.J. Wang (Jie Jin); B. Stengel (Bernd); D. Ruggiero; S.M. Bergmann (Sven); M. Kähönen (Mika); J. Viikari (Jorma); T. Nikopensius (Tiit); M.A. Province (Mike); H.M. Colhoun (H.); A.S.F. Doney (Alex); A. Robino (Antonietta); B.K. Krämer (Bernhard); L. Portas (Laura); I. Ford (Ian); B.M. Buckley (Brendan M.); M. Adam (Martin); G.-A. Thun (Gian-Andri); B. Paulweber (Bernhard); M. Haun (Margot); C. Sala (Cinzia); P. Mitchell (Paul); M. Ciullo; P. Vollenweider (Peter); O. Raitakari (Olli); A. Metspalu (Andres); C.N.A. Palmer (Colin); P. Gasparini (Paolo); M. Pirastu (Mario); J.W. Jukema (Jan Wouter); N.M. Probst-Hensch (Nicole M.); F. Kronenberg (Florian); D. Toniolo (Daniela); V. Gudnason (Vilmundur); A.R. Shuldiner (Alan); J. Coresh (Josef); R. Schmidt (Reinhold); L. Ferrucci (Luigi); C.M. van Duijn (Cornelia); I.B. Borecki (Ingrid); S.L.R. Kardia (Sharon); Y. Liu (YongMei); G.C. Curhan (Gary); I. Rudan (Igor); U. Gyllensten (Ulf); J.F. Wilson (James); A. Franke (Andre); P.P. Pramstaller (Peter Paul); R. Rettig (Rainer); I. Prokopenko (Inga); J.C.M. Witteman (Jacqueline); C. Hayward (Caroline); P.M. Ridker (Paul); M. Bochud (Murielle); I.M. Heid (Iris); D.S. Siscovick (David); C.S. Fox (Caroline); W.H.L. Kao (Wen); C.A. Böger (Carsten)

    2013-01-01

    textabstractMany common genetic variants identified by genome-wide association studies for complex traitsmap to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with

  3. Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris).

    Science.gov (United States)

    Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

    2006-04-01

    GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homologue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnRHR and the chordate GnRHR genes. The oct-GnRHR expressed in Xenopus (South African clawed frog) oocytes was responsive to oct-GnRH, but not to any other HPLC fractions of the Octopus brain extract. These results show that oct-GnRHR is an authentic receptor for oct-GnRH. Southern blotting of reverse-transcription PCR products revealed that the oct-GnRHR mRNA was widely distributed in the central and peripheral nervous systems and in several peripheral tissues. In situ hybridization showed that oct-GnRHR mRNA was expressed in some regions involved in autonomic functions, feeding, memory and movement. Oct-GnRH was shown to induce steroidogenesis of testosterone, progesterone and 17beta-oestradiol in Octopus ovary and testis, where oct-GnRHR was abundantly expressed. These results suggest that oct-GnRH, like its vertebrate counterparts, acts as a multifunctional neurotransmitter, neuromodulator and hormone-like factor, both in Octopus central nervous system and peripheral tissues, and that both structure and functions of the GnRH family are, at least partially, evolutionarily conserved between octopuses and chordates.

  4. Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris)

    Science.gov (United States)

    Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

    2005-01-01

    GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homo-logue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnRHR and the chordate GnRHR genes. The oct-GnRHR expressed in Xenopus (South African clawed frog) oocytes was responsive to oct-GnRH, but not to any other HPLC fractions of the Octopus brain extract. These results show that oct-GnRHR is an authentic receptor for oct-GnRH. Southern blotting of reverse-transcription PCR products revealed that the oct-GnRHR mRNA was widely distributed in the central and peripheral nervous systems and in several peripheral tissues. In situ hybridiz-ation showed that oct-GnRHR mRNA was expressed in some regions involved in autonomic functions, feeding, memory and movement. Oct-GnRH was shown to induce steroidogenesis of testosterone, progesterone and 17β-oestradiol in Octopus ovary and testis, where oct-GnRHR was abundantly expressed. These results suggest that oct-GnRH, like its vertebrate counterparts, acts as a multifunctional neurotransmitter, neuromodulator and hormone-like factor, both in Octopus central nervous system and peripheral tissues, and that both structure and functions of the GnRH family are, at least partially, evolutionarily conserved between octopuses and chordates. PMID:16367741

  5. An atlas of the thioredoxin fold class reveals the complexity of function-enabling adaptations.

    Directory of Open Access Journals (Sweden)

    Holly J Atkinson

    2009-10-01

    Full Text Available The group of proteins that contain a thioredoxin (Trx fold is huge and diverse. Assessment of the variation in catalytic machinery of Trx fold proteins is essential in providing a foundation for understanding their functional diversity and predicting the function of the many uncharacterized members of the class. The proteins of the Trx fold class retain common features-including variations on a dithiol CxxC active site motif-that lead to delivery of function. We use protein similarity networks to guide an analysis of how structural and sequence motifs track with catalytic function and taxonomic categories for 4,082 representative sequences spanning the known superfamilies of the Trx fold. Domain structure in the fold class is varied and modular, with 2.8% of sequences containing more than one Trx fold domain. Most member proteins are bacterial. The fold class exhibits many modifications to the CxxC active site motif-only 56.8% of proteins have both cysteines, and no functional groupings have absolute conservation of the expected catalytic motif. Only a small fraction of Trx fold sequences have been functionally characterized. This work provides a global view of the complex distribution of domains and catalytic machinery throughout the fold class, showing that each superfamily contains remnants of the CxxC active site. The unifying context provided by this work can guide the comparison of members of different Trx fold superfamilies to gain insight about their structure-function relationships, illustrated here with the thioredoxins and peroxiredoxins.

  6. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

    Science.gov (United States)

    Tuijnenburg, Paul; Lango Allen, Hana; Burns, Siobhan O; Greene, Daniel; Jansen, Machiel H; Staples, Emily; Stephens, Jonathan; Carss, Keren J; Biasci, Daniele; Baxendale, Helen; Thomas, Moira; Chandra, Anita; Kiani-Alikhan, Sorena; Longhurst, Hilary J; Seneviratne, Suranjith L; Oksenhendler, Eric; Simeoni, Ilenia; de Bree, Godelieve J; Tool, Anton T J; van Leeuwen, Ester M M; Ebberink, Eduard H T M; Meijer, Alexander B; Tuna, Salih; Whitehorn, Deborah; Brown, Matthew; Turro, Ernest; Thrasher, Adrian J; Smith, Kenneth G C; Thaventhiran, James E; Kuijpers, Taco W

    2018-03-02

    The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Multivoxel Patterns Reveal Functionally Differentiated Networks Underlying Auditory Feedback Processing of Speech

    DEFF Research Database (Denmark)

    Zheng, Zane Z.; Vicente-Grabovetsky, Alejandro; MacDonald, Ewen N.

    2013-01-01

    The everyday act of speaking involves the complex processes of speech motor control. An important component of control is monitoring, detection, and processing of errors when auditory feedback does not correspond to the intended motor gesture. Here we show, using fMRI and converging operations...... within a multivoxel pattern analysis framework, that this sensorimotor process is supported by functionally differentiated brain networks. During scanning, a real-time speech-tracking system was used to deliver two acoustically different types of distorted auditory feedback or unaltered feedback while...... human participants were vocalizing monosyllabic words, and to present the same auditory stimuli while participants were passively listening. Whole-brain analysis of neural-pattern similarity revealed three functional networks that were differentially sensitive to distorted auditory feedback during...

  8. A common thread in unconventional superconductivity. The functional renormalization group in multi-band systems

    International Nuclear Information System (INIS)

    Platt, Christian

    2012-01-01

    The superconducting properties of complex materials like the recently discovered iron-pnictides or strontium-ruthenate are often governed by multi-orbital effects. In order to unravel the superconductivity of those materials, we develop a multi-orbital implementation of the functional renormalization group and study the pairing states of several characteristic material systems. Starting with the iron-pnictides, we find competing spin-fluctuation channels that become attractive if the superconducting gap changes sign between the nested portions of the Fermi surface. Depending on material details like doping or pnictogen height, these spin fluctuations then give rise to s ± -wave pairing with or without gap nodes and, in some cases, also change the symmetry to d-wave. Near the transition from nodal s ± -wave to d-wave pairing, we predict the occurrence of a time-reversal symmetry-broken (s+id)-pairing state which avoids gap nodes and is therefore energetically favored. We further study the electronic instabilities of doped graphene, another fascinating material which has recently become accessible and which can effectively be regarded as multi-orbital system. Here, the hexagonal lattice structure assures the degeneracy of two d-wave pairing channels, and the system then realizes a chiral (d+id)-pairing state in a wide doping range around van-Hove filling. In addition, we also find spin-triplet pairing as well as an exotic spin-density wave phase which both become leading if the long-ranged hopping or interaction parameters are slightly modified, for example, by choosing different substrate materials. Finally, we consider the superconducting state of strontium-ruthenate, a possible candidate for chiral spin-triplet pairing with fascinating properties like the existence of half-quantum vortices obeying non-Abelian statistics. Using a microscopic three orbital description including spin-orbit coupling, we demonstrate that ferromagnetic fluctuations are still

  9. Functional photoreceptor loss revealed with adaptive optics: an alternate cause of color blindness.

    Science.gov (United States)

    Carroll, Joseph; Neitz, Maureen; Hofer, Heidi; Neitz, Jay; Williams, David R

    2004-06-01

    There is enormous variation in the X-linked L/M (long/middle wavelength sensitive) gene array underlying "normal" color vision in humans. This variability has been shown to underlie individual variation in color matching behavior. Recently, red-green color blindness has also been shown to be associated with distinctly different genotypes. This has opened the possibility that there may be important phenotypic differences within classically defined groups of color blind individuals. Here, adaptive optics retinal imaging has revealed a mechanism for producing dichromatic color vision in which the expression of a mutant cone photopigment gene leads to the loss of the entire corresponding class of cone photoreceptor cells. Previously, the theory that common forms of inherited color blindness could be caused by the loss of photoreceptor cells had been discounted. We confirm that remarkably, this loss of one-third of the cones does not impair any aspect of vision other than color.

  10. Bacterial 16S rRNA gene analysis revealed that bacteria related to Arcobacter spp. constitute an abundant and common component of the oyster microbiota (Tiostrea chilensis).

    Science.gov (United States)

    Romero, J; García-Varela, M; Laclette, J P; Espejo, R T

    2002-11-01

    To explore the bacterial microbiota in Chilean oyster (Tiostrea chilensis), a molecular approach that permits detection of different bacteria, independently of their capacity to grow in culture media, was used. Bacterial diversity was assessed by analysis of both the 16S rDNA and the 16S-23S intergenic region, obtained by PCR amplifications of DNA extracted from depurated oysters. RFLP of the PCR amplified 16S rDNA showed a prevailing pattern in most of the individuals analyzed, indicating that a few bacterial species were relatively abundant and common in oysters. Cloning and sequencing of the 16S rDNA with the prevailing RFLP pattern indicated that this rRNA was most closely related to Arcobacter spp. However, analysis by the size of the amplified 16S-23S rRNA intergenic regions revealed not Arcobacter spp. but Staphylococcus spp. related bacteria as a major and common component in oyster. These different results may be caused by the absence of target for one of the primers employed for amplification of the intergenic region. Neither of the two bacteria species found in large abundance was recovered after culturing under aerobic, anaerobic, or microaerophilic conditions. This result, however, is expected because the number of bacteria recovered after cultivation was less than 0.01% of the total. All together, these observations suggest that Arcobacter-related strains are probably abundant and common in the Chilean oyster bacterial microbiota.

  11. Extraction of unsaturated fatty acid-rich oil from common carp (Cyprinus carpio) roe and production of defatted roe hydrolysates with functional, antioxidant, and antibacterial properties.

    Science.gov (United States)

    Ghelichi, Sakhi; Shabanpour, Bahareh; Pourashouri, Parastoo; Hajfathalian, Mona; Jacobsen, Charlotte

    2018-03-01

    Common carp roe is a rich protein and oil source, which is usually discarded with no specific use. The aims of this study were to extract oil from the discarded roe and examine functional, antioxidant, and antibacterial properties of defatted roe hydrolysates (CDRHs) at various degrees of hydrolysis (DH). Gas chromatography of fatty acid methyl esters revealed that common carp roe oil contained high levels of unsaturated fatty acids. The results of high-performance liquid chromatography-mass spectrometry indicated that enzymatic hydrolysis of defatted roe yielded higher content of essential amino acids. CDRHs displayed higher solubility than untreated defatted roe, which increased with DH. Better emulsifying and foaming properties were observed at lower DH and non-isoelectric points. Furthermore, water and oil binding capacity decreased with DH. CDRHs exhibited antioxidant activity both in vitro and in 5% roe oil-in-water emulsions and inhibited the growth of certain bacterial strains. Common carp roe could be a promising source of unsaturated fatty acids and functional bioactive agents. Unsaturated fatty acid-rich oil extracted from common carp roe can be delivered into food systems by roe oil-in-water emulsions fortified by functional, antioxidant, and antibacterial hydrolysates from the defatted roe. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  12. Metagenomes reveal microbial structures, functional potentials, and biofouling-related genes in a membrane bioreactor.

    Science.gov (United States)

    Ma, Jinxing; Wang, Zhiwei; Li, Huan; Park, Hee-Deung; Wu, Zhichao

    2016-06-01

    Metagenomic sequencing was used to investigate the microbial structures, functional potentials, and biofouling-related genes in a membrane bioreactor (MBR). The results showed that the microbial community in the MBR was highly diverse. Notably, function analysis of the dominant genera indicated that common genes from different phylotypes were identified for important functional potentials with the observation of variation of abundances of genes in a certain taxon (e.g., Dechloromonas). Despite maintaining similar metabolic functional potentials with a parallel full-scale conventional activated sludge (CAS) system due to treating the identical wastewater, the MBR had more abundant nitrification-related bacteria and coding genes of ammonia monooxygenase, which could well explain its excellent ammonia removal in the low-temperature period. Furthermore, according to quantification of the genes involved in exopolysaccharide and extracellular polymeric substance (EPS) protein metabolism, the MBR did not show a much different potential in producing EPS compared to the CAS system, and bacteria from the membrane biofilm had lower abundances of genes associated with EPS biosynthesis and transport compared to the activated sludge in the MBR.

  13. Validation of Skeletal Muscle cis-Regulatory Module Predictions Reveals Nucleotide Composition Bias in Functional Enhancers

    Science.gov (United States)

    Kwon, Andrew T.; Chou, Alice Yi; Arenillas, David J.; Wasserman, Wyeth W.

    2011-01-01

    We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions. PMID:22144875

  14. Validation of skeletal muscle cis-regulatory module predictions reveals nucleotide composition bias in functional enhancers.

    Directory of Open Access Journals (Sweden)

    Andrew T Kwon

    2011-12-01

    Full Text Available We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions.

  15. Separable roles of UFO during floral development revealed by conditional restoration of gene function.

    Science.gov (United States)

    Laufs, Patrick; Coen, Enrico; Kronenberger, Jocelyne; Traas, Jan; Doonan, John

    2003-02-01

    The UNUSUAL FLORAL ORGANS (UFO) gene is required for several aspects of floral development in Arabidopsis including specification of organ identity in the second and third whorls and the proper pattern of primordium initiation in the inner three whorls. UFO is expressed in a dynamic pattern during the early phases of flower development. Here we dissect the role of UFO by ubiquitously expressing it in ufo loss-of-function flowers at different developmental stages and for various durations using an ethanol-inducible expression system. The previously known functions of UFO could be separated and related to its expression at specific stages of development. We show that a 24- to 48-hour period of UFO expression from floral stage 2, before any floral organs are visible, is sufficient to restore normal petal and stamen development. The earliest requirement for UFO is during stage 2, when the endogenous UFO gene is transiently expressed in the centre of the wild-type flower and is required to specify the initiation patterns of petal, stamen and carpel primordia. Petal and stamen identity is determined during stages 2 or 3, when UFO is normally expressed in the presumptive second and third whorl. Although endogenous UFO expression is absent from the stamen whorl from stage 4 onwards, stamen identity can be restored by UFO activation up to stage 6. We also observed floral phenotypes not observed in loss-of-function or constitutive gain-of-function backgrounds, revealing additional roles of UFO in outgrowth of petal primordia.

  16. Analyses of soil microbial community compositions and functional genes reveal potential consequences of natural forest succession.

    Science.gov (United States)

    Cong, Jing; Yang, Yunfeng; Liu, Xueduan; Lu, Hui; Liu, Xiao; Zhou, Jizhong; Li, Diqiang; Yin, Huaqun; Ding, Junjun; Zhang, Yuguang

    2015-05-06

    The succession of microbial community structure and function is a central ecological topic, as microbes drive the Earth's biogeochemical cycles. To elucidate the response and mechanistic underpinnings of soil microbial community structure and metabolic potential relevant to natural forest succession, we compared soil microbial communities from three adjacent natural forests: a coniferous forest (CF), a mixed broadleaf forest (MBF) and a deciduous broadleaf forest (DBF) on Shennongjia Mountain in central China. In contrary to plant communities, the microbial taxonomic diversity of the DBF was significantly (P the DBF. Furthermore, a network analysis of microbial carbon and nitrogen cycling genes showed the network for the DBF samples was relatively large and tight, revealing strong couplings between microbes. Soil temperature, reflective of climate regimes, was important in shaping microbial communities at both taxonomic and functional gene levels. As a first glimpse of both the taxonomic and functional compositions of soil microbial communities, our results suggest that microbial community structure and function potentials will be altered by future environmental changes, which have implications for forest succession.

  17. The phosphoproteome of Aspergillus nidulans reveals functional association with cellular processes involved in morphology and secretion.

    Science.gov (United States)

    Ramsubramaniam, Nikhil; Harris, Steven D; Marten, Mark R

    2014-11-01

    We describe the first phosphoproteome of the model filamentous fungus Aspergillus nidulans. Phosphopeptides were enriched using titanium dioxide, separated using a convenient ultra-long reverse phase gradient, and identified using a "high-high" strategy (high mass accuracy on the parent and fragment ions) with higher-energy collisional dissociation. Using this approach 1801 phosphosites, from 1637 unique phosphopeptides, were identified. Functional classification revealed phosphoproteins were overrepresented under GO categories related to fungal morphogenesis: "sites of polar growth," "vesicle mediated transport," and "cytoskeleton organization." In these same GO categories, kinase-substrate analysis of phosphoproteins revealed the majority were target substrates of CDK and CK2 kinase families, indicating these kinase families play a prominent role in fungal morphogenesis. Kinase-substrate analysis also identified 57 substrates for kinases known to regulate secretion of hydrolytic enzymes (e.g. PkaA, SchA, and An-Snf1). Altogether this data will serve as a benchmark that can be used to elucidate regulatory networks functionally associated with fungal morphogenesis and secretion. All MS data have been deposited in the ProteomeXchange with identifier PXD000715 (http://proteomecentral.proteomexchange.org/dataset/PXD000715). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Graph theoretical analysis reveals disrupted topological properties of whole brain functional networks in temporal lobe epilepsy.

    Science.gov (United States)

    Wang, Junjing; Qiu, Shijun; Xu, Yong; Liu, Zhenyin; Wen, Xue; Hu, Xiangshu; Zhang, Ruibin; Li, Meng; Wang, Wensheng; Huang, Ruiwang

    2014-09-01

    Temporal lobe epilepsy (TLE) is one of the most common forms of drug-resistant epilepsy. Previous studies have indicated that the TLE-related impairments existed in extensive local functional networks. However, little is known about the alterations in the topological properties of whole brain functional networks. In this study, we acquired resting-state BOLD-fMRI (rsfMRI) data from 26 TLE patients and 25 healthy controls, constructed their whole brain functional networks, compared the differences in topological parameters between the TLE patients and the controls, and analyzed the correlation between the altered topological properties and the epilepsy duration. The TLE patients showed significant increases in clustering coefficient and characteristic path length, but significant decrease in global efficiency compared to the controls. We also found altered nodal parameters in several regions in the TLE patients, such as the bilateral angular gyri, left middle temporal gyrus, right hippocampus, triangular part of left inferior frontal gyrus, left inferior parietal but supramarginal and angular gyri, and left parahippocampus gyrus. Further correlation analysis showed that the local efficiency of the TLE patients correlated positively with the epilepsy duration. Our results indicated the disrupted topological properties of whole brain functional networks in TLE patients. Our findings indicated the TLE-related impairments in the whole brain functional networks, which may help us to understand the clinical symptoms of TLE patients and offer a clue for the diagnosis and treatment of the TLE patients. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  19. Functional Fixedness and Functional Reduction as Common Sense Reasonings in Chemical Equilibrium and in Geometry and Polarity of Molecules.

    Science.gov (United States)

    Furio, C.; Calatayud, M. L.; Barcenas, S. L.; Padilla, O. M.

    2000-01-01

    Focuses on learning difficulties in procedural knowledge, and assesses the procedural difficulties of grade 12 and first- and third-year university students based on common sense reasoning in two areas of chemistry--chemical equilibrium and geometry, and polarity of molecules. (Contains 55 references.) (Author/YDS)

  20. Endozoicomonas genomes reveal functional adaptation and plasticity in bacterial strains symbiotically associated with diverse marine hosts

    KAUST Repository

    Neave, Matthew J.

    2017-01-17

    Endozoicomonas bacteria are globally distributed and often abundantly associated with diverse marine hosts including reef-building corals, yet their function remains unknown. In this study we generated novel Endozoicomonas genomes from single cells and metagenomes obtained directly from the corals Stylophora pistillata, Pocillopora verrucosa, and Acropora humilis. We then compared these culture-independent genomes to existing genomes of bacterial isolates acquired from a sponge, sea slug, and coral to examine the functional landscape of this enigmatic genus. Sequencing and analysis of single cells and metagenomes resulted in four novel genomes with 60–76% and 81–90% genome completeness, respectively. These data also confirmed that Endozoicomonas genomes are large and are not streamlined for an obligate endosymbiotic lifestyle, implying that they have free-living stages. All genomes show an enrichment of genes associated with carbon sugar transport and utilization and protein secretion, potentially indicating that Endozoicomonas contribute to the cycling of carbohydrates and the provision of proteins to their respective hosts. Importantly, besides these commonalities, the genomes showed evidence for differential functional specificity and diversification, including genes for the production of amino acids. Given this metabolic diversity of Endozoicomonas we propose that different genotypes play disparate roles and have diversified in concert with their hosts.

  1. Comparative genomics provides insights into the lifestyle and reveals functional heterogeneity of dark septate endophytic fungi.

    Science.gov (United States)

    Knapp, Dániel G; Németh, Julianna B; Barry, Kerrie; Hainaut, Matthieu; Henrissat, Bernard; Johnson, Jenifer; Kuo, Alan; Lim, Joanne Hui Ping; Lipzen, Anna; Nolan, Matt; Ohm, Robin A; Tamás, László; Grigoriev, Igor V; Spatafora, Joseph W; Nagy, László G; Kovács, Gábor M

    2018-04-20

    Dark septate endophytes (DSE) are a form-group of root endophytic fungi with elusive functions. Here, the genomes of two common DSE of semiarid areas, Cadophora sp. and Periconia macrospinosa were sequenced and analyzed with another 32 ascomycetes of different lifestyles. Cadophora sp. (Helotiales) and P. macrospinosa (Pleosporales) have genomes of 70.46 Mb and 54.99 Mb with 22,766 and 18,750 gene models, respectively. The majority of DSE-specific protein clusters lack functional annotation with no similarity to characterized proteins, implying that they have evolved unique genetic innovations. Both DSE possess an expanded number of carbohydrate active enzymes (CAZymes), including plant cell wall degrading enzymes (PCWDEs). Those were similar in three other DSE, and contributed a signal for the separation of root endophytes in principal component analyses of CAZymes, indicating shared genomic traits of DSE fungi. Number of secreted proteases and lipases, aquaporins, and genes linked to melanin synthesis were also relatively high in our fungi. In spite of certain similarities between our two DSE, we observed low levels of convergence in their gene family evolution. This suggests that, despite originating from the same habitat, these two fungi evolved along different evolutionary trajectories and display considerable functional differences within the endophytic lifestyle.

  2. Endozoicomonas genomes reveal functional adaptation and plasticity in bacterial strains symbiotically associated with diverse marine hosts

    KAUST Repository

    Neave, Matthew J.; Michell, Craig; Apprill, Amy; Voolstra, Christian R.

    2017-01-01

    Endozoicomonas bacteria are globally distributed and often abundantly associated with diverse marine hosts including reef-building corals, yet their function remains unknown. In this study we generated novel Endozoicomonas genomes from single cells and metagenomes obtained directly from the corals Stylophora pistillata, Pocillopora verrucosa, and Acropora humilis. We then compared these culture-independent genomes to existing genomes of bacterial isolates acquired from a sponge, sea slug, and coral to examine the functional landscape of this enigmatic genus. Sequencing and analysis of single cells and metagenomes resulted in four novel genomes with 60–76% and 81–90% genome completeness, respectively. These data also confirmed that Endozoicomonas genomes are large and are not streamlined for an obligate endosymbiotic lifestyle, implying that they have free-living stages. All genomes show an enrichment of genes associated with carbon sugar transport and utilization and protein secretion, potentially indicating that Endozoicomonas contribute to the cycling of carbohydrates and the provision of proteins to their respective hosts. Importantly, besides these commonalities, the genomes showed evidence for differential functional specificity and diversification, including genes for the production of amino acids. Given this metabolic diversity of Endozoicomonas we propose that different genotypes play disparate roles and have diversified in concert with their hosts.

  3. Metabolomics analysis reveals the metabolic and functional roles of flavonoids in light-sensitive tea leaves.

    Science.gov (United States)

    Zhang, Qunfeng; Liu, Meiya; Ruan, Jianyun

    2017-03-20

    As the predominant secondary metabolic pathway in tea plants, flavonoid biosynthesis increases with increasing temperature and illumination. However, the concentration of most flavonoids decreases greatly in light-sensitive tea leaves when they are exposed to light, which further improves tea quality. To reveal the metabolism and potential functions of flavonoids in tea leaves, a natural light-sensitive tea mutant (Huangjinya) cultivated under different light conditions was subjected to metabolomics analysis. The results showed that chlorotic tea leaves accumulated large amounts of flavonoids with ortho-dihydroxylated B-rings (e.g., catechin gallate, quercetin and its glycosides etc.), whereas total flavonoids (e.g., myricetrin glycoside, epigallocatechin gallate etc.) were considerably reduced, suggesting that the flavonoid components generated from different metabolic branches played different roles in tea leaves. Furthermore, the intracellular localization of flavonoids and the expression pattern of genes involved in secondary metabolic pathways indicate a potential photoprotective function of dihydroxylated flavonoids in light-sensitive tea leaves. Our results suggest that reactive oxygen species (ROS) scavenging and the antioxidation effects of flavonoids help chlorotic tea plants survive under high light stress, providing new evidence to clarify the functional roles of flavonoids, which accumulate to high levels in tea plants. Moreover, flavonoids with ortho-dihydroxylated B-rings played a greater role in photo-protection to improve the acclimatization of tea plants.

  4. Comparative expression profiling reveals gene functions in female meiosis and gametophyte development in Arabidopsis.

    Science.gov (United States)

    Zhao, Lihua; He, Jiangman; Cai, Hanyang; Lin, Haiyan; Li, Yanqiang; Liu, Renyi; Yang, Zhenbiao; Qin, Yuan

    2014-11-01

    Megasporogenesis is essential for female fertility, and requires the accomplishment of meiosis and the formation of functional megaspores. The inaccessibility and low abundance of female meiocytes make it particularly difficult to elucidate the molecular basis underlying megasporogenesis. We used high-throughput tag-sequencing analysis to identify genes expressed in female meiocytes (FMs) by comparing gene expression profiles from wild-type ovules undergoing megasporogenesis with those from the spl mutant ovules, which lack megasporogenesis. A total of 862 genes were identified as FMs, with levels that are consistently reduced in spl ovules in two biological replicates. Fluorescence-assisted cell sorting followed by RNA-seq analysis of DMC1:GFP-labeled female meiocytes confirmed that 90% of the FMs are indeed detected in the female meiocyte protoplast profiling. We performed reverse genetic analysis of 120 candidate genes and identified four FM genes with a function in female meiosis progression in Arabidopsis. We further revealed that KLU, a putative cytochrome P450 monooxygenase, is involved in chromosome pairing during female meiosis, most likely by affecting the normal expression pattern of DMC1 in ovules during female meiosis. Our studies provide valuable information for functional genomic analyses of plant germline development as well as insights into meiosis. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

  5. Edge reconstruction in armchair phosphorene nanoribbons revealed by discontinuous Galerkin density functional theory.

    Science.gov (United States)

    Hu, Wei; Lin, Lin; Yang, Chao

    2015-12-21

    With the help of our recently developed massively parallel DGDFT (Discontinuous Galerkin Density Functional Theory) methodology, we perform large-scale Kohn-Sham density functional theory calculations on phosphorene nanoribbons with armchair edges (ACPNRs) containing a few thousands to ten thousand atoms. The use of DGDFT allows us to systematically achieve a conventional plane wave basis set type of accuracy, but with a much smaller number (about 15) of adaptive local basis (ALB) functions per atom for this system. The relatively small number of degrees of freedom required to represent the Kohn-Sham Hamiltonian, together with the use of the pole expansion the selected inversion (PEXSI) technique that circumvents the need to diagonalize the Hamiltonian, results in a highly efficient and scalable computational scheme for analyzing the electronic structures of ACPNRs as well as their dynamics. The total wall clock time for calculating the electronic structures of large-scale ACPNRs containing 1080-10,800 atoms is only 10-25 s per self-consistent field (SCF) iteration, with accuracy fully comparable to that obtained from conventional planewave DFT calculations. For the ACPNR system, we observe that the DGDFT methodology can scale to 5000-50,000 processors. We use DGDFT based ab initio molecular dynamics (AIMD) calculations to study the thermodynamic stability of ACPNRs. Our calculations reveal that a 2 × 1 edge reconstruction appears in ACPNRs at room temperature.

  6. Reliable and rapid characterization of functional FCN2 gene variants reveals diverse geographical patterns

    Directory of Open Access Journals (Sweden)

    Ojurongbe Olusola

    2012-05-01

    Full Text Available Abstract Background Ficolin-2 coded by FCN2 gene is a soluble serum protein and an innate immune recognition element of the complement system. FCN2 gene polymorphisms reveal distinct geographical patterns and are documented to alter serum ficolin levels and modulate disease susceptibility. Methods We employed a real-time PCR based on Fluorescence Resonance Energy Transfer (FRET method to genotype four functional SNPs including -986 G > A (#rs3124952, -602 G > A (#rs3124953, -4A > G (#rs17514136 and +6424 G > T (#rs7851696 in the ficolin-2 (FCN2 gene. We characterized the FCN2 variants in individuals representing Brazilian (n = 176, Nigerian (n = 180, Vietnamese (n = 172 and European Caucasian ethnicity (n = 165. Results We observed that the genotype distribution of three functional SNP variants (−986 G > A, -602 G > A and -4A > G differ significantly between the populations investigated (p p  Conclusions The observed distribution of the FCN2 functional SNP variants may likely contribute to altered serum ficolin levels and this may depend on the different disease settings in world populations. To conclude, the use of FRET based real-time PCR especially for FCN2 gene will benefit a larger scientific community who extensively depend on rapid, reliable method for FCN2 genotyping.

  7. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Schuster, Mikkel B; Bereshchenko, Oksana

    2008-01-01

    Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p...... penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.......42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete...

  8. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage

    OpenAIRE

    Bachmann, Rosilla F.; Wang, Yun; Yuan, Peixiong; Zhou, Rulun; Li, Xiaoxia; Alesci, Salvatore; Du, Jing; Manji, Husseini K.

    2009-01-01

    Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially media...

  9. Common functional correlates of head-strike behavior in the pachycephalosaur Stegoceras validum (Ornithischia, Dinosauria and combative artiodactyls.

    Directory of Open Access Journals (Sweden)

    Eric Snively

    Full Text Available BACKGROUND: Pachycephalosaurs were bipedal herbivorous dinosaurs with bony domes on their heads, suggestive of head-butting as seen in bighorn sheep and musk oxen. Previous biomechanical studies indicate potential for pachycephalosaur head-butting, but bone histology appears to contradict the behavior in young and old individuals. Comparing pachycephalosaurs with fighting artiodactyls tests for common correlates of head-butting in their cranial structure and mechanics. METHODS/PRINCIPAL FINDINGS: Computed tomographic (CT scans and physical sectioning revealed internal cranial structure of ten artiodactyls and pachycephalosaurs Stegoceras validum and Prenocephale prenes. Finite element analyses (FEA, incorporating bone and keratin tissue types, determined cranial stress and strain from simulated head impacts. Recursive partition analysis quantified strengths of correlation between functional morphology and actual or hypothesized behavior. Strong head-strike correlates include a dome-like cephalic morphology, neurovascular canals exiting onto the cranium surface, large neck muscle attachments, and dense cortical bone above a sparse cancellous layer in line with the force of impact. The head-butting duiker Cephalophus leucogaster is the closest morphological analog to Stegoceras, with a smaller yet similarly rounded dome. Crania of the duiker, pachycephalosaurs, and bighorn sheep Ovis canadensis share stratification of thick cortical and cancellous layers. Stegoceras, Cephalophus, and musk ox crania experience lower stress and higher safety factors for a given impact force than giraffe, pronghorn, or the non-combative llama. CONCLUSIONS/SIGNIFICANCE: Anatomy, biomechanics, and statistical correlation suggest that some pachycephalosaurs were as competent at head-to-head impacts as extant analogs displaying such combat. Large-scale comparisons and recursive partitioning can greatly refine inference of behavioral capability for fossil animals.

  10. Chemical defence in avian brood parasites: production and function of repulsive secretions in common cuckoo chicks

    Czech Academy of Sciences Publication Activity Database

    Trnka, A.; Požgayová, Milica; Procházka, Petr; Čapek, Miroslav; Honza, Marcel

    2016-01-01

    Roč. 47, č. 2 (2016), s. 288-293 ISSN 0908-8857 R&D Projects: GA ČR(CZ) GAP506/12/2404 Institutional support: RVO:68081766 Keywords : brood parasitism * common cuckoo Cuculus canorus * malodorous secretion * nest predation * repellency Subject RIV: EG - Zoology Impact factor: 2.228, year: 2016

  11. High-resolution mapping reveals linkage between genes in common bean cultivar Ouro Negro conferring resistance to the rust, anthracnose, and angular leaf spot diseases.

    Science.gov (United States)

    Valentini, Giseli; Gonçalves-Vidigal, Maria Celeste; Hurtado-Gonzales, Oscar P; de Lima Castro, Sandra Aparecida; Cregan, Perry B; Song, Qijian; Pastor-Corrales, Marcial A

    2017-08-01

    Co-segregation analysis and high-throughput genotyping using SNP, SSR, and KASP markers demonstrated genetic linkage between Ur-14 and Co-3 4 /Phg-3 loci conferring resistance to the rust, anthracnose and angular leaf spot diseases of common bean. Rust, anthracnose, and angular leaf spot are major diseases of common bean in the Americas and Africa. The cultivar Ouro Negro has the Ur-14 gene that confers broad spectrum resistance to rust and the gene cluster Co-3 4 /Phg-3 containing two tightly linked genes conferring resistance to anthracnose and angular leaf spot, respectively. We used co-segregation analysis and high-throughput genotyping of 179 F 2:3 families from the Rudá (susceptible) × Ouro Negro (resistant) cross-phenotyped separately with races of the rust and anthracnose pathogens. The results confirmed that Ur-14 and Co-3 4 /Phg-3 cluster in Ouro Negro conferred resistance to rust and anthracnose, respectively, and that Ur-14 and the Co-3 4 /Phg-3 cluster were closely linked. Genotyping the F 2:3 families, first with 5398 SNPs on the Illumina BeadChip BARCBEAN6K_3 and with 15 SSR, and eight KASP markers, specifically designed for the candidate region containing Ur-14 and Co-3 4 /Phg-3, permitted the creation of a high-resolution genetic linkage map which revealed that Ur-14 was positioned at 2.2 cM from Co-3 4 /Phg-3 on the short arm of chromosome Pv04 of the common bean genome. Five flanking SSR markers were tightly linked at 0.1 and 0.2 cM from Ur-14, and two flanking KASP markers were tightly linked at 0.1 and 0.3 cM from Co-3 4 /Phg-3. Many other SSR, SNP, and KASP markers were also linked to these genes. These markers will be useful for the development of common bean cultivars combining the important Ur-14 and Co-3 4 /Phg-3 genes conferring resistance to three of the most destructive diseases of common bean.

  12. Genetic and systems level analysis of Drosophila sticky/citron kinase and dFmr1 mutants reveals common regulation of genetic networks

    Directory of Open Access Journals (Sweden)

    Zarnescu Daniela C

    2008-11-01

    Full Text Available Abstract Background In Drosophila, the genes sticky and dFmr1 have both been shown to regulate cytoskeletal dynamics and chromatin structure. These genes also genetically interact with Argonaute family microRNA regulators. Furthermore, in mammalian systems, both genes have been implicated in neuronal development. Given these genetic and functional similarities, we tested Drosophila sticky and dFmr1 for a genetic interaction and measured whole genome expression in both mutants to assess similarities in gene regulation. Results We found that sticky mutations can dominantly suppress a dFmr1 gain-of-function phenotype in the developing eye, while phenotypes produced by RNAi knock-down of sticky were enhanced by dFmr1 RNAi and a dFmr1 loss-of-function mutation. We also identified a large number of transcripts that were misexpressed in both mutants suggesting that sticky and dFmr1 gene products similarly regulate gene expression. By integrating gene expression data with a protein-protein interaction network, we found that mutations in sticky and dFmr1 resulted in misexpression of common gene networks, and consequently predicted additional specific phenotypes previously not known to be associated with either gene. Further phenotypic analyses validated these predictions. Conclusion These findings establish a functional link between two previously unrelated genes. Microarray analysis indicates that sticky and dFmr1 are both required for regulation of many developmental genes in a variety of cell types. The diversity of transcripts regulated by these two genes suggests a clear cause of the pleiotropy that sticky and dFmr1 mutants display and provides many novel, testable hypotheses about the functions of these genes. As both of these genes are implicated in the development and function of the mammalian brain, these results have relevance to human health as well as to understanding more general biological processes.

  13. Comparative Genomic Analyses of Multiple Pseudomonas Strains Infecting Corylus avellana Trees Reveal the Occurrence of Two Genetic Clusters with Both Common and Distinctive Virulence and Fitness Traits

    Science.gov (United States)

    Marcelletti, Simone; Scortichini, Marco

    2015-01-01

    The European hazelnut (Corylus avellana) is threatened in Europe by several pseudomonads which cause symptoms ranging from twig dieback to tree death. A comparison of the draft genomes of nine Pseudomonas strains isolated from symptomatic C. avellana trees was performed to identify common and distinctive genomic traits. The thorough assessment of genetic relationships among the strains revealed two clearly distinct clusters: P. avellanae and P. syringae. The latter including the pathovars avellanae, coryli and syringae. Between these two clusters, no recombination event was found. A genomic island of approximately 20 kb, containing the hrp/hrc type III secretion system gene cluster, was found to be present without any genomic difference in all nine pseudomonads. The type III secretion system effector repertoires were remarkably different in the two groups, with P. avellanae showing a higher number of effectors. Homologue genes of the antimetabolite mangotoxin and ice nucleation activity clusters were found solely in all P. syringae pathovar strains, whereas the siderophore yersiniabactin was only present in P. avellanae. All nine strains have genes coding for pectic enzymes and sucrose metabolism. By contrast, they do not have genes coding for indolacetic acid and anti-insect toxin. Collectively, this study reveals that genomically different Pseudomonas can converge on the same host plant by suppressing the host defence mechanisms with the use of different virulence weapons. The integration into their genomes of a horizontally acquired genomic island could play a fundamental role in their evolution, perhaps giving them the ability to exploit new ecological niches. PMID:26147218

  14. In vivo labelling of functional ribosomes reveals spatial regulation during starvation in Podospora anserina

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    Silar Philippe

    2000-11-01

    Full Text Available Abstract Background To date, in eukaryotes, ribosomal protein expression is known to be regulated at the transcriptional and/or translational levels. But other forms of regulation may be possible. Results Here, we report the successful tagging of functional ribosomal particles with a S7-GFP chimaeric protein, making it possible to observe in vivo ribosome dynamics in the filamentous fungus Podospora anserina. Microscopic observations revealed a novel kind of ribosomal protein regulation during the passage between cell growth and stationary phases, with a transient accumulation of ribosomal proteins and/or ribosome subunits in the nucleus, possibly the nucleolus, being observed at the beginning of stationary phase. Conclusion Nuclear sequestration can be another level of ribosomal protein regulation in eukaryotic cells.This may contribute to the regulation of cell growth and division.

  15. In vivo labelling of functional ribosomes reveals spatial regulation during starvation in Podospora anserina

    Science.gov (United States)

    Lalucque, Hervé; Silar, Philippe

    2000-01-01

    Background To date, in eukaryotes, ribosomal protein expression is known to be regulated at the transcriptional and/or translational levels. But other forms of regulation may be possible. Results Here, we report the successful tagging of functional ribosomal particles with a S7-GFP chimaeric protein, making it possible to observe in vivo ribosome dynamics in the filamentous fungus Podospora anserina. Microscopic observations revealed a novel kind of ribosomal protein regulation during the passage between cell growth and stationary phases, with a transient accumulation of ribosomal proteins and/or ribosome subunits in the nucleus, possibly the nucleolus, being observed at the beginning of stationary phase. Conclusion Nuclear sequestration can be another level of ribosomal protein regulation in eukaryotic cells.This may contribute to the regulation of cell growth and division. PMID:11112985

  16. Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases

    Energy Technology Data Exchange (ETDEWEB)

    P Lombardi; H Angell; D Whittington; E Flynn; K Rajashankar; D Christianson

    2011-12-31

    Polyamines are a ubiquitous class of polycationic small molecules that can influence gene expression by binding to nucleic acids. Reversible polyamine acetylation regulates nucleic acid binding and is required for normal cell cycle progression and proliferation. Here, we report the structures of Mycoplana ramosa acetylpolyamine amidohydrolase (APAH) complexed with a transition state analogue and a hydroxamate inhibitor and an inactive mutant complexed with two acetylpolyamine substrates. The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 {angstrom} long 'L'-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. The importance of dimerization for polyamine deacetylase function leads to the suggestion that a comparable dimeric or double-domain histone deacetylase could catalyze polyamine deacetylation reactions in eukaryotes.

  17. Sparse genetic tracing reveals regionally specific functional organization of mammalian nociceptors.

    Science.gov (United States)

    Olson, William; Abdus-Saboor, Ishmail; Cui, Lian; Burdge, Justin; Raabe, Tobias; Ma, Minghong; Luo, Wenqin

    2017-10-12

    The human distal limbs have a high spatial acuity for noxious stimuli but a low density of pain-sensing neurites. To elucidate mechanisms underlying regional differences in processing nociception, we sparsely traced non-peptidergic nociceptors across the body using a newly generated Mrgprd CreERT2 mouse line. We found that mouse plantar paw skin is also innervated by a low density of Mrgprd + nociceptors, while individual arbors in different locations are comparable in size. Surprisingly, the central arbors of plantar paw and trunk innervating nociceptors have distinct morphologies in the spinal cord. This regional difference is well correlated with a heightened signal transmission for plantar paw circuits, as revealed by both spinal cord slice recordings and behavior assays. Taken together, our results elucidate a novel somatotopic functional organization of the mammalian pain system and suggest that regional central arbor structure could facilitate the "enlarged representation" of plantar paw regions in the CNS.

  18. Cell array-based intracellular localization screening reveals novel functional features of human chromosome 21 proteins

    Directory of Open Access Journals (Sweden)

    Kahlem Pascal

    2006-06-01

    Full Text Available Abstract Background Trisomy of human chromosome 21 (Chr21 results in Down's syndrome, a complex developmental and neurodegenerative disease. Molecular analysis of Down's syndrome, however, poses a particular challenge, because the aneuploid region of Chr21 contains many genes of unknown function. Subcellular localization of human Chr21 proteins may contribute to further understanding of the functions and regulatory mechanisms of the genes that code for these proteins. Following this idea, we used a transfected-cell array technique to perform a rapid and cost-effective analysis of the intracellular distribution of Chr 21 proteins. Results We chose 89 genes that were distributed over the majority of 21q, ranging from RBM11 (14.5 Mb to MCM3AP (46.6 Mb, with part of them expressed aberrantly in the Down's syndrome mouse model. Open reading frames of these genes were cloned into a mammalian expression vector with an amino-terminal His6 tag. All of the constructs were arrayed on glass slides and reverse transfected into HEK293T cells for protein expression. Co-localization detection using a set of organelle markers was carried out for each Chr21 protein. Here, we report the subcellular localization properties of 52 proteins. For 34 of these proteins, their localization is described for the first time. Furthermore, the alteration in cell morphology and growth as a result of protein over-expression for claudin-8 and claudin-14 genes has been characterized. Conclusion The cell array-based protein expression and detection approach is a cost-effective platform for large-scale functional analyses, including protein subcellular localization and cell phenotype screening. The results from this study reveal novel functional features of human Chr21 proteins, which should contribute to further understanding of the molecular pathology of Down's syndrome.

  19. Master stability functions reveal diffusion-driven pattern formation in networks

    Science.gov (United States)

    Brechtel, Andreas; Gramlich, Philipp; Ritterskamp, Daniel; Drossel, Barbara; Gross, Thilo

    2018-03-01

    We study diffusion-driven pattern formation in networks of networks, a class of multilayer systems, where different layers have the same topology, but different internal dynamics. Agents are assumed to disperse within a layer by undergoing random walks, while they can be created or destroyed by reactions between or within a layer. We show that the stability of homogeneous steady states can be analyzed with a master stability function approach that reveals a deep analogy between pattern formation in networks and pattern formation in continuous space. For illustration, we consider a generalized model of ecological meta-food webs. This fairly complex model describes the dispersal of many different species across a region consisting of a network of individual habitats while subject to realistic, nonlinear predator-prey interactions. In this example, the method reveals the intricate dependence of the dynamics on the spatial structure. The ability of the proposed approach to deal with this fairly complex system highlights it as a promising tool for ecology and other applications.

  20. Comprehensive gene expression profiling reveals synergistic functional networks in cerebral vessels after hypertension or hypercholesterolemia.

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    Wei-Yi Ong

    Full Text Available Atherosclerotic stenosis of cerebral arteries or intracranial large artery disease (ICLAD is a major cause of stroke especially in Asians, Hispanics and Africans, but relatively little is known about gene expression changes in vessels at risk. This study compares comprehensive gene expression profiles in the middle cerebral artery (MCA of New Zealand White rabbits exposed to two stroke risk factors i.e. hypertension and/or hypercholesterolemia, by the 2-Kidney-1-Clip method, or dietary supplementation with cholesterol. Microarray and Ingenuity Pathway Analyses of the MCA of the hypertensive rabbits showed up-regulated genes in networks containing the node molecules: UBC (ubiquitin, P38 MAPK, ERK, NFkB, SERPINB2, MMP1 and APP (amyloid precursor protein; and down-regulated genes related to MAPK, ERK 1/2, Akt, 26 s proteasome, histone H3 and UBC. The MCA of hypercholesterolemic rabbits showed differentially expressed genes that are surprisingly, linked to almost the same node molecules as the hypertensive rabbits, despite a relatively low percentage of 'common genes' (21 and 7% between the two conditions. Up-regulated common genes were related to: UBC, SERPINB2, TNF, HNF4A (hepatocyte nuclear factor 4A and APP, and down-regulated genes, related to UBC. Increased HNF4A message and protein were verified in the aorta. Together, these findings reveal similar nodal molecules and gene pathways in cerebral vessels affected by hypertension or hypercholesterolemia, which could be a basis for synergistic action of risk factors in the pathogenesis of ICLAD.

  1. Comprehensive Gene Expression Profiling Reveals Synergistic Functional Networks in Cerebral Vessels after Hypertension or Hypercholesterolemia

    Science.gov (United States)

    Ong, Wei-Yi; Ng, Mary Pei-Ern; Loke, Sau-Yeen; Jin, Shalai; Wu, Ya-Jun; Tanaka, Kazuhiro; Wong, Peter Tsun-Hon

    2013-01-01

    Atherosclerotic stenosis of cerebral arteries or intracranial large artery disease (ICLAD) is a major cause of stroke especially in Asians, Hispanics and Africans, but relatively little is known about gene expression changes in vessels at risk. This study compares comprehensive gene expression profiles in the middle cerebral artery (MCA) of New Zealand White rabbits exposed to two stroke risk factors i.e. hypertension and/or hypercholesterolemia, by the 2-Kidney-1-Clip method, or dietary supplementation with cholesterol. Microarray and Ingenuity Pathway Analyses of the MCA of the hypertensive rabbits showed up-regulated genes in networks containing the node molecules: UBC (ubiquitin), P38 MAPK, ERK, NFkB, SERPINB2, MMP1 and APP (amyloid precursor protein); and down-regulated genes related to MAPK, ERK 1/2, Akt, 26 s proteasome, histone H3 and UBC. The MCA of hypercholesterolemic rabbits showed differentially expressed genes that are surprisingly, linked to almost the same node molecules as the hypertensive rabbits, despite a relatively low percentage of ‘common genes’ (21 and 7%) between the two conditions. Up-regulated common genes were related to: UBC, SERPINB2, TNF, HNF4A (hepatocyte nuclear factor 4A) and APP, and down-regulated genes, related to UBC. Increased HNF4A message and protein were verified in the aorta. Together, these findings reveal similar nodal molecules and gene pathways in cerebral vessels affected by hypertension or hypercholesterolemia, which could be a basis for synergistic action of risk factors in the pathogenesis of ICLAD. PMID:23874591

  2. Functional gene polymorphism to reveal species history: the case of the CRTISO gene in cultivated carrots.

    Directory of Open Access Journals (Sweden)

    Vanessa Soufflet-Freslon

    Full Text Available Carrot is a vegetable cultivated worldwide for the consumption of its root. Historical data indicate that root colour has been differentially selected over time and according to geographical areas. Root pigmentation depends on the relative proportion of different carotenoids for the white, yellow, orange and red types but only internally for the purple one. The genetic control for root carotenoid content might be partially associated with carotenoid biosynthetic genes. Carotenoid isomerase (CRTISO has emerged as a regulatory step in the carotenoid biosynthesis pathway and could be a good candidate to show how a metabolic pathway gene reflects a species genetic history.In this study, the nucleotide polymorphism and the linkage disequilibrium among the complete CRTISO sequence, and the deviation from neutral expectation were analysed by considering population subdivision revealed with 17 microsatellite markers. A sample of 39 accessions, which represented different geographical origins and root colours, was used. Cultivated carrot was divided into two genetic groups: one from Middle East and Asia (Eastern group, and another one mainly from Europe (Western group. The Western and Eastern genetic groups were suggested to be differentially affected by selection: a signature of balancing selection was detected within the first group whereas the second one showed no selection. A focus on orange-rooted carrots revealed that cultivars cultivated in Asia were mainly assigned to the Western group but showed CRTISO haplotypes common to Eastern carrots.The carotenoid pathway CRTISO gene data proved to be complementary to neutral markers in order to bring critical insight in the cultivated carrot history. We confirmed the occurrence of two migration events since domestication. Our results showed a European background in material from Japan and Central Asia. While confirming the introduction of European carrots in Japanese resources, the history of Central Asia

  3. Head kidney-derived macrophages of common carp (Cyprinus carpio L.) show plasticity and functional polarization upon differential stimulation

    NARCIS (Netherlands)

    Joerink, Maaike; Ribeiro, Carla M. S.; Stet, René J. M.; Hermsen, Trudi; Savelkoul, Huub F. J.; Wiegertjes, Geert F.

    2006-01-01

    Cells from the myeloid lineage are pluripotent. To investigate the potential of myeloid cell polarization in a primitive vertebrate species, we phenotypically and functionally characterized myeloid cells of common carp (Cyprinus carpio L.) during culture. Flow cytometric analysis, Ab labeling of

  4. Speech processing asymmetry revealed by dichotic listening and functional brain imaging.

    Science.gov (United States)

    Hugdahl, Kenneth; Westerhausen, René

    2016-12-01

    In this article, we review research in our laboratory from the last 25 to 30 years on the neuronal basis for laterality of speech perception focusing on the upper, posterior parts of the temporal lobes, and its functional and structural connections to other brain regions. We review both behavioral and brain imaging data, with a focus on dichotic listening experiments, and using a variety of imaging modalities. The data have come in most parts from healthy individuals and from studies on normally functioning brain, although we also review a few selected clinical examples. We first review and discuss the structural model for the explanation of the right-ear advantage (REA) and left hemisphere asymmetry for auditory language processing. A common theme across many studies have been our interest in the interaction between bottom-up, stimulus-driven, and top-down, instruction-driven, aspects of hemispheric asymmetry, and how perceptual factors interact with cognitive factors to shape asymmetry of auditory language information processing. In summary, our research have shown laterality for the initial processing of consonant-vowel syllables, first observed as a behavioral REA when subjects are required to report which syllable of a dichotic syllable-pair they perceive. In subsequent work we have corroborated the REA with brain imaging, and have shown that the REA is modulated through both bottom-up manipulations of stimulus properties, like sound intensity, and top-down manipulations of cognitive properties, like attention focus. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology.

    Science.gov (United States)

    Zhao, Yongzhong; Epstein, Richard J

    2011-05-01

    Familial tumor suppressor genes comprise two subgroups: caretaker genes (CTs) that repair DNA, and gatekeeper genes (GKs) that trigger cell death. Since GKs may also induce cell cycle delay and thus enhance cell survival by facilitating DNA repair, we hypothesized that the prosurvival phenotype of GKs could be selected during cancer progression, and we used a multivariable systems biology approach to test this. We performed multidimensional data analysis, non-negative matrix factorization and logistic regression to compare the features of GKs with those of their putative antagonists, the proto-oncogenes (POs), as well as with control groups of CTs and functionally unrelated congenital heart disease genes (HDs). GKs and POs closely resemble each other, but not CTs or HDs, in terms of gene structure (Pexpression level and breadth (Pimplied suggest a common functional attribute that is strongly negatively selected-that is, a shared phenotype that enhances cell survival. The counterintuitive finding of similar evolutionary pressures affecting GKs and POs raises an intriguing possibility: namely, that cancer microevolution is accelerated by an epistatic cascade in which upstream suppressor gene defects subvert the normal bifunctionality of wild-type GKs by constitutively shifting the phenotype away from apoptosis towards survival. If correct, this interpretation would explain the hitherto unexplained phenomenon of frequent wild-type GK (for example, p53) overexpression in tumors.

  6. Metagenomic analysis reveals that modern microbialites and polar microbial mats have similar taxonomic and functional potential

    Directory of Open Access Journals (Sweden)

    Richard Allen White III

    2015-09-01

    Full Text Available Within the subarctic climate of Clinton Creek, Yukon, Canada, lies an abandoned and flooded open-pit asbestos mine that harbors rapidly growing microbialites. To understand their formation we completed a metagenomic community profile of the microbialites and their surrounding sediments. Assembled metagenomic data revealed that bacteria within the phylum Proteobacteria numerically dominated this system, although the relative abundances of taxa within the phylum varied among environments. Bacteria belonging to Alphaproteobacteria and Gammaproteobacteria were dominant in the microbialites and sediments, respectively. The microbialites were also home to many other groups associated with microbialite formation including filamentous cyanobacteria and dissimilatory sulfate-reducing Deltaproteobacteria, consistent with the idea of a shared global microbialite microbiome. Other members were present that are typically not associated with microbialites including Gemmatimonadetes and iron-oxidizing Betaproteobacteria, which participate in carbon metabolism and iron cycling. Compared to the sediments, the microbialite microbiome has significantly more genes associated with photosynthetic processes (e.g., photosystem II reaction centers, carotenoid and chlorophyll biosynthesis and carbon fixation (e.g., CO dehydrogenase. The Clinton Creek microbialite communities had strikingly similar functional potentials to non-lithifying microbial mats from the Canadian High Arctic and Antarctica, but are functionally distinct, from non-lithifying mats or biofilms from Yellowstone. Clinton Creek microbialites also share metabolic genes (R2 0.900. These metagenomic profiles from an anthropogenic microbialite-forming ecosystem provide context to microbialite formation on a human-relevant timescale.

  7. Form and function relationships revealed by long-term research in a semiarid mountain catchment

    Science.gov (United States)

    McNamara, J. P.; Benner, S. G.; Chandler, D. G.; Flores, A. N.; Marshall, H. P.; Seyfried, M. S.; Poulos, M. J.; Pierce, J. L.

    2017-12-01

    Fifteen years of cumulative research in the Dry Creek Experimental Watershed in southwest Idaho, USA has revealed relationships between catchment form and function and contributed to improved fundamental understanding of Critical Zone structure, function, and evolution that would not have been possible through independent short term projects alone. The impacts of aspect and elevation on incident energy and water, coupled with climate seasonality, has produced tightly connected landforms properties and hydrologic processes. North-facing hillslopes have steeper slopes, thicker soil mantles, and finer soil texture than their south-facing counterparts. Finer soils enable higher water holding capacities on north facing slopes, which when coupled with thicker soils produces higher soil water storage capacity. The storage of water first as snow, then as soil moisture determines how upland ecosystems survive the seasonal and persistent water stress that happens each year, and sustains streamflow throughout the year. The cumulative body of local knowledge has improved general understanding of catchment science, serves as a resource for developing, evaluating, and improving conceptual and numerical of process-based models, and for data-driven hydrologic education.

  8. MOBIUS-STRIP-LIKE COLUMNAR FUNCTIONAL CONNECTIONS ARE REVEALED IN SOMATO-SENSORY RECEPTIVE FIELD CENTROIDS.

    Directory of Open Access Journals (Sweden)

    James Joseph Wright

    2014-10-01

    Full Text Available Receptive fields of neurons in the forelimb region of areas 3b and 1 of primary somatosensory cortex, in cats and monkeys, were mapped using extracellular recordings obtained sequentially from nearly radial penetrations. Locations of the field centroids indicated the presence of a functional system, in which cortical homotypic representations of the limb surfaces are entwined in three-dimensional Mobius-strip-like patterns of synaptic connections. Boundaries of somatosensory receptive field in nested groups irregularly overlie the centroid order, and are interpreted as arising from the superposition of learned connections upon the embryonic order. Since the theory of embryonic synaptic self-organisation used to model these results was devised and earlier used to explain findings in primary visual cortex, the present findings suggest the theory may be of general application throughout cortex, and may reveal a modular functional synaptic system, which, only in some parts of the cortex, and in some species, is manifest as anatomical ordering into columns.

  9. Absenteeism due to Functional Limitations Caused by Seven Common Chronic Diseases in US Workers.

    Science.gov (United States)

    Vuong, Tam D; Wei, Feifei; Beverly, Claudia J

    2015-07-01

    The study examined the relationship between functional limitation due to chronic diseases and absenteeism among full-time workers. The studied chronic diseases include arthritis/rheumatism, cancer, diabetes, heart disease, hypertension, lung disease, and stroke. We analyzed data from the 2011 to 2013 National Health Interview Survey. Economic impact was determined by workdays lost and lost income. Increase in absenteeism was observed for each studied condition. Employees with multiple conditions also saw increase absenteeism. Employers lose 28.2 million workdays annually ($4.95 billion in lost income) due to functional limitation caused by chronic diseases. The results show a burden on society due to functional limitation caused by studied chronic diseases. Employers should look into implementing intervention/prevention programs, such as the Chronic Disease Self-Management Programs, to help reduce the cost associated with absenteeism.

  10. Abnormal regional homogeneity in patients with essential tremor revealed by resting-state functional MRI.

    Directory of Open Access Journals (Sweden)

    Weidong Fang

    Full Text Available Essential tremor (ET is one of the most common movement disorders in human adults. It can be characterized as a progressive neurological disorder of which the most recognizable feature is a tremor of the arms or hands that is apparent during voluntary movements such as eating and writing. The pathology of ET remains unclear. Resting-state fMRI (RS-fMRI, as a non-invasive imaging technique, was employed to investigate abnormalities of functional connectivity in ET in the brain. Regional homogeneity (ReHo was used as a metric of RS-fMRI to assess the local functional connectivity abnormality in ET with 20 ET patients and 20 age- and gender-matched healthy controls (HC. The ET group showed decreased ReHo in the anterior and posterior bilateral cerebellar lobes, the bilateral thalamus and the insular lobe, and increased ReHo in the bilateral prefrontal and parietal cortices, the left primary motor cortex and left supplementary motor area. The abnormal ReHo value of ET patients in the bilateral anterior cerebellar lobes and the right posterior cerebellar lobe were negatively correlated with the tremor severity score, while positively correlated with that in the left primary motor cortex. These findings suggest that the abnormality in cerebello-thalamo-cortical motor pathway is involved in tremor generation and propagation, which may be related to motor-related symptoms in ET patients. Meanwhile, the abnormality in the prefrontal and parietal regions may be associated with non-motor symptoms in ET. These findings suggest that the ReHo could be utilized for investigations of functional-pathological mechanism of ET.

  11. Prokaryotic caspase homologs: phylogenetic patterns and functional characteristics reveal considerable diversity.

    Directory of Open Access Journals (Sweden)

    Johannes Asplund-Samuelsson

    Full Text Available Caspases accomplish initiation and execution of apoptosis, a programmed cell death process specific to metazoans. The existence of prokaryotic caspase homologs, termed metacaspases, has been known for slightly more than a decade. Despite their potential connection to the evolution of programmed cell death in eukaryotes, the phylogenetic distribution and functions of these prokaryotic metacaspase sequences are largely uncharted, while a few experiments imply involvement in programmed cell death. Aiming at providing a more detailed picture of prokaryotic caspase homologs, we applied a computational approach based on Hidden Markov Model search profiles to identify and functionally characterize putative metacaspases in bacterial and archaeal genomes. Out of the total of 1463 analyzed genomes, merely 267 (18% were identified to contain putative metacaspases, but their taxonomic distribution included most prokaryotic phyla and a few archaea (Euryarchaeota. Metacaspases were particularly abundant in Alphaproteobacteria, Deltaproteobacteria and Cyanobacteria, which harbor many morphologically and developmentally complex organisms, and a distinct correlation was found between abundance and phenotypic complexity in Cyanobacteria. Notably, Bacillus subtilis and Escherichia coli, known to undergo genetically regulated autolysis, lacked metacaspases. Pfam domain architecture analysis combined with operon identification revealed rich and varied configurations among the metacaspase sequences. These imply roles in programmed cell death, but also e.g. in signaling, various enzymatic activities and protein modification. Together our data show a wide and scattered distribution of caspase homologs in prokaryotes with structurally and functionally diverse sub-groups, and with a potentially intriguing evolutionary role. These features will help delineate future characterizations of death pathways in prokaryotes.

  12. Revealing the functional neuroanatomy of intrinsic alertness using fMRI: methodological peculiarities.

    Science.gov (United States)

    Clemens, Benjamin; Zvyagintsev, Mikhail; Sack, Alexander T; Sack, Alexander; Heinecke, Armin; Willmes, Klaus; Sturm, Walter

    2011-01-01

    Clinical observations and neuroimaging data revealed a right-hemisphere fronto-parietal-thalamic-brainstem network for intrinsic alertness, and additional left fronto-parietal activity during phasic alertness. The primary objective of this fMRI study was to map the functional neuroanatomy of intrinsic alertness as precisely as possible in healthy participants, using a novel assessment paradigm already employed in clinical settings. Both the paradigm and the experimental design were optimized to specifically assess intrinsic alertness, while at the same time controlling for sensory-motor processing. The present results suggest that the processing of intrinsic alertness is accompanied by increased activity within the brainstem, thalamus, anterior cingulate gyrus, right insula, and right parietal cortex. Additionally, we found increased activation in the left hemisphere around the middle frontal gyrus (BA 9), the insula, the supplementary motor area, and the cerebellum. Our results further suggest that rather minute aspects of the experimental design may induce aspects of phasic alertness, which in turn might lead to additional brain activation in left-frontal areas not normally involved in intrinsic alertness. Accordingly, left BA 9 activation may be related to co-activation of the phasic alertness network due to the switch between rest and task conditions functioning as an external warning cue triggering the phasic alertness network. Furthermore, activation of the intrinsic alertness network during fixation blocks due to enhanced expectancy shortly before the switch to the task block might, when subtracted from the task block, lead to diminished activation in the typical right hemisphere intrinsic alertness network. Thus, we cautiously suggest that--as a methodological artifact--left frontal activations might show up due to phasic alertness involvement and intrinsic alertness activations might be weakened due to contrasting with fixation blocks, when assessing the

  13. Characterization and biological function analysis of the TRIM47 gene from common carp (Cyprinus carpio).

    Science.gov (United States)

    Wang, Yeda; Kuang, Ming; Lu, Yuanan; Lin, Li; Liu, Xueqin

    2017-09-05

    The TRIM family protein was known to play an important role in many cellular processes, including potential antiviral activity, which has attracted lots of attention. In this study, a TRIM47 homolog from common carp (Cyprinus carpio) was cloned and the full length coding DNA sequence (CDS) of this gene was analyzed, results showed that there was a 97% similarity between common carp and zebrafish (Danio rerio), but only 18% similarity with that of human (Homo sapiens) and mouse (Mus musculus). The tissue distribution analysis showed TRIM47 had the highest mRNA level in the brain, a few immune related organs such as liver and kidney also had a relatively high level of TRIM47 expression. SVCV infection decreased TRIM47 mRNA level significantly both in vitro and in vivo, but its expression was not affected by the virus at the protein level. The recombinant plasmid pcDNA4-TRIM47-His was constructed, the subcellular localization in FHM cells showed that TRIM47 uniformly distributed in the cytoplasm at the form of tiny spots, and partially localized in the mitochondria. Overexpression TRIM47 in FHM cells significantly decreased the mRNA level of SVCV-G gene, and it was accompanied with the increasing of IFN1, a member of type I IFN, at the case of SVCV stimulation. In summary, our results had first demonstrated that TRIM47 of the common carp played an important role in viral resistance processes as well as the regulation of IFN signaling pathway. Copyright © 2017. Published by Elsevier B.V.

  14. Extraction of unsaturated fatty acid-rich oil from common carp (Cyprinus carpio) roe and production of defatted roe hydrolysates with functional, antioxidant, and antibacterial properties

    DEFF Research Database (Denmark)

    Ghelichi, Sakhi; Shabanpour, Bahareh; Pourashouri, Parastoo

    2018-01-01

    content of essential amino acids. CDRHs displayed higher solubility than untreated defatted roe, which increased with DH. Better emulsifying and foaming properties were observed at lower DH and non-isoelectric points. Furthermore, water and oil binding capacity decreased with DH. CDRHs exhibited......Common carp roe is a rich protein and oil source, which is usually discarded with no specific use. The aims of this study were to extract oil from the discarded roe and examine functional, antioxidant, and antibacterial properties of defatted roe hydrolysates (CDRHs) at various degrees...... of hydrolysis (DH). Gas chromatography (GC) of fatty acid methyl esters (FAMEs) revealed that common carp roe oil contained high level of unsaturated fatty acids. The results of high-performance liquid chromatography-mass spectrometry (HPLC-MS) indicated that enzymatic hydrolysis of defatted roe yielded higher...

  15. Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response : Interaction with SSRIs

    NARCIS (Netherlands)

    Klok, Melanie D.; Vreeburg, Sophie A.; Penninx, Brenda W. J. H.; Zitman, Frans G.; de Kloet, E. Ron; DeRijk, Roel H.

    Background: Cortisol controls the activity of the hypothalamic pituitary adrenal (HPA) axis during stress and during the circadian cycle through central mineralocorticoid (MR) and glucocorticoid receptors (GR). Changes in MR and GR functioning, therefore, may affect HPA axis activity. In this study

  16. Metagenomics, metatranscriptomics and single cell genomics reveal functional response of active Oceanospirillales to Gulf oil spill

    Energy Technology Data Exchange (ETDEWEB)

    Mason, Olivia U.; Hazen, Terry C.; Borglin, Sharon; Chain, Patrick S. G.; Dubinsky, Eric A.; Fortney, Julian L.; Han, James; Holman, Hoi-Ying N.; Hultman, Jenni; Lamendella, Regina; Mackelprang, Rachel; Malfatti, Stephanie; Tom, Lauren M.; Tringe, Susannah G.; Woyke, Tanja; Zhou, Jizhong; Rubin, Edward M.; Jansson, Janet K.

    2012-06-12

    The Deepwater Horizon oil spill in the Gulf of Mexico resulted in a deep-sea hydrocarbon plume that caused a shift in the indigenous microbial community composition with unknown ecological consequences. Early in the spill history, a bloom of uncultured, thus uncharacterized, members of the Oceanospirillales was previously detected, but their role in oil disposition was unknown. Here our aim was to determine the functional role of the Oceanospirillales and other active members of the indigenous microbial community using deep sequencing of community DNA and RNA, as well as single-cell genomics. Shotgun metagenomic and metatranscriptomic sequencing revealed that genes for motility, chemotaxis and aliphatic hydrocarbon degradation were significantly enriched and expressed in the hydrocarbon plume samples compared with uncontaminated seawater collected from plume depth. In contrast, although genes coding for degradation of more recalcitrant compounds, such as benzene, toluene, ethylbenzene, total xylenes and polycyclic aromatic hydrocarbons, were identified in the metagenomes, they were expressed at low levels, or not at all based on analysis of the metatranscriptomes. Isolation and sequencing of two Oceanospirillales single cells revealed that both cells possessed genes coding for n-alkane and cycloalkane degradation. Specifically, the near-complete pathway for cyclohexane oxidation in the Oceanospirillales single cells was elucidated and supported by both metagenome and metatranscriptome data. The draft genome also included genes for chemotaxis, motility and nutrient acquisition strategies that were also identified in the metagenomes and metatranscriptomes. These data point towards a rapid response of members of the Oceanospirillales to aliphatic hydrocarbons in the deep sea.

  17. Crystal structure analysis reveals functional flexibility in the selenocysteine-specific tRNA from mouse.

    Directory of Open Access Journals (Sweden)

    Oleg M Ganichkin

    Full Text Available Selenocysteine tRNAs (tRNA(Sec exhibit a number of unique identity elements that are recognized specifically by proteins of the selenocysteine biosynthetic pathways and decoding machineries. Presently, these identity elements and the mechanisms by which they are interpreted by tRNA(Sec-interacting factors are incompletely understood.We applied rational mutagenesis to obtain well diffracting crystals of murine tRNA(Sec. tRNA(Sec lacking the single-stranded 3'-acceptor end ((ΔGCCARNA(Sec yielded a crystal structure at 2.0 Å resolution. The global structure of (ΔGCCARNA(Sec resembles the structure of human tRNA(Sec determined at 3.1 Å resolution. Structural comparisons revealed flexible regions in tRNA(Sec used for induced fit binding to selenophosphate synthetase. Water molecules located in the present structure were involved in the stabilization of two alternative conformations of the anticodon stem-loop. Modeling of a 2'-O-methylated ribose at position U34 of the anticodon loop as found in a sub-population of tRNA(Secin vivo showed how this modification favors an anticodon loop conformation that is functional during decoding on the ribosome. Soaking of crystals in Mn(2+-containing buffer revealed eight potential divalent metal ion binding sites but the located metal ions did not significantly stabilize specific structural features of tRNA(Sec.We provide the most highly resolved structure of a tRNA(Sec molecule to date and assessed the influence of water molecules and metal ions on the molecule's conformation and dynamics. Our results suggest how conformational changes of tRNA(Sec support its interaction with proteins.

  18. A comparison of two common sample preparation techniques for lipid and fatty acid analysis in three different coral morphotypes reveals quantitative and qualitative differences.

    Science.gov (United States)

    Conlan, Jessica A; Rocker, Melissa M; Francis, David S

    2017-01-01

    Lipids are involved in a host of biochemical and physiological processes in corals. Therefore, changes in lipid composition reflect changes in the ecology, nutrition, and health of corals. As such, accurate lipid extraction, quantification, and identification is critical to obtain comprehensive insight into a coral's condition. However, discrepancies exist in sample preparation methodology globally, and it is currently unknown whether these techniques generate analogous results. This study compared the two most common sample preparation techniques for lipid analysis in corals: (1) tissue isolation by air-spraying and (2) crushing the coral in toto . Samples derived from each preparation technique were subsequently analysed to quantify lipids and their constituent classes and fatty acids in four common, scleractinian coral species representing three distinct morphotypes ( Acropora millepora , Montipora crassotuberculata , Porites cylindrica , and Pocillopora damicornis ). Results revealed substantial amounts of organic material, including lipids, retained in the skeletons of all species following air-spraying, causing a marked underestimation of total lipid concentration using this method. Moreover, lipid class and fatty acid compositions between the denuded skeleton and sprayed tissue were substantially different. In particular, the majority of the total triacylglycerol and total fatty acid concentrations were retained in the skeleton (55-69% and 56-64%, respectively). As such, the isolated, sprayed tissue cannot serve as a reliable proxy for lipid quantification or identification in the coral holobiont. The in toto crushing method is therefore recommended for coral sample preparation prior to lipid analysis to capture the lipid profile of the entire holobiont, permitting accurate diagnoses of coral condition.

  19. A comparison of two common sample preparation techniques for lipid and fatty acid analysis in three different coral morphotypes reveals quantitative and qualitative differences

    Directory of Open Access Journals (Sweden)

    Jessica A. Conlan

    2017-08-01

    Full Text Available Lipids are involved in a host of biochemical and physiological processes in corals. Therefore, changes in lipid composition reflect changes in the ecology, nutrition, and health of corals. As such, accurate lipid extraction, quantification, and identification is critical to obtain comprehensive insight into a coral’s condition. However, discrepancies exist in sample preparation methodology globally, and it is currently unknown whether these techniques generate analogous results. This study compared the two most common sample preparation techniques for lipid analysis in corals: (1 tissue isolation by air-spraying and (2 crushing the coral in toto. Samples derived from each preparation technique were subsequently analysed to quantify lipids and their constituent classes and fatty acids in four common, scleractinian coral species representing three distinct morphotypes (Acropora millepora, Montipora crassotuberculata, Porites cylindrica, and Pocillopora damicornis. Results revealed substantial amounts of organic material, including lipids, retained in the skeletons of all species following air-spraying, causing a marked underestimation of total lipid concentration using this method. Moreover, lipid class and fatty acid compositions between the denuded skeleton and sprayed tissue were substantially different. In particular, the majority of the total triacylglycerol and total fatty acid concentrations were retained in the skeleton (55–69% and 56–64%, respectively. As such, the isolated, sprayed tissue cannot serve as a reliable proxy for lipid quantification or identification in the coral holobiont. The in toto crushing method is therefore recommended for coral sample preparation prior to lipid analysis to capture the lipid profile of the entire holobiont, permitting accurate diagnoses of coral condition.

  20. Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

    DEFF Research Database (Denmark)

    van Nuenen, BF; Siebner, Hartwig; Weiss, MM

    2008-01-01

    inherited Parkinson disease alters the cortical control of sequential finger movements. METHODS: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During f...... rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. CONCLUSION: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional...... recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function...

  1. Periodicities common to the solar atmosphere rotation and the functioning of human organism

    International Nuclear Information System (INIS)

    Tyagun, N.F.

    1995-01-01

    The study is made of the occurrence rates of menstrual cycle periods for ∼ 2000 women. Peaks on the distribution histogram, corresponding to 21, 25, 28 and 30 days, coincide with a set of axial rotation periods of the solar atmosphere. It is proposed that the functioning of human organism is determined not only by the Moon bu by the rithmics of solar system. 10 refs., 1 fig

  2. Functional neuronal processing of body odors differs from that of similar common odors.

    Science.gov (United States)

    Lundström, Johan N; Boyle, Julie A; Zatorre, Robert J; Jones-Gotman, Marilyn

    2008-06-01

    Visual and auditory stimuli of high social and ecological importance are processed in the brain by specialized neuronal networks. To date, this has not been demonstrated for olfactory stimuli. By means of positron emission tomography, we sought to elucidate the neuronal substrates behind body odor perception to answer the question of whether the central processing of body odors differs from perceptually similar nonbody odors. Body odors were processed by a network that was distinctly separate from common odors, indicating a separation in the processing of odors based on their source. Smelling a friend's body odor activated regions previously seen for familiar stimuli, whereas smelling a stranger activated amygdala and insular regions akin to what has previously been demonstrated for fearful stimuli. The results provide evidence that social olfactory stimuli of high ecological relevance are processed by specialized neuronal networks similar to what has previously been demonstrated for auditory and visual stimuli.

  3. A microcontroller system for investigating the catch effect: functional electrical stimulation of the common peroneal nerve.

    Science.gov (United States)

    Hart, D J; Taylor, P N; Chappell, P H; Wood, D E

    2006-06-01

    Correction of drop foot in hemiplegic gait is achieved by electrical stimulation of the common peroneal nerve with a series of pulses at a fixed frequency. However, during normal gait, the electromyographic signals from the tibialis anterior muscle indicate that muscle force is not constant but varies during the swing phase. The application of double pulses for the correction of drop foot may enhance the gait by generating greater torque at the ankle and thereby increase the efficiency of the stimulation with reduced fatigue. A flexible controller has been designed around the Odstock Drop Foot Stimulator to deliver different profiles of pulses implementing doublets and optimum series. A peripheral interface controller (PIC) microcontroller with some external circuits has been designed and tested to accommodate six profiles. Preliminary results of the measurements from a normal subject seated in a multi-moment chair (an isometric torque measurement device) indicate that profiles containing doublets and optimum spaced pulses look favourable for clinical use.

  4. Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx

    Science.gov (United States)

    Yamagishi, Yuya; Tessier-Lavigne, Marc

    2015-01-01

    Calcium is a key regulator of axon degeneration caused by trauma and disease, but its specific spatial and temporal dynamics in injured axons remain unclear. To clarify the function of calcium in axon degeneration, we observed calcium dynamics in single injured neurons in live zebrafish larvae and tested the temporal requirement for calcium in zebrafish neurons and cultured mouse DRG neurons. Using laser axotomy to induce Wallerian degeneration (WD) in zebrafish peripheral sensory axons, we monitored calcium dynamics from injury to fragmentation, revealing two stereotyped phases of axonal calcium influx. First, axotomy triggered a transient local calcium wave originating at the injury site. This initial calcium wave only disrupted mitochondria near the injury site and was not altered by expression of the protective WD slow (WldS) protein. Inducing multiple waves with additional axotomies did not change the kinetics of degeneration. In contrast, a second phase of calcium influx occurring minutes before fragmentation spread as a wave throughout the axon, entered mitochondria, and was abolished by WldS expression. In live zebrafish, chelating calcium after the first wave, but before the second wave, delayed the progress of fragmentation. In cultured DRG neurons, chelating calcium early in the process of WD did not alter degeneration, but chelating calcium late in WD delayed fragmentation. We propose that a terminal calcium wave is a key instructive component of the axon degeneration program. SIGNIFICANCE STATEMENT Axon degeneration resulting from trauma or neurodegenerative disease can cause devastating deficits in neural function. Understanding the molecular and cellular events that execute axon degeneration is essential for developing treatments to address these conditions. Calcium is known to contribute to axon degeneration, but its temporal requirements in this process have been unclear. Live calcium imaging in severed zebrafish neurons and temporally controlled

  5. Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness

    International Nuclear Information System (INIS)

    Jami, Mohammad-Saeid; Huang, Xin; Peng, Hong; Fu, Kai; Li, Yan; Singh, Rakesh K; Ding, Shi-Jian; Hou, Jinxuan; Liu, Miao; Varney, Michelle L; Hassan, Hesham; Dong, Jixin; Geng, Liying; Wang, Jing; Yu, Fang

    2014-01-01

    KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it

  6. Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA

    Directory of Open Access Journals (Sweden)

    Goldmuntz Elizabeth

    2005-05-01

    Full Text Available Abstract Background PITX2 is a bicoid-related homeodomain transcription factor that plays an important role in asymmetric cardiogenesis. Loss of function experiments in mice cause severe heart malformations, including transposition of the great arteries (TGA. TGA accounts for 5–7% of all congenital heart diseases affecting 0.2 per 1000 live births, thereby representing the most frequent cyanotic heart defect diagnosed in the neonatal period. Methods To address whether altered PITX2 function could also contribute to the formation of dTGA in humans, we screened 96 patients with dTGA by means of dHPLC and direct sequencing for mutations within the PITX2 gene. Results Several SNPs could be detected, but no stop or frame shift mutation. In particular, we found seven intronic and UTR variants, two silent mutations and two polymorphisms within the coding region. Conclusion As most sequence variants were also found in controls we conclude that mutations in PITX2 are not a common cause of dTGA.

  7. Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease.

    Science.gov (United States)

    Lewis, Wesley R; Malarkey, Erik B; Tritschler, Douglas; Bower, Raqual; Pasek, Raymond C; Porath, Jonathan D; Birket, Susan E; Saunier, Sophie; Antignac, Corinne; Knowles, Michael R; Leigh, Margaret W; Zariwala, Maimoona A; Challa, Anil K; Kesterson, Robert A; Rowe, Steven M; Drummond, Iain A; Parant, John M; Hildebrandt, Friedhelm; Porter, Mary E; Yoder, Bradley K; Berbari, Nicolas F

    2016-07-01

    Ciliopathies are genetic disorders arising from dysfunction of microtubule-based cellular appendages called cilia. Different cilia types possess distinct stereotypic microtubule doublet arrangements with non-motile or 'primary' cilia having a 9+0 and motile cilia have a 9+2 array of microtubule doublets. Primary cilia are critical sensory and signaling centers needed for normal mammalian development. Defects in their structure/function result in a spectrum of clinical and developmental pathologies including abnormal neural tube and limb patterning. Altered patterning phenotypes in the limb and neural tube are due to perturbations in the hedgehog (Hh) signaling pathway. Motile cilia are important in fluid movement and defects in motility result in chronic respiratory infections, altered left-right asymmetry, and infertility. These features are the hallmarks of Primary Ciliary Dyskinesia (PCD, OMIM 244400). While mutations in several genes are associated with PCD in patients and animal models, the genetic lesion in many cases is unknown. We assessed the in vivo functions of Growth Arrest Specific 8 (GAS8). GAS8 shares strong sequence similarity with the Chlamydomonas Nexin-Dynein Regulatory Complex (NDRC) protein 4 (DRC4) where it is needed for proper flagella motility. In mammalian cells, the GAS8 protein localizes not only to the microtubule axoneme of motile cilia, but also to the base of non-motile cilia. Gas8 was recently implicated in the Hh signaling pathway as a regulator of Smoothened trafficking into the cilium. Here, we generate the first mouse with a Gas8 mutation and show that it causes severe PCD phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8. Rescue experiments in Chlamydomonas revealed a subtle defect in swim velocity compared to controls. Further experiments using CRISPR/Cas9 homology driven repair (HDR) to generate one of these human missense variants in

  8. Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

    Science.gov (United States)

    Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K; Miyazaki, Hideki; Michael, Iacovos P; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

    2016-02-16

    Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

  9. Proteomic analysis of chromoplasts from six crop species reveals insights into chromoplast function and development.

    Science.gov (United States)

    Wang, Yong-Qiang; Yang, Yong; Fei, Zhangjun; Yuan, Hui; Fish, Tara; Thannhauser, Theodore W; Mazourek, Michael; Kochian, Leon V; Wang, Xiaowu; Li, Li

    2013-02-01

    Chromoplasts are unique plastids that accumulate massive amounts of carotenoids. To gain a general and comparative characterization of chromoplast proteins, this study performed proteomic analysis of chromoplasts from six carotenoid-rich crops: watermelon, tomato, carrot, orange cauliflower, red papaya, and red bell pepper. Stromal and membrane proteins of chromoplasts were separated by 1D gel electrophoresis and analysed using nLC-MS/MS. A total of 953-2262 proteins from chromoplasts of different crop species were identified. Approximately 60% of the identified proteins were predicted to be plastid localized. Functional classification using MapMan bins revealed large numbers of proteins involved in protein metabolism, transport, amino acid metabolism, lipid metabolism, and redox in chromoplasts from all six species. Seventeen core carotenoid metabolic enzymes were identified. Phytoene synthase, phytoene desaturase, ζ-carotene desaturase, 9-cis-epoxycarotenoid dioxygenase, and carotenoid cleavage dioxygenase 1 were found in almost all crops, suggesting relative abundance of them among the carotenoid pathway enzymes. Chromoplasts from different crops contained abundant amounts of ATP synthase and adenine nucleotide translocator, which indicates an important role of ATP production and transport in chromoplast development. Distinctive abundant proteins were observed in chromoplast from different crops, including capsanthin/capsorubin synthase and fibrillins in pepper, superoxide dismutase in watermelon, carrot, and cauliflower, and glutathione-S-transferease in papaya. The comparative analysis of chromoplast proteins among six crop species offers new insights into the general metabolism and function of chromoplasts as well as the uniqueness of chromoplasts in specific crop species. This work provides reference datasets for future experimental study of chromoplast biogenesis, development, and regulation in plants.

  10. Effects of prefrontal tDCS on executive function: Methodological considerations revealed by meta-analysis.

    Science.gov (United States)

    Imburgio, Michael J; Orr, Joseph M

    2018-05-01

    A meta-analysis of studies using single-session transcranial direct current stimulation (tDCS) to target the dorsolateral prefrontal cortex (DLPFC) was undertaken to examine the effect of stimulation on executive function (EF) in healthy samples. 27 studies were included in analyses, yielding 71 effect sizes. The most relevant measure for each task was determined a priori and used to calculate Hedge's g. Methodological characteristics of each study were examined individually as potential moderators of effect size. Stimulation effects on three domains of EF (inhibition of prepotent responses, mental set shifting, and information updating and monitoring) were analyzed separately. In line with previous work, the current study found no significant effect of anodal unilateral tDCS, cathodal unilateral tDCS, or bilateral tDCS on EF. Further moderator and subgroup analyses were only carried out for anodal unilateral montages due to the small number of studies using other montages. Subgroup analyses revealed a significant effect of anodal unilateral tDCS on updating tasks, but not on inhibition or set-shifting tasks. Cathode location significantly moderated the effect of anodal unilateral tDCS. Extracranial cathodes yielded a significant effect on EF while cranial cathodes yielded no effect. Anode size also significantly moderated effect of anodal unilateral tDCS, with smaller anodes being more effective than larger anodes. In summary, anodal DLPFC stimulation is more effective at improving updating ability than inhibition and set-shifting ability, but anodal stimulation can significantly improve general executive function when extracranial cathodes or small anodes are used. Future meta-analyses may examine how stimulation's effects on specific behavioral tasks, rather than broader domains, might be affected by methodological moderators. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease.

    Directory of Open Access Journals (Sweden)

    Wesley R Lewis

    2016-07-01

    Full Text Available Ciliopathies are genetic disorders arising from dysfunction of microtubule-based cellular appendages called cilia. Different cilia types possess distinct stereotypic microtubule doublet arrangements with non-motile or 'primary' cilia having a 9+0 and motile cilia have a 9+2 array of microtubule doublets. Primary cilia are critical sensory and signaling centers needed for normal mammalian development. Defects in their structure/function result in a spectrum of clinical and developmental pathologies including abnormal neural tube and limb patterning. Altered patterning phenotypes in the limb and neural tube are due to perturbations in the hedgehog (Hh signaling pathway. Motile cilia are important in fluid movement and defects in motility result in chronic respiratory infections, altered left-right asymmetry, and infertility. These features are the hallmarks of Primary Ciliary Dyskinesia (PCD, OMIM 244400. While mutations in several genes are associated with PCD in patients and animal models, the genetic lesion in many cases is unknown. We assessed the in vivo functions of Growth Arrest Specific 8 (GAS8. GAS8 shares strong sequence similarity with the Chlamydomonas Nexin-Dynein Regulatory Complex (NDRC protein 4 (DRC4 where it is needed for proper flagella motility. In mammalian cells, the GAS8 protein localizes not only to the microtubule axoneme of motile cilia, but also to the base of non-motile cilia. Gas8 was recently implicated in the Hh signaling pathway as a regulator of Smoothened trafficking into the cilium. Here, we generate the first mouse with a Gas8 mutation and show that it causes severe PCD phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8. Rescue experiments in Chlamydomonas revealed a subtle defect in swim velocity compared to controls. Further experiments using CRISPR/Cas9 homology driven repair (HDR to generate one of these human missense

  12. Evaluation of the regional lung function revealed in radioaerosol scintigram of chronic obstructive pulmonary disease, 1

    International Nuclear Information System (INIS)

    Suzuki, Teruyasu

    1980-01-01

    We classified the findings of radioaerosol inhalation scintigrams of patients with various stages of obstructive pulmonary disease (COPD) into 4 grades, according to the extent of peripheral irregularity and central hot spot formation; Stage I represents normal homogeneous distribution, stage II represents peripheral irregularity, stage III represents additional hot spot formation and stage IV represents further regional defect. This aerosol grading criteria was then compared with routine and specific lung function tests. The aerosol grading criterion correlated well with FEV sub(1.0)% which is a good indicator of the severity of COPD. The central hot spot formation correlated well with FEV sub(1.0)% and respiratory resistance (R.p.) determined by the oscillation method, both of which are good indicators of abnormality in central airway resistance. Peripheral irregularity correlated well with: 1) flows at 50%VC and 25%VC in a maximum forced expiratory flow volume curve; 2) closing volume (CV/VC%); 3) delta N 2 %/l in N 2 single washout test; and 4) the regional delay of 133 Xe washout process, all of which are sensitive indicators of small airway disease. It is therefore reasonable to conclude that the radioaerosol scintigram reveals the regional lung function both in terms of airway resistance (R) and compliance (C). This criterion was useful in quantitatively evaluating the regional ventilation distribution of COPD and the therapeutic effect on bronchial asthma. The mechanism of aerosol praticle deposition related to characteristic central hot spot formation accompanied with peripheral irregularity in a radioaerosol scintigram of COPD, needs further exploration concerning the aerodynamic behavior of aerosol particles in the airways both during inspiration and expiration. (author)

  13. The most common cause of non-functioning kidney nephrectomy: Urolithiasis

    Directory of Open Access Journals (Sweden)

    Şenol Adanur

    2014-09-01

    Full Text Available Objective: Our aim is to evaluate and present the characteristics of patients underwent nephrectomy due to nonfunctional kidney secondary to urolithiasis in our clinic. Methods:Totally 696 patients were anlyzed retrospectively who underwent nephrectomy in our clinic between January 2000 and December 2012. Etiologies and characteristics of nephrectomy applied patients due to nontumoral non-functional kidney related with urinary tract stones are evaluated. Diagnoses of the patients were confirmed by using urinary system ultrasonography, ab dominal computed tomography, intravenous urography and renal scintigraphy. Results:Nephrectomy was performed for 280 (40.2% patients due to tumor formation and for 416 (59.8% patients due to non-functional kidney of totally 696 patients.43.8% (182 of non-funtional kidney cases were resulted by upper urinary tract stones. Mean age of nephrectomy performed urolithiasis patients were 43.7±16.9 years. 53.3% (97 of patients were male and 46.7% (85 patients were female. Preoperative mean creatinine value of patients were detected 2.98±0.47 mg/dl. Renal stone local izatian was ureteropelvic junction in 81.3% (148, ureter in 14.3% (26 and renal+ureter in 4.4% (8 of the patients. 66.8% of reteropelvic junction stones were 10-30 mm in size. Conclusion: Upper urinary tract stones are primer responsible of non-functional kidney development besides forming most of the non-tumor related nephrectomies. Routine urinary system examination should be suggested to patients with a history of urolithiasis in order to prevent later probable organ losses.

  14. X-ray CT Scanning Reveals Long-Term Copper Pollution Effects on Functional Soil Structure

    DEFF Research Database (Denmark)

    Naveed, Muhammad; Møldrup, Per; Homstrup, Martin

    Soil structure plays the main role in the ability of the soil to fulfill essential soil functions such as the root growth, rate of water infiltration and retention, transport of gaseous and chemicals/pollutants through the soil. Soil structure is a dynamic soil property and affected by various...... factors such as soil type, land use, and soil contamination. In this study, we quantified the soil structure using X-ray CT scanning and revealed the effect of a long history of Copper (Cu) pollution on it. A fallow field at Hygum Denmark provides this opportunity as it had a long history of Copper...... sulphate contamination in a gradient with Cu content varies from 21 mg kg-1 to 3837 mg kg-1. Total 20 intact soil columns (diameter of 10 cm and height of 8 cm) were sampled at five locations along the Cu-gradient from a depth of 5 to 15 cm below surface level. The soil columns were scanned at a voxel...

  15. Proteomic analysis reveals a novel function of the kinase Sat4p in Saccharomyces cerevisiae mitochondria.

    Directory of Open Access Journals (Sweden)

    Uta Gey

    Full Text Available The Saccharomyces cerevisiae kinase Sat4p has been originally identified as a protein involved in salt tolerance and stabilization of plasma membrane transporters, implicating a cytoplasmic localization. Our study revealed an additional mitochondrial (mt localization, suggesting a dual function for Sat4p. While no mt related phenotype was observed in the absence of Sat4p, its overexpression resulted in significant changes of a specific mitochondrial subproteome. As shown by a comparative two dimensional difference gel electrophoresis (2D-DIGE approach combined with mass spectrometry, particularly two groups of proteins were affected: the iron-sulfur containing aconitase-type proteins (Aco1p, Lys4p and the lipoamide-containing subproteome (Lat1p, Kgd2p and Gcv3p. The lipoylation sites of all three proteins could be assigned by nanoLC-MS/MS to Lys75 (Lat1p, Lys114 (Kgd2p and Lys102 (Gcv3p, respectively. Sat4p overexpression resulted in accumulation of the delipoylated protein variants and in reduced levels of aconitase-type proteins, accompanied by a decrease in the activities of the respective enzyme complexes. We propose a regulatory role of Sat4p in the late steps of the maturation of a specific subset of mitochondrial iron-sulfur cluster proteins, including Aco1p and lipoate synthase Lip5p. Impairment of the latter enzyme may account for the observed lipoylation defects.

  16. Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans

    Directory of Open Access Journals (Sweden)

    Tavia Caplan

    2018-05-01

    Full Text Available Summary: Candida albicans is a leading cause of death due to fungal infection. Treatment of systemic candidiasis often relies on echinocandins, which disrupt cell wall synthesis. Resistance is readily acquired via mutations in the drug target gene, FKS1. Both basal tolerance and resistance to echinocandins require cellular stress responses. We performed a systematic analysis of 3,030 C. albicans mutants to define circuitry governing cellular responses to echinocandins. We identified 16 genes for which deletion or transcriptional repression enhanced echinocandin susceptibility, including components of the Pkc1-MAPK signaling cascade. We discovered that the molecular chaperone Hsp90 is required for the stability of Pkc1 and Bck1, establishing key mechanisms through which Hsp90 mediates echinocandin resistance. We also discovered that perturbation of the CCT chaperonin complex causes enhanced echinocandin sensitivity, altered cell wall architecture, and aberrant septin localization. Thus, we provide insights into the mechanisms by which cellular chaperones enable crucial responses to echinocandin-induced stress. : Caplan et al. screen 3,030 Candida albicans mutants to define circuitry governing cellular responses to echinocandins, the first-line therapy for systemic candidiasis. They reveal that the molecular chaperone Hsp90 is required for stability of Pkc1 and Bck1 and that the CCT chaperonin complex is a key modulator of echinocandin susceptibility. Keywords: fungal pathogen, Candida albicans, echinocandins, Hsp90, Pkc1, CCT complex, client protein, stress response, functional genomic screen, drug resistance

  17. Structure-guided mutational analysis reveals the functional requirements for product specificity of DOT1 enzymes.

    Science.gov (United States)

    Dindar, Gülcin; Anger, Andreas M; Mehlhorn, Christine; Hake, Sandra B; Janzen, Christian J

    2014-11-12

    DOT1 enzymes are conserved methyltransferases that catalyse the methylation of lysine 79 on histone H3 (H3K79). Most eukaryotes contain one DOT1 enzyme, whereas African trypanosomes have two homologues, DOT1A and DOT1B, with different enzymatic activities. DOT1A mediates mono- and dimethylation of H3K76, the homologue of H3K79 in other organisms, whereas DOT1B additionally catalyses H3K76 trimethylation. However, it is unclear how these different enzymatic activities are achieved. Here we employ a trypanosomal nucleosome reconstitution system and structure-guided homology modelling to identify critical residues within and outside the catalytic centre that modulate product specificity. Exchange of these residues transfers the product specificity from one enzyme to the other, and reveals the existence of distinct regulatory domains adjacent to the catalytic centre. Our study provides the first evidence that a few crucial residues in DOT1 enzymes are sufficient to catalyse methyl-state-specific reactions. These results might also have far-reaching consequences for the functional understanding of homologous enzymes in higher eukaryotes.

  18. Intelligence, creativity, and cognitive control: The common and differential involvement of executive functions in intelligence and creativity

    Science.gov (United States)

    Benedek, Mathias; Jauk, Emanuel; Sommer, Markus; Arendasy, Martin; Neubauer, Aljoscha C.

    2014-01-01

    Intelligence and creativity are known to be correlated constructs suggesting that they share a common cognitive basis. The present study assessed three specific executive abilities – updating, shifting, and inhibition – and examined their common and differential relations to fluid intelligence and creativity (i.e., divergent thinking ability) within a latent variable model approach. Additionally, it was tested whether the correlation of fluid intelligence and creativity can be explained by a common executive involvement. As expected, fluid intelligence was strongly predicted by updating, but not by shifting or inhibition. Creativity was predicted by updating and inhibition, but not by shifting. Moreover, updating (and the personality factor openness) was found to explain a relevant part of the shared variance between intelligence and creativity. The findings provide direct support for the executive involvement in creative thought and shed further light on the functional relationship between intelligence and creativity. PMID:25278640

  19. Functional tests of a prototype for the CMS-ATLAS common non-event data handling framework

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00366910; The ATLAS collaboration; Formica, Andrea

    2017-01-01

    Since 2014 the ATLAS and CMS experiments share a common vision on the database infrastructure for the handling of the non-event data in forthcoming LHC runs. The wide commonality in the use cases has allowed to agree on a common overall design solution that is meeting the requirements of both experiments. A first prototype has been completed in 2016 and has been made available to both experiments. The prototype is based on a web service implementing a REST api with a set of functions for the management of conditions data. In this contribution, we describe this prototype architecture and the tests that have been performed within the CMS computing infrastructure, with the aim of validating the support of the main use cases and of suggesting future improvements.

  20. Dietary supplementation with hybrid palm oil alters liver function in the common Marmoset.

    Science.gov (United States)

    Spreafico, Flavia; Sales, Rafael Carvalho; Gil-Zamorano, Judit; Medeiros, Priscylla da Costa; Latasa, Maria-Jesús; Lima, Monique Ribeiro; de Souza, Sergio Augusto Lopes; Martin-Hernández, Roberto; Gómez-Coronado, Diego; Iglesias-Gutierrez, Eduardo; Mantilla-Escalante, Diana C; das Graças Tavares do Carmo, Maria; Dávalos, Alberto

    2018-02-09

    Hybrid palm oil, which contains higher levels of oleic acid and lower saturated fatty acids in comparison with African palm oil, has been proposed to be somehow equivalent to extra virgin olive oil. However, the biological effects of its consumption are poorly described. Here we have explored the effects of its overconsumption on lipid metabolism in a non-human primate model, the common marmoset. Dietary supplementation of marmoset with hyperlipidic diet containing hybrid palm oil for 3 months did not modify plasma lipids levels, but increased glucose levels as compared to the supplementation with African palm oil. Liver volume was unexpectedly found to be more increased in marmosets consuming hybrid palm oil than in those consuming African palm oil. Hepatic total lipid content and circulating transaminases were dramatically increased in animals consuming hybrid palm oil, as well as an increased degree of fibrosis. Analysis of liver miRNAs showed a selective modulation of certain miRNAs by hybrid palm oil, some of which were predicted to target genes involved in cell adhesion molecules and peroxisomal pathways. Our data suggest that consumption of hybrid palm oil should be monitored carefully, as its overconsumption compared to that of African palm oil could involve important alterations to hepatic metabolism.

  1. Cumulative role of rare and common putative functional genetic variants at NPAS3 in schizophrenia susceptibility.

    Science.gov (United States)

    González-Peñas, Javier; Arrojo, Manuel; Paz, Eduardo; Brenlla, Julio; Páramo, Mario; Costas, Javier

    2015-10-01

    Schizophrenia may be considered a human-specific disorder arisen as a maladaptive by-product of human-specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human-specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human-specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human-chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty-one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome-wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk. © 2015 Wiley Periodicals, Inc.

  2. Estimating a Smooth Common Transfer Function with a Panel of Time Series - Inflow of Larvae Cod as an Example

    Directory of Open Access Journals (Sweden)

    Elizabeth Hansen

    2012-07-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";} The annual response variable in an ecological monitoring study often relates linearly to the weighted cumulative effect of some daily covariate, after adjusting for other annual covariates. Here we consider the problem of non-parametrically estimating the weights involved in computing the aforementioned cumulative effect, with a panel of short and contemporaneously correlated time series whose responses share the common cumulative effect of a daily covariate. The sequence of (unknown daily weights constitutes the so-called transfer function. Specifically, we consider the problem of estimating a smooth common transfer function shared by a panel of short time series that are contemporaneously correlated. We propose an estimation scheme using a likelihood approach that penalizes the roughness of the common transfer function. We illustrate the proposed method with a simulation study and a biological example of indirectly estimating the spawning date distribution of North Sea cod.

  3. A comparative sequence analysis reveals a common GBD/FH3-FH1-FH2-DAD architecture in formins from Dictyostelium, fungi and metazoa

    Directory of Open Access Journals (Sweden)

    Uyeda Taro QP

    2005-03-01

    Full Text Available Abstract Background Formins are multidomain proteins defined by a conserved FH2 (formin homology 2 domain with actin nucleation activity preceded by a proline-rich FH1 (formin homology 1 domain. Formins act as profilin-modulated processive actin nucleators conserved throughout a wide range of eukaryotes. Results We present a detailed sequence analysis of the 10 formins (ForA to J identified in the genome of the social amoeba Dictyostelium discoideum. With the exception of ForI and ForC all other formins conform to the domain structure GBD/FH3-FH1-FH2-DAD, where DAD is the Diaphanous autoinhibition domain and GBD/FH3 is the Rho GTPase-binding domain/formin homology 3 domain that we propose to represent a single domain. ForC lacks a FH1 domain, ForI lacks recognizable GBD/FH3 and DAD domains and ForA, E and J have additional unique domains. To establish the relationship between formins of Dictyostelium and other organisms we constructed a phylogenetic tree based on the alignment of FH2 domains. Real-time PCR was used to study the expression pattern of formin genes. Expression of forC, D, I and J increased during transition to multi-cellular stages, while the rest of genes displayed less marked developmental variations. During sexual development, expression of forH and forI displayed a significant increase in fusion competent cells. Conclusion Our analysis allows some preliminary insight into the functionality of Dictyostelium formins: all isoforms might display actin nucleation activity and, with the exception of ForI, might also be susceptible to autoinhibition and to regulation by Rho GTPases. The architecture GBD/FH3-FH1-FH2-DAD appears common to almost all Dictyostelium, fungal and metazoan formins, for which we propose the denomination of conventional formins, and implies a common regulatory mechanism.

  4. A comparative sequence analysis reveals a common GBD/FH3-FH1-FH2-DAD architecture in formins from Dictyostelium, fungi and metazoa.

    Science.gov (United States)

    Rivero, Francisco; Muramoto, Tetsuya; Meyer, Ann-Kathrin; Urushihara, Hideko; Uyeda, Taro Q P; Kitayama, Chikako

    2005-03-01

    Formins are multidomain proteins defined by a conserved FH2 (formin homology 2) domain with actin nucleation activity preceded by a proline-rich FH1 (formin homology 1) domain. Formins act as profilin-modulated processive actin nucleators conserved throughout a wide range of eukaryotes. We present a detailed sequence analysis of the 10 formins (ForA to J) identified in the genome of the social amoeba Dictyostelium discoideum. With the exception of ForI and ForC all other formins conform to the domain structure GBD/FH3-FH1-FH2-DAD, where DAD is the Diaphanous autoinhibition domain and GBD/FH3 is the Rho GTPase-binding domain/formin homology 3 domain that we propose to represent a single domain. ForC lacks a FH1 domain, ForI lacks recognizable GBD/FH3 and DAD domains and ForA, E and J have additional unique domains. To establish the relationship between formins of Dictyostelium and other organisms we constructed a phylogenetic tree based on the alignment of FH2 domains. Real-time PCR was used to study the expression pattern of formin genes. Expression of forC, D, I and J increased during transition to multi-cellular stages, while the rest of genes displayed less marked developmental variations. During sexual development, expression of forH and forI displayed a significant increase in fusion competent cells. Our analysis allows some preliminary insight into the functionality of Dictyostelium formins: all isoforms might display actin nucleation activity and, with the exception of ForI, might also be susceptible to autoinhibition and to regulation by Rho GTPases. The architecture GBD/FH3-FH1-FH2-DAD appears common to almost all Dictyostelium, fungal and metazoan formins, for which we propose the denomination of conventional formins, and implies a common regulatory mechanism.

  5. A Common Decision of Compartmental Models on the Base of Laplace Transform and Retain Function Concept

    International Nuclear Information System (INIS)

    Dimitrov, L.; Tzvetkova, A.; Nikolov, A.

    1997-01-01

    The compartmental models have a variety of applications in the analysis of the transport of radioactive and non-radioactive material in complex systems as atmosphere, hydrosphere, food chains, human body. The analysis of the biokinetic behaviour of the radioactive material into a human body gives a possibility for correct assessment of the dose from internal irradiation. Skrable has given a decision of non-cyclic linear compartmental models in case of a single intake of material in the compartments as an initial condition. The main purpose of our article is to write down a procedure for analysis of a general compartmental model in case of continuous intake of material into the compartments. This procedure is related to retain function concept and had developed on the base of Laplace transform. On the base on the proposed procedure a non-cyclic linear compartmental model decisions are given in case of both a single and a continuous intake. The Laplace images of cyclic and circular linear compartmental model decisions and their originals in some cases are given too. (author)

  6. Fluid Phase Lipid Areas and Bilayer Thicknesses of Commonly Used Phosphatidylcholines as a Function of Temperature

    International Nuclear Information System (INIS)

    Kucerka, Norbert; Nieh, Mu-Ping; Katsaras, John

    2011-01-01

    The structural parameters of fluid phase bilayers composed of phosphatidylcholines with fully saturated, mixed, and branched fatty acid chains, at several temperatures, have been determined by simultaneously analyzing small-angle neutron and X-ray scattering data. Bilayer parameters, such as area per lipid and overall bilayer thickness have been obtained in conjunction with intrabilayer structural parameters (e.g. hydrocarbon region thickness). The results have allowed us to assess the effect of temperature and hydrocarbon chain composition on bilayer structure. For example, we found that for all lipids there is, not surprisingly, an increase in fatty acid chain trans-gauche isomerization with increasing temperature. Moreover, this increase in trans-gauche isomerization scales with fatty acid chain length in mixed chain lipids. However, in the case of lipids with saturated fatty acid chains, trans-gauche isomerization is increasingly tempered by attractive chain-chain van der Waals interactions with increasing chain length. Finally, our results confirm a strong dependence of lipid chain dynamics as a function of double bond position along fatty acid chains.

  7. Linked functional network abnormalities during intrinsic and extrinsic activity in schizophrenia as revealed by a data-fusion approach.

    Science.gov (United States)

    Hashimoto, Ryu-Ichiro; Itahashi, Takashi; Okada, Rieko; Hasegawa, Sayaka; Tani, Masayuki; Kato, Nobumasa; Mimura, Masaru

    2018-01-01

    Abnormalities in functional brain networks in schizophrenia have been studied by examining intrinsic and extrinsic brain activity under various experimental paradigms. However, the identified patterns of abnormal functional connectivity (FC) vary depending on the adopted paradigms. Thus, it is unclear whether and how these patterns are inter-related. In order to assess relationships between abnormal patterns of FC during intrinsic activity and those during extrinsic activity, we adopted a data-fusion approach and applied partial least square (PLS) analyses to FC datasets from 25 patients with chronic schizophrenia and 25 age- and sex-matched normal controls. For the input to the PLS analyses, we generated a pair of FC maps during the resting state (REST) and the auditory deviance response (ADR) from each participant using the common seed region in the left middle temporal gyrus, which is a focus of activity associated with auditory verbal hallucinations (AVHs). PLS correlation (PLS-C) analysis revealed that patients with schizophrenia have significantly lower loadings of a component containing positive FCs in default-mode network regions during REST and a component containing positive FCs in the auditory and attention-related networks during ADR. Specifically, loadings of the REST component were significantly correlated with the severities of positive symptoms and AVH in patients with schizophrenia. The co-occurrence of such altered FC patterns during REST and ADR was replicated using PLS regression, wherein FC patterns during REST are modeled to predict patterns during ADR. These findings provide an integrative understanding of altered FCs during intrinsic and extrinsic activity underlying core schizophrenia symptoms.

  8. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

    Science.gov (United States)

    Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

    2015-01-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

  9. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Directory of Open Access Journals (Sweden)

    Michelle R Jones

    2015-08-01

    Full Text Available Genome wide association studies (GWAS have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS, a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  10. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Science.gov (United States)

    Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

    2015-08-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  11. Proteomic Profiles Reveal the Function of Different Vegetative Tissues of Moringa oleifera.

    Science.gov (United States)

    Wang, Lei; Zou, Qiong; Wang, Jinxing; Zhang, Junjie; Liu, Zeping; Chen, Xiaoyang

    2016-12-01

    Moringa oleifera is a rich source of bioactive compounds and is widely used in traditional medicine and food for its nutritional value; however, the protein and peptide components of different tissues are rarely discussed. Here, we describe the first investigation of M. oleifera proteomes using mass spectrometry and bioinformatics methods. We aimed to elucidate the protein profiles of M. oleifera leaves, stem, bark, and root. Totally 202 proteins were identified from four vegetative organs. We identified 101 proteins from leaves, 51 from stem, 94 from bark and 67 from root, finding that only five proteins existed in both four vegetative parts. The calculated pI of most of the proteins is distributed in 5-10 and the molecular weight distributed below 100 kDa. Functional classification analysis revealed that proteins which are involved in catalytic activities are the most abundant both in leaves, stem, bark and root. Identification of several heat shock proteins in four vegetative tissues might be adaptive for resistance to high temperature environmental stresses of tropical or subtropical areas. Some enzymes involved in antioxidant processes were also identified in M. oleifera leaves, stem, bark and root. Among the four tissues studies here, leaves protein content and molecular diversity were the highest. The identification of the flocculating protein MO2.1 and MO2.2 in the bark and root provides clue to clarify the antimicrobial molecular mechanisms of root and bark. This study provides information on the protein compositions of M. oleifera vegetative tissues that will be beneficial for potential drug and food supplement development and plant physiology research.

  12. Epileptic Networks in Focal Cortical Dysplasia Revealed Using Electroencephalography–Functional Magnetic Resonance Imaging

    Science.gov (United States)

    Thornton, Rachel; Vulliemoz, Serge; Rodionov, Roman; Carmichael, David W; Chaudhary, Umair J; Diehl, Beate; Laufs, Helmut; Vollmar, Christian; McEvoy, Andrew W; Walker, Matthew C; Bartolomei, Fabrice; Guye, Maxime; Chauvel, Patrick; Duncan, John S; Lemieux, Louis

    2011-01-01

    Objective Surgical treatment of focal epilepsy in patients with focal cortical dysplasia (FCD) is most successful if all epileptogenic tissue is resected. This may not be evident on structural magnetic resonance imaging (MRI), so intracranial electroencephalography (icEEG) is needed to delineate the seizure onset zone (SOZ). EEG-functional MRI (fMRI) can reveal interictal discharge (IED)-related hemodynamic changes in the irritative zone (IZ). We assessed the value of EEG-fMRI in patients with FCD-associated focal epilepsy by examining the relationship between IED-related hemodynamic changes, icEEG findings, and postoperative outcome. Methods Twenty-three patients with FCD-associated focal epilepsy undergoing presurgical evaluation including icEEG underwent simultaneous EEG-fMRI at 3T. IED-related hemodynamic changes were modeled, and results were overlaid on coregistered T1-weighted MRI scans fused with computed tomography scans showing the intracranial electrodes. IED-related hemodynamic changes were compared with the SOZ on icEEG and postoperative outcome at 1 year. Results Twelve of 23 patients had IEDs during recording, and 11 of 12 had significant IED-related hemodynamic changes. The fMRI results were concordant with the SOZ in 5 of 11 patients, all of whom had a solitary SOZ on icEEG. Four of 5 had >50% reduction in seizure frequency following resective surgery. The remaining 6 of 11 patients had widespread or discordant regions of IED-related fMRI signal change. Five of 6 had either a poor surgical outcome (<50% reduction in seizure frequency) or widespread SOZ precluding surgery. Interpretation Comparison of EEG-fMRI with icEEG suggests that EEG-fMRI may provide useful additional information about the SOZ in FCD. Widely distributed discordant regions of IED-related hemodynamic change appear to be associated with a widespread SOZ and poor postsurgical outcome. ANN NEUROL 2011 PMID:22162063

  13. Nicotinic Receptor Alpha7 Expression during Tooth Morphogenesis Reveals Functional Pleiotropy

    Science.gov (United States)

    Rogers, Scott W.; Gahring, Lorise C.

    2012-01-01

    The expression of nicotinic acetylcholine receptor (nAChR) subtype, alpha7, was investigated in the developing teeth of mice that were modified through homologous recombination to express a bi-cistronic IRES-driven tau-enhanced green fluorescent protein (GFP); alpha7GFP) or IRES-Cre (alpha7Cre). The expression of alpha7GFP was detected first in cells of the condensing mesenchyme at embryonic (E) day E13.5 where it intensifies through E14.5. This expression ends abruptly at E15.5, but was again observed in ameloblasts of incisors at E16.5 or molar ameloblasts by E17.5–E18.5. This expression remains detectable until molar enamel deposition is completed or throughout life as in the constantly erupting mouse incisors. The expression of alpha7GFP also identifies all stages of innervation of the tooth organ. Ablation of the alpha7-cell lineage using a conditional alpha7Cre×ROSA26-LoxP(diphtheria toxin A) strategy substantially reduced the mesenchyme and this corresponded with excessive epithelium overgrowth consistent with an instructive role by these cells during ectoderm patterning. However, alpha7knock-out (KO) mice exhibited normal tooth size and shape indicating that under normal conditions alpha7 expression is dispensable to this process. The function of ameloblasts in alpha7KO mice is altered relative to controls. High resolution micro-computed tomography analysis of adult mandibular incisors revealed enamel volume of the alpha7KO was significantly reduced and the organization of enamel rods was altered relative to controls. These results demonstrate distinct and varied spatiotemporal expression of alpha7 during tooth development, and they suggest that dysfunction of this receptor would have diverse impacts upon the adult organ. PMID:22666322

  14. Functional Coding Variation in Recombinant Inbred Mouse Lines Reveals Novel Serotonin Transporter-Associated Phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Carneiro, Ana [Vanderbilt University; Airey, David [University of Tennessee Health Science Center, Memphis; Thompson, Brent [Vanderbilt University; Zhu, C [Vanderbilt University; Rinchik, Eugene M [ORNL; Lu, Lu [University of Tennessee Health Science Center, Memphis; Chesler, Elissa J [ORNL; Erikson, Keith [University of North Carolina; Blakely, Randy [Vanderbilt University

    2009-01-01

    The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology or treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism and obsessive-compulsive disorder (OCD). Here we utilize naturally occurring polymorphisms in recombinant inbred (RI) lines to identify novel phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by two nonsynonymous coding variants (Gly39 and Lys152 (GK)). At these positions, many other mouse lines, including DBA/2J, encode Glu39 and Arg152 (ER haplotype), assignments found also in hSERT. Synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant. Heterologous expression studies confirmed a reduced SERT turnover rate for the GK variant. Experimental and in silico approaches using RI lines (C57Bl/6J X DBA/2J=BXD) identifies multiple anatomical, biochemical and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are multiple traits associated with anxiety and alcohol consumption, as well as of the control of dopamine (DA) signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates ironregulated DA phenotypes. Our studies provide a novel example of the power of coordinated in vitro, in vivo and in silico approaches using murine RI lines to elucidate and quantify the system-level impact of gene variation.

  15. Pan-cancer stratification of solid human epithelial tumors and cancer cell lines reveals commonalities and tissue-specific features of the CpG island methylator phenotype.

    Science.gov (United States)

    Sánchez-Vega, Francisco; Gotea, Valer; Margolin, Gennady; Elnitski, Laura

    2015-01-01

    The term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients. Even though there have been numerous studies of CIMP in individual cancer types, a uniform analysis across tissues is still lacking. We analyze genome-wide patterns of CpG island hypermethylation in 5,253 solid epithelial tumors from 15 cancer types from TCGA and 23 cancer cell lines from ENCODE. We identify differentially methylated loci that define CIMP+ and CIMP- samples, and we use unsupervised clustering to provide a robust molecular stratification of tumor methylomes for 12 cancer types and all cancer cell lines. With a minimal set of 89 discriminative loci, we demonstrate accurate pan-cancer separation of the 12 CIMP+/- subpopulations, based on their average levels of methylation. Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing. Enrichment analyses indicate shared canonical pathways and upstream regulators for CIMP-targeted regions across cancer types. Furthermore, genomic alterations showing consistent associations with CIMP+/- status include genes involved in DNA repair, chromatin remodeling genes, and several histone methyltransferases. Associations of CIMP status with specific clinical features, including overall survival in several cancer types, highlight the importance of the CIMP+/- designation for individual tumor evaluation and personalized medicine. We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors. Our stratification of solid tumors and cancer cell lines based on CIMP status is data-driven and agnostic to tumor type by design, which protects against known biases that have hindered

  16. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition

    Science.gov (United States)

    Rodríguez-Cortez, Virginia C.; del Pino-Molina, Lucia; Rodríguez-Ubreva, Javier; Ciudad, Laura; Gómez-Cabrero, David; Company, Carlos; Urquiza, José M.; Tegnér, Jesper; Rodríguez-Gallego, Carlos; López-Granados, Eduardo; Ballestar, Esteban

    2015-01-01

    Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals. PMID:26081581

  17. Biphasic functional regulation in hippocampus of rat with chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid artery.

    Directory of Open Access Journals (Sweden)

    Jihye Bang

    Full Text Available BACKGROUND: Chronic cerebral hypoperfusion induced by permanent occlusion of the bilateral common carotid artery (BCCAO in rats has been commonly used for the study of Alzheimer's disease and vascular dementia. Despite the apparent cognitive dysfunction in rats with BCCAO, the molecular markers or pathways involved in the pathological alternation have not been clearly identified. METHODS: Temporal changes (sham, 21, 35, 45, 55 and 70 days in gene expression in the hippocampus of rats after BCCAO were measured using time-course microarray analysis. Gene Ontology (GO and pathway analyses were performed to identify the functional involvement of temporally regulated genes in BCCAO. RESULTS: Two major gene expression patterns were observed in the hippocampus of rats after BCCAO. One pattern, which was composed of 341 early up-regulated genes after the surgical procedure, was dominantly involved in immune-related biological functions (false discovery rate [FDR]<0.01. Another pattern composed of 182 temporally delayed down-regulated genes was involved in sensory perception such as olfactory and cognition functions (FDR<0.01. In addition to the two gene expression patterns, the temporal change of GO and the pathway activities using all differentially expressed genes also confirmed that an immune response was the main early change, whereas sensory functions were delayed responses. Moreover, we identified FADD and SOCS3 as possible core genes in the sensory function loss process using text-based mining and interaction network analysis. CONCLUSIONS: The biphasic regulatory mechanism first reported here could provide molecular evidence of BCCAO-induced impaired memory in rats as well as mechanism of the development of vascular dementia.

  18. Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements.

    Science.gov (United States)

    Liu, Shu; Bolger, Joshua K; Kirkland, Lindsay O; Premnath, Padmavathy N; McInnes, Campbell

    2010-12-17

    An alternative strategy for inhibition of the cyclin dependent kinases (CDKs) in antitumor drug discovery is afforded through the substrate recruitment site on the cyclin positive regulatory subunit. Critical CDK substrates such as the Rb and E2F families must undergo cyclin groove binding before phosphorylation, and hence inhibitors of this interaction also block substrate specific kinase activity. This approach offers the potential to generate highly selective and cell cycle specific CDK inhibitors and to reduce the inhibition of transcription mediated through CDK7 and 9, commonly observed with ATP competitive compounds. While highly potent peptide and small molecule inhibitors of CDK2/cyclin A, E substrate recruitment have been reported, little information has been generated on the determinants of inhibitor binding to the cyclin groove of the CDK4/cyclin D1 complex. CDK4/cyclin D is a validated anticancer drug target and continues to be widely pursued in the development of new therapeutics based on cell cycle blockade. We have therefore investigated the structural basis for peptide binding to its cyclin groove and have examined the features contributing to potency and selectivity of inhibitors. Peptidic inhibitors of CDK4/cyclin D of pRb phosphorylation have been synthesized, and their complexes with CDK4/cyclin D1 crystal structures have been generated. Based on available structural information, comparisons of the cyclin grooves of cyclin A2 and D1 are presented and provide insights into the determinants for peptide binding and the basis for differential binding and inhibition. In addition, a complex structure has been generated in order to model the interactions of the CDKI, p27(KIP)¹, with cyclin D1. This information has been used to shed light onto the endogenous inhibition of CDK4 and also to identify unique aspects of cyclin D1 that can be exploited in the design of cyclin groove based CDK inhibitors. Peptidic and nonpeptidic compounds have been

  19. Comparative and functional triatomine genomics reveals reductions and expansions in insecticide resistance-related gene families.

    Science.gov (United States)

    Traverso, Lucila; Lavore, Andrés; Sierra, Ivana; Palacio, Victorio; Martinez-Barnetche, Jesús; Latorre-Estivalis, José Manuel; Mougabure-Cueto, Gaston; Francini, Flavio; Lorenzo, Marcelo G; Rodríguez, Mario Henry; Ons, Sheila; Rivera-Pomar, Rolando V

    2017-02-01

    Triatomine insects are vectors of Trypanosoma cruzi, a protozoan parasite that is the causative agent of Chagas' disease. This is a neglected disease affecting approximately 8 million people in Latin America. The existence of diverse pyrethroid resistant populations of at least two species demonstrates the potential of triatomines to develop high levels of insecticide resistance. Therefore, the incorporation of strategies for resistance management is a main concern for vector control programs. Three enzymatic superfamilies are thought to mediate xenobiotic detoxification and resistance: Glutathione Transferases (GSTs), Cytochromes P450 (CYPs) and Carboxyl/Cholinesterases (CCEs). Improving our knowledge of key triatomine detoxification enzymes will strengthen our understanding of insecticide resistance processes in vectors of Chagas' disease. The discovery and description of detoxification gene superfamilies in normalized transcriptomes of three triatomine species: Triatoma dimidiata, Triatoma infestans and Triatoma pallidipennis is presented. Furthermore, a comparative analysis of these superfamilies among the triatomine transcriptomes and the genome of Rhodnius prolixus, also a triatomine vector of Chagas' disease, and other well-studied insect genomes was performed. The expression pattern of detoxification genes in R. prolixus transcriptomes from key organs was analyzed. The comparisons reveal gene expansions in Sigma class GSTs, CYP3 in CYP superfamily and clade E in CCE superfamily. Moreover, several CYP families identified in these triatomines have not yet been described in other insects. Conversely, several groups of insecticide resistance related enzymes within each enzyme superfamily are reduced or lacking in triatomines. Furthermore, our qRT-PCR results showed an increase in the expression of a CYP4 gene in a T. infestans population resistant to pyrethroids. These results could point to an involvement of metabolic detoxification mechanisms on the high

  20. Comparative and functional triatomine genomics reveals reductions and expansions in insecticide resistance-related gene families.

    Directory of Open Access Journals (Sweden)

    Lucila Traverso

    2017-02-01

    Full Text Available Triatomine insects are vectors of Trypanosoma cruzi, a protozoan parasite that is the causative agent of Chagas' disease. This is a neglected disease affecting approximately 8 million people in Latin America. The existence of diverse pyrethroid resistant populations of at least two species demonstrates the potential of triatomines to develop high levels of insecticide resistance. Therefore, the incorporation of strategies for resistance management is a main concern for vector control programs. Three enzymatic superfamilies are thought to mediate xenobiotic detoxification and resistance: Glutathione Transferases (GSTs, Cytochromes P450 (CYPs and Carboxyl/Cholinesterases (CCEs. Improving our knowledge of key triatomine detoxification enzymes will strengthen our understanding of insecticide resistance processes in vectors of Chagas' disease.The discovery and description of detoxification gene superfamilies in normalized transcriptomes of three triatomine species: Triatoma dimidiata, Triatoma infestans and Triatoma pallidipennis is presented. Furthermore, a comparative analysis of these superfamilies among the triatomine transcriptomes and the genome of Rhodnius prolixus, also a triatomine vector of Chagas' disease, and other well-studied insect genomes was performed. The expression pattern of detoxification genes in R. prolixus transcriptomes from key organs was analyzed. The comparisons reveal gene expansions in Sigma class GSTs, CYP3 in CYP superfamily and clade E in CCE superfamily. Moreover, several CYP families identified in these triatomines have not yet been described in other insects. Conversely, several groups of insecticide resistance related enzymes within each enzyme superfamily are reduced or lacking in triatomines. Furthermore, our qRT-PCR results showed an increase in the expression of a CYP4 gene in a T. infestans population resistant to pyrethroids. These results could point to an involvement of metabolic detoxification mechanisms

  1. Whole-brain analytic measures of network communication reveal increased structure-function correlation in right temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Jonathan Wirsich

    2016-01-01

    In rTLE patients, we found a widespread hypercorrelated functional network. Network communication analysis revealed greater unspecific branching of the shortest path (search information in the structural connectome and a higher global correlation between the structural and functional connectivity for the patient group. We also found evidence for a preserved structural rich-club in the patient group. In sum, global augmentation of structure-function correlation might be linked to a smaller functional repertoire in rTLE patients, while sparing the central core of the brain which may represent a pathway that facilitates the spread of seizures.

  2. Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis.

    Science.gov (United States)

    Chen, Wei; Zhao, Wenshan; Yang, Aiting; Xu, Anjian; Wang, Huan; Cong, Min; Liu, Tianhui; Wang, Ping; You, Hong

    2017-12-15

    Liver fibrosis, characterized with the excessive accumulation of extracellular matrix (ECM) proteins, represents the final common pathway of chronic liver inflammation. Ever-increasing evidence indicates microRNAs (miRNAs) dysregulation has important implications in the different stages of liver fibrosis. However, our knowledge of miRNA-gene regulation details pertaining to such disease remains unclear. The publicly available Gene Expression Omnibus (GEO) datasets of patients suffered from cirrhosis were extracted for integrated analysis. Differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using GEO2R web tool. Putative target gene prediction of DEMs was carried out using the intersection of five major algorithms: DIANA-microT, TargetScan, miRanda, PICTAR5 and miRWalk. Functional miRNA-gene regulatory network (FMGRN) was constructed based on the computational target predictions at the sequence level and the inverse expression relationships between DEMs and DEGs. DAVID web server was selected to perform KEGG pathway enrichment analysis. Functional miRNA-gene regulatory module was generated based on the biological interpretation. Internal connections among genes in liver fibrosis-related module were determined using String database. MiRNA-gene regulatory modules related to liver fibrosis were experimentally verified in recombinant human TGFβ1 stimulated and specific miRNA inhibitor treated LX-2 cells. We totally identified 85 and 923 dysregulated miRNAs and genes in liver cirrhosis biopsy samples compared to their normal controls. All evident miRNA-gene pairs were identified and assembled into FMGRN which consisted of 990 regulations between 51 miRNAs and 275 genes, forming two big sub-networks that were defined as down-network and up-network, respectively. KEGG pathway enrichment analysis revealed that up-network was prominently involved in several KEGG pathways, in which "Focal adhesion", "PI3K-Akt signaling pathway" and "ECM

  3. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function

    NARCIS (Netherlands)

    Noël, Emily S; Momenah, Tarek S; Al-Dagriri, Khalid; Al-Suwaid, Abdulrahman; Al-Shahrani, Safar; Jiang, Hui; Willekers, Sven; Oostveen, Yara Y; Chocron, Sonja; Postma, Alex V; Bhuiyan, Zahurul A; Bakkers, Jeroen

    Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects, such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects

  4. A zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals its Specific Role in Laterality Organ Function

    NARCIS (Netherlands)

    Noël, Emily S; Momenah, Tarek S; Al-Dagriri, Khalid; Al-Suwaid, Abdulrahman; Al-Shahrani, Safar; Jiang, Hui; Willekers, Sven; Oostveen, Yara Y; Chocron, Sonja; Postma, Alex V; Bhuiyan, Zahurul A; Bakkers, Jeroen

    Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects

  5. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function

    NARCIS (Netherlands)

    Noël, Emily S.; Momenah, Tarek S.; Al-Dagriri, Khalid; Al-Suwaid, Abdulrahman; Al-Shahrani, Safar; Jiang, Hui; Willekers, Sven; Oostveen, Yara Y.; Chocron, Sonja; Postma, Alex V.; Bhuiyan, Zahurul A.; Bakkers, Jeroen

    2016-01-01

    Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects, such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects

  6. Assessment of platelet function in healthy cats in response to commonly prescribed antiplatelet drugs using three point-of-care platelet function tests.

    Science.gov (United States)

    Ho, Kimberly K; Abrams-Ogg, Anthony Cg; Wood, R Darren; O'Sullivan, M Lynne; Kirby, Gordon M; Blois, Shauna L

    2017-06-01

    Objectives The objective was to determine if decreased platelet function could be detected after treatment with aspirin and/or clopidogrel in healthy cats using three point-of-care platelet function tests that evaluate platelet function by different methods: Multiplate (by impedance), Platelet Function Analyzer 100 (by mechanical aperture closure) and Plateletworks (by platelet counting). Methods Thirty-six healthy cats were randomly assigned to receive one of three oral treatments over an 8 day period: (1) aspirin 5 mg q72h; (2) aspirin 20.25 mg q72h; or (3) clopidogrel 18.75 mg q24h. Cats treated with 5 and 20.25 mg aspirin also received clopidogrel on days 4-8. Platelet aggregation in response to adenosine diphosphate and collagen ± arachidonic acid was assessed on days 1 (baseline), 4 and 8. Aspirin and clopidogrel metabolites were measured by high-performance liquid chromatography. Platelet function in response to treatment was analyzed by ANCOVA, linear regression and Spearman correlation. Results The only solitary aspirin effect was detected using Plateletworks with collagen in cats treated with 20.25 mg. The only effect detected by Multiplate was using arachidonic acid in cats treated with both aspirin 20.25 mg and clopidogrel. All clopidogrel treatment effects were detected by Platelet Function Analyzer 100, Plateletworks (adenosine diphosphate) and Plateletworks (collagen). Drug metabolites were present in all cats, but concentrations were minimally correlated to platelet function test results. Conclusions and relevance Platelet Function Analyzer 100 and Plateletworks using adenosine diphosphate ± collagen agonists may be used to detect decreased platelet function in response to clopidogrel treatment. Either aspirin is not as effective an antiplatelet drug as clopidogrel, or the tests used were not optimal to measure aspirin effect. Cats with heart disease are commonly prescribed antiplatelet drugs to decrease the risk of aortic thromboembolism

  7. Linear and Non-Linear Dose-Response Functions Reveal a Hormetic Relationship Between Stress and Learning

    OpenAIRE

    Zoladz, Phillip R.; Diamond, David M.

    2008-01-01

    Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear dose-response functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as ...

  8. Functional profiles reveal unique ecological roles of various biological soil crust organisms

    Science.gov (United States)

    Bowker, M.A.; Mau, R.L.; Maestre, F.T.; Escolar, C.; Castillo-Monroy, A. P.

    2011-01-01

    1. At the heart of the body of research on biodiversity effects on ecosystem function is the debate over whether different species tend to be functionally singular or redundant. When we consider ecosystem multi-function, the provision of multiple ecosystem functions simultaneously, we may find that seemingly redundant species may in fact play unique roles in ecosystems. 2. Over the last few decades, the significance of biological soil crusts (BSCs) as ecological boundaries and ecosystem engineers, and their multi-functional nature, has become increasingly well documented. We compiled 'functional profiles' of the organisms in this understudied community, to determine whether functional singularity emerges when multiple ecosystem functions are considered. 3. In two data sets, one representing multiple sites around the semi-arid regions of Spain (regional scale), and another from a single site in central Spain (local scale), we examined correlations between the abundance or frequency of BSC species in a community, and multiple surrogates of ecosystem functioning. There was a wide array of apparent effects of species on specific functions. 4. Notably, in gypsiferous soils and at regional scale, we found that indicators of carbon (C) and phosphorus cycling were apparently suppressed and promoted by the lichens Diploschistes diacapsis and Squamarina lentigera, respectively. The moss Pleurochaete squarrosa appears to promote C cycling in calcareous soils at this spatial scale. At the local scale in gypsiferous soils, D. diacapsis positively correlated with carbon cycling, but negatively with nitrogen cycling, whereas numerous lichens exhibited the opposite profile. 5. We found a high degree of functional singularity, i.e. that species were highly individualistic in their effects on multiple functions. Many functional attributes were not easily predictable from existing functional grouping systems based primarily on morphology. 6. Our results suggest that maintaining

  9. The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function

    International Nuclear Information System (INIS)

    Das, Debanu; Finn, Robert D.; Carlton, Dennis; Miller, Mitchell D.; Abdubek, Polat; Astakhova, Tamara; Axelrod, Herbert L.; Bakolitsa, Constantina; Chen, Connie; Chiu, Hsiu-Ju; Chiu, Michelle; Clayton, Thomas; Deller, Marc C.; Duan, Lian; Ellrott, Kyle; Ernst, Dustin; Farr, Carol L.; Feuerhelm, Julie; Grant, Joanna C.; Grzechnik, Anna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K.; Klock, Heath E.; Knuth, Mark W.; Kozbial, Piotr; Krishna, S. Sri; Kumar, Abhinav; Marciano, David; McMullan, Daniel; Morse, Andrew T.; Nigoghossian, Edward; Nopakun, Amanda; Okach, Linda; Puckett, Christina; Reyes, Ron; Rife, Christopher L.; Sefcovic, Natasha; Tien, Henry J.; Trame, Christine B.; Bedem, Henry van den; Weekes, Dana; Wooten, Tiffany; Xu, Qingping; Hodgson, Keith O.; Wooley, John; Elsliger, Marc-André; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A.

    2010-01-01

    The crystal structure of the BVU2987 gene product from B. vulgatus (UniProt A6L4L1) reveals that members of the new Pfam family PF11396 (domain of unknown function; DUF2874) are similar to β-lactamase inhibitor protein and YpmB. Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA-OmlA proteins and hence are likely to function as inhibitory proteins

  10. Whole brain resting-state analysis reveals decreased functional connectivity in major depression

    NARCIS (Netherlands)

    Veer, I.M.; Beckmann, C.F.; van Tol, M.J.; Ferrarini, L.; Milles, J.; Veltman, D.J.; Aleman, A.; van Buchem, M.A.; van der Wee, N.J.; Rombouts, S.A.R.B.

    2010-01-01

    Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always

  11. Nationwide analysis of adrenocortical carcinoma reveals higher perioperative morbidity in functional tumors.

    Science.gov (United States)

    Parikh, Punam P; Rubio, Gustavo A; Farra, Josefina C; Lew, John I

    2017-08-25

    Current adrenalectomy outcomes for functional adrenocortical carcinoma (ACC) remain unclear. This study examines nationwide in-hospital post-adrenalectomy outcomes for ACC. A retrospective analysis of the Nationwide Inpatient Sample database (2006-2011) to identify unilateral adrenalectomy patients for functional or nonfunctional ACC was performed. Patient demographics, comorbidities and postoperative outcomes were evaluated by t-test, Chi-square and multivariate regression. Of 2199 patients who underwent adrenalectomy, 87% had nonfunctional and 13% had functional ACC (86% hypercortisolism, 16% hyperaldosteronism, 4% hyperandrogenism). Functional ACC patients had significantly more comorbidities, and experienced certain postoperative complications more frequently including wound issues, adrenocortical insufficiency and acute kidney injury with longer hospital stay compared to nonfunctional ACC (P analysis, functional ACC was an independent prognosticator for wound complications (28.1, 95%CI 4.59-176.6). Patients with functional ACC manifest significant comorbidities with certain in-hospital complications. Such high-risk patients require appropriate preoperative medical optimization prior to adrenalectomy. Patients with functional adrenocortical carcinoma (ACC) have significant preoperative comorbidities and experience higher rates of certain postoperative complications including wound complications, hematoma formation, adrenal insufficiency, pulmonary embolism and acute kidney injury. Functional ACC patients also necessitate longer hospitalizations. These patients should undergo appropriate preoperative counseling in preparation for adrenalectomy. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Evolutionary analysis reveals regulatory and functional landscape of coding and non-coding RNA editing.

    Science.gov (United States)

    Zhang, Rui; Deng, Patricia; Jacobson, Dionna; Li, Jin Billy

    2017-02-01

    Adenosine-to-inosine RNA editing diversifies the transcriptome and promotes functional diversity, particularly in the brain. A plethora of editing sites has been recently identified; however, how they are selected and regulated and which are functionally important are largely unknown. Here we show the cis-regulation and stepwise selection of RNA editing during Drosophila evolution and pinpoint a large number of functional editing sites. We found that the establishment of editing and variation in editing levels across Drosophila species are largely explained and predicted by cis-regulatory elements. Furthermore, editing events that arose early in the species tree tend to be more highly edited in clusters and enriched in slowly-evolved neuronal genes, thus suggesting that the main role of RNA editing is for fine-tuning neurological functions. While nonsynonymous editing events have been long recognized as playing a functional role, in addition to nonsynonymous editing sites, a large fraction of 3'UTR editing sites is evolutionarily constrained, highly edited, and thus likely functional. We find that these 3'UTR editing events can alter mRNA stability and affect miRNA binding and thus highlight the functional roles of noncoding RNA editing. Our work, through evolutionary analyses of RNA editing in Drosophila, uncovers novel insights of RNA editing regulation as well as its functions in both coding and non-coding regions.

  13. Investigation of pancreas indocrine function in order to reveal subclinical insulin resistence in women with acne

    OpenAIRE

    Filippova, T.; Rudykh, N.; Shevchuk, A.

    2008-01-01

    Changed glycemic curves and indices of insulin resistance, the increase of insulin basal level in comparison with healthy persons, presence of antibodies to insulin antigen, decrease of level sex hormone bilding globulin were revealed in patients with acne. It can be considered as sign of formation of subclinical insulin resistance.

  14. ‘Candidatus Competibacter’-lineage genomes retrieved from metagenomes reveal functional metabolic diversity

    DEFF Research Database (Denmark)

    McIlroy, Simon Jon; Albertsen, Mads; Andresen, Eva Kammer

    2014-01-01

    as for denitrification, nitrogen fixation, fermentation, trehalose synthesis and utilisation of glucose and lactate. Genetic comparison of P metabolism pathways with sequenced PAOs revealed the absence of the Pit phosphate transporter in the Competibacter-lineage genomes—identifying a key metabolic difference...

  15. High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia

    OpenAIRE

    Drewes, Julia L.; White, James R.; Dejea, Christine M.; Fathi, Payam; Iyadorai, Thevambiga; Vadivelu, Jamuna; Roslani, April C.; Wick, Elizabeth C.; Mongodin, Emmanuel F.; Loke, Mun Fai; Thulasi, Kumar; Gan, Han Ming; Goh, Khean Lee; Chong, Hoong Yin; Kumar, Sandip

    2017-01-01

    Colorectal cancer (CRC) remains the third most common cancer worldwide, with a growing incidence among young adults. Multiple studies have presented associations between the gut microbiome and CRC, suggesting a link with cancer risk. Although CRC microbiome studies continue to profile larger patient cohorts with increasingly economical and rapid DNA sequencing platforms, few common associations with CRC have been identified, in part due to limitations in taxonomic resolution and differences i...

  16. Lateral Variations of the Mantle Transition Zone Structure beneath the Southeastern Tibetan Plateau Revealed by P-wave Receiver Functions

    Science.gov (United States)

    Bai, Y.; Ai, Y.; Jiang, M.; He, Y.; Chen, Q.

    2017-12-01

    The deep structure of the southeastern Tibetan plateau is of great scientific importance to a better understanding of the India-Eurasia collision as well as the evolution of the magnificent Tibetan plateau. In this study, we collected 566 permanent and temporary seismic stations deployed in SE Tibet, with a total of 77853 high quality P-wave receiver functions been extracted by maximum entropy deconvolution method. On the basis of the Common Conversion Point (CCP) stacking technique, we mapped the topography of the 410km and 660km discontinuities (hereinafter called the `410' and the `660'), and further investigated the lateral variation of the mantle transition zone (MTZ) thickness beneath this region. The background velocity model deduced from H-κ stacking results and a previous body-wave tomographic research was applied for the correction of the crustal and upper mantle heterogeneities beneath SE Tibet for CCP stacking. Our results reveal two significantly thickened MTZ anomalies aligned nearly in the south-north direction. The magnitude of both anomalies are 30km above the global average of 250km. The southern anomaly located beneath the Dianzhong sub-block and the Indo-China block is characterized by a slightly deeper `410' and a greater-than-normal `660', while the northern anomaly beneath western Sichuan has an uplifted `410' and a depressed `660'. Combining with previous studies in the adjacent region, we suggest that slab break-off may occurred during the eastward subduction of the Burma plate, with the lower part of the cold slab penetrated into the MTZ and stagnated at the bottom of the `660' which may cause the southern anomaly in our receiver function images. The origin of the Tengchong volcano is probably connected to the upwelling of the asthenospheric material caused by the slab break-off or to the ascending of the hot and wet material triggered by the dehydration of stagnant slab in the MTZ. The anomaly in the north, on the other hand, might be

  17. Use and satisfaction with key functions of a common commercial electronic health record: a survey of primary care providers.

    Science.gov (United States)

    Makam, Anil N; Lanham, Holly J; Batchelor, Kim; Samal, Lipika; Moran, Brett; Howell-Stampley, Temple; Kirk, Lynne; Cherukuri, Manjula; Santini, Noel; Leykum, Luci K; Halm, Ethan A

    2013-08-09

    Despite considerable financial incentives for adoption, there is little evidence available about providers' use and satisfaction with key functions of electronic health records (EHRs) that meet "meaningful use" criteria. We surveyed primary care providers (PCPs) in 11 general internal medicine and family medicine practices affiliated with 3 health systems in Texas about their use and satisfaction with performing common tasks (documentation, medication prescribing, preventive services, problem list) in the Epic EHR, a common commercial system. Most practices had greater than 5 years of experience with the Epic EHR. We used multivariate logistic regression to model predictors of being a structured documenter, defined as using electronic templates or prepopulated dot phrases to document at least two of the three note sections (history, physical, assessment and plan). 146 PCPs responded (70%). The majority used free text to document the history (51%) and assessment and plan (54%) and electronic templates to document the physical exam (57%). Half of PCPs were structured documenters (55%) with family medicine specialty (adjusted OR 3.3, 95% CI, 1.4-7.8) and years since graduation (nonlinear relationship with youngest and oldest having lowest probabilities) being significant predictors. Nearly half (43%) reported spending at least one extra hour beyond each scheduled half-day clinic completing EHR documentation. Three-quarters were satisfied with documenting completion of pneumococcal vaccinations and half were satisfied with documenting cancer screening (57% for breast, 45% for colorectal, and 46% for cervical). Fewer were satisfied with reminders for overdue pneumococcal vaccination (48%) and cancer screening (38% for breast, 37% for colorectal, and 31% for cervical). While most believed the problem list was helpful (70%) and kept an up-to-date list for their patients (68%), half thought they were unreliable and inaccurate (51%). Dissatisfaction with and suboptimal use

  18. Functional Analysis and Marker Development of TaCRT-D Gene in Common Wheat (Triticum aestivum L.

    Directory of Open Access Journals (Sweden)

    Jiping Wang

    2017-09-01

    Full Text Available Calreticulin (CRT, an endoplasmic reticulum (ER-localized Ca2+-binding/buffering protein, is highly conserved and extensively expressed in animal and plant cells. To understand the function of CRTs in wheat (Triticum aestivum L., particularly their roles in stress tolerance, we cloned the full-length genomic sequence of the TaCRT-D isoform from D genome of common hexaploid wheat, and characterized its function by transgenic Arabidopsis system. TaCRT-D exhibited different expression patterns in wheat seedling under different abiotic stresses. Transgenic Arabidopsis plants overexpressing ORF of TaCRT-D displayed more tolerance to drought, cold, salt, mannitol, and other abiotic stresses at both seed germination and seedling stages, compared with the wild-type controls. Furthermore, DNA polymorphism analysis and gene mapping were employed to develop the functional markers of this gene for marker-assistant selection in wheat breeding program. One SNP, S440 (T→C was detected at the TaCRT-D locus by genotyping a wheat recombinant inbred line (RIL population (114 lines developed from Opata 85 × W7984. The TaCRT-D was then fine mapped between markers Xgwm645 and Xgwm664 on chromosome 3DL, corresponding to genetic distances of 3.5 and 4.4 cM, respectively, using the RIL population and Chinese Spring nulli-tetrasomic lines. Finally, the genome-specific and allele-specific markers were developed for the TaCRT-D gene. These findings indicate that TaCRT-D function importantly in plant stress responses, providing a gene target for genetic engineering to increase plant stress tolerance and the functional markers of TaCRT-D for marker-assistant selection in wheat breeding.

  19. Functional Analysis and Marker Development of TaCRT-D Gene in Common Wheat (Triticum aestivum L.).

    Science.gov (United States)

    Wang, Jiping; Li, Runzhi; Mao, Xinguo; Jing, Ruilian

    2017-01-01

    Calreticulin (CRT), an endoplasmic reticulum (ER)-localized Ca 2+ -binding/buffering protein, is highly conserved and extensively expressed in animal and plant cells. To understand the function of CRTs in wheat ( Triticum aestivum L.), particularly their roles in stress tolerance, we cloned the full-length genomic sequence of the TaCRT-D isoform from D genome of common hexaploid wheat, and characterized its function by transgenic Arabidopsis system. TaCRT-D exhibited different expression patterns in wheat seedling under different abiotic stresses. Transgenic Arabidopsis plants overexpressing ORF of TaCRT-D displayed more tolerance to drought, cold, salt, mannitol, and other abiotic stresses at both seed germination and seedling stages, compared with the wild-type controls. Furthermore, DNA polymorphism analysis and gene mapping were employed to develop the functional markers of this gene for marker-assistant selection in wheat breeding program. One SNP, S440 (T→C) was detected at the TaCRT-D locus by genotyping a wheat recombinant inbred line (RIL) population (114 lines) developed from Opata 85 × W7984. The TaCRT-D was then fine mapped between markers Xgwm645 and Xgwm664 on chromosome 3DL, corresponding to genetic distances of 3.5 and 4.4 cM, respectively, using the RIL population and Chinese Spring nulli-tetrasomic lines. Finally, the genome-specific and allele-specific markers were developed for the TaCRT-D gene. These findings indicate that TaCRT-D function importantly in plant stress responses, providing a gene target for genetic engineering to increase plant stress tolerance and the functional markers of TaCRT-D for marker-assistant selection in wheat breeding.

  20. Improving patients' understanding of terms and phrases commonly used in self-reported measures of sexual function.

    Science.gov (United States)

    Alexander, Angel M; Flynn, Kathryn E; Hahn, Elizabeth A; Jeffery, Diana D; Keefe, Francis J; Reeve, Bryce B; Schultz, Wesley; Reese, Jennifer Barsky; Shelby, Rebecca A; Weinfurt, Kevin P

    2014-08-01

    There is a significant gap in research regarding the readability and comprehension of existing sexual function measures. Patient-reported outcome measures may use terms not well understood by respondents with low literacy. This study aims to test comprehension of words and phrases typically used in sexual function measures to improve validity for all individuals, including those with low literacy. We recruited 20 men and 28 women for cognitive interviews on version 2.0 of the Patient-Reported Outcome Measurement Information System(®) (PROMIS(®) ) Sexual Function and Satisfaction measures. We assessed participants' reading level using the word reading subtest of the Wide Range Achievement Test. Sixteen participants were classified as having low literacy. In the first round of cognitive interviews, each survey item was reviewed by five or more people, at least two of whom had lower than a ninth-grade reading level (low literacy). Patient feedback was incorporated into a revised version of the items. In the second round of interviews, an additional three or more people (at least one with low literacy) reviewed each revised item. Participants with low literacy had difficulty comprehending terms such as aroused, orgasm, erection, ejaculation, incontinence, and vaginal penetration. Women across a range of literacy levels had difficulty with clinical terms like labia and clitoris. We modified unclear terms to include parenthetical descriptors or slang equivalents, which generally improved comprehension. Common words and phrases used across measures of self-reported sexual function are not universally understood. Researchers should appreciate these misunderstandings as a potential source of error in studies using self-reported measures of sexual function. This study also provides evidence for the importance of including individuals with low literacy in cognitive pretesting during the measure development. © 2014 International Society for Sexual Medicine.

  1. Functionalization of Planet-Satellite Nanostructures Revealed by Nanoscopic Localization of Distinct Macromolecular Species

    KAUST Repository

    Rossner, Christian; Roddatis, Vladimir; Lopatin, Sergei; Vana, Philipp

    2016-01-01

    The development of a straightforward method is reported to form hybrid polymer/gold planet-satellite nanostructures (PlSNs) with functional polymer. Polyacrylate type polymer with benzyl chloride in its backbone as a macromolecular tracer

  2. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse

    OpenAIRE

    Zhang, Ye; Sloan, Steven A.; Clarke, Laura E.; Caneda, Christine; Plaza, Colton A.; Blumenthal, Paul D.; Vogel, Hannes; Steinberg, Gary K.; Edwards, Michael S. B.; Li, Gordon; Duncan, John A.; Cheshier, Samuel H.; Shuer, Lawrence M.; Chang, Edward F.; Grant, Gerald A.

    2015-01-01

    The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains, and to maintain these cells in serum-free cultures. We found that human astrocytes have similar abilities to murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to exist...

  3. Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function.

    Science.gov (United States)

    Di, Chao; Xu, Wenying; Su, Zhen; Yuan, Joshua S

    2010-10-07

    PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms. The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With Arabidopsis as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function. PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out

  4. An integrative architecture for general intelligence and executive function revealed by lesion mapping

    Science.gov (United States)

    Colom, Roberto; Solomon, Jeffrey; Krueger, Frank; Forbes, Chad; Grafman, Jordan

    2012-01-01

    Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in executive control, the broader functional networks that support high-level cognition and give rise to general intelligence remain to be well characterized. Here, we investigated the neural substrates of the general factor of intelligence (g) and executive function in 182 patients with focal brain damage using voxel-based lesion–symptom mapping. The Wechsler Adult Intelligence Scale and Delis–Kaplan Executive Function System were used to derive measures of g and executive function, respectively. Impaired performance on these measures was associated with damage to a distributed network of left lateralized brain areas, including regions of frontal and parietal cortex and white matter association tracts, which bind these areas into a coordinated system. The observed findings support an integrative framework for understanding the architecture of general intelligence and executive function, supporting their reliance upon a shared fronto-parietal network for the integration and control of cognitive representations and making specific recommendations for the application of the Wechsler Adult Intelligence Scale and Delis–Kaplan Executive Function System to the study of high-level cognition in health and disease. PMID:22396393

  5. Revealing microbial functional activities in the Red Sea sponge S tylissa carteri by metatranscriptomics

    KAUST Repository

    Moitinho-Silva, Lucas

    2014-07-09

    The persistence of coral reef ecosystems relies on the symbiotic relationship between scleractinian corals and intracellular, photosynthetic dinoflagellates in the genus Symbiodinium. Genetic evidence indicates that these symbionts are biologically diverse and exhibit discrete patterns of environmental and host distribution. This makes the assessment of Symbiodinium diversity critical to understanding the symbiosis ecology of corals. Here, we applied pyrosequencing to the elucidation of Symbiodinium diversity via analysis of the internal transcribed spacer 2 (ITS2) region, a multicopy genetic marker commonly used to analyse Symbiodinium diversity. Replicated data generated from isoclonal Symbiodinium cultures showed that all genomes contained numerous, yet mostly rare, ITS2 sequence variants. Pyrosequencing data were consistent with more traditional denaturing gradient gel electrophoresis (DGGE) approaches to the screening of ITS2 PCR amplifications, where the most common sequences appeared as the most intense bands. Further, we developed an operational taxonomic unit (OTU)-based pipeline for Symbiodinium ITS2 diversity typing to provisionally resolve ecologically discrete entities from intragenomic variation. A genetic distance cut-off of 0.03 collapsed intragenomic ITS2 variants of isoclonal cultures into single OTUs. When applied to the analysis of field-collected coral samples, our analyses confirm that much of the commonly observed Symbiodinium ITS2 diversity can be attributed to intragenomic variation. We conclude that by analysing Symbiodinium populations in an OTU-based framework, we can improve objectivity, comparability and simplicity when assessing ITS2 diversity in field-based studies.

  6. Revealing microbial functional activities in the Red Sea sponge S tylissa carteri by metatranscriptomics

    KAUST Repository

    Moitinho-Silva, Lucas; Seridi, Loqmane; Ryu, Tae Woo; Voolstra, Christian R.; Ravasi, Timothy; Hentschel, Ute

    2014-01-01

    The persistence of coral reef ecosystems relies on the symbiotic relationship between scleractinian corals and intracellular, photosynthetic dinoflagellates in the genus Symbiodinium. Genetic evidence indicates that these symbionts are biologically diverse and exhibit discrete patterns of environmental and host distribution. This makes the assessment of Symbiodinium diversity critical to understanding the symbiosis ecology of corals. Here, we applied pyrosequencing to the elucidation of Symbiodinium diversity via analysis of the internal transcribed spacer 2 (ITS2) region, a multicopy genetic marker commonly used to analyse Symbiodinium diversity. Replicated data generated from isoclonal Symbiodinium cultures showed that all genomes contained numerous, yet mostly rare, ITS2 sequence variants. Pyrosequencing data were consistent with more traditional denaturing gradient gel electrophoresis (DGGE) approaches to the screening of ITS2 PCR amplifications, where the most common sequences appeared as the most intense bands. Further, we developed an operational taxonomic unit (OTU)-based pipeline for Symbiodinium ITS2 diversity typing to provisionally resolve ecologically discrete entities from intragenomic variation. A genetic distance cut-off of 0.03 collapsed intragenomic ITS2 variants of isoclonal cultures into single OTUs. When applied to the analysis of field-collected coral samples, our analyses confirm that much of the commonly observed Symbiodinium ITS2 diversity can be attributed to intragenomic variation. We conclude that by analysing Symbiodinium populations in an OTU-based framework, we can improve objectivity, comparability and simplicity when assessing ITS2 diversity in field-based studies.

  7. Simultaneous functional photoacoustic microscopy and electrocorticography reveal the impact of rtPA on dynamic neurovascular functions after cerebral ischemia.

    Science.gov (United States)

    Bandla, Aishwarya; Liao, Lun-De; Chan, Su Jing; Ling, Ji Min; Liu, Yu-Hang; Shih, Yen-Yu Ian; Pan, Han-Chi; Wong, Peter Tsun-Hon; Lai, Hsin-Yi; King, Nicolas Kon Kam; Chen, You-Yin; Ng, Wai Hoe; Thakor, Nitish V

    2018-06-01

    The advance of thrombolytic therapy has been hampered by the lack of optimization of the therapy during the hyperacute phase of focal ischemia. Here, we investigate neurovascular dynamics using a custom-designed hybrid electrocorticography (ECoG)-functional photoacoustic microscopy (fPAM) imaging system during the hyperacute phase (first 6 h) of photothrombotic ischemia (PTI) in male Wistar rats following recombinant tissue plasminogen activator (rtPA)-mediated thrombolysis. We reported, for the first time, the changes in neural activity and cerebral hemodynamic responses following rtPA infusion at different time points post PTI. Interestingly, very early administration of rtPA ( 4 h post PTI) resulted in the deterioration of neurovascular function. A therapeutic window between 1 and 3 h post PTI was found to improve recovery of neurovascular function (i.e. significant restoration of neural activity to 93 ± 4.2% of baseline and hemodynamics to 81 ± 2.1% of baseline, respectively). The novel combination of fPAM and ECoG enables direct mapping of neurovascular dynamics and serves as a platform to evaluate potential interventions for stroke.

  8. Functional assays and metagenomic analyses reveals differences between the microbial communities inhabiting the soil horizons of a Norway spruce plantation.

    Directory of Open Access Journals (Sweden)

    Stéphane Uroz

    Full Text Available In temperate ecosystems, acidic forest soils are among the most nutrient-poor terrestrial environments. In this context, the long-term differentiation of the forest soils into horizons may impact the assembly and the functions of the soil microbial communities. To gain a more comprehensive understanding of the ecology and functional potentials of these microbial communities, a suite of analyses including comparative metagenomics was applied on independent soil samples from a spruce plantation (Breuil-Chenue, France. The objectives were to assess whether the decreasing nutrient bioavailability and pH variations that naturally occurs between the organic and mineral horizons affects the soil microbial functional biodiversity. The 14 Gbp of pyrosequencing and Illumina sequences generated in this study revealed complex microbial communities dominated by bacteria. Detailed analyses showed that the organic soil horizon was significantly enriched in sequences related to Bacteria, Chordata, Arthropoda and Ascomycota. On the contrary the mineral horizon was significantly enriched in sequences related to Archaea. Our analyses also highlighted that the microbial communities inhabiting the two soil horizons differed significantly in their functional potentials according to functional assays and MG-RAST analyses, suggesting a functional specialisation of these microbial communities. Consistent with this specialisation, our shotgun metagenomic approach revealed a significant increase in the relative abundance of sequences related glycoside hydrolases in the organic horizon compared to the mineral horizon that was significantly enriched in glycoside transferases. This functional stratification according to the soil horizon was also confirmed by a significant correlation between the functional assays performed in this study and the functional metagenomic analyses. Together, our results suggest that the soil stratification and particularly the soil resource

  9. Intraoperative mapping during repeat awake craniotomy reveals the functional plasticity of adult cortex.

    Science.gov (United States)

    Southwell, Derek G; Hervey-Jumper, Shawn L; Perry, David W; Berger, Mitchel S

    2016-05-01

    OBJECT To avoid iatrogenic injury during the removal of intrinsic cerebral neoplasms such as gliomas, direct electrical stimulation (DES) is used to identify cortical and subcortical white matter pathways critical for language, motor, and sensory function. When a patient undergoes more than 1 brain tumor resection as in the case of tumor recurrence, the use of DES provides an unusual opportunity to examine brain plasticity in the setting of neurological disease. METHODS The authors examined 561 consecutive cases in which patients underwent DES mapping during surgery forglioma resection. "Positive" and "negative" sites-discrete cortical regions where electrical stimulation did (positive) or did not (negative) produce transient sensory, motor, or language disturbance-were identified prior to tumor resection and documented by intraoperative photography for categorization into functional maps. In this group of 561 patients, 18 were identified who underwent repeat surgery in which 1 or more stimulation sites overlapped with those tested during the initial surgery. The authors compared intraoperative sensory, motor, or language mapping results between initial and repeat surgeries, and evaluated the clinical outcomes for these patients. RESULTS A total of 117 sites were tested for sensory (7 sites, 6.0%), motor (9 sites, 7.7%), or language (101 sites, 86.3%) function during both initial and repeat surgeries. The mean interval between surgical procedures was 4.1 years. During initial surgeries, 95 (81.2%) of 117 sites were found to be negative and 22 (18.8%) of 117 sites were found to be positive. During repeat surgeries, 103 (88.0%) of 117 sites were negative and 14 (12.0%) of 117 were positive. Of the 95 sites that were negative at the initial surgery, 94 (98.9%) were also negative at the repeat surgery, while 1 (1.1%) site was found to be positive. Of the 22 sites that were initially positive, 13 (59.1%) remained positive at repeat surgery, while 9 (40.9%) had become

  10. Exercise reveals impairments in left ventricular systolic function in patients with metabolic syndrome.

    Science.gov (United States)

    Fournier, Sara B; Reger, Brian L; Donley, David A; Bonner, Daniel E; Warden, Bradford E; Gharib, Wissam; Failinger, Conard F; Olfert, Melissa D; Frisbee, Jefferson C; Olfert, I Mark; Chantler, Paul D

    2014-01-01

    Metabolic syndrome (MetS) is the manifestation of a cluster of cardiovascular risk factors and is associated with a threefold increase in the risk of cardiovascular morbidity and mortality, which is suggested to be mediated, in part, by resting left ventricular (LV) systolic dysfunction. However, to what extent resting LV systolic function is impaired in MetS is controversial, and there are no data indicating whether LV systolic function is impaired during exercise. Accordingly, the objective of this study was to examine comprehensively the LV and arterial responses to exercise in individuals with MetS without diabetes and/or overt cardiovascular disease in comparison to a healthy control population. Cardiovascular function was characterized using Doppler echocardiography and gas exchange in individuals with MetS (n = 27) versus healthy control subjects (n = 20) at rest and during peak exercise. At rest, individuals with MetS displayed normal LV systolic function but reduced LV diastolic function compared with healthy control subjects. During peak exercise, individuals with MetS had impaired contractility, pump performance and vasodilator reserve capacity versus control subjects. A blunted contractile reserve response resulted in diminished arterial-ventricular coupling reserve and limited aerobic capacity in individuals with MetS versus control subjects. These findings are of clinical importance, because they provide insight into the pathophysiological changes in MetS that may predispose this population of individuals to an increased risk of cardiovascular morbidity and mortality.

  11. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients.

    Science.gov (United States)

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM.

  12. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Qiu eXiangzhe

    2016-05-01

    Full Text Available Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM. However, the DM-related changes in the topological properties in functional brain networks are almost unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs, followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized shortest path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing the functional evidence for the abnormalities of brain networks in DM.

  13. The scaling behavior of hand motions reveals self-organization during an executive function task

    Science.gov (United States)

    Anastas, Jason R.; Stephen, Damian G.; Dixon, James A.

    2011-05-01

    Recent approaches to cognition explain cognitive phenomena in terms of interaction-dominant dynamics. In the current experiment, we extend this approach to executive function, a construct used to describe flexible, goal-oriented behavior. Participants were asked to perform a widely used executive function task, card sorting, under two conditions. In one condition, participants were given a rule with which to sort the cards. In the other condition, participants had to induce the rule from experimenter feedback. The motion of each participant’s hand was tracked during the sorting task. Detrended fluctuation analysis was performed on the inter-point time series using a windowing strategy to capture changes over each trial. For participants in the induction condition, the Hurst exponent sharply increased and then decreased. The Hurst exponents for the explicit condition did not show this pattern. Our results suggest that executive function may be understood in terms of changes in stability that arise from interaction-dominant dynamics.

  14. Context-dependent memory traces in the crab's mushroom bodies: Functional support for a common origin of high-order memory centers.

    Science.gov (United States)

    Maza, Francisco Javier; Sztarker, Julieta; Shkedy, Avishag; Peszano, Valeria Natacha; Locatelli, Fernando Federico; Delorenzi, Alejandro

    2016-12-06

    The hypothesis of a common origin for the high-order memory centers in bilateral animals is based on the evidence that several key features, including gene expression and neuronal network patterns, are shared across several phyla. Central to this hypothesis is the assumption that the arthropods' higher order neuropils of the forebrain [the mushroom bodies (MBs) of insects and the hemiellipsoid bodies (HBs) of crustaceans] are homologous structures. However, even though involvement in memory processes has been repeatedly demonstrated for the MBs, direct proof of such a role in HBs is lacking. Here, through neuroanatomical and immunohistochemical analysis, we identified, in the crab Neohelice granulata, HBs that resemble the calyxless MBs found in several insects. Using in vivo calcium imaging, we revealed training-dependent changes in neuronal responses of vertical and medial lobes of the HBs. These changes were stimulus-specific, and, like in the hippocampus and MBs, the changes reflected the context attribute of the memory trace, which has been envisioned as an essential feature for the HBs. The present study constitutes functional evidence in favor of a role for the HBs in memory processes, and provides key physiological evidence supporting a common origin of the arthropods' high-order memory centers.

  15. Context-dependent memory traces in the crab’s mushroom bodies: Functional support for a common origin of high-order memory centers

    Science.gov (United States)

    Maza, Francisco Javier; Sztarker, Julieta; Shkedy, Avishag; Peszano, Valeria Natacha; Locatelli, Fernando Federico; Delorenzi, Alejandro

    2016-01-01

    The hypothesis of a common origin for the high-order memory centers in bilateral animals is based on the evidence that several key features, including gene expression and neuronal network patterns, are shared across several phyla. Central to this hypothesis is the assumption that the arthropods’ higher order neuropils of the forebrain [the mushroom bodies (MBs) of insects and the hemiellipsoid bodies (HBs) of crustaceans] are homologous structures. However, even though involvement in memory processes has been repeatedly demonstrated for the MBs, direct proof of such a role in HBs is lacking. Here, through neuroanatomical and immunohistochemical analysis, we identified, in the crab Neohelice granulata, HBs that resemble the calyxless MBs found in several insects. Using in vivo calcium imaging, we revealed training-dependent changes in neuronal responses of vertical and medial lobes of the HBs. These changes were stimulus-specific, and, like in the hippocampus and MBs, the changes reflected the context attribute of the memory trace, which has been envisioned as an essential feature for the HBs. The present study constitutes functional evidence in favor of a role for the HBs in memory processes, and provides key physiological evidence supporting a common origin of the arthropods’ high-order memory centers. PMID:27856766

  16. Functional tests of a prototype for the CMS-ATLAS common non-event data handling framework

    CERN Document Server

    Formica, Andrea; The ATLAS collaboration

    2016-01-01

    Since the 2014 the experiments ATLAS and CMS have started to share a common vision for the Condition Database infrastructure required for the forthcoming LHC runs. The large commonality in the use cases to be satisfied has allowed to agree to an overall design solution which could meet the requirements for both experiments. A first prototype implementing these solutions has been completed in 2015 and made available to both the experiments. The prototype is based on a web service implementing a REST api with a set of functions for the management of conditions data. The objects which constitute the elements of the data model are seen as resources on which CRUD operations can be performed via standard HTTP methods. The choice to insert a REST api in the architecture has several advantages: 1) the conditions data are exchanged in a neutral format ( JSON or XML), allowing to be processed by different technologies in different frameworks. 2) the client is agnostic with respect to the underlying technology adopted f...

  17. Inferring common cognitive mechanisms from brain blood-flow lateralisation data obtained with functional transcranial Doppler ultrasound.

    Directory of Open Access Journals (Sweden)

    Georg eMeyer

    2014-06-01

    Full Text Available Current neuroimaging techniques with high spatial resolution constrain participant motion so that many natural tasks cannot be carried out. The aim of this paper is to show how a time-locked correlation-analysis of cerebral blood flow velocity (CBFV lateralisation data, obtained with functional TransCranial Doppler (fTCD ultrasound, can be used to infer cerebral activation patterns across tasks. In a first experiment we demonstrate that the proposed analysis method results in data that are comparable with the standard Lateralisation Index (LI for within-task comparisons of CBFV patterns, recorded during cued word generation (CWG at two difficulty levels.In the main experiment we demonstrate that the proposed analysis method shows correlated blood-flow patterns for two different cognitive tasks that are known to draw on common brain areas, CWG and Music Synthesis. We show that CBFV patterns for Music and CWG are correlated only for participants with prior musical training.CBFV patterns for tasks that draw on distinct brain areas, the Tower of London and CWG, are not correlated.The proposed methodology extends conventional fTCD analysis by including temporal information in the analysis of cerebral blood-flow patterns to provide a robust, non-invasive method to infer whether common brain areas are used in different cognitive tasks. It complements conventional high resolution imaging techniques.

  18. Hypothesizing Music Intervention Enhances Brain Functional Connectivity Involving Dopaminergic Recruitment: Common Neuro-correlates to Abusable Drugs.

    Science.gov (United States)

    Blum, Kenneth; Simpatico, Thomas; Febo, Marcelo; Rodriquez, Chris; Dushaj, Kristina; Li, Mona; Braverman, Eric R; Demetrovics, Zsolt; Oscar-Berman, Marlene; Badgaiyan, Rajendra D

    2017-07-01

    The goal of this review is to explore the clinical significance of music listening on neuroplasticity and dopaminergic activation by understanding the role of music therapy in addictive behavior treatment. fMRI data has shown that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc]) and may control the emotional stimuli's effect on autonomic and physiological responses (e.g., hypothalamus). Music listening has been proven to induce the endorphinergic response blocked by naloxone, a common opioid antagonist. NAc opioid transmission is linked to the ventral tegmental area (VTA) dopamine release. There are remarkable commonalities between listening to music and the effect of drugs on mesolimbic dopaminergic activation. It has been found that musical training before the age of 7 results in changes in white-matter connectivity, protecting carriers with low dopaminergic function (DRD2A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity. In this article, we briefly review a few studies on the neurochemical effects of music and propose that these findings are relevant to the positive clinical findings observed in the literature. We hypothesize that music intervention enhances brain white matter plasticity through dopaminergic recruitment and that more research is needed to explore the efficacy of these therapies.

  19. Whole brain resting-state analysis reveals decreased functional connectivity in major depression

    Directory of Open Access Journals (Sweden)

    Ilya M. Veer

    2010-09-01

    Full Text Available Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always controlled for. Therefore, the aim of the current study was to investigate whole-brain functional connectivity, unbiased by a priori definition of regions or networks of interest, in medication-free depressive patients without comorbidity. We analyzed resting-state fMRI data of 19 medication-free patients with a recent diagnosis of major depression (within six months before inclusion and no comorbidity, and 19 age- and gender-matched controls. Independent component analysis was employed on the concatenated data sets of all participants. Thirteen functionally relevant networks were identified, describing the entire study sample. Next, individual representations of the networks were created using a dual regression method. Statistical inference was subsequently done on these spatial maps using voxelwise permutation tests. Abnormal functional connectivity was found within three resting-state networks in depression: 1 decreased bilateral amygdala and left anterior insula connectivity in an affective network, 2 reduced connectivity of the left frontal pole in a network associated with attention and working memory, and 3 decreased bilateral lingual gyrus connectivity within ventromedial visual regions. None of these effects were associated with symptom severity or grey matter density. We found abnormal resting-state functional connectivity not previously associated with major depression, which might relate to abnormal affect regulation and mild cognitive deficits, both associated with the symptomatology of the disorder.

  20. Integrating abundance and functional traits reveals new global hotspots of fish diversity.

    Science.gov (United States)

    Stuart-Smith, Rick D; Bates, Amanda E; Lefcheck, Jonathan S; Duffy, J Emmett; Baker, Susan C; Thomson, Russell J; Stuart-Smith, Jemina F; Hill, Nicole A; Kininmonth, Stuart J; Airoldi, Laura; Becerro, Mikel A; Campbell, Stuart J; Dawson, Terence P; Navarrete, Sergio A; Soler, German A; Strain, Elisabeth M A; Willis, Trevor J; Edgar, Graham J

    2013-09-26

    Species richness has dominated our view of global biodiversity patterns for centuries. The dominance of this paradigm is reflected in the focus by ecologists and conservation managers on richness and associated occurrence-based measures for understanding drivers of broad-scale diversity patterns and as a biological basis for management. However, this is changing rapidly, as it is now recognized that not only the number of species but the species present, their phenotypes and the number of individuals of each species are critical in determining the nature and strength of the relationships between species diversity and a range of ecological functions (such as biomass production and nutrient cycling). Integrating these measures should provide a more relevant representation of global biodiversity patterns in terms of ecological functions than that provided by simple species counts. Here we provide comparisons of a traditional global biodiversity distribution measure based on richness with metrics that incorporate species abundances and functional traits. We use data from standardized quantitative surveys of 2,473 marine reef fish species at 1,844 sites, spanning 133 degrees of latitude from all ocean basins, to identify new diversity hotspots in some temperate regions and the tropical eastern Pacific Ocean. These relate to high diversity of functional traits amongst individuals in the community (calculated using Rao's Q), and differ from previously reported patterns in functional diversity and richness for terrestrial animals, which emphasize species-rich tropical regions only. There is a global trend for greater evenness in the number of individuals of each species, across the reef fish species observed at sites ('community evenness'), at higher latitudes. This contributes to the distribution of functional diversity hotspots and contrasts with well-known latitudinal gradients in richness. Our findings suggest that the contribution of species diversity to a range of

  1. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

    OpenAIRE

    Hettmer, Simone; Schinzel, Anna C; Tchessalova, Daria; Schneider, Michaela; Parker, Christina L; Bronson, Roderick T; Richards, Nigel GJ; Hahn, William C; Wagers, Amy J

    2015-01-01

    eLife digest Sarcoma is a type of cancer that forms in the connective tissues of the body, such as bone, cartilage, muscle and fat. Usually, treatment involves surgical removal of the tumor and/or radiation to kill the tumor cells. However, if sarcomas spread to other parts of the body, the treatment options are limited. Genetic studies have revealed several genetic changes that contribute to the formation of sarcomas. Many sarcomas have a mutation in a gene that encodes a protein called Ras....

  2. Computational Approaches Reveal New Insights into Regulation and Function of Non; coding RNAs and their Targets

    KAUST Repository

    Alam, Tanvir

    2016-01-01

    Regulation and function of protein-coding genes are increasingly well-understood, but no comparable evidence exists for non-coding RNA (ncRNA) genes, which appear to be more numerous than protein-coding genes. We developed a novel machine

  3. Mapping functional connectivity in barrel-related columns reveals layer- and cell type-specific microcircuits.

    NARCIS (Netherlands)

    Schubert, D.; Kotter, R.; Staiger, J.F.

    2007-01-01

    Synaptic circuits bind together functional modules of the neocortex. We aim to clarify in a rodent model how intra- and transcolumnar microcircuits in the barrel cortex are laid out to segregate and also integrate sensory information. The primary somatosensory (barrel) cortex of rodents is the ideal

  4. Tissue Doppler echocardiography reveals impaired cardiac function in patients with reversible ischaemia

    DEFF Research Database (Denmark)

    Hoffmann, Søren; Mogelvang, Rasmus; Sogaard, Peter

    2011-01-01

    AIMS: To determine if echocardiographic tissue Doppler imaging (TDI) performed at rest detects reduced myocardial function in patients with reversible ischaemia. METHODS AND RESULTS: Eighty-four patients with angina pectoris, no previous history of ischaemic heart disease and normal left ventricu...

  5. Functional characterisation of an intron retaining K+ transporter of barley reveals intron-mediated alternate splicing

    KAUST Repository

    Shahzad, K.; Rauf, M.; Ahmed, M.; Malik, Z. A.; Habib, I.; Ahmed, Z.; Mahmood, K.; Ali, R.; Masmoudi, K.; Lemtiri-Chlieh, Fouad; Gehring, Christoph A; Berkowitz, G. A.; Saeed, N. A.

    2015-01-01

    Intron retention in transcripts and the presence of 5 and 3 splice sites within these introns mediate alternate splicing, which is widely observed in animals and plants. Here, functional characterisation of the K+ transporter, HvHKT2;1, with stably

  6. Lipid profiling and transcriptomic analysis reveals a functional interplay between estradiol and growth hormone in liver

    DEFF Research Database (Denmark)

    Fernández-Pérez, Leandro; Santana-Farré, Ruymán; Mirecki-Garrido, Mercedes de

    2014-01-01

    17β-estradiol (E2) may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2,...

  7. Revealing complex function, process and pathway interactions with high-throughput expression and biological annotation data.

    Science.gov (United States)

    Singh, Nitesh Kumar; Ernst, Mathias; Liebscher, Volkmar; Fuellen, Georg; Taher, Leila

    2016-10-20

    The biological relationships both between and within the functions, processes and pathways that operate within complex biological systems are only poorly characterized, making the interpretation of large scale gene expression datasets extremely challenging. Here, we present an approach that integrates gene expression and biological annotation data to identify and describe the interactions between biological functions, processes and pathways that govern a phenotype of interest. The product is a global, interconnected network, not of genes but of functions, processes and pathways, that represents the biological relationships within the system. We validated our approach on two high-throughput expression datasets describing organismal and organ development. Our findings are well supported by the available literature, confirming that developmental processes and apoptosis play key roles in cell differentiation. Furthermore, our results suggest that processes related to pluripotency and lineage commitment, which are known to be critical for development, interact mainly indirectly, through genes implicated in more general biological processes. Moreover, we provide evidence that supports the relevance of cell spatial organization in the developing liver for proper liver function. Our strategy can be viewed as an abstraction that is useful to interpret high-throughput data and devise further experiments.

  8. Diversity and functions of bacterial community in drinking water biofilms revealed by high-throughput sequencing

    Science.gov (United States)

    Chao, Yuanqing; Mao, Yanping; Wang, Zhiping; Zhang, Tong

    2015-06-01

    The development of biofilms in drinking water (DW) systems may cause various problems to water quality. To investigate the community structure of biofilms on different pipe materials and the global/specific metabolic functions of DW biofilms, PCR-based 454 pyrosequencing data for 16S rRNA genes and Illumina metagenomic data were generated and analysed. Considerable differences in bacterial diversity and taxonomic structure were identified between biofilms formed on stainless steel and biofilms formed on plastics, indicating that the metallic materials facilitate the formation of higher diversity biofilms. Moreover, variations in several dominant genera were observed during biofilm formation. Based on PCA analysis, the global functions in the DW biofilms were similar to other DW metagenomes. Beyond the global functions, the occurrences and abundances of specific protective genes involved in the glutathione metabolism, the SoxRS system, the OxyR system, RpoS regulated genes, and the production/degradation of extracellular polymeric substances were also evaluated. A near-complete and low-contamination draft genome was constructed from the metagenome of the DW biofilm, based on the coverage and tetranucleotide frequencies, and identified as a Bradyrhizobiaceae-like bacterium according to a phylogenetic analysis. Our findings provide new insight into DW biofilms, especially in terms of their metabolic functions.

  9. Functional SNPs in the human ficolin (FCN) genes reveal distinct geographical patterns

    DEFF Research Database (Denmark)

    Hummelshøj, Tina; Munthe-Fog, Lea; Madsen, Hans O

    2008-01-01

    -Xaa-Yaa repeats and a Trp279STOP introduces a stop codon, thereby destroying the fibrinogen-like domain of Ficolin-1. In contrast to FCN1 and FCN2, the number of SNPs in FCN3 was very low. In conclusion, large ethnic differences in the FCN genes that will affect the concentration, structure, and function...

  10. Activation of auditory white matter tracts as revealed by functional magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Tae, Woo Suk [Kangwon National University, Neuroscience Research Institute, School of Medicine, Chuncheon (Korea, Republic of); Yakunina, Natalia; Nam, Eui-Cheol [Kangwon National University, Neuroscience Research Institute, School of Medicine, Chuncheon (Korea, Republic of); Kangwon National University, Department of Otolaryngology, School of Medicine, Chuncheon, Kangwon-do (Korea, Republic of); Kim, Tae Su [Kangwon National University Hospital, Department of Otolaryngology, Chuncheon (Korea, Republic of); Kim, Sam Soo [Kangwon National University, Neuroscience Research Institute, School of Medicine, Chuncheon (Korea, Republic of); Kangwon National University, Department of Radiology, School of Medicine, Chuncheon (Korea, Republic of)

    2014-07-15

    The ability of functional magnetic resonance imaging (fMRI) to detect activation in brain white matter (WM) is controversial. In particular, studies on the functional activation of WM tracts in the central auditory system are scarce. We utilized fMRI to assess and characterize the entire auditory WM pathway under robust experimental conditions involving the acquisition of a large number of functional volumes, the application of broadband auditory stimuli of high intensity, and the use of sparse temporal sampling to avoid scanner noise effects and increase signal-to-noise ratio. Nineteen healthy volunteers were subjected to broadband white noise in a block paradigm; each run had four sound-on/off alternations and was repeated nine times for each subject. Sparse sampling (TR = 8 s) was used. In addition to traditional gray matter (GM) auditory center activation, WM activation was detected in the isthmus and midbody of the corpus callosum (CC), tapetum, auditory radiation, lateral lemniscus, and decussation of the superior cerebellar peduncles. At the individual level, 13 of 19 subjects (68 %) had CC activation. Callosal WM exhibited a temporal delay of approximately 8 s in response to the stimulation compared with GM. These findings suggest that direct evaluation of the entire functional network of the central auditory system may be possible using fMRI, which may aid in understanding the neurophysiological basis of the central auditory system and in developing treatment strategies for various central auditory disorders. (orig.)

  11. Activation of auditory white matter tracts as revealed by functional magnetic resonance imaging

    International Nuclear Information System (INIS)

    Tae, Woo Suk; Yakunina, Natalia; Nam, Eui-Cheol; Kim, Tae Su; Kim, Sam Soo

    2014-01-01

    The ability of functional magnetic resonance imaging (fMRI) to detect activation in brain white matter (WM) is controversial. In particular, studies on the functional activation of WM tracts in the central auditory system are scarce. We utilized fMRI to assess and characterize the entire auditory WM pathway under robust experimental conditions involving the acquisition of a large number of functional volumes, the application of broadband auditory stimuli of high intensity, and the use of sparse temporal sampling to avoid scanner noise effects and increase signal-to-noise ratio. Nineteen healthy volunteers were subjected to broadband white noise in a block paradigm; each run had four sound-on/off alternations and was repeated nine times for each subject. Sparse sampling (TR = 8 s) was used. In addition to traditional gray matter (GM) auditory center activation, WM activation was detected in the isthmus and midbody of the corpus callosum (CC), tapetum, auditory radiation, lateral lemniscus, and decussation of the superior cerebellar peduncles. At the individual level, 13 of 19 subjects (68 %) had CC activation. Callosal WM exhibited a temporal delay of approximately 8 s in response to the stimulation compared with GM. These findings suggest that direct evaluation of the entire functional network of the central auditory system may be possible using fMRI, which may aid in understanding the neurophysiological basis of the central auditory system and in developing treatment strategies for various central auditory disorders. (orig.)

  12. Replicated landscape genetic and network analyses reveal wide variation in functional connectivity for American pikas.

    Science.gov (United States)

    Castillo, Jessica A; Epps, Clinton W; Jeffress, Mackenzie R; Ray, Chris; Rodhouse, Thomas J; Schwalm, Donelle

    2016-09-01

    Landscape connectivity is essential for maintaining viable populations, particularly for species restricted to fragmented habitats or naturally arrayed in metapopulations and facing rapid climate change. The importance of assessing both structural connectivity (physical distribution of favorable habitat patches) and functional connectivity (how species move among habitat patches) for managing such species is well understood. However, the degree to which functional connectivity for a species varies among landscapes, and the resulting implications for conservation, have rarely been assessed. We used a landscape genetics approach to evaluate resistance to gene flow and, thus, to determine how landscape and climate-related variables influence gene flow for American pikas (Ochotona princeps) in eight federally managed sites in the western United States. We used empirically derived, individual-based landscape resistance models in conjunction with predictive occupancy models to generate patch-based network models describing functional landscape connectivity. Metareplication across landscapes enabled identification of limiting factors for dispersal that would not otherwise have been apparent. Despite the cool microclimates characteristic of pika habitat, south-facing aspects consistently represented higher resistance to movement, supporting the previous hypothesis that exposure to relatively high temperatures may limit dispersal in American pikas. We found that other barriers to dispersal included areas with a high degree of topographic relief, such as cliffs and ravines, as well as streams and distances greater than 1-4 km depending on the site. Using the empirically derived network models of habitat patch connectivity, we identified habitat patches that were likely disproportionately important for maintaining functional connectivity, areas in which habitat appeared fragmented, and locations that could be targeted for management actions to improve functional connectivity

  13. Structural fragment clustering reveals novel structural and functional motifs in α-helical transmembrane proteins

    Directory of Open Access Journals (Sweden)

    Vassilev Boris

    2010-04-01

    Full Text Available Abstract Background A large proportion of an organism's genome encodes for membrane proteins. Membrane proteins are important for many cellular processes, and several diseases can be linked to mutations in them. With the tremendous growth of sequence data, there is an increasing need to reliably identify membrane proteins from sequence, to functionally annotate them, and to correctly predict their topology. Results We introduce a technique called structural fragment clustering, which learns sequential motifs from 3D structural fragments. From over 500,000 fragments, we obtain 213 statistically significant, non-redundant, and novel motifs that are highly specific to α-helical transmembrane proteins. From these 213 motifs, 58 of them were assigned to function and checked in the scientific literature for a biological assessment. Seventy percent of the motifs are found in co-factor, ligand, and ion binding sites, 30% at protein interaction interfaces, and 12% bind specific lipids such as glycerol or cardiolipins. The vast majority of motifs (94% appear across evolutionarily unrelated families, highlighting the modularity of functional design in membrane proteins. We describe three novel motifs in detail: (1 a dimer interface motif found in voltage-gated chloride channels, (2 a proton transfer motif found in heme-copper oxidases, and (3 a convergently evolved interface helix motif found in an aspartate symporter, a serine protease, and cytochrome b. Conclusions Our findings suggest that functional modules exist in membrane proteins, and that they occur in completely different evolutionary contexts and cover different binding sites. Structural fragment clustering allows us to link sequence motifs to function through clusters of structural fragments. The sequence motifs can be applied to identify and characterize membrane proteins in novel genomes.

  14. Direct model-based predictive control scheme without cost function for voltage source inverters with reduced common-mode voltage

    Science.gov (United States)

    Kim, Jae-Chang; Moon, Sung-Ki; Kwak, Sangshin

    2018-04-01

    This paper presents a direct model-based predictive control scheme for voltage source inverters (VSIs) with reduced common-mode voltages (CMVs). The developed method directly finds optimal vectors without using repetitive calculation of a cost function. To adjust output currents with the CMVs in the range of -Vdc/6 to +Vdc/6, the developed method uses voltage vectors, as finite control resources, excluding zero voltage vectors which produce the CMVs in the VSI within ±Vdc/2. In a model-based predictive control (MPC), not using zero voltage vectors increases the output current ripples and the current errors. To alleviate these problems, the developed method uses two non-zero voltage vectors in one sampling step. In addition, the voltage vectors scheduled to be used are directly selected at every sampling step once the developed method calculates the future reference voltage vector, saving the efforts of repeatedly calculating the cost function. And the two non-zero voltage vectors are optimally allocated to make the output current approach the reference current as close as possible. Thus, low CMV, rapid current-following capability and sufficient output current ripple performance are attained by the developed method. The results of a simulation and an experiment verify the effectiveness of the developed method.

  15. Short-Term Biliary Stent Placement Contributing Common Bile Duct Stone Disappearance with Preservation of Duodenal Papilla Function

    Directory of Open Access Journals (Sweden)

    Tatsuki Ueda

    2016-01-01

    Full Text Available Aims. To investigate the effect of biliary stent placement without endoscopic sphincterotomy (EST on common bile duct stones (CBDS disappearance and the contribution of preserving the duodenal papilla function to reduce recurrence of CBDS. Methods. Sixty-six patients admitted for acute obstructive cholangitis due to CBDS who underwent biliary stent placement without EST for 2 years from March 2011 were evaluated retrospectively. The second endoscopic retrograde cholangiopancreatography (ERCP was performed for treatment of CBDS 3 to 4 months after the first ERCP. We estimated the rate of stone disappearance at the time of second ERCP. Results. CBDS disappearance was observed in 32 (48.5% of 66 patients. The diameter of the bile ducts and the diameter of CBDS in patients with CBDS disappearance were significantly smaller than in those with CBDS requiring extraction (p=0.007 and p<0.001, resp.. Stone disappearance was evident when the diameter of bile ducts and that of CBDS were <10 and 7 mm, respectively (p=0.002. Conclusions. Short-term stent placement without EST eliminates CBDS while preserving duodenal papilla function and may be suitable for treating CBDS in patients with nondilated bile ducts and small CBDS.

  16. Effects of Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea on Cognitive Functions: Evidence for a Common Nature

    Directory of Open Access Journals (Sweden)

    Georgia Andreou

    2014-01-01

    Full Text Available Patients with chronic obstructive pulmonary disease (COPD and obstructive sleep apnea syndrome (OSAS show similar neurocognitive impairments. Effects are more apparent in severe cases, whereas in moderate and mild cases the effects are equivocal. The exact mechanism that causes cognitive dysfunctions in both diseases is still unknown and only suggestions have been made for each disease separately. The primary objective of this review is to present COPD and OSAS impact on cognitive functions. Secondly, it aims to examine the potential mechanisms by which COPD and OSAS can be linked and provide evidence for a common nature that affects cognitive functions in both diseases. Patients with COPD and OSAS compared to normal distribution show significant deficits in the cognitive abilities of attention, psychomotor speed, memory and learning, visuospatial and constructional abilities, executive skills, and language. The severity of these deficits in OSAS seems to correlate with the physiological events such as sleep defragmentation, apnea/hypopnea index, and hypoxemia, whereas cognitive impairments in COPD are associated with hypoventilation, hypoxemia, and hypercapnia. These factors as well as vascocerebral diseases and changes in systemic hemodynamic seem to act in an intermingling and synergistic way on the cause of cognitive dysfunctions in both diseases. However, low blood oxygen pressure seems to be the dominant factor that contributes to the presence of cognitive deficits in both COPD and OSAS.

  17. Functional Analysis of In-frame Indel ARID1A Mutations Reveals New Regulatory Mechanisms of Its Tumor Suppressor Functions

    Directory of Open Access Journals (Sweden)

    Bin Guan

    2012-10-01

    Full Text Available AT-rich interactive domain 1A (ARID1A has emerged as a new tumor suppressor in which frequent somatic mutations have been identified in several types of human cancers. Although most ARID1A somatic mutations are frame-shift or nonsense mutations that contribute to mRNA decay and loss of protein expression, 5% of ARID1A mutations are in-frame insertions or deletions (indels that involve only a small stretch of peptides. Naturally occurring in-frame indel mutations provide unique and useful models to explore the biology and regulatory role of ARID1A. In this study, we analyzed indel mutations identified in gynecological cancers to determine how these mutations affect the tumor suppressor function of ARID1A. Our results demonstrate that all in-frame mutants analyzed lost their ability to inhibit cellular proliferation or activate transcription of CDKN1A, which encodes p21, a downstream effector of ARID1A. We also showed that ARID1A is a nucleocytoplasmic protein whose stability depends on its subcellular localization. Nuclear ARID1A is less stable than cytoplasmic ARID1A because ARID1A is rapidly degraded by the ubiquitin-proteasome system in the nucleus. In-frame deletions affecting the consensus nuclear export signal reduce steady-state protein levels of ARID1A. This defect in nuclear exportation leads to nuclear retention and subsequent degradation. Our findings delineate a mechanism underlying the regulation of ARID1A subcellular distribution and protein stability and suggest that targeting the nuclear ubiquitin-proteasome system can increase the amount of the ARID1A protein in the nucleus and restore its tumor suppressor functions.

  18. Functionalization of Planet-Satellite Nanostructures Revealed by Nanoscopic Localization of Distinct Macromolecular Species

    KAUST Repository

    Rossner, Christian

    2016-09-26

    The development of a straightforward method is reported to form hybrid polymer/gold planet-satellite nanostructures (PlSNs) with functional polymer. Polyacrylate type polymer with benzyl chloride in its backbone as a macromolecular tracer is synthesized to study its localization within PlSNs by analyzing the elemental distribution of chlorine. The functionalized nanohybrid structures are analyzed by scanning transmission electron microscopy, electron energy loss spectroscopy, and spectrum imaging. The results show that the RAFT (reversible addition-fragmentation chain transfer) polymers\\' sulfur containing end groups are colocalized at the gold cores, both within nanohybrids of simple core-shell morphology and within higher order PlSNs, providing microscopic evidence for the affinity of the RAFT group toward gold surfaces. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA., Weinheim.

  19. Functional Asymmetries Revealed in Visually Guided Saccades: An fMRI Study

    Energy Technology Data Exchange (ETDEWEB)

    Petit, L.; Zago, L.; Vigneau, M.; Crivello, F.; Mazoyer, B.; Mellet, E.; Tzourio-Mazoyer, N. [Centre for Imaging, Neurosciences and Applications to Pathologies, UMR6232 CNRS CEA (France); Mazoyer, B. [Centre Hospitalier Universitaire, Caen (France); Andersson, F. [Institut Federatif de Recherche 135, Imagerie fonctionnelle, Tours (France); Mazoyer, B. [Institut Universitaire de France, Paris (France)

    2009-07-01

    Because eye movements are a fundamental tool for spatial exploration, we hypothesized that the neural bases of these movements in humans should be under right cerebral dominance, as already described for spatial attention. We used functional magnetic resonance imaging in 27 right-handed participants who alternated central fixation with either large or small visually guided saccades (VGS), equally performed in both directions. Hemispheric functional asymmetry was analyzed to identify whether brain regions showing VGS activation elicited hemispheric asymmetries. Hemispheric anatomical asymmetry was also estimated to assess its influence on the VGS functional lateralization. Right asymmetrical activations of a saccadic/attentional system were observed in the lateral frontal eye fields (FEF), the anterior part of the intra-parietal sulcus (aIPS), the posterior third of the superior temporal sulcus (STS), the occipito-temporal junction (MT/V5 area), the middle occipital gyrus, and medially along the calcarine fissure (V1). The present rightward functional asymmetries were not related to differences in gray matter (GM) density/sulci positions between right and left hemispheres in the pre-central, intra-parietal, superior temporal, and extrastriate regions. Only V1 asymmetries were explained for almost 20% of the variance by a difference in the position of the right and left calcarine fissures. Left asymmetrical activations of a saccadic motor system were observed in the medial FEF and in the motor strip eye field along the Rolando sulcus. They were not explained by GM asymmetries. We suggest that the leftward saccadic motor asymmetry is part of a general dominance of the left motor cortex in right-handers, which must include an effect of sighting dominance. Our results demonstrate that, although bilateral by nature, the brain network involved in the execution of VGSs, irrespective of their direction, presented specific right and left asymmetries that were not related to

  20. Functional Asymmetries Revealed in Visually Guided Saccades: An fMRI Study

    International Nuclear Information System (INIS)

    Petit, L.; Zago, L.; Vigneau, M.; Crivello, F.; Mazoyer, B.; Mellet, E.; Tzourio-Mazoyer, N.; Mazoyer, B.; Andersson, F.; Mazoyer, B.

    2009-01-01

    Because eye movements are a fundamental tool for spatial exploration, we hypothesized that the neural bases of these movements in humans should be under right cerebral dominance, as already described for spatial attention. We used functional magnetic resonance imaging in 27 right-handed participants who alternated central fixation with either large or small visually guided saccades (VGS), equally performed in both directions. Hemispheric functional asymmetry was analyzed to identify whether brain regions showing VGS activation elicited hemispheric asymmetries. Hemispheric anatomical asymmetry was also estimated to assess its influence on the VGS functional lateralization. Right asymmetrical activations of a saccadic/attentional system were observed in the lateral frontal eye fields (FEF), the anterior part of the intra-parietal sulcus (aIPS), the posterior third of the superior temporal sulcus (STS), the occipito-temporal junction (MT/V5 area), the middle occipital gyrus, and medially along the calcarine fissure (V1). The present rightward functional asymmetries were not related to differences in gray matter (GM) density/sulci positions between right and left hemispheres in the pre-central, intra-parietal, superior temporal, and extrastriate regions. Only V1 asymmetries were explained for almost 20% of the variance by a difference in the position of the right and left calcarine fissures. Left asymmetrical activations of a saccadic motor system were observed in the medial FEF and in the motor strip eye field along the Rolando sulcus. They were not explained by GM asymmetries. We suggest that the leftward saccadic motor asymmetry is part of a general dominance of the left motor cortex in right-handers, which must include an effect of sighting dominance. Our results demonstrate that, although bilateral by nature, the brain network involved in the execution of VGSs, irrespective of their direction, presented specific right and left asymmetries that were not related to

  1. Decoupling phylogenetic and functional diversity to reveal hidden signals in community assembly

    Czech Academy of Sciences Publication Activity Database

    de Bello, Francesco; Šmilauer, P.; Diniz-Filho, J. A. F.; Carmona, C. P.; Lososová, Z.; Herben, Tomáš; Götzenberger, Lars

    2017-01-01

    Roč. 8, č. 10 (2017), s. 1200-1211 ISSN 2041-210X R&D Projects: GA ČR(CZ) GA16-15012S; GA ČR GB14-36079G EU Projects: European Commission(XE) 267243 Institutional support: RVO:67985939 Keywords : community ecology * phylogenetic diversity * functional diversity Subject RIV: EH - Ecology, Behaviour OBOR OECD: Ecology Impact factor: 5.708, year: 2016

  2. A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile.

    Science.gov (United States)

    Ismail, Hanafy M; Barton, Victoria E; Panchana, Matthew; Charoensutthivarakul, Sitthivut; Biagini, Giancarlo A; Ward, Stephen A; O'Neill, Paul M

    2016-05-23

    In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities.

  3. The functional micro-organization of grid cells revealed by cellular-resolution imaging.

    Science.gov (United States)

    Heys, James G; Rangarajan, Krsna V; Dombeck, Daniel A

    2014-12-03

    Establishing how grid cells are anatomically arranged, on a microscopic scale, in relation to their firing patterns in the environment would facilitate a greater microcircuit-level understanding of the brain's representation of space. However, all previous grid cell recordings used electrode techniques that provide limited descriptions of fine-scale organization. We therefore developed a technique for cellular-resolution functional imaging of medial entorhinal cortex (MEC) neurons in mice navigating a virtual linear track, enabling a new experimental approach to study MEC. Using these methods, we show that grid cells are physically clustered in MEC compared to nongrid cells. Additionally, we demonstrate that grid cells are functionally micro-organized: the similarity between the environment firing locations of grid cell pairs varies as a function of the distance between them according to a "Mexican hat"-shaped profile. This suggests that, on average, nearby grid cells have more similar spatial firing phases than those further apart. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Dynamic changes in protein functional linkage networks revealed by integration with gene expression data.

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    Shubhada R Hegde

    2008-11-01

    Full Text Available Response of cells to changing environmental conditions is governed by the dynamics of intricate biomolecular interactions. It may be reasonable to assume, proteins being the dominant macromolecules that carry out routine cellular functions, that understanding the dynamics of protein:protein interactions might yield useful insights into the cellular responses. The large-scale protein interaction data sets are, however, unable to capture the changes in the profile of protein:protein interactions. In order to understand how these interactions change dynamically, we have constructed conditional protein linkages for Escherichia coli by integrating functional linkages and gene expression information. As a case study, we have chosen to analyze UV exposure in wild-type and SOS deficient E. coli at 20 minutes post irradiation. The conditional networks exhibit similar topological properties. Although the global topological properties of the networks are similar, many subtle local changes are observed, which are suggestive of the cellular response to the perturbations. Some such changes correspond to differences in the path lengths among the nodes of carbohydrate metabolism correlating with its loss in efficiency in the UV treated cells. Similarly, expression of hubs under unique conditions reflects the importance of these genes. Various centrality measures applied to the networks indicate increased importance for replication, repair, and other stress proteins for the cells under UV treatment, as anticipated. We thus propose a novel approach for studying an organism at the systems level by integrating genome-wide functional linkages and the gene expression data.

  5. Psychophysical "blinding" methods reveal a functional hierarchy of unconscious visual processing.

    Science.gov (United States)

    Breitmeyer, Bruno G

    2015-09-01

    Numerous non-invasive experimental "blinding" methods exist for suppressing the phenomenal awareness of visual stimuli. Not all of these suppressive methods occur at, and thus index, the same level of unconscious visual processing. This suggests that a functional hierarchy of unconscious visual processing can in principle be established. The empirical results of extant studies that have used a number of different methods and additional reasonable theoretical considerations suggest the following tentative hierarchy. At the highest levels in this hierarchy is unconscious processing indexed by object-substitution masking. The functional levels indexed by crowding, the attentional blink (and other attentional blinding methods), backward pattern masking, metacontrast masking, continuous flash suppression, sandwich masking, and single-flash interocular suppression, fall at progressively lower levels, while unconscious processing at the lowest levels is indexed by eye-based binocular-rivalry suppression. Although unconscious processing levels indexed by additional blinding methods is yet to be determined, a tentative placement at lower levels in the hierarchy is also given for unconscious processing indexed by Troxler fading and adaptation-induced blindness, and at higher levels in the hierarchy indexed by attentional blinding effects in addition to the level indexed by the attentional blink. The full mapping of levels in the functional hierarchy onto cortical activation sites and levels is yet to be determined. The existence of such a hierarchy bears importantly on the search for, and the distinctions between, neural correlates of conscious and unconscious vision. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Comprehensive proteome analysis of lysosomes reveals the diverse function of macrophages in immune responses.

    Science.gov (United States)

    Gao, Yanpan; Chen, Yanyu; Zhan, Shaohua; Zhang, Wenhao; Xiong, Feng; Ge, Wei

    2017-01-31

    Phagocytosis and autophagy in macrophages have been shown to be essential to both innate and adaptive immunity. Lysosomes are the main catabolic subcellular organelles responsible for degradation and recycling of both extracellular and intracellular material, which are the final steps in phagocytosis and autophagy. However, the molecular mechanisms underlying lysosomal functions after infection remain obscure. In this study, we conducted a quantitative proteomics analysis of the changes in constitution and glycosylation of proteins in lysosomes derived from murine RAW 264.7 macrophage cells treated with different types of pathogens comprising examples of bacteria (Listeria monocytogenes, L. m), DNA viruses (herpes simplex virus type-1, HSV-1) and RNA viruses (vesicular stomatitis virus, VSV). In total, 3,704 lysosome-related proteins and 300 potential glycosylation sites on 193 proteins were identified. Comparative analysis showed that the aforementioned pathogens induced distinct alterations in the proteome of the lysosome, which is closely associated with the immune functions of macrophages, such as toll-like receptor activation, inflammation and antigen-presentation. The most significant changes in proteins and fluctuations in glycosylation were also determined. Furthermore, Western blot analysis showed that the changes in expression of these proteins were undetectable at the whole cell level. Thus, our study provides unique insights into the function of lysosomes in macrophage activation and immune responses.

  7. Continental cichlid radiations: functional diversity reveals the role of changing ecological opportunity in the Neotropics.

    Science.gov (United States)

    Arbour, Jessica Hilary; López-Fernández, Hernán

    2016-08-17

    Adaptive radiations have been hypothesized to contribute broadly to the diversity of organisms. Models of adaptive radiation predict that ecological opportunity and ecological release, the availability of empty ecological niches and the response by adapting lineages to occupy them, respectively, drive patterns of phenotypic and lineage diversification. Adaptive radiations driven by 'ecological opportunity' are well established in island systems; it is less clear if ecological opportunity influences continent-wide diversification. We use Neotropical cichlid fishes to test if variation in rates of functional evolution is consistent with changing ecological opportunity. Across a functional morphological axis associated with ram-suction feeding traits, evolutionary rates declined through time as lineages diversified in South America. Evolutionary rates of ram-suction functional morphology also appear to have accelerated as cichlids colonized Central America and encountered renewed opportunity. Our results suggest that ecological opportunity may play an important role in shaping patterns of morphological diversity of even broadly distributed lineages like Neotropical cichlids. © 2016 The Author(s).

  8. Sex differences in functional activation patterns revealed by increased emotion processing demands.

    Science.gov (United States)

    Hall, Geoffrey B C; Witelson, Sandra F; Szechtman, Henry; Nahmias, Claude

    2004-02-09

    Two [O(15)] PET studies assessed sex differences regional brain activation in the recognition of emotional stimuli. Study I revealed that the recognition of emotion in visual faces resulted in bilateral frontal activation in women, and unilateral right-sided activation in men. In study II, the complexity of the emotional face task was increased through tje addition of associated auditory emotional stimuli. Men again showed unilateral frontal activation, in this case to the left; whereas women did not show bilateral frontal activation, but showed greater limbic activity. These results suggest that when processing broader cross-modal emotional stimuli, men engage more in associative cognitive strategies while women draw more on primary emotional references.

  9. Evolution of the snake body form reveals homoplasy in amniote Hox gene function.

    Science.gov (United States)

    Head, Jason J; Polly, P David

    2015-04-02

    Hox genes regulate regionalization of the axial skeleton in vertebrates, and changes in their expression have been proposed to be a fundamental mechanism driving the evolution of new body forms. The origin of the snake-like body form, with its deregionalized pre-cloacal axial skeleton, has been explained as either homogenization of Hox gene expression domains, or retention of standard vertebrate Hox domains with alteration of downstream expression that suppresses development of distinct regions. Both models assume a highly regionalized ancestor, but the extent of deregionalization of the primaxial domain (vertebrae, dorsal ribs) of the skeleton in snake-like body forms has never been analysed. Here we combine geometric morphometrics and maximum-likelihood analysis to show that the pre-cloacal primaxial domain of elongate, limb-reduced lizards and snakes is not deregionalized compared with limbed taxa, and that the phylogenetic structure of primaxial morphology in reptiles does not support a loss of regionalization in the evolution of snakes. We demonstrate that morphometric regional boundaries correspond to mapped gene expression domains in snakes, suggesting that their primaxial domain is patterned by a normally functional Hox code. Comparison of primaxial osteology in fossil and modern amniotes with Hox gene distributions within Amniota indicates that a functional, sequentially expressed Hox code patterned a subtle morphological gradient along the anterior-posterior axis in stem members of amniote clades and extant lizards, including snakes. The highly regionalized skeletons of extant archosaurs and mammals result from independent evolution in the Hox code and do not represent ancestral conditions for clades with snake-like body forms. The developmental origin of snakes is best explained by decoupling of the primaxial and abaxial domains and by increases in somite number, not by changes in the function of primaxial Hox genes.

  10. Evidence of functional connectivity between auditory cortical areas revealed by amplitude modulation sound processing.

    Science.gov (United States)

    Guéguin, Marie; Le Bouquin-Jeannès, Régine; Faucon, Gérard; Chauvel, Patrick; Liégeois-Chauvel, Catherine

    2007-02-01

    The human auditory cortex includes several interconnected areas. A better understanding of the mechanisms involved in auditory cortical functions requires a detailed knowledge of neuronal connectivity between functional cortical regions. In human, it is difficult to track in vivo neuronal connectivity. We investigated the interarea connection in vivo in the auditory cortex using a method of directed coherence (DCOH) applied to depth auditory evoked potentials (AEPs). This paper presents simultaneous AEPs recordings from insular gyrus (IG), primary and secondary cortices (Heschl's gyrus and planum temporale), and associative areas (Brodmann area [BA] 22) with multilead intracerebral electrodes in response to sinusoidal modulated white noises in 4 epileptic patients who underwent invasive monitoring with depth electrodes for epilepsy surgery. DCOH allowed estimation of the causality between 2 signals recorded from different cortical sites. The results showed 1) a predominant auditory stream within the primary auditory cortex from the most medial region to the most lateral one whatever the modulation frequency, 2) unidirectional functional connection from the primary to secondary auditory cortex, 3) a major auditory propagation from the posterior areas to the anterior ones, particularly at 8, 16, and 32 Hz, and 4) a particular role of Heschl's sulcus dispatching information to the different auditory areas. These findings suggest that cortical processing of auditory information is performed in serial and parallel streams. Our data showed that the auditory propagation could not be associated to a unidirectional traveling wave but to a constant interaction between these areas that could reflect the large adaptive and plastic capacities of auditory cortex. The role of the IG is discussed.

  11. A novel flow cytometric HTS assay reveals functional modulators of ATP binding cassette transporter ABCB6.

    Science.gov (United States)

    Polireddy, Kishore; Khan, Mohiuddin Md Taimur; Chavan, Hemantkumar; Young, Susan; Ma, Xiaochao; Waller, Anna; Garcia, Matthew; Perez, Dominique; Chavez, Stephanie; Strouse, Jacob J; Haynes, Mark K; Bologa, Cristian G; Oprea, Tudor I; Tegos, George P; Sklar, Larry A; Krishnamurthy, Partha

    2012-01-01

    ABCB6 is a member of the adenosine triphosphate (ATP)-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS), can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6's ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity.

  12. A novel flow cytometric HTS assay reveals functional modulators of ATP binding cassette transporter ABCB6.

    Directory of Open Access Journals (Sweden)

    Kishore Polireddy

    Full Text Available ABCB6 is a member of the adenosine triphosphate (ATP-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS, can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6's ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity.

  13. Revealing molecular mechanisms by integrating high-dimensional functional screens with protein interaction data.

    Directory of Open Access Journals (Sweden)

    Angela Simeone

    2014-09-01

    Full Text Available Functional genomics screens using multi-parametric assays are powerful approaches for identifying genes involved in particular cellular processes. However, they suffer from problems like noise, and often provide little insight into molecular mechanisms. A bottleneck for addressing these issues is the lack of computational methods for the systematic integration of multi-parametric phenotypic datasets with molecular interactions. Here, we present Integrative Multi Profile Analysis of Cellular Traits (IMPACT. The main goal of IMPACT is to identify the most consistent phenotypic profile among interacting genes. This approach utilizes two types of external information: sets of related genes (IMPACT-sets and network information (IMPACT-modules. Based on the notion that interacting genes are more likely to be involved in similar functions than non-interacting genes, this data is used as a prior to inform the filtering of phenotypic profiles that are similar among interacting genes. IMPACT-sets selects the most frequent profile among a set of related genes. IMPACT-modules identifies sub-networks containing genes with similar phenotype profiles. The statistical significance of these selections is subsequently quantified via permutations of the data. IMPACT (1 handles multiple profiles per gene, (2 rescues genes with weak phenotypes and (3 accounts for multiple biases e.g. caused by the network topology. Application to a genome-wide RNAi screen on endocytosis showed that IMPACT improved the recovery of known endocytosis-related genes, decreased off-target effects, and detected consistent phenotypes. Those findings were confirmed by rescreening 468 genes. Additionally we validated an unexpected influence of the IGF-receptor on EGF-endocytosis. IMPACT facilitates the selection of high-quality phenotypic profiles using different types of independent information, thereby supporting the molecular interpretation of functional screens.

  14. Presbycusis Disrupts Spontaneous Activity Revealed by Resting-State Functional MRI

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    Yu-Chen Chen

    2018-03-01

    Full Text Available Purpose: Presbycusis, age-related hearing loss, is believed to involve neural changes in the central nervous system, which is associated with an increased risk of cognitive impairment. The goal of this study was to determine if presbycusis disrupted spontaneous neural activity in specific brain areas involved in auditory processing, attention and cognitive function using resting-state functional magnetic resonance imaging (fMRI approach.Methods: Hearing and resting-state fMRI measurements were obtained from 22 presbycusis patients and 23 age-, sex- and education-matched healthy controls. To identify changes in spontaneous neural activity associated with age-related hearing loss, we compared the amplitude of low-frequency fluctuations (ALFF and regional homogeneity (ReHo of fMRI signals in presbycusis patients vs. controls and then determined if these changes were linked to clinical measures of presbycusis.Results: Compared with healthy controls, presbycusis patients manifested decreased spontaneous activity mainly in the superior temporal gyrus (STG, parahippocampal gyrus (PHG, precuneus and inferior parietal lobule (IPL as well as increased neural activity in the middle frontal gyrus (MFG, cuneus and postcentral gyrus (PoCG. A significant negative correlation was observed between ALFF/ReHo activity in the STG and average hearing thresholds in presbycusis patients. Increased ALFF/ReHo activity in the MFG was positively correlated with impaired Trail-Making Test B (TMT-B scores, indicative of impaired cognitive function involving the frontal lobe.Conclusions: Presbycusis patients have disrupted spontaneous neural activity reflected by ALFF and ReHo measurements in several brain regions; these changes are associated with specific cognitive performance and speech/language processing. These findings mainly emphasize the crucial role of aberrant resting-state ALFF/ReHo patterns in presbycusis patients and will lead to a better understanding of the

  15. Presbycusis Disrupts Spontaneous Activity Revealed by Resting-State Functional MRI.

    Science.gov (United States)

    Chen, Yu-Chen; Chen, Huiyou; Jiang, Liang; Bo, Fan; Xu, Jin-Jing; Mao, Cun-Nan; Salvi, Richard; Yin, Xindao; Lu, Guangming; Gu, Jian-Ping

    2018-01-01

    Purpose : Presbycusis, age-related hearing loss, is believed to involve neural changes in the central nervous system, which is associated with an increased risk of cognitive impairment. The goal of this study was to determine if presbycusis disrupted spontaneous neural activity in specific brain areas involved in auditory processing, attention and cognitive function using resting-state functional magnetic resonance imaging (fMRI) approach. Methods : Hearing and resting-state fMRI measurements were obtained from 22 presbycusis patients and 23 age-, sex- and education-matched healthy controls. To identify changes in spontaneous neural activity associated with age-related hearing loss, we compared the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) of fMRI signals in presbycusis patients vs. controls and then determined if these changes were linked to clinical measures of presbycusis. Results : Compared with healthy controls, presbycusis patients manifested decreased spontaneous activity mainly in the superior temporal gyrus (STG), parahippocampal gyrus (PHG), precuneus and inferior parietal lobule (IPL) as well as increased neural activity in the middle frontal gyrus (MFG), cuneus and postcentral gyrus (PoCG). A significant negative correlation was observed between ALFF/ReHo activity in the STG and average hearing thresholds in presbycusis patients. Increased ALFF/ReHo activity in the MFG was positively correlated with impaired Trail-Making Test B (TMT-B) scores, indicative of impaired cognitive function involving the frontal lobe. Conclusions : Presbycusis patients have disrupted spontaneous neural activity reflected by ALFF and ReHo measurements in several brain regions; these changes are associated with specific cognitive performance and speech/language processing. These findings mainly emphasize the crucial role of aberrant resting-state ALFF/ReHo patterns in presbycusis patients and will lead to a better understanding of the

  16. Structural-Functional Analysis Reveals a Specific Domain Organization in Family GH20 Hexosaminidases.

    Science.gov (United States)

    Val-Cid, Cristina; Biarnés, Xevi; Faijes, Magda; Planas, Antoni

    2015-01-01

    Hexosaminidases are involved in important biological processes catalyzing the hydrolysis of N-acetyl-hexosaminyl residues in glycosaminoglycans and glycoconjugates. The GH20 enzymes present diverse domain organizations for which we propose two minimal model architectures: Model A containing at least a non-catalytic GH20b domain and the catalytic one (GH20) always accompanied with an extra α-helix (GH20b-GH20-α), and Model B with only the catalytic GH20 domain. The large Bifidobacterium bifidum lacto-N-biosidase was used as a model protein to evaluate the minimal functional unit due to its interest and structural complexity. By expressing different truncated forms of this enzyme, we show that Model A architectures cannot be reduced to Model B. In particular, there are two structural requirements general to GH20 enzymes with Model A architecture. First, the non-catalytic domain GH20b at the N-terminus of the catalytic GH20 domain is required for expression and seems to stabilize it. Second, the substrate-binding cavity at the GH20 domain always involves a remote element provided by a long loop from the catalytic domain itself or, when this loop is short, by an element from another domain of the multidomain structure or from the dimeric partner. Particularly, the lacto-N-biosidase requires GH20b and the lectin-like domain at the N- and C-termini of the catalytic GH20 domain to be fully soluble and functional. The lectin domain provides this remote element to the active site. We demonstrate restoration of activity of the inactive GH20b-GH20-α construct (model A architecture) by a complementation assay with the lectin-like domain. The engineering of minimal functional units of multidomain GH20 enzymes must consider these structural requirements.

  17. Targeted Gene-Silencing Reveals the Functional Significance of Myocardin Signaling in the Failing Heart

    Science.gov (United States)

    Torrado, Mario; Iglesias, Raquel; Centeno, Alberto; López, Eduardo; Mikhailov, Alexander T.

    2011-01-01

    Background Myocardin (MYOCD), a potent transcriptional coactivator of smooth muscle (SM) and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF). However, the molecular and functional consequences of myocd upregulation in HF are still unclear. Methodology/Principal Findings The goal of the present study was to investigate if targeted inhibition of upregulated expression of myocd could influence failing heart gene expression and function. To this end, we used the doxorubicin (Dox)-induced diastolic HF (DHF) model in neonatal piglets, in which, as we show, not only myocd but also myocd-dependent SM-marker genes are highly activated in failing left ventricular (LV) myocardium. In this model, intra-myocardial delivery of short-hairpin RNAs, designed to target myocd variants expressed in porcine heart, leads on day 2 post-delivery to: (1) a decrease in the activated expression of myocd and myocd-dependent SM-marker genes in failing myocardium to levels seen in healthy control animals, (2) amelioration of impaired diastolic dysfunction, and (3) higher survival rates of DHF piglets. The posterior restoration of elevated myocd expression (on day 7 post-delivery) led to overexpression of myocd-dependent SM-marker genes in failing LV-myocardium that was associated with a return to altered diastolic function. Conclusions/Significance These data provide the first evidence that a moderate inhibition (e.g., normalization) of the activated MYOCD signaling in the diseased heart may be promising from a therapeutic point of view. PMID:22028870

  18. Targeted gene-silencing reveals the functional significance of myocardin signaling in the failing heart.

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    Mario Torrado

    Full Text Available BACKGROUND: Myocardin (MYOCD, a potent transcriptional coactivator of smooth muscle (SM and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF. However, the molecular and functional consequences of myocd upregulation in HF are still unclear. METHODOLOGY/PRINCIPAL FINDINGS: The goal of the present study was to investigate if targeted inhibition of upregulated expression of myocd could influence failing heart gene expression and function. To this end, we used the doxorubicin (Dox-induced diastolic HF (DHF model in neonatal piglets, in which, as we show, not only myocd but also myocd-dependent SM-marker genes are highly activated in failing left ventricular (LV myocardium. In this model, intra-myocardial delivery of short-hairpin RNAs, designed to target myocd variants expressed in porcine heart, leads on day 2 post-delivery to: (1 a decrease in the activated expression of myocd and myocd-dependent SM-marker genes in failing myocardium to levels seen in healthy control animals, (2 amelioration of impaired diastolic dysfunction, and (3 higher survival rates of DHF piglets. The posterior restoration of elevated myocd expression (on day 7 post-delivery led to overexpression of myocd-dependent SM-marker genes in failing LV-myocardium that was associated with a return to altered diastolic function. CONCLUSIONS/SIGNIFICANCE: These data provide the first evidence that a moderate inhibition (e.g., normalization of the activated MYOCD signaling in the diseased heart may be promising from a therapeutic point of view.

  19. A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.

    Science.gov (United States)

    Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L; Adams, Marvin E; Froehner, Stanley C

    2015-10-13

    Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

  20. Computer Simulations Reveal Multiple Functions for Aromatic Residues in Cellulase Enzymes (Fact Sheet)

    Energy Technology Data Exchange (ETDEWEB)

    2012-07-01

    NREL researchers use high-performance computing to demonstrate fundamental roles of aromatic residues in cellulase enzyme tunnels. National Renewable Energy Laboratory (NREL) computer simulations of a key industrial enzyme, the Trichoderma reesei Family 6 cellulase (Cel6A), predict that aromatic residues near the enzyme's active site and at the entrance and exit tunnel perform different functions in substrate binding and catalysis, depending on their location in the enzyme. These results suggest that nature employs aromatic-carbohydrate interactions with a wide variety of binding affinities for diverse functions. Outcomes also suggest that protein engineering strategies in which mutations are made around the binding sites may require tailoring specific to the enzyme family. Cellulase enzymes ubiquitously exhibit tunnels or clefts lined with aromatic residues for processing carbohydrate polymers to monomers, but the molecular-level role of these aromatic residues remains unknown. In silico mutation of the aromatic residues near the catalytic site of Cel6A has little impact on the binding affinity, but simulation suggests that these residues play a major role in the glucopyranose ring distortion necessary for cleaving glycosidic bonds to produce fermentable sugars. Removal of aromatic residues at the entrance and exit of the cellulase tunnel, however, dramatically impacts the binding affinity. This suggests that these residues play a role in acquiring cellulose chains from the cellulose crystal and stabilizing the reaction product, respectively. These results illustrate that the role of aromatic-carbohydrate interactions varies dramatically depending on the position in the enzyme tunnel. As aromatic-carbohydrate interactions are present in all carbohydrate-active enzymes, the results have implications for understanding protein structure-function relationships in carbohydrate metabolism and recognition, carbon turnover in nature, and protein engineering

  1. 3D topology of orientation columns in visual cortex revealed by functional optical coherence tomography.

    Science.gov (United States)

    Nakamichi, Yu; Kalatsky, Valery A; Watanabe, Hideyuki; Sato, Takayuki; Rajagopalan, Uma Maheswari; Tanifuji, Manabu

    2018-04-01

    Orientation tuning is a canonical neuronal response property of six-layer visual cortex that is encoded in pinwheel structures with center orientation singularities. Optical imaging of intrinsic signals enables us to map these surface two-dimensional (2D) structures, whereas lack of appropriate techniques has not allowed us to visualize depth structures of orientation coding. In the present study, we performed functional optical coherence tomography (fOCT), a technique capable of acquiring a 3D map of the intrinsic signals, to study the topology of orientation coding inside the cat visual cortex. With this technique, for the first time, we visualized columnar assemblies in orientation coding that had been predicted from electrophysiological recordings. In addition, we found that the columnar structures were largely distorted around pinwheel centers: center singularities were not rigid straight lines running perpendicularly to the cortical surface but formed twisted string-like structures inside the cortex that turned and extended horizontally through the cortex. Looping singularities were observed with their respective termini accessing the same cortical surface via clockwise and counterclockwise orientation pinwheels. These results suggest that a 3D topology of orientation coding cannot be fully anticipated from 2D surface measurements. Moreover, the findings demonstrate the utility of fOCT as an in vivo mesoscale imaging method for mapping functional response properties of cortex in the depth axis. NEW & NOTEWORTHY We used functional optical coherence tomography (fOCT) to visualize three-dimensional structure of the orientation columns with millimeter range and micrometer spatial resolution. We validated vertically elongated columnar structure in iso-orientation domains. The columnar structure was distorted around pinwheel centers. An orientation singularity formed a string with tortuous trajectories inside the cortex and connected clockwise and counterclockwise

  2. Scientific and methodic approaches to reveal stability essence at the industrial enterprises and its functional components

    Directory of Open Access Journals (Sweden)

    Lyulyov Oleksii Valentynovych

    2016-12-01

    Full Text Available The article deals with theoretical analysis of the scientific approaches concerning definition of the concept “stability”, which exist in the scientific literature. There are five different approaches to interpret the concept “enterprise stability”, as an open economic system. On this base, the author’s definition of the enterprise stability is formed. Due to the carried out analysis of the main tendencies in changes of the industry development factors for 2006-2015 and future expectations, the main functional constituents of the enterprise stability. The author suggests to use an approach of self-organizational artificial neural networks to evaluate stability degree at the industrial enterprises.

  3. Lipid profiling and transcriptomic analysis reveals a functional interplay between estradiol and growth hormone in liver.

    Directory of Open Access Journals (Sweden)

    Leandro Fernández-Pérez

    Full Text Available 17β-estradiol (E2 may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo-xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH-regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPARα. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a

  4. A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration

    DEFF Research Database (Denmark)

    Scheel, Troels K H; Luna, Joseph M; Liniger, Matthias

    2016-01-01

    , critically depended on the interaction of cellular miR-17 and let-7 with the viral 3' UTR. Unlike canonical miRNA interactions, miR-17 and let-7 binding enhanced pestivirus translation and RNA stability. miR-17 sequestration by pestiviruses conferred reduced AGO binding and functional de...... immunoprecipitation (CLIP) of the Argonaute (AGO) proteins to characterize strengths and specificities of miRNA interactions in the context of 15 different RNA virus infections, including several clinically relevant pathogens. Notably, replication of pestiviruses, a major threat to milk and meat industries...

  5. Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling

    Science.gov (United States)

    Tambalo, Stefano; Peruzzotti-Jametti, Luca; Rigolio, Roberta; Fiorini, Silvia; Bontempi, Pietro; Mallucci, Giulia; Balzarotti, Beatrice; Marmiroli, Paola; Sbarbati, Andrea; Cavaletti, Guido

    2015-01-01

    Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS. SIGNIFICANCE STATEMENT Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune

  6. Developmental Reorganization of the Core and Extended Face Networks Revealed by Global Functional Connectivity.

    Science.gov (United States)

    Wang, Xu; Zhu, Qi; Song, Yiying; Liu, Jia

    2017-08-28

    Prior studies on development of functional specialization in human brain mainly focus on age-related increases in regional activation and connectivity among regions. However, a few recent studies on the face network demonstrate age-related decrease in face-specialized activation in the extended face network (EFN), in addition to increase in activation in the core face network (CFN). Here we used a voxel-based global brain connectivity approach to investigate whether development of the face network exhibited both increase and decrease in network connectivity. We found the voxel-wise resting-state functional connectivity (FC) within the CFN increased with age in bilateral posterior superior temporal sulcus, suggesting the integration of the CFN during development. Interestingly, the FC of the voxels in the EFN to the right fusiform face area and occipital face area decreased with age, suggesting that the CFN segregated from the EFN during development. Moreover, the age-related connectivity in the CFN was related to behavioral performance in face processing. Overall, our study demonstrated developmental reorganization of the face network achieved by both integration within the CFN and segregation of the CFN from the EFN, which may account for the simultaneous increases and decreases in neural activation during the development of the face network. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Genetic analysis of yeast RPA1 reveals its multiple functions in DNA metabolism

    International Nuclear Information System (INIS)

    Umezu, K.; Sugawara, N.; Chen, C.; Haber, J.E.; Kolodner, R.D.

    1998-01-01

    Replication protein A (RPA) is a single-stranded DNA-binding protein identified as an essential factor for SV40 DNA replication in vitro. To understand the in vivo functions of RPA, we mutagenized the Saccharomyces cerevisiae RFA1 gene and identified 19 ultraviolet light (UV) irradiation- and methyl methane sulfonate (MMS)-sensitive mutants and 5 temperature-sensitive mutants. The UV- and MMS-sensitive mutants showed up to 10 4 to 10 5 times increased sensitivity to these agents. Some of the UV- and MMSsensitive mutants were killed by an HO-induced double-strand break atMAT. Physical analysis of recombination in one UV- and MMS-sensitive rfa1 mutant demonstrated that it was defective for mating type switching and single-strand annealing recombination. Two temperature-sensitive mutants were characterized in detail, and at the restrictive temperature were found to have an arrest phenotype and DNA content indicative of incomplete DNA replication. DNA sequence analysis indicated that most of the mutations altered amino acids that were conserved between yeast, human, and Xenopus RPA1. Taken together, we conclude that RPA1 has multiple roles in vivo and functions in DNA replication, repair, and recombination, like the single-stranded DNA-binding proteins of bacteria and phages. (author)

  8. Structural and functional properties of hemoglobins from unicellular organisms as revealed by resonance Raman spectroscopy.

    Science.gov (United States)

    Egawa, Tsuyoshi; Yeh, Syun-Ru

    2005-01-01

    Hemoglobins have been discovered in organisms from virtually all kingdoms. Their presence in unicellular organisms suggests that the gene for hemoglobin is very ancient and that the hemoglobins must have functions other than oxygen transport, in view of the fact that O2 delivery is a diffusion-controlled process in these organisms. Based on sequence alignment, three groups of hemoglobins have been characterized in unicellular organisms. The group-one hemoglobins, termed truncated hemoglobins, consist of proteins with 110-140 amino acid residues and a novel two-over-two alpha-helical sandwich motif. The group-two hemoglobins, termed flavohemoglobins, consist of a hemoglobin domain, with a classical three-over-three alpha-helical sandwich motif, and a flavin-containing reductase domain that is covalently attached to it. The group-three hemoglobins consist of myoglobin-like proteins that have high sequence homology and structural similarity to the hemoglobin domain of flavohemoglobins. In this review, recent resonance Raman studies of each group of these proteins are presented. Their implications are discussed in the context of the structural and functional properties of these novel hemoglobins.

  9. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

    Science.gov (United States)

    Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

    2016-08-18

    Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

  10. Structural Studies Reveal the Functional Modularity of the Scc2-Scc4 Cohesin Loader

    Directory of Open Access Journals (Sweden)

    William C.H. Chao

    2015-08-01

    Full Text Available The remarkable accuracy of eukaryotic cell division is partly maintained by the cohesin complex acting as a molecular glue to prevent premature sister chromatid separation. The loading of cohesin onto chromosomes is catalyzed by the Scc2-Scc4 loader complex. Here, we report the crystal structure of Scc4 bound to the N terminus of Scc2 and show that Scc4 is a tetratricopeptide repeat (TPR superhelix. The Scc2 N terminus adopts an extended conformation and is entrapped by the core of the Scc4 superhelix. Electron microscopy (EM analysis reveals that the Scc2-Scc4 loader complex comprises three domains: a head, body, and hook. Deletion studies unambiguously assign the Scc2N-Scc4 as the globular head domain, whereas in vitro cohesin loading assays show that the central body and the hook domains are sufficient to catalyze cohesin loading onto circular DNA, but not chromatinized DNA in vivo, suggesting a possible role for Scc4 as a chromatin adaptor.

  11. Decreased functional connectivity of the amygdala in Alzheimer's disease revealed by resting-state fMRI

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Hongxiang [Department of Radiology, Chinese PLA General Hospital, Beijing, 100853 (China); Liu, Yong, E-mail: yliu@nlpr.ia.ac.cn [Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190 (China); National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190 (China); Zhou, Bo; Zhang, Zengqiang [Department of Neurology, Institute of Geriatrics and Gerontology, Chinese PLA General Hospital, Beijing, 100853 (China); An, Ningyu [Department of Radiology, Chinese PLA General Hospital, Beijing, 100853 (China); Wang, Pan; Wang, Luning [Department of Neurology, Institute of Geriatrics and Gerontology, Chinese PLA General Hospital, Beijing, 100853 (China); Zhang, Xi, E-mail: zhangxi@301hospital.com.cn [Department of Neurology, Institute of Geriatrics and Gerontology, Chinese PLA General Hospital, Beijing, 100853 (China); Jiang, Tianzi [Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190 (China); National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190 (China); Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054 (China); The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072 (Australia)

    2013-09-15

    Alzheimer's disease (AD), the most common cause of dementia, is thought to be a progressive neurodegenerative disease that is clinically characterised by a decline of memory and other cognitive functions. Mild cognitive impairment (MCI) is considered to be the prodromal stage of AD. However, the relationship between AD and MCI and the development process remains unclear. The amygdala is one of the most vulnerable structures in the early stages of AD. To our knowledge, this is the first report on the alteration of the functional connectivity of the amygdala in AD and MCI subjects. We hypothesised that the amygdala-cortical loop is impaired in AD and that these alterations relate to the disease severity. In our study, we used resting-state functional MRIs to investigate the altered amygdala connectivity patterns in 35 AD patients, 27 MCI patients and 27 age- and gender-matched normal controls (NC). Compared with the NC, the decreased functional connectivity found in the AD patients was mainly located between the amygdala and the regions that are included in the default mode, context conditioning and extinction networks. Importantly, the decreased functional connectivity between the amygdala and some of the identified regions was positively correlated with MMSE, which indicated that the cognitive function impairment is related to an altered functional connectivity pattern.

  12. Decreased functional connectivity of the amygdala in Alzheimer's disease revealed by resting-state fMRI

    International Nuclear Information System (INIS)

    Yao, Hongxiang; Liu, Yong; Zhou, Bo; Zhang, Zengqiang; An, Ningyu; Wang, Pan; Wang, Luning; Zhang, Xi; Jiang, Tianzi

    2013-01-01

    Alzheimer's disease (AD), the most common cause of dementia, is thought to be a progressive neurodegenerative disease that is clinically characterised by a decline of memory and other cognitive functions. Mild cognitive impairment (MCI) is considered to be the prodromal stage of AD. However, the relationship between AD and MCI and the development process remains unclear. The amygdala is one of the most vulnerable structures in the early stages of AD. To our knowledge, this is the first report on the alteration of the functional connectivity of the amygdala in AD and MCI subjects. We hypothesised that the amygdala-cortical loop is impaired in AD and that these alterations relate to the disease severity. In our study, we used resting-state functional MRIs to investigate the altered amygdala connectivity patterns in 35 AD patients, 27 MCI patients and 27 age- and gender-matched normal controls (NC). Compared with the NC, the decreased functional connectivity found in the AD patients was mainly located between the amygdala and the regions that are included in the default mode, context conditioning and extinction networks. Importantly, the decreased functional connectivity between the amygdala and some of the identified regions was positively correlated with MMSE, which indicated that the cognitive function impairment is related to an altered functional connectivity pattern

  13. Computational Approaches Reveal New Insights into Regulation and Function of Non; coding RNAs and their Targets

    KAUST Repository

    Alam, Tanvir

    2016-11-28

    Regulation and function of protein-coding genes are increasingly well-understood, but no comparable evidence exists for non-coding RNA (ncRNA) genes, which appear to be more numerous than protein-coding genes. We developed a novel machine-learning model to distinguish promoters of long ncRNA (lncRNA) genes from those of protein-coding genes. This represents the first attempt to make this distinction based on properties of the associated gene promoters. From our analyses, several transcription factors (TFs), which are known to be regulated by lncRNAs, also emerged as potential global regulators of lncRNAs, suggesting that lncRNAs and TFs may participate in bidirectional feedback regulatory network. Our results also raise the possibility that, due to the historical dependence on protein-coding gene in defining the chromatin states of active promoters, an adjustment of these chromatin signature profiles to incorporate lncRNAs is warranted in the future. Secondly, we developed a novel method to infer functions for lncRNA and microRNA (miRNA) transcripts based on their transcriptional regulatory networks in 119 tissues and 177 primary cells of human. This method for the first time combines information of cell/tissueVspecific expression of a transcript and the TFs and transcription coVfactors (TcoFs) that control activation of that transcript. Transcripts were annotated using statistically enriched GO terms, pathways and diseases across cells/tissues and associated knowledgebase (FARNA) is developed. FARNA, having the most comprehensive function annotation of considered ncRNAs across the widest spectrum of cells/tissues, has a potential to contribute to our understanding of ncRNA roles and their regulatory mechanisms in human. Thirdly, we developed a novel machine-learning model to identify LD motif (a protein interaction motif) of paxillin, a ncRNA target that is involved in cell motility and cancer metastasis. Our recognition model identified new proteins not

  14. Crustal Structure and Deformation of the Sichuan-Yunnan Region Revealed by receiver Function Data

    Science.gov (United States)

    Zeng, S.; Zheng, Y.

    2017-12-01

    Sichuan-Yunnan and its surrounding areas locates in the southeast side to the Tibetan Plateau, due to the intrusion of the Indian Plate under the Tibetan Plateau, materials escape from the Tibetan Plateau and flow southward to southeastward. Because of such tectonic environment, the Sichuan-Yunnan region is experiencing high tectonic movement, and is capable of highly diffused seismicity. Based on dynamic simulation and field survey investigations, tectonic and geological studies proposed a decoupling model in this region and lower crustal flow may inflate in the crust. However, this idea needs more evidences, especially anisotropic structures to support it, since the anisotropic structures are usually directly related to the movement of materials, or to the tectonic distributions. In the past several years, a number of works have been done on the anisotropic structures in the Tibetan Plateau and its surroundings. In usually, previous studies were mainly carried out by two kinds of methods. First, the shear wave splitting of SKS, which mainly reflects the accumulation effect of the anisotropy of the crust to the mantle; the other way is use surface wave to investigate the anisotropic features at different azimuths and depths. In the recent years, receiver function is used to determine the inclination and anisotropy of the subsurface structure, comparing with the other two methods, receiver functions can provide higher resolution and reliable anisotropic features in the crust. Following the method of Liu and Niu(2012), we collected teleseismic data from the Himalayan first term network, and picked out high quality data based on the waveform SNR ratio, as well as the azimuthal distributions. Comparing with previous work (e.g., Sun et al.,2012), our work can provide more receiver functions results with higher reliability. We find that the crust beneath the Sichuan-Yunnan region has a thickness of 30-60 km and Vp/Vs ratio of 1.70-1.80. The Moho depth from northwest to

  15. Metatranscriptome Sequencing Reveals Insights into the Gene Expression and Functional Potential of Rumen Wall Bacteria

    Directory of Open Access Journals (Sweden)

    Evelyne Mann

    2018-01-01

    Full Text Available Microbiota of the rumen wall constitute an important niche of rumen microbial ecology and their composition has been elucidated in different ruminants during the last years. However, the knowledge about the function of rumen wall microbes is still limited. Rumen wall biopsies were taken from three fistulated dairy cows under a standard forage-based diet and after 4 weeks of high concentrate feeding inducing a subacute rumen acidosis (SARA. Extracted RNA was used for metatranscriptome sequencing using Illumina HiSeq sequencing technology. The gene expression of the rumen wall microbial community was analyzed by mapping 35 million sequences against the Kyoto Encyclopedia for Genes and Genomes (KEGG database and determining differentially expressed genes. A total of 1,607 functional features were assigned with high expression of genes involved in central metabolism, galactose, starch and sucrose metabolism. The glycogen phosphorylase (EC:2.4.1.1 which degrades (1->4-alpha-D-glucans was among the highest expressed genes being transcribed by 115 bacterial genera. Energy metabolism genes were also highly expressed, including the pyruvate orthophosphate dikinase (EC:2.7.9.1 involved in pyruvate metabolism, which was covered by 177 genera. Nitrogen metabolism genes, in particular glutamate dehydrogenase (EC:1.4.1.4, glutamine synthetase (EC:6.3.1.2 and glutamate synthase (EC:1.4.1.13, EC:1.4.1.14 were also found to be highly expressed and prove rumen wall microbiota to be actively involved in providing host-relevant metabolites for exchange across the rumen wall. In addition, we found all four urease subunits (EC:3.5.1.5 transcribed by members of the genera Flavobacterium, Corynebacterium, Helicobacter, Clostridium, and Bacillus, and the dissimilatory sulfate reductase (EC 1.8.99.5 dsrABC, which is responsible for the reduction of sulfite to sulfide. We also provide in situ evidence for cellulose and cellobiose degradation, a key step in fiber-rich feed

  16. Early stages of functional diversification in the Rab GTPase gene family revealed by genomic and localization studies in Paramecium species.

    Science.gov (United States)

    Bright, Lydia J; Gout, Jean-Francois; Lynch, Michael

    2017-04-15

    New gene functions arise within existing gene families as a result of gene duplication and subsequent diversification. To gain insight into the steps that led to the functional diversification of paralogues, we tracked duplicate retention patterns, expression-level divergence, and subcellular markers of functional diversification in the Rab GTPase gene family in three Paramecium aurelia species. After whole-genome duplication, Rab GTPase duplicates are more highly retained than other genes in the genome but appear to be diverging more rapidly in expression levels, consistent with early steps in functional diversification. However, by localizing specific Rab proteins in Paramecium cells, we found that paralogues from the two most recent whole-genome duplications had virtually identical localization patterns, and that less closely related paralogues showed evidence of both conservation and diversification. The functionally conserved paralogues appear to target to compartments associated with both endocytic and phagocytic recycling functions, confirming evolutionary and functional links between the two pathways in a divergent eukaryotic lineage. Because the functionally diversifying paralogues are still closely related to and derived from a clade of functionally conserved Rab11 genes, we were able to pinpoint three specific amino acid residues that may be driving the change in the localization and thus the function in these proteins. © 2017 Bright et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  17. Functional comparison of the nematode Hox gene lin-39 in C. elegans and P. pacificus reveals evolutionary conservation of protein function despite divergence of primary sequences.

    Science.gov (United States)

    Grandien, K; Sommer, R J

    2001-08-15

    Hox transcription factors have been implicated in playing a central role in the evolution of animal morphology. Many studies indicate the evolutionary importance of regulatory changes in Hox genes, but little is known about the role of functional changes in Hox proteins. In the nematodes Pristionchus pacificus and Caenorhabditis elegans, developmental processes can be compared at the cellular, genetic, and molecular levels and differences in gene function can be identified. The Hox gene lin-39 is involved in the regulation of nematode vulva development. Comparison of known lin-39 mutations in P. pacificus and C. elegans revealed both conservation and changes of gene function. Here, we study evolutionary changes of lin-39 function using hybrid transgenes and site-directed mutagenesis in an in vivo assay using C. elegans lin-39 mutants. Our data show that despite the functional differences of LIN-39 between the two species, Ppa-LIN-39, when driven by Cel-lin-39 regulatory elements, can functionally replace Cel-lin-39. Furthermore, we show that the MAPK docking and phosphorylation motifs unique for Cel-LIN-39 are dispensable for Cel-lin-39 function. Therefore, the evolution of lin-39 function is driven by changes in regulatory elements rather than changes in the protein itself.

  18. Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy.

    Science.gov (United States)

    Shanmugam, Anusuya; Natarajan, Jeyakumar

    2012-06-01

    Multi drug resistance capacity for Mycobacterium leprae (MDR-Mle) demands the profound need for developing new anti-leprosy drugs. Since most of the drugs target a single enzyme, mutation in the active site renders the antibiotic ineffective. However, structural and mechanistic information on essential bacterial enzymes in a pathway could lead to the development of antibiotics that targets multiple enzymes. Peptidoglycan is an important component of the cell wall of M. leprae. The biosynthesis of bacterial peptidoglycan represents important targets for the development of new antibacterial drugs. Biosynthesis of peptidoglycan is a multi-step process that involves four key Mur ligase enzymes: MurC (EC:6.3.2.8), MurD (EC:6.3.2.9), MurE (EC:6.3.2.13) and MurF (EC:6.3.2.10). Hence in our work, we modeled the three-dimensional structure of the above Mur ligases using homology modeling method and analyzed its common binding features. The residues playing an important role in the catalytic activity of each of the Mur enzymes were predicted by docking these Mur ligases with their substrates and ATP. The conserved sequence motifs significant for ATP binding were predicted as the probable residues for structure based drug designing. Overall, the study was successful in listing significant and common binding residues of Mur enzymes in peptidoglycan pathway for multi targeted therapy.

  19. Different patterns of auditory cortex activation revealed by functional magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Formisano, E; Pepino, A; Bracale, M [Department of Electronic Engineering, Biomedical Unit, Universita di Napoli, Federic II, Italy, Via Claudio 21, 80125 Napoli (Italy); Di Salle, F [Department of Biomorphological and Functional Sciences, Radiologucal Unit, Universita di Napoli, Federic II, Italy, Via Claudio 21, 80125 Napoli (Italy); Lanfermann, H; Zanella, F E [Department of Neuroradiology, J.W. Goethe Universitat, Frankfurt/M. (Germany)

    1999-12-31

    In the last few years, functional Magnetic Resonance Imaging (fMRI) has been widely accepted as an effective tool for mapping brain activities in both the sensorimotor and the cognitive field. The present work aims to assess the possibility of using fMRI methods to study the cortical response to different acoustic stimuli. Furthermore, we refer to recent data collected at Frankfurt University on the cortical pattern of auditory hallucinations. Healthy subjects showed broad bilateral activation, mostly located in the transverse gyrus of Heschl. The analysis of the cortical activation induced by different stimuli has pointed out a remarkable difference in the spatial and temporal features of the auditory cortex response to pulsed tones and pure tones. The activated areas during episodes of auditory hallucinations match the location of primary auditory cortex as defined in control measurements with the same patients and in the experiments on healthy subjects. (authors) 17 refs., 4 figs.

  20. Revealing the Supramolecular Nature of Side-Chain Terpyridine-Functionalized Polymer Networks

    Directory of Open Access Journals (Sweden)

    Jérémy Brassinne

    2015-01-01

    Full Text Available Nowadays, finely controlling the mechanical properties of polymeric materials is possible by incorporating supramolecular motifs into their architecture. In this context, the synthesis of a side-chain terpyridine-functionalized poly(2-(dimethylaminoethyl methacrylate is reported via reversible addition-fragmentation chain transfer polymerization. By addition of transition metal ions, concentrated aqueous solutions of this polymer turn into metallo-supramolecular hydrogels whose dynamic mechanical properties are investigated by rotational rheometry. Hence, the possibility for the material to relax mechanical constrains via dissociation of transient cross-links is brought into light. In addition, the complex phenomena occurring under large oscillatory shear are interpreted in the context of transient networks.

  1. Functional MRI reveals expert-novice differences during sport-related anticipation.

    Science.gov (United States)

    Wright, Michael J; Bishop, Daniel T; Jackson, Robin C; Abernethy, Bruce

    2010-01-27

    We examined the effect of expertise on cortical activation during sports anticipation using functional MRI. In experiment 1, recreational players predicted badminton stroke direction and the pattern of active clusters was consistent with a proposed perception-of-action network. This pattern was not replicated in a stimulus-matched, action-unrelated control task. In experiment 2, players of three different skill levels anticipated stroke direction from clips occluded either 160 ms before or 80 ms after racquet-shuttle contact. Early-occluded sequences produced more activation than late-occluded sequences overall, in most cortical regions of interest, but experts showed an additional enhancement in medial, dorsolateral and ventrolateral frontal cortex. Anticipation in open-skill sports engages cortical areas integral to observing and understanding others' actions; such activity is enhanced in experts.

  2. Different patterns of auditory cortex activation revealed by functional magnetic resonance imaging

    International Nuclear Information System (INIS)

    Formisano, E.; Pepino, A.; Bracale, M.; Di Salle, F.; Lanfermann, H.; Zanella, F.E.

    1998-01-01

    In the last few years, functional Magnetic Resonance Imaging (fMRI) has been widely accepted as an effective tool for mapping brain activities in both the sensorimotor and the cognitive field. The present work aims to assess the possibility of using fMRI methods to study the cortical response to different acoustic stimuli. Furthermore, we refer to recent data collected at Frankfurt University on the cortical pattern of auditory hallucinations. Healthy subjects showed broad bilateral activation, mostly located in the transverse gyrus of Heschl. The analysis of the cortical activation induced by different stimuli has pointed out a remarkable difference in the spatial and temporal features of the auditory cortex response to pulsed tones and pure tones. The activated areas during episodes of auditory hallucinations match the location of primary auditory cortex as defined in control measurements with the same patients and in the experiments on healthy subjects. (authors)

  3. Nanobodies targeting norovirus capsid reveal functional epitopes and potential mechanisms of neutralization.

    Directory of Open Access Journals (Sweden)

    Anna D Koromyslova

    2017-11-01

    Full Text Available Norovirus is the leading cause of gastroenteritis worldwide. Despite recent developments in norovirus propagation in cell culture, these viruses are still challenging to grow routinely. Moreover, little is known on how norovirus infects the host cells, except that histo-blood group antigens (HBGAs are important binding factors for infection and cell entry. Antibodies that bind at the HBGA pocket and block attachment to HBGAs are believed to neutralize the virus. However, additional neutralization epitopes elsewhere on the capsid likely exist and impeding the intrinsic structural dynamics of the capsid could be equally important. In the current study, we investigated a panel of Nanobodies in order to probe functional epitopes that could trigger capsid rearrangement and/ or interfere with HBGA binding interactions. The precise binding sites of six Nanobodies (Nano-4, Nano-14, Nano-26, Nano-27, Nano-32, and Nano-42 were identified using X-ray crystallography. We showed that these Nanobodies bound on the top, side, and bottom of the norovirus protruding domain. The impact of Nanobody binding on norovirus capsid morphology was analyzed using electron microscopy and dynamic light scattering. We discovered that distinct Nanobody epitopes were associated with varied changes in particle structural integrity and assembly. Interestingly, certain Nanobody-induced capsid morphological changes lead to the capsid protein degradation and viral RNA exposure. Moreover, Nanobodies employed multiple inhibition mechanisms to prevent norovirus attachment to HBGAs, which included steric obstruction (Nano-14, allosteric interference (Nano-32, and violation of normal capsid morphology (Nano-26 and Nano-85. Finally, we showed that two Nanobodies (Nano-26 and Nano-85 not only compromised capsid integrity and inhibited VLPs attachment to HBGAs, but also recognized a broad panel of norovirus genotypes with high affinities. Consequently, Nano-26 and Nano-85 have a great

  4. Nanobodies targeting norovirus capsid reveal functional epitopes and potential mechanisms of neutralization

    Science.gov (United States)

    2017-01-01

    Norovirus is the leading cause of gastroenteritis worldwide. Despite recent developments in norovirus propagation in cell culture, these viruses are still challenging to grow routinely. Moreover, little is known on how norovirus infects the host cells, except that histo-blood group antigens (HBGAs) are important binding factors for infection and cell entry. Antibodies that bind at the HBGA pocket and block attachment to HBGAs are believed to neutralize the virus. However, additional neutralization epitopes elsewhere on the capsid likely exist and impeding the intrinsic structural dynamics of the capsid could be equally important. In the current study, we investigated a panel of Nanobodies in order to probe functional epitopes that could trigger capsid rearrangement and/ or interfere with HBGA binding interactions. The precise binding sites of six Nanobodies (Nano-4, Nano-14, Nano-26, Nano-27, Nano-32, and Nano-42) were identified using X-ray crystallography. We showed that these Nanobodies bound on the top, side, and bottom of the norovirus protruding domain. The impact of Nanobody binding on norovirus capsid morphology was analyzed using electron microscopy and dynamic light scattering. We discovered that distinct Nanobody epitopes were associated with varied changes in particle structural integrity and assembly. Interestingly, certain Nanobody-induced capsid morphological changes lead to the capsid protein degradation and viral RNA exposure. Moreover, Nanobodies employed multiple inhibition mechanisms to prevent norovirus attachment to HBGAs, which included steric obstruction (Nano-14), allosteric interference (Nano-32), and violation of normal capsid morphology (Nano-26 and Nano-85). Finally, we showed that two Nanobodies (Nano-26 and Nano-85) not only compromised capsid integrity and inhibited VLPs attachment to HBGAs, but also recognized a broad panel of norovirus genotypes with high affinities. Consequently, Nano-26 and Nano-85 have a great potential to

  5. Combined structural and functional imaging reveals cortical deactivations in grapheme-colour synaesthesia

    Directory of Open Access Journals (Sweden)

    Erik eO'Hanlon

    2013-10-01

    Full Text Available Synaesthesia is a heritable condition in which particular stimuli generate specific and consistent sensory percepts or associations in another modality or processing stream. Functional neuroimaging studies have identified potential correlates of these experiences, including, in some but not all cases, the hyperactivation of visuotemporal areas and of parietal areas thought to be involved in perceptual binding. Structural studies have identified a similarly variable spectrum of differences between synaesthetes and controls. However, it remains unclear the extent to which these neural correlates reflect the synaesthetic experience itself or additional phenotypes associated with the condition. Here, we acquired both structural and functional neuroimaging data comparing thirteen grapheme-colour synaesthetes with eleven non-synaesthetes. Using voxel-based morphometry and diffusion tensor imaging, we identify a number of clusters of increased volume of grey matter, of white matter or of increased fractional anisotropy in synaesthetes versus controls. To assess the possible involvement of these areas in the synaesthetic experience, we used nine areas of increased grey matter volume as regions of interest in an fMRI experiment that characterised the contrast in response to stimuli which induced synaesthesia (i.e. letters versus those which did not (non-meaningful symbols. Two of these areas, in left lateral occipital cortex and in postcentral gyrus, showed sensitivity to this contrast in synaesthetes but not controls. Unexpectedly, in both regions, the letter stimuli produced a strong negative BOLD signal in synaesthetes. An additional whole-brain fMRI analysis identified fourteen areas, three of which were driven mainly by a negative BOLD response to letters in synaesthetes. Our findings suggest that cortical deactivations may be involved in the conscious experience of internally generated synaesthetic percepts

  6. Metatranscriptomes reveal functional variation in diatom communities from the Antarctic Peninsula

    KAUST Repository

    Pearson, Gareth A

    2015-04-14

    Functional genomics of diatom-dominated communities fromthe Antarctic Peninsula was studied using comparative metatranscriptomics. Samples obtained from diatom-rich communities in the Bransfield Strait, the western Weddell Sea and sea ice in the Bellingshausen Sea/Wilkins Ice Shelf yielded more than 500K pyrosequencing reads that were combined to produce a global metatranscriptome assembly. Multi-gene phylogenies recovered three distinct communities, and diatom-assigned contigs further indicated little read-sharing between communities, validating an assembly-based annotation and analysis approach. Although functional analysis recovered a core of abundant shared annotations that were expressed across the three diatom communities, over 40% of annotations (but accounting for <10% of sequences) were community-specific. The two pelagic communities differed in their expression of N-metabolism and acquisition genes, which was almost absent in post-bloom conditions in the Weddell Sea community, while enrichment of transporters for ammonia and urea in Bransfield Strait diatoms suggests a physiological stance towards acquisition of reduced N-sources. The depletion of carbohydrate and energy metabolism pathways in sea ice relative to pelagic communities, together with increased light energy dissipation (via LHCSR proteins), photorespiration, and NO3 - uptake and utilization all pointed to irradiance stress and/or inorganic carbon limitation within sea ice. Ice-binding proteins and cold-shock transcription factors were also enriched in sea ice diatoms. Surprisingly, the abundance of gene transcripts for the translational machinery tracked decreasing environmental temperature across only a 4 °C range, possibly reflecting constraints on translational efficiency and protein production in cold environments. © 2015 International Society for Microbial Ecology All rights reserved.

  7. Expression analysis of Arabidopsis vacuolar sorting receptor 3 reveals a putative function in guard cells.

    Science.gov (United States)

    Avila, Emily L; Brown, Michelle; Pan, Songqin; Desikan, Radhika; Neill, Steven J; Girke, Thomas; Surpin, Marci; Raikhel, Natasha V

    2008-01-01

    Vacuolar sorting receptors (VSRs) are responsible for the proper targeting of soluble cargo proteins to their destination compartments. The Arabidopsis genome encodes seven VSRs. In this work, the spatio-temporal expression of one of the members of this gene family, AtVSR3, was determined by RT-PCR and promoter::reporter gene fusions. AtVSR3 was expressed specifically in guard cells. Consequently, a reverse genetics approach was taken to determine the function of AtVSR3 by using RNA interference (RNAi) technology. Plants expressing little or no AtVSR3 transcript had a compressed life cycle, bolting approximately 1 week earlier and senescing up to 2 weeks earlier than the wild-type parent line. While the development and distribution of stomata in AtVSR3 RNAi plants appeared normal, stomatal function was altered. The guard cells of mutant plants did not close in response to abscisic acid treatment, and the mean leaf temperatures of the RNAi plants were on average 0.8 degrees C lower than both wild type and another vacuolar sorting receptor mutant, atvsr1-1. Furthermore, the loss of AtVSR3 protein caused the accumulation of nitric oxide and hydrogen peroxide, signalling molecules implicated in the regulation of stomatal opening and closing. Finally, proteomics and western blot analyses of cellular proteins isolated from wild-type and AtVSR3 RNAi leaves showed that phospholipase Dgamma, which may play a role in abscisic acid signalling, accumulated to higher levels in AtVSR3 RNAi guard cells. Thus, AtVSR3 may play an important role in responses to plant stress.

  8. Lithosphere structure in Madagascar as revealed from receiver functions and surface waves analysis.

    Science.gov (United States)

    Rindraharisaona, E. J.; Tilmann, F. J.; Yuan, X.; Dreiling, J.; Priestley, K. F.; Barruol, G.; Wysession, M. E.

    2017-12-01

    The geological history of Madagascar makes it an ideal place to study the lithospheric structure and its evolution. It comprises Archean to Proterozoic units on the central eastern part, which is surrounded by a Triassic to Jurassic basin formation in the west and Cretaceous volcanics along the coasts. Quaternary volcanic rocks have been embedded in crystalline and sedimentary rocks. The aim of the present work is to characterize the crustal structure and determine the imprint of the dominant geodynamic events that have affected Madagascar: the Pan-African orogeny, the breakup of Gondwanaland and Neogene tectonic activity. From 2011 to 2014 different temporary seismic arrays were deployed in Madagascar. We based the current study mostly on SELASOMA project, which is composed of 50 seismic stations that were installed traversing southern Madagascar from the west to the east, sampling the different geological units. To measured seismic dispersion curves, one a wide period ranges using ambient noise, Rayleigh and Love surface waves. To compute the average crustal Vp/Vs ratio internal crustal structure and discontinuities in the mantle, we use both P- and S-waves receiver functions. To better resolve of the crustal structure, we jointly inverted P-wave receiver functions and Rayleigh wave group velocity.The crustal extension during the Carboniferous to Cenozoic has thinned the igneous crust down to 15 km in the western Morondava basin by removing much of the lower crust, while the thickness of the upper crust is nearly identical in the sedimentary basin and under Proterozoic and Archaean rocks of the eastern two thirds of Southern Madagascar. In general, the Archean crust is thicker than the Proterozoic, because mafic component is missing in the Proterozoic domain while it forms the bottom of the Archean crust. The lithosphere thickness in the southern part of Madagascar is estimated to be between 90 and 125 km.

  9. Simple analytical model reveals the functional role of embodied sensorimotor interaction in hexapod gaits

    Science.gov (United States)

    Aoi, Shinya; Nachstedt, Timo; Manoonpong, Poramate; Wörgötter, Florentin; Matsuno, Fumitoshi

    2018-01-01

    Insects have various gaits with specific characteristics and can change their gaits smoothly in accordance with their speed. These gaits emerge from the embodied sensorimotor interactions that occur between the insect’s neural control and body dynamic systems through sensory feedback. Sensory feedback plays a critical role in coordinated movements such as locomotion, particularly in stick insects. While many previously developed insect models can generate different insect gaits, the functional role of embodied sensorimotor interactions in the interlimb coordination of insects remains unclear because of their complexity. In this study, we propose a simple physical model that is amenable to mathematical analysis to explain the functional role of these interactions clearly. We focus on a foot contact sensory feedback called phase resetting, which regulates leg retraction timing based on touchdown information. First, we used a hexapod robot to determine whether the distributed decoupled oscillators used for legs with the sensory feedback generate insect-like gaits through embodied sensorimotor interactions. The robot generated two different gaits and one had similar characteristics to insect gaits. Next, we proposed the simple model as a minimal model that allowed us to analyze and explain the gait mechanism through the embodied sensorimotor interactions. The simple model consists of a rigid body with massless springs acting as legs, where the legs are controlled using oscillator phases with phase resetting, and the governed equations are reduced such that they can be explained using only the oscillator phases with some approximations. This simplicity leads to analytical solutions for the hexapod gaits via perturbation analysis, despite the complexity of the embodied sensorimotor interactions. This is the first study to provide an analytical model for insect gaits under these interaction conditions. Our results clarified how this specific foot contact sensory

  10. Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior.

    Science.gov (United States)

    Baldo, Brian A; Pratt, Wayne E; Will, Matthew J; Hanlon, Erin C; Bakshi, Vaishali P; Cador, Martine

    2013-11-01

    Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing

  11. Metatranscriptomes reveal functional variation in diatom communities from the Antarctic Peninsula

    KAUST Repository

    Pearson, Gareth A; Lago-Leston, Asuncion; Cá novas, Fernando; Cox, Cymon J; Verret, Frederic; Lasternas, Sebastian; Duarte, Carlos M.; Agusti, Susana; Serrã o, Ester A

    2015-01-01

    Functional genomics of diatom-dominated communities fromthe Antarctic Peninsula was studied using comparative metatranscriptomics. Samples obtained from diatom-rich communities in the Bransfield Strait, the western Weddell Sea and sea ice in the Bellingshausen Sea/Wilkins Ice Shelf yielded more than 500K pyrosequencing reads that were combined to produce a global metatranscriptome assembly. Multi-gene phylogenies recovered three distinct communities, and diatom-assigned contigs further indicated little read-sharing between communities, validating an assembly-based annotation and analysis approach. Although functional analysis recovered a core of abundant shared annotations that were expressed across the three diatom communities, over 40% of annotations (but accounting for <10% of sequences) were community-specific. The two pelagic communities differed in their expression of N-metabolism and acquisition genes, which was almost absent in post-bloom conditions in the Weddell Sea community, while enrichment of transporters for ammonia and urea in Bransfield Strait diatoms suggests a physiological stance towards acquisition of reduced N-sources. The depletion of carbohydrate and energy metabolism pathways in sea ice relative to pelagic communities, together with increased light energy dissipation (via LHCSR proteins), photorespiration, and NO3 - uptake and utilization all pointed to irradiance stress and/or inorganic carbon limitation within sea ice. Ice-binding proteins and cold-shock transcription factors were also enriched in sea ice diatoms. Surprisingly, the abundance of gene transcripts for the translational machinery tracked decreasing environmental temperature across only a 4 °C range, possibly reflecting constraints on translational efficiency and protein production in cold environments. © 2015 International Society for Microbial Ecology All rights reserved.

  12. Dissection of Ire1 functions reveals stress response mechanisms uniquely evolved in Candida glabrata.

    Directory of Open Access Journals (Sweden)

    Taiga Miyazaki

    2013-01-01

    Full Text Available Proper protein folding in the endoplasmic reticulum (ER is vital in all eukaryotes. When misfolded proteins accumulate in the ER lumen, the transmembrane kinase/endoribonuclease Ire1 initiates splicing of HAC1 mRNA to generate the bZIP transcription factor Hac1, which subsequently activates its target genes to increase the protein-folding capacity of the ER. This cellular machinery, called the unfolded protein response (UPR, is believed to be an evolutionarily conserved mechanism in eukaryotes. In this study, we comprehensively characterized mutant phenotypes of IRE1 and other related genes in the human fungal pathogen Candida glabrata. Unexpectedly, Ire1 was required for the ER stress response independently of Hac1 in this fungus. C. glabrata Ire1 did not cleave mRNAs encoding Hac1 and other bZIP transcription factors identified in the C. glabrata genome. Microarray analysis revealed that the transcriptional response to ER stress is not mediated by Ire1, but instead is dependent largely on calcineurin signaling and partially on the Slt2 MAPK pathway. The loss of Ire1 alone did not confer increased antifungal susceptibility in C. glabrata contrary to UPR-defective mutants in other fungi. Taken together, our results suggest that the canonical Ire1-Hac1 UPR is not conserved in C. glabrata. It is known in metazoans that active Ire1 nonspecifically cleaves and degrades a subset of ER-localized mRNAs to reduce the ER load. Intriguingly, this cellular response could occur in an Ire1 nuclease-dependent fashion in C. glabrata. We also uncovered the attenuated virulence of the C. glabrata Δire1 mutant in a mouse model of disseminated candidiasis. This study has unveiled the unique evolution of ER stress response mechanisms in C. glabrata.

  13. Genome-wide functional analysis of plasmodium protein phosphatases reveals key regulators of parasite development and differentiation

    KAUST Repository

    Guttery, David S.

    2014-07-09

    Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria. © 2014 The Authors.

  14. Genome-wide functional analysis of plasmodium protein phosphatases reveals key regulators of parasite development and differentiation

    KAUST Repository

    Guttery, David  S.; Poulin, Benoit; Ramaprasad, Abhinay; Wall, Richard  J.; Ferguson, David  J.P.; Brady, Declan; Patzewitz, Eva-Maria; Whipple, Sarah; Straschil, Ursula; Wright, Megan  H.; Mohamed, Alyaa  M.A.H.; Radhakrishnan, Anand; Arold, Stefan T.; Tate, Edward  W.; Holder, Anthony  A.; Wickstead, Bill; Pain, Arnab; Tewari, Rita

    2014-01-01

    Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria. © 2014 The Authors.

  15. Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

    Science.gov (United States)

    Voora, Deepak; Cyr, Derek; Lucas, Joseph; Chi, Jen-Tsan; Dungan, Jennifer; McCaffrey, Timothy A; Katz, Richard; Newby, L Kristin; Kraus, William E; Becker, Richard C; Ortel, Thomas L; Ginsburg, Geoffrey S

    2013-10-01

    The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin. Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events. Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization. A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B. RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI. Copyright © 2013 American College of Cardiology Foundation. Published by

  16. Moho Depth Variations in the Northeastern North China Craton Revealed by Receiver Function Imaging

    Science.gov (United States)

    Zhang, P.; Chen, L.; Yao, H.; Fang, L.

    2016-12-01

    The North China Craton (NCC), one of the oldest cratons in the world, has attracted wide attention in Earth Science for decades because of the unusual Mesozoic destruction of its cratonic lithosphere. Understanding the deep processes and mechanism of this craton destruction demands detailed knowledge about the deep structure of the region. In this study, we used two-year teleseismic receiver function data from the North China Seismic Array consisting of 200 broadband stations deployed in the northeastern NCC to image the Moho undulation of the region. A 2-D wave equation-based poststack depth migration method was employed to construct the structural images along 19 profiles, and a pseudo 3D crustal velocity model of the region based on previous ambient noise tomography and receiver function study was adopted in the migration. We considered both the Ps and PpPs phases, but in some cases we also conducted PpSs+PsPs migration using different back azimuth ranges of the data, and calculated the travel times of all the considered phases to constrain the Moho depths. By combining the structure images along the 19 profiles, we got a high-resolution Moho depth map beneath the northeastern NCC. Our results broadly consist with the results of previous active source studies [http://www.craton.cn/data], and show a good correlation of the Moho depths with geological and tectonic features. Generally, the Moho depths are distinctly different on the opposite sides of the North-South Gravity Lineament. The Moho in the west are deeper than 40 km and shows a rapid uplift from 40 km to 30 km beneath the Taihang Mountain Range in the middle. To the east in the Bohai Bay Basin, the Moho further shallows to 30-26 km depth and undulates by 3 km, coinciding well with the depressions and uplifts inside the basin. The Moho depth beneath the Yin-Yan Mountains in the north gradually decreases from 42 km in the west to 25 km in the east, varying much smoother than that to the south.

  17. Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain

    OpenAIRE

    Hill, Justine M.; Vaidyanathan, Hema; Ramos, Joe W.; Ginsberg, Mark H.; Werner, Milton H.

    2002-01-01

    PEA-15 is a multifunctional protein that modulates signaling pathways which control cell proliferation and cell death. In particular, PEA-15 regulates the actions of the ERK MAP kinase cascade by binding to ERK and altering its subcellular localization. The three-dimensional structure of PEA-15 has been determined using NMR spectroscopy and its interaction with ERK defined by characterization of mutants that modulate ERK function. PEA-15 is composed of an N-terminal death effector domain (DED...

  18. Electron microprobe analysis (WDS EPMA) of Zhamanshin glass reveals the impactor and a common role of accretion in the origin of splash-form impact glass

    International Nuclear Information System (INIS)

    Vetvicka, I; Frank, J; Drtina, J

    2010-01-01

    Impact glass samples collected during expeditions to the Zhamashin and Lonar craters were subjected to a morphology survey and compared to Wabar, Henbury and Darwin impact glasses to reveal that the accretion of fibres and spherules is not exclusive for irghizites but occurs in other splash form glasses over the world. WDS EPMA and LA-ICP-MS assays of Zhamanshin and Lonar glasses enabled the definition of akmurynites as Zhamanshin glass of specific morphology, chemistry and absence of extraterrestrial contamination. However, extraterrestrial contamination in irghizites was verified and further WDS EPMA analyses led to the conclusion that the Zhamanshin crater had been formed by the impact of a primitive achondrite of Lodran chemistry.

  19. The genomes of the fungal plant pathogens Cladosporium fulvum and Dothistroma septosporum reveal adaptation to different hosts and lifestyles but also signatures of common ancestry.

    Directory of Open Access Journals (Sweden)

    Pierre J G M de Wit

    Full Text Available We sequenced and compared the genomes of the Dothideomycete fungal plant pathogens Cladosporium fulvum (Cfu (syn. Passalora fulva and Dothistroma septosporum (Dse that are closely related phylogenetically, but have different lifestyles and hosts. Although both fungi grow extracellularly in close contact with host mesophyll cells, Cfu is a biotroph infecting tomato, while Dse is a hemibiotroph infecting pine. The genomes of these fungi have a similar set of genes (70% of gene content in both genomes are homologs, but differ significantly in size (Cfu >61.1-Mb; Dse 31.2-Mb, which is mainly due to the difference in repeat content (47.2% in Cfu versus 3.2% in Dse. Recent adaptation to different lifestyles and hosts is suggested by diverged sets of genes. Cfu contains an α-tomatinase gene that we predict might be required for detoxification of tomatine, while this gene is absent in Dse. Many genes encoding secreted proteins are unique to each species and the repeat-rich areas in Cfu are enriched for these species-specific genes. In contrast, conserved genes suggest common host ancestry. Homologs of Cfu effector genes, including Ecp2 and Avr4, are present in Dse and induce a Cf-Ecp2- and Cf-4-mediated hypersensitive response, respectively. Strikingly, genes involved in production of the toxin dothistromin, a likely virulence factor for Dse, are conserved in Cfu, but their expression differs markedly with essentially no expression by Cfu in planta. Likewise, Cfu has a carbohydrate-degrading enzyme catalog that is more similar to that of necrotrophs or hemibiotrophs and a larger pectinolytic gene arsenal than Dse, but many of these genes are not expressed in planta or are pseudogenized. Overall, comparison of their genomes suggests that these closely related plant pathogens had a common ancestral host but since adapted to different hosts and lifestyles by a combination of differentiated gene content, pseudogenization, and gene regulation.

  20. The Genomes of the Fungal Plant Pathogens Cladosporium fulvum and Dothistroma septosporum Reveal Adaptation to Different Hosts and Lifestyles But Also Signatures of Common Ancestry

    Energy Technology Data Exchange (ETDEWEB)

    de Wit, Pierre J. G. M.; van der Burgt, Ate; Okmen, Bilal; Stergiopoulos, Ioannis; Abd-Elsalam, Kamel A.; Aerts, Andrea L.; Bahkali, Ali H.; Beenen, Henriek G.; Chettri, Oranav; Cos, Murray P.; Datema, Erwin; de Vries, Ronald P.; DHillon, Braham; Ganley, Austen R.; Griffiths, Scott A.; Guo, Yanan; Gamelin, Richard C.; Henrissat, Bernard; Kabir, M. Shahjahan; Jashni, Mansoor Karimi; Kema, Gert; Klaubauf, Sylvia; Lapidus, Alla; Levasseur, Anthony; Lindquist, Erika; Mehrabi, Rahim; Ohm, Robin A.; Owen, Timothy J.; Salamov, Asaf; Schwelm, Arne; Schijlen, Elio; Sun, Hui; van den Burg, Harrold A.; van Burg, Roeland C. H. J.; Zhang, Shuguang; Goodwin, Stephen B.; Grigoriev, Igor V.; Collemare, Jerome; Bradshaw, Rosie E.

    2012-05-04

    We sequenced and compared the genomes of the Dothideomycete fungal plant pathogens Cladosporium fulvum (Cfu) (syn. Passalora fulva) and Dothistroma septosporum (Dse) that are closely related phylogenetically, but have different lifestyles and hosts. Although both fungi grow extracellularly in close contact with host mesophyll cells, Cfu is a biotroph infecting tomato, while Dse is a hemibiotroph infecting pine. The genomes of these fungi have a similar set of genes (70percent of gene content in both genomes are homologs), but differ significantly in size (Cfu >61.1-Mb; Dse 31.2-Mb), which is mainly due to the difference in repeat content (47.2percent in Cfu versus 3.2percent in Dse). Recent adaptation to different lifestyles and hosts is suggested by diverged sets of genes. Cfu contains an tomatinase gene that we predict might be required for detoxification of tomatine, while this gene is absent in Dse. Many genes encoding secreted proteins are unique to each species and the repeat-rich areas in Cfu are enriched for these species-specific genes. In contrast, conserved genes suggest common host ancestry. Homologs of Cfu effector genes, including Ecp2 and Avr4, are present in Dse and induce a Cf-Ecp2- and Cf-4-mediated hypersensitive response, respectively. Strikingly, genes involved in production of the toxin dothistromin, a likely virulence factor for Dse, are conserved in Cfu, but their expression differs markedly with essentially no expression by Cfu in planta. Likewise, Cfu has a carbohydrate-degrading enzyme catalog that is more similar to that of necrotrophs or hemibiotrophs and a larger pectinolytic gene arsenal than Dse, but many of these genes are not expressed in planta or are pseudogenized. Overall, comparison of their genomes suggests that these closely related plant pathogens had a common ancestral host but since adapted to different hosts and lifestyles by a combination of differentiated gene content, pseudogenization, and gene regulation.

  1. Temporal dynamics of hot desert microbial communities reveal structural and functional responses to water input.

    Science.gov (United States)

    Armstrong, Alacia; Valverde, Angel; Ramond, Jean-Baptiste; Makhalanyane, Thulani P; Jansson, Janet K; Hopkins, David W; Aspray, Thomas J; Seely, Mary; Trindade, Marla I; Cowan, Don A

    2016-09-29

    The temporal dynamics of desert soil microbial communities are poorly understood. Given the implications for ecosystem functioning under a global change scenario, a better understanding of desert microbial community stability is crucial. Here, we sampled soils in the central Namib Desert on sixteen different occasions over a one-year period. Using Illumina-based amplicon sequencing of the 16S rRNA gene, we found that α-diversity (richness) was more variable at a given sampling date (spatial variability) than over the course of one year (temporal variability). Community composition remained essentially unchanged across the first 10 months, indicating that spatial sampling might be more important than temporal sampling when assessing β-diversity patterns in desert soils. However, a major shift in microbial community composition was found following a single precipitation event. This shift in composition was associated with a rapid increase in CO 2 respiration and productivity, supporting the view that desert soil microbial communities respond rapidly to re-wetting and that this response may be the result of both taxon-specific selection and changes in the availability or accessibility of organic substrates. Recovery to quasi pre-disturbance community composition was achieved within one month after rainfall.

  2. Functional Insights Revealed by the Kinetic Mechanism of CRISPR/Cas9.

    Science.gov (United States)

    Raper, Austin T; Stephenson, Anthony A; Suo, Zucai

    2018-02-28

    The discovery of prokaryotic adaptive immunity prompted widespread use of the RNA-guided clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) endonuclease Cas9 for genetic engineering. However, its kinetic mechanism remains undefined, and details of DNA cleavage are poorly characterized. Here, we establish a kinetic mechanism of Streptococcus pyogenes Cas9 from guide-RNA binding through DNA cleavage and product release. Association of DNA to the binary complex of Cas9 and guide-RNA is rate-limiting during the first catalytic turnover, while DNA cleavage from a pre-formed ternary complex of Cas9, guide-RNA, and DNA is rapid. Moreover, an extremely slow release of DNA products essentially restricts Cas9 to be a single-turnover enzyme. By simultaneously measuring the contributions of the HNH and RuvC nuclease activities of Cas9 to DNA cleavage, we also uncovered the kinetic basis by which HNH conformationally regulates the RuvC cleavage activity. Together, our results provide crucial kinetic and functional details regarding Cas9 which will inform gene-editing experiments, guide future research to understand off-target DNA cleavage by Cas9, and aid in the continued development of Cas9 as a biotechnological tool.

  3. Situating and teaching 21st century zoology: revealing pattern in the form and function of animals.

    Science.gov (United States)

    Russell, Anthony P

    2009-09-01

    The current challenges (increasing levels of integration in the biological sciences) facing the teaching of zoology and the structure of the zoology curriculum are explored herein. General context is provided and a more focused scrutiny of the situation in North America is presented. The changing emphases in more broadly-based biological sciences programs in North America are outlined, and their influence on the role of zoology as part of fundamental biological training is considered. The longer term impact of such changes in emphasis on the teaching of zoology is discussed, and the central role that zoology can play in dealing with both science content and science education is advanced. Based upon a focal workshop on the future of the zoology curriculum in Canada, a perspective on the challenges facing curriculum evolution is provided. Extensive curriculum redesign is called for to ensure that zoology provides a broad-scale integrative approach to the understanding of biodiversity in evolutionary, ecological and functional contexts. Barriers to, and drivers of change are identified and the need for collaborative approaches to curricular evolution is emphasized. © 2009 ISZS, Blackwell Publishing and IOZ/CAS.

  4. Bite of the cats: relationships between functional integration and mechanical performance as revealed by mandible geometry.

    Science.gov (United States)

    Piras, Paolo; Maiorino, Leonardo; Teresi, Luciano; Meloro, Carlo; Lucci, Federico; Kotsakis, Tassos; Raia, Pasquale

    2013-11-01

    Cat-like carnivorous mammals represent a relatively homogeneous group of species whose morphology appears constrained by exclusive adaptations for meat eating. We present the most comprehensive data set of extant and extinct cat-like species to test for evolutionary transformations in size, shape and mechanical performance, that is, von Mises stress and surface traction, of the mandible. Size and shape were both quantified by means of geometric morphometrics, whereas mechanical performance was assessed applying finite element models to 2D geometry of the mandible. Additionally, we present the first almost complete composite phylogeny of cat-like carnivorans for which well-preserved mandibles are known, including representatives of 35 extant and 59 extinct species of Felidae, Nimravidae, and Barbourofelidae. This phylogeny was used to test morphological differentiation, allometry, and covariation of mandible parts within and among clades. After taking phylogeny into account, we found that both allometry and mechanical variables exhibit a significant impact on mandible shape. We also tested whether mechanical performance was linked to morphological integration. Mechanical stress at the coronoid process is higher in sabertoothed cats than in any other clade. This is strongly related to the high degree of covariation within modules of sabertooths mandibles. We found significant correlation between integration at the clade level and per-clade averaged stress values, on both original data and by partialling out interclade allometry from shapes when calculating integration. This suggests a strong interaction between natural selection and the evolution of developmental and functional modules at the clade level.

  5. Tracking of plus-ends reveals microtubule functional diversity in different cell types

    Science.gov (United States)

    Shaebani, M. Reza; Pasula, Aravind; Ott, Albrecht; Santen, Ludger

    2016-07-01

    Many cellular processes are tightly connected to the dynamics of microtubules (MTs). While in neuronal axons MTs mainly regulate intracellular trafficking, they participate in cytoskeleton reorganization in many other eukaryotic cells, enabling the cell to efficiently adapt to changes in the environment. We show that the functional differences of MTs in different cell types and regions is reflected in the dynamic properties of MT tips. Using plus-end tracking proteins EB1 to monitor growing MT plus-ends, we show that MT dynamics and life cycle in axons of human neurons significantly differ from that of fibroblast cells. The density of plus-ends, as well as the rescue and catastrophe frequencies increase while the growth rate decreases toward the fibroblast cell margin. This results in a rather stable filamentous network structure and maintains the connection between nucleus and membrane. In contrast, plus-ends are uniformly distributed along the axons and exhibit diverse polymerization run times and spatially homogeneous rescue and catastrophe frequencies, leading to MT segments of various lengths. The probability distributions of the excursion length of polymerization and the MT length both follow nearly exponential tails, in agreement with the analytical predictions of a two-state model of MT dynamics.

  6. Temporal dynamics of hot desert microbial communities reveal structural and functional responses to water input

    Energy Technology Data Exchange (ETDEWEB)

    Armstrong, Alacia; Valverde, Angel; Ramond, Jean-Baptiste; Makhalanyane, Thulani P.; Jansson, Janet K.; Hopkins, David W.; Aspray, Thomas J.; Seely, Mary; Trindade, Marla I.; Cowan, Don A.

    2016-09-29

    The temporal dynamics of desert soil microbial communities are poorly understood. Given the implications for ecosystem functioning under a global change scenario, a better understanding of desert microbial community stability is crucial. Here, we sampled soils in the central Namib Desert on sixteen different occasions over a one-year period. Using Illumina-based amplicon sequencing of the 16S rRNA gene, we found that α-diversity (richness) was more variable at a given sampling date (spatial variability) than over the course of one year (temporal variability). Community composition remained essentially unchanged across the first 10 months, indicating that spatial sampling might be more important than temporal sampling when assessing β-diversity patterns in desert soils. However, a major shift in microbial community composition was found following a single precipitation event. This shift in composition was associated with a rapid increase in CO2 respiration and productivity, supporting the view that desert soil microbial communities respond rapidly to re-wetting and that this response may be the result of both taxon-specific selection and changes in the availability or accessibility of organic substrates. Recovery to quasi pre-disturbance community composition was achieved within one month after rainfall.

  7. Revealing turning points in ecosystem functioning over the Northern Eurasian agricultural frontier.

    Science.gov (United States)

    Horion, Stéphanie; Prishchepov, Alexander V; Verbesselt, Jan; de Beurs, Kirsten; Tagesson, Torbern; Fensholt, Rasmus

    2016-08-01

    The collapse of the Soviet Union in 1991 has been a turning point in the World history that left a unique footprint on the Northern Eurasian ecosystems. Conducting large scale mapping of environmental change and separating between naturogenic and anthropogenic drivers is a difficult endeavor in such highly complex systems. In this research a piece-wise linear regression method was used for breakpoint detection in Rain-Use Efficiency (RUE) time series and a classification of ecosystem response types was produced. Supported by earth observation data, field data, and expert knowledge, this study provides empirical evidence regarding the occurrence of drastic changes in RUE (assessment of the timing, the direction and the significance of these changes) in Northern Eurasian ecosystems between 1982 and 2011. About 36% of the study area (3.4 million km(2) ) showed significant (P agricultural land abandonment. Our study also showed that recurrent droughts deeply affected vegetation productivity throughout the observation period, with a general worsening of the drought conditions in recent years. Moreover, recent human-induced turning points in ecosystem functioning were detected and attributed to ongoing recultivation and change in irrigation practices in the Volgograd region, and to increased salinization and increased grazing intensity around Lake Balkhash. The ecosystem-state assessment method introduced here proved to be a valuable support that highlighted hotspots of potentially altered ecosystems and allowed for disentangling human from climatic disturbances. © 2016 John Wiley & Sons Ltd.

  8. Magnetic resonance imaging reveals functional anatomy and biomechanics of a living dragon tree

    Science.gov (United States)

    Hesse, Linnea; Masselter, Tom; Leupold, Jochen; Spengler, Nils; Speck, Thomas; Korvink, Jan Gerrit

    2016-01-01

    Magnetic resonance imaging (MRI) was used to gain in vivo insight into load-induced displacements of inner plant tissues making a non-invasive and non-destructive stress and strain analysis possible. The central aim of this study was the identification of a possible load-adapted orientation of the vascular bundles and their fibre caps as the mechanically relevant tissue in branch-stem-attachments of Dracaena marginata. The complex three-dimensional deformations that occur during mechanical loading can be analysed on the basis of quasi-three-dimensional data representations of the outer surface, the inner tissue arrangement (meristem and vascular system), and the course of single vascular bundles within the branch-stem-attachment region. In addition, deformations of vascular bundles could be quantified manually and by using digital image correlation software. This combination of qualitative and quantitative stress and strain analysis leads to an improved understanding of the functional morphology and biomechanics of D. marginata, a plant that is used as a model organism for optimizing branched technical fibre-reinforced lightweight trusses in order to increase their load bearing capacity. PMID:27604526

  9. Revealing Soil Structure and Functional Macroporosity along a Clay Gradient Using X-ray Computed Tomography

    DEFF Research Database (Denmark)

    Naveed, Muhammad; Møldrup, Per; Arthur, Emmanuel

    2013-01-01

    clay content, respectively) at a field site in Lerbjerg, Denmark. The water-holding capacity of soils markedly increased with increasing soil clay content, while significantly higher air permeability was observed for the L1 to L3 soils than for the L4 to L6 soils. Higher air permeability values......The influence of clay content in soil-pore structure development and the relative importance of macroporosity in governing convective fluid flow are two key challenges toward better understanding and quantifying soil ecosystem functions. In this study, soil physical measurements (soil-water...... retention and air permeability) and x-ray computed tomography (CT) scanning were combined and used from two scales on intact soil columns (100 and 580 cm3). The columns were sampled along a natural clay gradient at six locations (L1, L2, L3, L4, L5 and L6 with 0.11, 0.16, 0.21, 0.32, 0.38 and 0.46 kg kg−1...

  10. Network-based analysis reveals functional connectivity related to internet addiction tendency

    Directory of Open Access Journals (Sweden)

    Tanya eWen

    2016-02-01

    Full Text Available IntroductionPreoccupation and compulsive use of the internet can have negative psychological effects, such that it is increasingly being recognized as a mental disorder. The present study employed network-based statistics to explore how whole-brain functional connections at rest is related to the extent of individual’s level of internet addiction, indexed by a self-rated questionnaire. We identified two topologically significant networks, one with connections that are positively correlated with internet addiction tendency, and one with connections negatively correlated with internet addiction tendency. The two networks are interconnected mostly at frontal regions, which might reflect alterations in the frontal region for different aspects of cognitive control (i.e., for control of internet usage and gaming skills. Next, we categorized the brain into several large regional subgroupings, and found that the majority of proportions of connections in the two networks correspond to the cerebellar model of addiction which encompasses the four-circuit model. Lastly, we observed that the brain regions with the most inter-regional connections associated with internet addiction tendency replicate those often seen in addiction literature, and is corroborated by our meta-analysis of internet addiction studies. This research provides a better understanding of large-scale networks involved in internet addiction tendency and shows that pre-clinical levels of internet addiction are associated with similar regions and connections as clinical cases of addiction.

  11. Chemical Transport Knockout for Oxidized Vitamin C, Dehydroascorbic Acid, Reveals Its Functions in vivo

    Directory of Open Access Journals (Sweden)

    Hongbin Tu

    2017-09-01

    Full Text Available Despite its transport by glucose transporters (GLUTs in vitro, it is unknown whether dehydroascorbic acid (oxidized vitamin C, DHA has any in vivo function. To investigate, we created a chemical transport knockout model using the vitamin C analog 6-bromo-ascorbate. This analog is transported on sodium-dependent vitamin C transporters but its oxidized form, 6-bromo-dehydroascorbic acid, is not transported by GLUTs. Mice (gulo−/− unable to synthesize ascorbate (vitamin C were raised on 6-bromo-ascorbate. Despite normal survival, centrifugation of blood produced hemolysis secondary to near absence of red blood cell (RBC ascorbate/6-bromo-ascorbate. Key findings with clinical implications were that RBCs in vitro transported dehydroascorbic acid but not bromo-dehydroascorbic acid; RBC ascorbate in vivo was obtained only via DHA transport; ascorbate via DHA transport in vivo was necessary for RBC structural integrity; and internal RBC ascorbate was essential to maintain ascorbate plasma concentrations in vitro/in vivo.

  12. Acquisition of omptin reveals cryptic virulence function of autotransporter YapE in Yersinia pestis

    Science.gov (United States)

    Pennington, Jarrod; Miller, Virginia L.

    2013-01-01

    SUMMARY Autotransporters, the largest family of secreted proteins in Gram negative bacteria, perform a variety of functions, including adherence, cytotoxicity, and immune evasion. In Yersinia pestis the autotransporter YapE has adhesive properties and contributes to bubonic infection of the mouse model. Here, we demonstrate that omptin cleavage of Y. pestis YapE is required to mediate bacterial aggregation and adherence to eukaryotic cells. We demonstrate that omptin cleavage is specific for the Y. pestis and Y. pseudotuberculosis YapE orthologs but is not conserved in the Y. enterocolitica protein. We also show that cleavage of YapE occurs in Y. pestis but not in the enteric Yersinia species, and requires the omptin Pla (plasminogen activator protease), which is encoded on the Y. pestis-specific plasmid pPCP1. Together, these data show that post-translation modification of YapE appears to be specific to Y. pestis, was acquired along with the acquisition of pPCP1 during the divergence of Y. pestis from Y. pseudotuberculosis, and are the first evidence of a novel mechanism to regulate bacterial adherence. PMID:23701256

  13. Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.

    Science.gov (United States)

    Zhyvoloup, Alexander; Melamed, Anat; Anderson, Ian; Planas, Delphine; Lee, Chen-Hsuin; Kriston-Vizi, Janos; Ketteler, Robin; Merritt, Andy; Routy, Jean-Pierre; Ancuta, Petronela; Bangham, Charles R M; Fassati, Ariberto

    2017-07-01

    HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

  14. Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.

    Directory of Open Access Journals (Sweden)

    Alexander Zhyvoloup

    2017-07-01

    Full Text Available HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

  15. Language processing of auditory cortex revealed by functional magnetic resonance imaging in presbycusis patients.

    Science.gov (United States)

    Chen, Xianming; Wang, Maoxin; Deng, Yihong; Liang, Yonghui; Li, Jianzhong; Chen, Shiyan

    2016-01-01

    Contralateral temporal lobe activation decreases with aging, regardless of hearing status, with elderly individuals showing reduced right ear advantage. Aging and hearing loss possibly lead to presbycusis speech discrimination decline. To evaluate presbycusis patients' auditory cortex activation under verbal stimulation. Thirty-six patients were enrolled: 10 presbycusis patients (mean age = 64 years, range = 60-70), 10 in the healthy aged group (mean age = 66 years, range = 60-70), and 16 young healthy volunteers (mean age = 25 years, range = 23-28). These three groups underwent simultaneous 1 kHz and 90 dB single-syllable word stimuli and (blood-oxygen-level-dependent functional magnetic resonance imaging) BOLD fMRI examinations. The main activation regions were superior temporal and middle temporal gyrus. For all aged subjects, the right region of interest (ROI) activation volume was decreased compared with the young group. With left ear stimulation, bilateral ROI activation intensity held. With right ear stimulation, the aged group's activation intensity was higher. Using monaural stimulation in the young group, contralateral temporal lobe activation volume and intensity were higher vs ipsilateral, while they were lower in the aged and presbycusis groups. On left and right ear auditory tasks, the young group showed right ear advantage, while the aged and presbycusis groups showed reduced right ear advantage.

  16. Pam heterozygous mice reveal essential role for Cu in amygdalar behavioral and synaptic function.

    Science.gov (United States)

    Gaier, Eric D; Eipper, Betty A; Mains, Richard E

    2014-05-01

    Copper (Cu) is an essential element with many biological roles, but its roles in the mammalian nervous system are poorly understood. Mice deficient in the cuproenzyme peptidylglycine α-amidating monooxygenase (Pam(+/-) mice) were initially generated to study neuropeptide amidation. Pam(+/-) mice exhibit profound deficits in a few behavioral tasks, including enhancements in innate fear along with deficits in acquired fear. Interestingly, several Pam(+/-) phenotypes were recapitulated in Cu-restricted wild-type mice and rescued in Cu-supplemented Pam(+/-) mice. These behaviors correspond to enhanced excitability and deficient synaptic plasticity in the amygdala of Pam(+/-) mice, which are also rescued by Cu supplementation. Cu and ATP7A are present at synapses, in key positions to respond to and influence synaptic activity. Further study demonstrated that extracellular Cu is necessary for wild-type synaptic plasticity and sufficient to induce long-term potentiation. These experiments support roles for PAM in Cu homeostasis and for synaptic Cu in amygdalar function. © 2014 New York Academy of Sciences.

  17. Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures.

    Science.gov (United States)

    Bohlen, Christopher J; Bennett, F Chris; Tucker, Andrew F; Collins, Hannah Y; Mulinyawe, Sara B; Barres, Ben A

    2017-05-17

    Microglia, the resident macrophages of the CNS, engage in various CNS-specific functions that are critical for development and health. To better study microglia and the properties that distinguish them from other tissue macrophage populations, we have optimized serum-free culture conditions to permit robust survival of highly ramified adult microglia under defined-medium conditions. We find that astrocyte-derived factors prevent microglial death ex vivo and that this activity results from three primary components, CSF-1/IL-34, TGF-β2, and cholesterol. Using microglial cultures that have never been exposed to serum, we demonstrate a dramatic and lasting change in phagocytic capacity after serum exposure. Finally, we find that mature microglia rapidly lose signature gene expression after isolation, and that this loss can be reversed by engrafting cells back into an intact CNS environment. These data indicate that the specialized gene expression profile of mature microglia requires continuous instructive signaling from the intact CNS. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Function of the ATR N-terminal domain revealed by an ATM/ATR chimera

    International Nuclear Information System (INIS)

    Chen Xinping; Zhao Runxiang; Glick, Gloria G.; Cortez, David

    2007-01-01

    The ATM and ATR kinases function at the apex of checkpoint signaling pathways. These kinases share significant sequence similarity, phosphorylate many of the same substrates, and have overlapping roles in initiating cell cycle checkpoints. However, they sense DNA damage through distinct mechanisms. ATR primarily senses single stranded DNA (ssDNA) through its interaction with ATRIP, and ATM senses double strand breaks through its interaction with Nbs1. We determined that the N-terminus of ATR contains a domain that binds ATRIP. Attaching this domain to ATM allowed the fusion protein (ATM*) to bind ATRIP and associate with RPA-coated ssDNA. ATM* also gained the ability to localize efficiently to stalled replication forks as well as double strand breaks. Despite having normal kinase activity when tested in vitro and being phosphorylated on S1981 in vivo, ATM* is defective in checkpoint signaling and does not complement cellular deficiencies in either ATM or ATR. These data indicate that the N-terminus of ATR is sufficient to bind ATRIP and to promote localization to sites of replication stress

  19. Whole-brain analytic measures of network communication reveal increased structure-function correlation in right temporal lobe epilepsy.

    Science.gov (United States)

    Wirsich, Jonathan; Perry, Alistair; Ridley, Ben; Proix, Timothée; Golos, Mathieu; Bénar, Christian; Ranjeva, Jean-Philippe; Bartolomei, Fabrice; Breakspear, Michael; Jirsa, Viktor; Guye, Maxime

    2016-01-01

    The in vivo structure-function relationship is key to understanding brain network reorganization due to pathologies. This relationship is likely to be particularly complex in brain network diseases such as temporal lobe epilepsy, in which disturbed large-scale systems are involved in both transient electrical events and long-lasting functional and structural impairments. Herein, we estimated this relationship by analyzing the correlation between structural connectivity and functional connectivity in terms of analytical network communication parameters. As such, we targeted the gradual topological structure-function reorganization caused by the pathology not only at the whole brain scale but also both in core and peripheral regions of the brain. We acquired diffusion (dMRI) and resting-state fMRI (rsfMRI) data in seven right-lateralized TLE (rTLE) patients and fourteen healthy controls and analyzed the structure-function relationship by using analytical network communication metrics derived from the structural connectome. In rTLE patients, we found a widespread hypercorrelated functional network. Network communication analysis revealed greater unspecific branching of the shortest path (search information) in the structural connectome and a higher global correlation between the structural and functional connectivity for the patient group. We also found evidence for a preserved structural rich-club in the patient group. In sum, global augmentation of structure-function correlation might be linked to a smaller functional repertoire in rTLE patients, while sparing the central core of the brain which may represent a pathway that facilitates the spread of seizures.

  20. Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease*

    Science.gov (United States)

    Dewhurst, Henry; Sundararaman, Niveda

    2016-01-01

    Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable

  1. Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease.

    Science.gov (United States)

    Torres, Matthew P; Dewhurst, Henry; Sundararaman, Niveda

    2016-11-01

    Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable

  2. Detailed Configuration of the Underthrusting Indian Lithosphere Beneath Western Tibet Revealed by Receiver Function Images

    Science.gov (United States)

    Xu, Qiang; Zhao, Junmeng; Yuan, Xiaohui; Liu, Hongbing; Pei, Shunping

    2017-10-01

    We analyze the teleseismic waveform data recorded by 42 temporary stations from the Y2 and ANTILOPE-1 arrays using the P and S receiver function techniques to investigate the lithospheric structure beneath western Tibet. The Moho is reliably identified as a prominent feature at depths of 55-82 km in the stacked traces and in depth migrated images. It has a concave shape and reaches the deepest location at about 80 km north of the Indus-Yarlung suture (IYS). An intracrustal discontinuity is observed at 55 km depth below the southern Lhasa terrane, which could represent the upper border of the eclogitized underthrusting Indian lower crust. Underthrusting of the Indian crust has been widely observed beneath the Lhasa terrane and correlates well with the Bouguer gravity low, suggesting that the gravity anomalies in the Lhasa terrane are induced by topography of the Moho. At 20 km depth, a midcrustal low-velocity zone (LVZ) is observed beneath the Tethyan Himalaya and southern Lhasa terrane, suggesting a layer of partial melts that decouples the thrust/fold deformation of the upper crust from the shortening and underthrusting in the lower crust. The Sp conversions at the lithosphere-asthenosphere boundary (LAB) can be recognized at depths of 130-200 km, showing that the Indian lithospheric mantle is underthrusting with a ramp-flat shape beneath southern Tibet and probably is detached from the lower crust immediately under the IYS. Our observations reconstruct the configuration of the underthrusting Indian lithosphere and indicate significant along strike variations.

  3. Functional and evolutionary characterization of Ohr proteins in eukaryotes reveals many active homologs among pathogenic fungi

    Directory of Open Access Journals (Sweden)

    D.A. Meireles

    2017-08-01

    Full Text Available Ohr and OsmC proteins comprise two subfamilies within a large group of proteins that display Cys-based, thiol dependent peroxidase activity. These proteins were previously thought to be restricted to prokaryotes, but we show here, using iterated sequence searches, that Ohr/OsmC homologs are also present in 217 species of eukaryotes with a massive presence in Fungi (186 species. Many of these eukaryotic Ohr proteins possess an N-terminal extension that is predicted to target them to mitochondria. We obtained recombinant proteins for four eukaryotic members of the Ohr/OsmC family and three of them displayed lipoyl peroxidase activity. Further functional and biochemical characterization of the Ohr homologs from the ascomycete fungus Mycosphaerella fijiensis Mf_1 (MfOhr, the causative agent of Black Sigatoka disease in banana plants, was pursued. Similarly to what has been observed for the bacterial proteins, we found that: (i the peroxidase activity of MfOhr was supported by DTT or dihydrolipoamide (dithiols, but not by β-mercaptoethanol or GSH (monothiols, even in large excess; (ii MfOhr displayed preference for organic hydroperoxides (CuOOH and tBOOH over hydrogen peroxide; (iii MfOhr presented extraordinary reactivity towards linoleic acid hydroperoxides (k=3.18 (±2.13×108 M−1 s−1. Both Cys87 and Cys154 were essential to the peroxidase activity, since single mutants for each Cys residue presented no activity and no formation of intramolecular disulfide bond upon treatment with hydroperoxides. The pKa value of the Cysp residue was determined as 5.7±0.1 by a monobromobimane alkylation method. Therefore, eukaryotic Ohr peroxidases share several biochemical features with prokaryotic orthologues and are preferentially located in mitochondria. Keywords: Ohr/OsmC, Thiol-dependent peroxidases, Phylogeny

  4. Functional and evolutionary characterization of Ohr proteins in eukaryotes reveals many active homologs among pathogenic fungi.

    Science.gov (United States)

    Meireles, D A; Domingos, R M; Gaiarsa, J W; Ragnoni, E G; Bannitz-Fernandes, R; da Silva Neto, J F; de Souza, R F; Netto, L E S

    2017-08-01

    Ohr and OsmC proteins comprise two subfamilies within a large group of proteins that display Cys-based, thiol dependent peroxidase activity. These proteins were previously thought to be restricted to prokaryotes, but we show here, using iterated sequence searches, that Ohr/OsmC homologs are also present in 217 species of eukaryotes with a massive presence in Fungi (186 species). Many of these eukaryotic Ohr proteins possess an N-terminal extension that is predicted to target them to mitochondria. We obtained recombinant proteins for four eukaryotic members of the Ohr/OsmC family and three of them displayed lipoyl peroxidase activity. Further functional and biochemical characterization of the Ohr homologs from the ascomycete fungus Mycosphaerella fijiensis Mf_1 (MfOhr), the causative agent of Black Sigatoka disease in banana plants, was pursued. Similarly to what has been observed for the bacterial proteins, we found that: (i) the peroxidase activity of MfOhr was supported by DTT or dihydrolipoamide (dithiols), but not by β-mercaptoethanol or GSH (monothiols), even in large excess; (ii) MfOhr displayed preference for organic hydroperoxides (CuOOH and tBOOH) over hydrogen peroxide; (iii) MfOhr presented extraordinary reactivity towards linoleic acid hydroperoxides (k=3.18 (±2.13)×10 8 M -1 s -1 ). Both Cys 87 and Cys 154 were essential to the peroxidase activity, since single mutants for each Cys residue presented no activity and no formation of intramolecular disulfide bond upon treatment with hydroperoxides. The pK a value of the Cys p residue was determined as 5.7±0.1 by a monobromobimane alkylation method. Therefore, eukaryotic Ohr peroxidases share several biochemical features with prokaryotic orthologues and are preferentially located in mitochondria. Copyright © 2017. Published by Elsevier B.V.

  5. Structure-function analysis of Staphylococcus aureus amidase reveals the determinants of peptidoglycan recognition and cleavage.

    Science.gov (United States)

    Büttner, Felix Michael; Zoll, Sebastian; Nega, Mulugeta; Götz, Friedrich; Stehle, Thilo

    2014-04-18

    The bifunctional major autolysin AtlA of Staphylococcus aureus cleaves the bacterium's peptidoglycan network (PGN) at two distinct sites during cell division. Deletion of the enzyme results in large cell clusters with disordered division patterns, indicating that AtlA could be a promising target for the development of new antibiotics. One of the two functions of AtlA is performed by the N-acetylmuramyl-l-alanine amidase AmiA, which cleaves the bond between the carbohydrate and the peptide moieties of PGN. To establish the structural requirements of PGN recognition and the enzymatic mechanism of cleavage, we solved the crystal structure of the catalytic domain of AmiA (AmiA-cat) in complex with a peptidoglycan-derived ligand at 1.55 Å resolution. The peptide stem is clearly visible in the structure, forming extensive contacts with protein residues by docking into an elongated groove. Less well defined electron density and the analysis of surface features indicate likely positions of the carbohydrate backbone and the pentaglycine bridge. Substrate specificity analysis supports the importance of the pentaglycine bridge for fitting into the binding cleft of AmiA-cat. PGN of S. aureus with l-lysine tethered with d-alanine via a pentaglycine bridge is completely hydrolyzed, whereas PGN of Bacillus subtilis with meso-diaminopimelic acid directly tethered with d-alanine is not hydrolyzed. An active site mutant, H370A, of AmiA-cat was completely inactive, providing further support for the proposed catalytic mechanism of AmiA. The structure reported here is not only the first of any bacterial amidase in which both the PGN component and the water molecule that carries out the nucleophilic attack on the carbonyl carbon of the scissile bond are present; it is also the first peptidoglycan amidase complex structure of an important human pathogen.

  6. Functional characterisation of an intron retaining K+ transporter of barley reveals intron-mediated alternate splicing

    KAUST Repository

    Shahzad, K.

    2015-01-01

    Intron retention in transcripts and the presence of 5 and 3 splice sites within these introns mediate alternate splicing, which is widely observed in animals and plants. Here, functional characterisation of the K+ transporter, HvHKT2;1, with stably retained introns from barley (Hordeum vulgare) in yeast (Saccharomyces cerevisiae), and transcript profiling in yeast and transgenic tobacco (Nicotiana tabacum) is presented. Expression of intron-retaining HvHKT2;1 cDNA (HvHKT2;1-i) in trk1, trk2 yeast strain defective in K+ uptake restored growth in medium containing hygromycin in the presence of different concentrations of K+ and mediated hypersensitivity to Na+. HvHKT2;1-i produces multiple transcripts via alternate splicing of two regular introns and three exons in different compositions. HKT isoforms with retained introns and exon skipping variants were detected in relative expression analysis of (i) HvHKT2;1-i in barley under native conditions, (ii) in transgenic tobacco plants constitutively expressing HvHKT2;1-i, and (iii) in trk1, trk2 yeast expressing HvHKT2;1-i under control of an inducible promoter. Mixed proportions of three HKT transcripts: HvHKT2;1-e (first exon region), HvHKT2;1-i1 (first intron) and HvHKT2;1-i2 (second intron) were observed. The variation in transcript accumulation in response to changing K+ and Na+ concentrations was observed in both heterologous and plant systems. These findings suggest a link between intron-retaining transcripts and different splice variants to ion homeostasis, and their possible role in salt stress.

  7. Computer animations of color markings reveal the function of visual threat signals in Neolamprologus pulcher.

    Science.gov (United States)

    Balzarini, Valentina; Taborsky, Michael; Villa, Fabienne; Frommen, Joachim G

    2017-02-01

    Visual signals, including changes in coloration and color patterns, are frequently used by animals to convey information. During contests, body coloration and its changes can be used to assess an opponent's state or motivation. Communication of aggressive propensity is particularly important in group-living animals with a stable dominance hierarchy, as the outcome of aggressive interactions determines the social rank of group members. Neolamprologus pulcher is a cooperatively breeding cichlid showing frequent within-group aggression. Both sexes exhibit two vertical black stripes on the operculum that vary naturally in shape and darkness. During frontal threat displays these patterns are actively exposed to the opponent, suggesting a signaling function. To investigate the role of operculum stripes during contests we manipulated their darkness in computer animated pictures of the fish. We recorded the responses in behavior and stripe darkness of test subjects to which these animated pictures were presented. Individuals with initially darker stripes were more aggressive against the animations and showed more operculum threat displays. Operculum stripes of test subjects became darker after exposure to an animation exhibiting a pale operculum than after exposure to a dark operculum animation, highlighting the role of the darkness of this color pattern in opponent assessment. We conclude that (i) the black stripes on the operculum of N. pulcher are a reliable signal of aggression and dominance, (ii) these markings play an important role in opponent assessment, and (iii) 2D computer animations are well suited to elicit biologically meaningful short-term aggressive responses in this widely used model system of social evolution.

  8. Transcriptomics of aged Drosophila motor neurons reveals a matrix metalloproteinase that impairs motor function.

    Science.gov (United States)

    Azpurua, Jorge; Mahoney, Rebekah E; Eaton, Benjamin A

    2018-04-01

    The neuromuscular junction (NMJ) is responsible for transforming nervous system signals into motor behavior and locomotion. In the fruit fly Drosophila melanogaster, an age-dependent decline in motor function occurs, analogous to the decline experienced in mice, humans, and other mammals. The molecular and cellular underpinnings of this decline are still poorly understood. By specifically profiling the transcriptome of Drosophila motor neurons across age using custom microarrays, we found that the expression of the matrix metalloproteinase 1 (dMMP1) gene reproducibly increased in motor neurons in an age-dependent manner. Modulation of physiological aging also altered the rate of dMMP1 expression, validating dMMP1 expression as a bona fide aging biomarker for motor neurons. Temporally controlled overexpression of dMMP1 specifically in motor neurons was sufficient to induce deficits in climbing behavior and cause a decrease in neurotransmitter release at neuromuscular synapses. These deficits were reversible if the dMMP1 expression was shut off again immediately after the onset of motor dysfunction. Additionally, repression of dMMP1 enzymatic activity via overexpression of a tissue inhibitor of metalloproteinases delayed the onset of age-dependent motor dysfunction. MMPs are required for proper tissue architecture during development. Our results support the idea that matrix metalloproteinase 1 is acting as a downstream effector of antagonistic pleiotropy in motor neurons and is necessary for proper development, but deleterious when reactivated at an advanced age. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. RNA interference reveals allatotropin functioning in larvae and adults of Spodoptera frugiperda (Lepidoptera, Noctuidae

    Directory of Open Access Journals (Sweden)

    I.T.E. Hassanien

    2014-05-01

    Full Text Available The allatotropin of S. frugiperda (Spofr-AT and its cDNA sequence were characterized 10 years ago, but no functional analyses of the peptide are available. Here we used the RNA interference technique to study the effects of Spofr-AT gene suppression on juvenile hormone (JH and ecdysteroid titers in the hemolymph of larvae, virgin and mated females, and of males. Spofr-AT gene silencing in last instar larvae resulted in an increase in the amount of JH III and 20-hydroxyecdysone in the hemolymph of the animals, corresponding to an acceleration of the prepupal commitment and transformation to the pupa. Mated females showed much higher JH titers in their hemolymph than virgins and laid almost twice the number of eggs. Spofr-AT gene silencing in freshly ecdysed females led to a further increase in egg production and oviposition, but had only a minor effect on the hemoylmph JH titer. Mated females contain considerable amounts of JH I and JH II in their hemoylmph, which are thought to be received from males during copulation. To confirm this hypothesis, we measured the amount of JH homologs in the male accessory reproductive glands (MARG before mating and in the bursa copulatrix (BC of the female after mating. MARG contained high amounts of JH I and JH II, which are transferred to the BC during copulation. One day after mating, JH disappeared from the BC and was then found in the hemolymph of the females. In conclusion, Spofr-AT acts as a true allatotropin in larvae and adults of both sexes of the armyworm.

  10. Audiovisual functional magnetic resonance imaging adaptation reveals multisensory integration effects in object-related sensory cortices.

    Science.gov (United States)

    Doehrmann, Oliver; Weigelt, Sarah; Altmann, Christian F; Kaiser, Jochen; Naumer, Marcus J

    2010-03-03

    Information integration across different sensory modalities contributes to object recognition, the generation of associations and long-term memory representations. Here, we used functional magnetic resonance imaging adaptation to investigate the presence of sensory integrative effects at cortical levels as early as nonprimary auditory and extrastriate visual cortices, which are implicated in intermediate stages of object processing. Stimulation consisted of an adapting audiovisual stimulus S(1) and a subsequent stimulus S(2) from the same basic-level category (e.g., cat). The stimuli were carefully balanced with respect to stimulus complexity and semantic congruency and presented in four experimental conditions: (1) the same image and vocalization for S(1) and S(2), (2) the same image and a different vocalization, (3) different images and the same vocalization, or (4) different images and vocalizations. This two-by-two factorial design allowed us to assess the contributions of auditory and visual stimulus repetitions and changes in a statistically orthogonal manner. Responses in visual regions of right fusiform gyrus and right lateral occipital cortex were reduced for repeated visual stimuli (repetition suppression). Surprisingly, left lateral occipital cortex showed stronger responses to repeated auditory stimuli (repetition enhancement). Similarly, auditory regions of interest of the right middle superior temporal gyrus and sulcus exhibited repetition suppression to auditory repetitions and repetition enhancement to visual repetitions. Our findings of crossmodal repetition-related effects in cortices of the respective other sensory modality add to the emerging view that in human subjects sensory integrative mechanisms operate on earlier cortical processing levels than previously assumed.

  11. Structure-Function Analysis of Staphylococcus aureus Amidase Reveals the Determinants of Peptidoglycan Recognition and Cleavage*

    Science.gov (United States)

    Büttner, Felix Michael; Zoll, Sebastian; Nega, Mulugeta; Götz, Friedrich; Stehle, Thilo

    2014-01-01

    The bifunctional major autolysin AtlA of Staphylococcus aureus cleaves the bacterium's peptidoglycan network (PGN) at two distinct sites during cell division. Deletion of the enzyme results in large cell clusters with disordered division patterns, indicating that AtlA could be a promising target for the development of new antibiotics. One of the two functions of AtlA is performed by the N-acetylmuramyl-l-alanine amidase AmiA, which cleaves the bond between the carbohydrate and the peptide moieties of PGN. To establish the structural requirements of PGN recognition and the enzymatic mechanism of cleavage, we solved the crystal structure of the catalytic domain of AmiA (AmiA-cat) in complex with a peptidoglycan-derived ligand at 1.55 Å resolution. The peptide stem is clearly visible in the structure, forming extensive contacts with protein residues by docking into an elongated groove. Less well defined electron density and the analysis of surface features indicate likely positions of the carbohydrate backbone and the pentaglycine bridge. Substrate specificity analysis supports the importance of the pentaglycine bridge for fitting into the binding cleft of AmiA-cat. PGN of S. aureus with l-lysine tethered with d-alanine via a pentaglycine bridge is completely hydrolyzed, whereas PGN of Bacillus subtilis with meso-diaminopimelic acid directly tethered with d-alanine is not hydrolyzed. An active site mutant, H370A, of AmiA-cat was completely inactive, providing further support for the proposed catalytic mechanism of AmiA. The structure reported here is not only the first of any bacterial amidase in which both the PGN component and the water molecule that carries out the nucleophilic attack on the carbonyl carbon of the scissile bond are present; it is also the first peptidoglycan amidase complex structure of an important human pathogen. PMID:24599952

  12. Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

    Directory of Open Access Journals (Sweden)

    Garcia Juan L

    2010-08-01

    Full Text Available Abstract Background Gliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow in vitro forming neurospheres and that can be isolated in vivo using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM. Methods Eight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA; Results Gene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders. Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups

  13. Gustatory imagery reveals functional connectivity from the prefrontal to insular cortices traced with magnetoencephalography.

    Science.gov (United States)

    Kobayashi, Masayuki; Sasabe, Tetsuya; Shigihara, Yoshihito; Tanaka, Masaaki; Watanabe, Yasuyoshi

    2011-01-01

    Our experience and prejudice concerning food play an important role in modulating gustatory information processing; gustatory memory stored in the central nervous system influences gustatory information arising from the peripheral nervous system. We have elucidated the mechanism of the "top-down" modulation of taste perception in humans using functional magnetic resonance imaging (fMRI) and demonstrated that gustatory imagery is mediated by the prefrontal (PFC) and insular cortices (IC). However, the temporal order of activation of these brain regions during gustatory imagery is still an open issue. To explore the source of "top-down" signals during gustatory imagery tasks, we analyzed the temporal activation patterns of activated regions in the cerebral cortex using another non-invasive brain imaging technique, magnetoencephalography (MEG). Gustatory imagery tasks were presented by words (Letter G-V) or pictures (Picture G-V) of foods/beverages, and participants were requested to recall their taste. In the Letter G-V session, 7/9 (77.8%) participants showed activation in the IC with a latency of 401.7±34.7 ms (n = 7) from the onset of word exhibition. In 5/7 (71.4%) participants who exhibited IC activation, the PFC was activated prior to the IC at a latency of 315.2±56.5 ms (n = 5), which was significantly shorter than the latency to the IC activation. In the Picture G-V session, the IC was activated in 6/9 (66.7%) participants, and only 1/9 (11.1%) participants showed activation in the PFC. There was no significant dominance between the right and left IC or PFC during gustatory imagery. These results support those from our previous fMRI study in that the Letter G-V session rather than the Picture G-V session effectively activates the PFC and IC and strengthen the hypothesis that the PFC mediates "top-down" control of retrieving gustatory information from the storage of long-term memories and in turn activates the IC.

  14. Gustatory imagery reveals functional connectivity from the prefrontal to insular cortices traced with magnetoencephalography.

    Directory of Open Access Journals (Sweden)

    Masayuki Kobayashi

    Full Text Available Our experience and prejudice concerning food play an important role in modulating gustatory information processing; gustatory memory stored in the central nervous system influences gustatory information arising from the peripheral nervous system. We have elucidated the mechanism of the "top-down" modulation of taste perception in humans using functional magnetic resonance imaging (fMRI and demonstrated that gustatory imagery is mediated by the prefrontal (PFC and insular cortices (IC. However, the temporal order of activation of these brain regions during gustatory imagery is still an open issue. To explore the source of "top-down" signals during gustatory imagery tasks, we analyzed the temporal activation patterns of activated regions in the cerebral cortex using another non-invasive brain imaging technique, magnetoencephalography (MEG. Gustatory imagery tasks were presented by words (Letter G-V or pictures (Picture G-V of foods/beverages, and participants were requested to recall their taste. In the Letter G-V session, 7/9 (77.8% participants showed activation in the IC with a latency of 401.7±34.7 ms (n = 7 from the onset of word exhibition. In 5/7 (71.4% participants who exhibited IC activation, the PFC was activated prior to the IC at a latency of 315.2±56.5 ms (n = 5, which was significantly shorter than the latency to the IC activation. In the Picture G-V session, the IC was activated in 6/9 (66.7% participants, and only 1/9 (11.1% participants showed activation in the PFC. There was no significant dominance between the right and left IC or PFC during gustatory imagery. These results support those from our previous fMRI study in that the Letter G-V session rather than the Picture G-V session effectively activates the PFC and IC and strengthen the hypothesis that the PFC mediates "top-down" control of retrieving gustatory information from the storage of long-term memories and in turn activates the IC.

  15. Anatomical Reconstruction and Functional Imaging Reveal an Ordered Array of Skylight Polarization Detectors in Drosophila.

    Science.gov (United States)

    Weir, Peter T; Henze, Miriam J; Bleul, Christiane; Baumann-Klausener, Franziska; Labhart, Thomas; Dickinson, Michael H

    2016-05-11

    Many insects exploit skylight polarization as a compass cue for orientation and navigation. In the fruit fly, Drosophila melanogaster, photoreceptors R7 and R8 in the dorsal rim area (DRA) of the compound eye are specialized to detect the electric vector (e-vector) of linearly polarized light. These photoreceptors are arranged in stacked pairs with identical fields of view and spectral sensitivities, but mutually orthogonal microvillar orientations. As in larger flies, we found that the microvillar orientation of the distal photoreceptor R7 changes in a fan-like fashion along the DRA. This anatomical arrangement suggests that the DRA constitutes a detector for skylight polarization, in which different e-vectors maximally excite different positions in the array. To test our hypothesis, we measured responses to polarized light of varying e-vector angles in the terminals of R7/8 cells using genetically encoded calcium indicators. Our data confirm a progression of preferred e-vector angles from anterior to posterior in the DRA, and a strict orthogonality between the e-vector preferences of paired R7/8 cells. We observed decreased activity in photoreceptors in response to flashes of light polarized orthogonally to their preferred e-vector angle, suggesting reciprocal inhibition between photoreceptors in the same medullar column, which may serve to increase polarization contrast. Together, our results indicate that the polarization-vision system relies on a spatial map of preferred e-vector angles at the earliest stage of sensory processing. The fly's visual system is an influential model system for studying neural computation, and much is known about its anatomy, physiology, and development. The circuits underlying motion processing have received the most attention, but researchers are increasingly investigating other functions, such as color perception and object recognition. In this work, we investigate the early neural processing of a somewhat exotic sense, called

  16. Genetic assessment of connectivity in the common reef sponge, Callyspongia vaginalis (Demospongiae: Haplosclerida) reveals high population structure along the Florida reef tract

    Science.gov (United States)

    Debiasse, M. B.; Richards, V. P.; Shivji, M. S.

    2010-03-01

    The genetic population structure of the common branching vase sponge, Callyspongia vaginalis, was determined along the entire length (465 km) of the Florida reef system from Palm Beach to the Dry Tortugas based on sequences of the mitochondrial cytochrome c oxidase subunit 1 (COI) gene. Populations of C. vaginalis were highly structured (overall ΦST = 0.33), in some cases over distances as small as tens of kilometers. However, nonsignificant pairwise ΦST values were also found between a few relatively distant sampling sites suggesting that some long distance larval dispersal may occur via ocean currents or transport in sponge fragments along continuous, shallow coastlines. Indeed, sufficient gene flow appears to occur along the Florida reef tract to obscure a signal of isolation by distance, but not to homogenize COI haplotype frequencies. The strong genetic differentiation among most of the sampling locations suggests that recruitment in this species is largely local source-driven, pointing to the importance of further elucidating general connectivity patterns along the Florida reef tract to guide the spatial scale of management efforts.

  17. Epidemiological Characteristics and Clinical Treatment Outcome of Typhoid Fever in Ningbo, China, 2005-2014: Pulsed-Field Gel Electorophoresis Results Revealing Great Proportion of Common Transmission Sources.

    Science.gov (United States)

    Song, Qifa; Yang, Yuanbin; Lin, Wenping; Yi, Bo; Xu, Guozhang

    2017-09-25

    We aimed to describe the molecular epidemiological characteristics and clinical treatment outcome of typhoid fever in Ningbo, China during 2005-2014. Eighty-eight Salmonella Typhi isolates were obtained from 307 hospitalized patients. Three prevalent pulsed-field gel electrophoresis (PFGE) patterns of 54 isolates from 3 outbreaks were identified. Overall, there were 64 (72.7%) isolates from clustered cases and 24 (27.3%) isolates from sporadic cases. Resistance to nalidixic acid (NAL) (n = 47; 53.4%) and ampicillin (AMP) (n = 40; 45.4%) and rare resistance to tetracycline (TET) (n = 2; 2.3%) and gentamicin (GEN) (n = 2; 2.3%) were observed. No isolates resistant to cefotaxime (CTX), chloramphenicol (CL), ciprofloxacin (CIP), and trimethoprim-sulfamethoxazole (SXT) were found. The occurrence of reduced sensitivity to CIP was 52.3% (n = 46). The medians of fever clearance time in cases with and without complications were 7 (interquartile range (IQR): 4-10) and 5 (IQR: 3-7) days (P = 0.001), respectively, when patients were treated with CIP or levofloxacin (LEV) and/or third-generation cephalosporins (CEP). Rates of serious complications were at low levels: peritonitis (2.3%), intestinal hemorrhage (6.8%), and intestinal perforation (1.1%). The present study revealed a long-term clustering trend with respect to PFGE patterns, occasional outbreaks, and the rapid spread of AMP resistance and decreased CIP susceptibility among S. Typhi isolates in recent years.

  18. A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition.

    Science.gov (United States)

    Favalli, Nicholas; Biendl, Stefan; Hartmann, Marco; Piazzi, Jacopo; Sladojevich, Filippo; Gräslund, Susanne; Brown, Peter J; Näreoja, Katja; Schüler, Herwig; Scheuermann, Jörg; Franzini, Raphael; Neri, Dario

    2018-06-01

    A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a K d value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Y-chromosome variation in Altaian Kazakhs reveals a common paternal gene pool for Kazakhs and the influence of Mongolian expansions.

    Science.gov (United States)

    Dulik, Matthew C; Osipova, Ludmila P; Schurr, Theodore G

    2011-03-11

    Kazakh populations have traditionally lived as nomadic pastoralists that seasonally migrate across the steppe and surrounding mountain ranges in Kazakhstan and southern Siberia. To clarify their population history from a paternal perspective, we analyzed the non-recombining portion of the Y-chromosome from Kazakh populations living in southern Altai Republic, Russia, using a high-resolution analysis of 60 biallelic markers and 17 STRs. We noted distinct differences in the patterns of genetic variation between maternal and paternal genetic systems in the Altaian Kazakhs. While they possess a variety of East and West Eurasian mtDNA haplogroups, only three East Eurasian paternal haplogroups appear at significant frequencies (C3*, C3c and O3a3c*). In addition, the Y-STR data revealed low genetic diversity within these lineages. Analysis of the combined biallelic and STR data also demonstrated genetic differences among Kazakh populations from across Central Asia. The observed differences between Altaian Kazakhs and indigenous Kazakhs were not the result of admixture between Altaian Kazakhs and indigenous Altaians. Overall, the shared paternal ancestry of Kazakhs differentiates them from other Central Asian populations. In addition, all of them showed evidence of genetic influence by the 13(th) century CE Mongol Empire. Ultimately, the social and cultural traditions of the Kazakhs shaped their current pattern of genetic variation.

  20. Y-chromosome variation in Altaian Kazakhs reveals a common paternal gene pool for Kazakhs and the influence of Mongolian expansions.

    Directory of Open Access Journals (Sweden)

    Matthew C Dulik

    Full Text Available Kazakh populations have traditionally lived as nomadic pastoralists that seasonally migrate across the steppe and surrounding mountain ranges in Kazakhstan and southern Siberia. To clarify their population history from a paternal perspective, we analyzed the non-recombining portion of the Y-chromosome from Kazakh populations living in southern Altai Republic, Russia, using a high-resolution analysis of 60 biallelic markers and 17 STRs. We noted distinct differences in the patterns of genetic variation between maternal and paternal genetic systems in the Altaian Kazakhs. While they possess a variety of East and West Eurasian mtDNA haplogroups, only three East Eurasian paternal haplogroups appear at significant frequencies (C3*, C3c and O3a3c*. In addition, the Y-STR data revealed low genetic diversity within these lineages. Analysis of the combined biallelic and STR data also demonstrated genetic differences among Kazakh populations from across Central Asia. The observed differences between Altaian Kazakhs and indigenous Kazakhs were not the result of admixture between Altaian Kazakhs and indigenous Altaians. Overall, the shared paternal ancestry of Kazakhs differentiates them from other Central Asian populations. In addition, all of them showed evidence of genetic influence by the 13(th century CE Mongol Empire. Ultimately, the social and cultural traditions of the Kazakhs shaped their current pattern of genetic variation.

  1. Linear and non-linear dose-response functions reveal a hormetic relationship between stress and learning.

    Science.gov (United States)

    Zoladz, Phillip R; Diamond, David M

    2008-10-16

    Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear dose-response functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as well as the excitatory effects of several neuromodulators, including corticosteroids, norepinephrine, corticotropin-releasing hormone, acetylcholine and dopamine. We propose that this rapid activation of the amygdala-hippocampus brain memory system results in a linear dose-response relation between emotional strength and memory formation. More prolonged stress, however, leads to an inhibition of hippocampal function, which can be attributed to compensatory cellular responses that protect hippocampal neurons from excitotoxicity. This inhibition of hippocampal functioning in response to prolonged stress is potentially relevant to the well-described curvilinear dose-response relationship between arousal and memory. Our emphasis on the temporal features of stress-brain interactions addresses how stress can activate, as well as impair, hippocampal functioning to produce a hormetic relationship between stress and learning.

  2. Oxidation of linoleic and palmitic acid in pre-hibernating and hibernating common noctule bats revealed by 13C breath testing.

    Science.gov (United States)

    Rosner, Elisabeth; Voigt, Christian C

    2018-02-19

    Mammals fuel hibernation by oxidizing saturated and unsaturated fatty acids from triacylglycerols in adipocytes, yet the relative importance of these two categories as an oxidative fuel may change during hibernation. We studied the selective use of fatty acids as an oxidative fuel in noctule bats ( Nyctalus noctula ). Pre-hibernating noctule bats that were fed 13 C-enriched linoleic acid (LA) showed 12 times higher tracer oxidation rates compared with conspecifics fed 13 C-enriched palmitic acid (PA). After this experiment, we supplemented the diet of bats with the same fatty acids on five subsequent days to enrich their fat depots with the respective tracer. We then compared the excess 13 C enrichment (excess atom percentage, APE) in breath of bats for torpor and arousal events during early and late hibernation. We observed higher APE values in breath of bats fed 13 C-enriched LA than in bats fed 13 C-enriched PA for both states (torpor and arousal), and also for both periods. Thus, hibernating bats selectively oxidized endogenous LA instead of PA, probably because of faster transportation rates of polyunsaturated fatty acids compared with saturated fatty acids. We did not observe changes in APE values in the breath of torpid animals between early and late hibernation. Skin temperature of torpid animals increased by 0.7°C between early and late hibernation in bats fed PA, whereas it decreased by -0.8°C in bats fed LA, highlighting that endogenous LA may fulfil two functions when available in excess: serving as an oxidative fuel and supporting cell membrane functionality. © 2018. Published by The Company of Biologists Ltd.

  3. The structure of bradyzoite-specific enolase from Toxoplasma gondii reveals insights into its dual cytoplasmic and nuclear functions

    Energy Technology Data Exchange (ETDEWEB)

    Ruan, Jiapeng [Northwestern University, 320 E. Superior Street, Morton 7-601, Chicago, IL 60611 (United States); Mouveaux, Thomas [Université Lille Nord de France, (France); Light, Samuel H.; Minasov, George; Anderson, Wayne F. [Northwestern University, 320 E. Superior Street, Morton 7-601, Chicago, IL 60611 (United States); Tomavo, Stanislas [Université Lille Nord de France, (France); Ngô, Huân M., E-mail: h-ngo@northwestern.edu [Northwestern University, 320 E. Superior Street, Morton 7-601, Chicago, IL 60611 (United States); BrainMicro LLC, 21 Pendleton Street, New Haven, CT 06511 (United States)

    2015-03-01

    The second crystal structure of a parasite protein preferentially enriched in the brain cyst of T. gondii has been solved at 2.75 Å resolution. Bradyzoite enolase 1 is reported to have differential functions as a glycolytic enzyme and a transcriptional regulator in bradyzoites. In addition to catalyzing a central step in glycolysis, enolase assumes a remarkably diverse set of secondary functions in different organisms, including transcription regulation as documented for the oncogene c-Myc promoter-binding protein 1. The apicomplexan parasite Toxoplasma gondii differentially expresses two nuclear-localized, plant-like enolases: enolase 1 (TgENO1) in the latent bradyzoite cyst stage and enolase 2 (TgENO2) in the rapidly replicative tachyzoite stage. A 2.75 Å resolution crystal structure of bradyzoite enolase 1, the second structure to be reported of a bradyzoite-specific protein in Toxoplasma, captures an open conformational state and reveals that distinctive plant-like insertions are located on surface loops. The enolase 1 structure reveals that a unique residue, Glu164, in catalytic loop 2 may account for the lower activity of this cyst-stage isozyme. Recombinant TgENO1 specifically binds to a TTTTCT DNA motif present in the cyst matrix antigen 1 (TgMAG1) gene promoter as demonstrated by gel retardation. Furthermore, direct physical interactions of both nuclear TgENO1 and TgENO2 with the TgMAG1 gene promoter are demonstrated in vivo using chromatin immunoprecipitation (ChIP) assays. Structural and biochemical studies reveal that T. gondii enolase functions are multifaceted, including the coordination of gene regulation in parasitic stage development. Enolase 1 provides a potential lead in the design of drugs against Toxoplasma brain cysts.

  4. Psychometric viability of measures of functional performance commonly used for people with dementia: a systematic review of measurement properties.

    Science.gov (United States)

    Fox, Benjamin; Henwood, Timothy; Keogh, Justin; Neville, Christine

    2016-08-01

    Confidence in findings can only be drawn from measurement tools that have sound psychometric properties for the population with which they are used. Within a dementia specific population, measures of physical function have been poorly justified in exercise intervention studies, with justification of measures based on validity or reliability studies from dissimilar clinical populations, such as people with bronchitis or healthy older adults without dementia. To review the reliability and validity of quantitative measures of pre-identified physical function, as commonly used within exercise intervention literature for adults with dementia. Participants were adults, aged 65 years and older, with a confirmed medical diagnosis of dementia. n/a Desired studies were observational and cross-sectional and that assessed measures from a pre-identified list of measures of physical function. Studies that assessed the psychometric constructs of reliability and validity were targeted. COSMIN taxology was used to define reliability and validity. This included, but were not limited to, Intra-Class Correlations, Kappa, Cronbach's Alpha, Chi Squared, Standard Error of Measurement, Minimal Detectable Change and Limits of Agreement. Published material was sourced from the following four databases: MEDLINE, EMBASE, CINAHL and ISI Web of Science. Grey literature was searched for using ALOIS, Google Scholar and ProQuest. The COSMIN checklist was used to assess methodological quality of included studies. Assessment was completed by two reviewers independently. Reliability and validity data was extracted from included studies using standardized Joanna Briggs Institute data collection forms. Extraction was completed by two reviewers. A narrative synthesis of measurement properties of the tools used to measure physical function was performed. Quantitative meta-analysis was conducted for Intra-Class Correlation Coefficients only. With respect to relative reliability, studies reporting assessed

  5. Functional characterization and crystal structure of thermostable amylase from Thermotoga petrophila, reveals high thermostability and an unusual form of dimerization

    DEFF Research Database (Denmark)

    Hameed, Uzma; Price, Ian; Ikram-Ul-Haq

    2017-01-01

    and able to hydrolyze starch into dextrin between 90 and 100°C, with optimum activity at 98°C and pH8.5. The activity increased in the presence of Rb(1+), K(1+) and Ca(2+) ions, whereas other ions inhibited activity. The crystal structure of Tp-AmyS at 1.7Å resolution showed common features of the GH-13...... of salivary amylase from a previous crystal structure, and thus could be a functional feature of some amylases....

  6. Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes

    DEFF Research Database (Denmark)

    Zhao, Xiaolu; Leon, Ileana R; Bak, Steffen

    2011-01-01

    . In skeletal muscle, mitochondrial dysfunction is linked to insulin resistance in humans with obesity and type 2 diabetes. We performed a phosphoproteomic study of functional mitochondria isolated from human muscle biopsies with the aim to obtain a comprehensive overview of mitochondrial phosphoproteins...... in insulin resistance. We also assigned phosphorylation sites in mitochondrial proteins involved in amino acid degradation, importers and transporters, calcium homeostasis, and apoptosis. Bioinformatics analysis of kinase motifs revealed that many of these mitochondrial phosphoproteins are substrates....... Future comparative phosphoproteome analysis of mitochondria from healthy and diseased individuals will provide insights into the role of abnormal phosphorylation in pathologies, such as type 2 diabetes....

  7. Coupled cryoconite ecosystem structure-function relationships are revealed by comparing bacterial communities in alpine and Arctic glaciers

    DEFF Research Database (Denmark)

    Edwards, Arwyn; Mur, Luis A. J.; Girdwood, Susan E.

    2014-01-01

    Cryoconite holes are known as foci of microbial diversity and activity on polar glacier surfaces, but are virtually unexplored microbial habitats in alpine regions. In addition, whether cryoconite community structure reflects ecosystem functionality is poorly understood. Terminal restriction...... revealed Proteobacteria were particularly abundant, with Cyanobacteria likely acting as ecosystem engineers in both alpine and Arctic cryoconite communities. However, despite these generalities, significant differences in bacterial community structures, compositions and metabolomes are found between alpine...... fragment length polymorphism and Fourier transform infrared metabolite fingerprinting of cryoconite from glaciers in Austria, Greenland and Svalbard demonstrated cryoconite bacterial communities are closely correlated with cognate metabolite fingerprints. The influence of bacterial-associated fatty acids...

  8. Identification and functional analysis of flowering related microRNAs in common wild rice (Oryza rufipogon Griff.).

    Science.gov (United States)

    Chen, Zongxiang; Li, Fuli; Yang, Songnan; Dong, Yibo; Yuan, Qianhua; Wang, Feng; Li, Weimin; Jiang, Ying; Jia, Shirong; Pei, Xinwu

    2013-01-01

    MicroRNAs (miRNAs) is a class of non-coding RNAs involved in post- transcriptional control of gene expression, via degradation and/or translational inhibition. Six-hundred sixty-one rice miRNAs are known that are important in plant development. However, flowering-related miRNAs have not been characterized in Oryza rufipogon Griff. It was approved by supervision department of Guangdong wild rice protection. We analyzed flowering-related miRNAs in O. rufipogon using high-throughput sequencing (deep sequencing) to understand the changes that occurred during rice domestication, and to elucidate their functions in flowering. Three O. rufipogon sRNA libraries, two vegetative stage (CWR-V1 and CWR-V2) and one flowering stage (CWR-F2) were sequenced using Illumina deep sequencing. A total of 20,156,098, 21,531,511 and 20,995,942 high quality sRNA reads were obtained from CWR-V1, CWR-V2 and CWR-F2, respectively, of which 3,448,185, 4,265,048 and 2,833,527 reads matched known miRNAs. We identified 512 known rice miRNAs in 214 miRNA families and predicted 290 new miRNAs. Targeted functional annotation, GO and KEGG pathway analyses predicted that 187 miRNAs regulate expression of flowering-related genes. Differential expression analysis of flowering-related miRNAs showed that: expression of 95 miRNAs varied significantly between the libraries, 66 are flowering-related miRNAs, such as oru-miR97, oru-miR117, oru-miR135, oru-miR137, et al. 17 are early-flowering -related miRNAs, including osa-miR160f, osa-miR164d, osa-miR167d, osa-miR169a, osa-miR172b, oru-miR4, et al., induced during the floral transition. Real-time PCR revealed the same expression patterns as deep sequencing. miRNAs targets were confirmed for cleavage by 5'-RACE in vivo, and were negatively regulated by miRNAs. This is the first investigation of flowering miRNAs in wild rice. The result indicates that variation in miRNAs occurred during rice domestication and lays a foundation for further study of phase change

  9. Identification and functional analysis of flowering related microRNAs in common wild rice (Oryza rufipogon Griff..

    Directory of Open Access Journals (Sweden)

    Zongxiang Chen

    Full Text Available BACKGROUND: MicroRNAs (miRNAs is a class of non-coding RNAs involved in post- transcriptional control of gene expression, via degradation and/or translational inhibition. Six-hundred sixty-one rice miRNAs are known that are important in plant development. However, flowering-related miRNAs have not been characterized in Oryza rufipogon Griff. It was approved by supervision department of Guangdong wild rice protection. We analyzed flowering-related miRNAs in O. rufipogon using high-throughput sequencing (deep sequencing to understand the changes that occurred during rice domestication, and to elucidate their functions in flowering. RESULTS: Three O. rufipogon sRNA libraries, two vegetative stage (CWR-V1 and CWR-V2 and one flowering stage (CWR-F2 were sequenced using Illumina deep sequencing. A total of 20,156,098, 21,531,511 and 20,995,942 high quality sRNA reads were obtained from CWR-V1, CWR-V2 and CWR-F2, respectively, of which 3,448,185, 4,265,048 and 2,833,527 reads matched known miRNAs. We identified 512 known rice miRNAs in 214 miRNA families and predicted 290 new miRNAs. Targeted functional annotation, GO and KEGG pathway analyses predicted that 187 miRNAs regulate expression of flowering-related genes. Differential expression analysis of flowering-related miRNAs showed that: expression of 95 miRNAs varied significantly between the libraries, 66 are flowering-related miRNAs, such as oru-miR97, oru-miR117, oru-miR135, oru-miR137, et al. 17 are early-flowering -related miRNAs, including osa-miR160f, osa-miR164d, osa-miR167d, osa-miR169a, osa-miR172b, oru-miR4, et al., induced during the floral transition. Real-time PCR revealed the same expression patterns as deep sequencing. miRNAs targets were confirmed for cleavage by 5'-RACE in vivo, and were negatively regulated by miRNAs. CONCLUSIONS: This is the first investigation of flowering miRNAs in wild rice. The result indicates that variation in miRNAs occurred during rice domestication and

  10. Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

    Directory of Open Access Journals (Sweden)

    Miriam Matamales

    Full Text Available Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17% aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the

  11. A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events.

    Directory of Open Access Journals (Sweden)

    Angela N Brooks

    Full Text Available Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35 have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA. Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML, in which U2AF1 is somatically mutated in 3-4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3' splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3' splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.

  12. Multigene phylogeny of the scyphozoan jellyfish