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Sample records for integrated molecular signature

  1. Are there molecular signatures?

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    Bennett, W.P.

    1995-10-01

    This report describes molecular signatures and mutational spectrum analysis. The mutation spectrum is defined as the type and location of DNA base change. There are currently about five well documented cases. Mutations and radon-associated tumors are discussed.

  2. Multi-study integration of brain cancer transcriptomes reveals organ-level molecular signatures.

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    Jaeyun Sung

    Full Text Available We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood.

  3. Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes

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    Li Min

    2017-02-01

    Full Text Available BACKGROUND: Gastric cancer (GC is the fifth leading cause of cancer-related deaths worldwide. As an effective and easily performed method, microscopy-based Lauren classification has been widely accepted by gastrointestinal surgeons and pathologists for GC subtyping, but molecular characteristics of different Lauren subtypes were poorly revealed. METHODS: GSE62254 was used as a derivation cohort, and GSE15459 was used as a validation cohort. The difference between diffuse and intestinal GC on the gene expression level was measured. Gene ontology (GO enrichment analysis was performed for both subgroups. Hierarchical clustering and heatmap exhibition were also performed. Kaplan-Meier plot and Cox proportional hazards model were used to evaluate survival grouped by the given genes or hierarchical clusters. RESULTS: A total of 4598 genes were found differentially expressed between diffuse and intestinal GC. Immunity- and cell adhesion–related GOs were enriched for diffuse GC, whereas DNA repair– and cell cycle–related GOs were enriched for intestinal GC. We proposed a 40-gene signature (χ2 = 30.71, P < .001 that exhibits better discrimination for prognosis than Lauren classification (χ2 = 12.11, P = .002. FRZB [RR (95% CI = 1.824 (1.115-2.986, P = .017] and EFEMP1 [RR (95% CI = 1.537 (0.969-2.437, P = .067] were identified as independent prognostic factors only in diffuse GC but not in intestinal GC patients. KRT23 [RR (95% CI = 1.616 (0.938-2.785, P = .083] was identified as an independent prognostic factor only in intestinal GC patients but not in diffuse GC patients. Similar results were achieved in the validation cohort. CONCLUSION: We found that GCs with different Lauren classifications had different molecular characteristics and identified FRZB, EFEMP1, and KRT23 as subtype-specific prognostic factors for GC patients.

  4. Signature molecular descriptor : advanced applications.

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    Visco, Donald Patrick, Jr. (Tennessee Technological University, Cookeville, TN)

    2010-04-01

    In this work we report on the development of the Signature Molecular Descriptor (or Signature) for use in the solution of inverse design problems as well as in highthroughput screening applications. The ultimate goal of using Signature is to identify novel and non-intuitive chemical structures with optimal predicted properties for a given application. We demonstrate this in three studies: green solvent design, glucocorticoid receptor ligand design and the design of inhibitors for Factor XIa. In many areas of engineering, compounds are designed and/or modified in incremental ways which rely upon heuristics or institutional knowledge. Often multiple experiments are performed and the optimal compound is identified in this brute-force fashion. Perhaps a traditional chemical scaffold is identified and movement of a substituent group around a ring constitutes the whole of the design process. Also notably, a chemical being evaluated in one area might demonstrate properties very attractive in another area and serendipity was the mechanism for solution. In contrast to such approaches, computer-aided molecular design (CAMD) looks to encompass both experimental and heuristic-based knowledge into a strategy that will design a molecule on a computer to meet a given target. Depending on the algorithm employed, the molecule which is designed might be quite novel (re: no CAS registration number) and/or non-intuitive relative to what is known about the problem at hand. While CAMD is a fairly recent strategy (dating to the early 1980s), it contains a variety of bottlenecks and limitations which have prevented the technique from garnering more attention in the academic, governmental and industrial institutions. A main reason for this is how the molecules are described in the computer. This step can control how models are developed for the properties of interest on a given problem as well as how to go from an output of the algorithm to an actual chemical structure. This report

  5. Tissue-Specific Molecular Biomarker Signatures of Type 2 Diabetes: An Integrative Analysis of Transcriptomics and Protein-Protein Interaction Data.

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    Calimlioglu, Beste; Karagoz, Kubra; Sevimoglu, Tuba; Kilic, Elif; Gov, Esra; Arga, Kazim Yalcin

    2015-09-01

    Type 2 diabetes mellitus is a major global public health burden. A complex metabolic disease, type 2 diabetes affects multiple different tissues, demanding a "systems medicine" approach to biomarker and novel diagnostic discovery, not to mention data integration across omics-es. In the present study, transcriptomics data from different tissues including beta-cells, pancreatic islets, arterial tissue, peripheral blood mononuclear cells, liver, and skeletal muscle of 228 samples were integrated with protein-protein interaction data and genome scale metabolic models to unravel the molecular and tissue-specific biomarker signatures of type 2 diabetes mellitus. Classifying differentially expressed genes, reconstruction and topological analysis of active protein-protein interaction subnetworks indicated that genomic reprogramming depends on the type of tissue, whereas there are common signatures at different levels. Among all tissue and cell types, Mannosidase Alpha Class 1A Member 2 was the common signature at genome level, and activation-ppara reaction, which stimulates a nuclear receptor protein, was found out as the mutual reporter at metabolic level. Moreover, miR-335 and miR-16-5p came into prominence in regulation of transcription at different tissues. On the other hand, distinct signatures were observed for different tissues at the metabolome level. Various coenzyme-A derivatives were significantly enriched metabolites in pancreatic islets, whereas skeletal muscle was enriched for cholesterol, malate, L-carnitine, and several amino acids. Results have showed utmost importance concerning relations between T2D and cancer, blood coagulation, neurodegenerative diseases, and specific metabolic and signaling pathways.

  6. Molecular signatures of ribosomal evolution.

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    Roberts, Elijah; Sethi, Anurag; Montoya, Jonathan; Woese, Carl R; Luthey-Schulten, Zaida

    2008-09-16

    Ribosomal signatures, idiosyncrasies in the ribosomal RNA (rRNA) and/or proteins, are characteristic of the individual domains of life. As such, insight into the early evolution of the domains can be gained from a comparative analysis of their respective signatures in the translational apparatus. In this work, we identify signatures in both the sequence and structure of the rRNA and analyze their contributions to the universal phylogenetic tree using both sequence- and structure-based methods. Domain-specific ribosomal proteins can be considered signatures in their own right. Although it is commonly assumed that they developed after the universal ribosomal proteins, we present evidence that at least one may have been present before the divergence of the organismal lineages. We find correlations between the rRNA signatures and signatures in the ribosomal proteins showing that the rRNA signatures coevolved with both domain-specific and universal ribosomal proteins. Finally, we show that the genomic organization of the universal ribosomal components contains these signatures as well. From these studies, we propose the ribosomal signatures are remnants of an evolutionary-phase transition that occurred as the cell lineages began to coalesce and so should be reflected in corresponding signatures throughout the fabric of the cell and its genome.

  7. On reliable discovery of molecular signatures

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    Björkegren Johan

    2009-01-01

    Full Text Available Abstract Background Molecular signatures are sets of genes, proteins, genetic variants or other variables that can be used as markers for a particular phenotype. Reliable signature discovery methods could yield valuable insight into cell biology and mechanisms of human disease. However, it is currently not clear how to control error rates such as the false discovery rate (FDR in signature discovery. Moreover, signatures for cancer gene expression have been shown to be unstable, that is, difficult to replicate in independent studies, casting doubts on their reliability. Results We demonstrate that with modern prediction methods, signatures that yield accurate predictions may still have a high FDR. Further, we show that even signatures with low FDR may fail to replicate in independent studies due to limited statistical power. Thus, neither stability nor predictive accuracy are relevant when FDR control is the primary goal. We therefore develop a general statistical hypothesis testing framework that for the first time provides FDR control for signature discovery. Our method is demonstrated to be correct in simulation studies. When applied to five cancer data sets, the method was able to discover molecular signatures with 5% FDR in three cases, while two data sets yielded no significant findings. Conclusion Our approach enables reliable discovery of molecular signatures from genome-wide data with current sample sizes. The statistical framework developed herein is potentially applicable to a wide range of prediction problems in bioinformatics.

  8. Molecular signatures of thyroid follicular neoplasia

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    Borup, R.; Rossing, M.; Henao, Ricardo

    2010-01-01

    The molecular pathways leading to thyroid follicular neoplasia are incompletely understood, and the diagnosis of follicular tumors is a clinical challenge. To provide leads to the pathogenesis and diagnosis of the tumors, we examined the global transcriptome signatures of follicular thyroid...... a mechanism for cancer progression, which is why we exploited the results in order to generate a molecular classifier that could identify 95% of all carcinomas. Validation employing public domain and cross-platform data demonstrated that the signature was robust and could diagnose follicular nodules...... and robust genetic signature for the diagnosis of FA and FC. Endocrine-Related Cancer (2010) 17 691-708...

  9. Molecular Systems Pharmacology: Isoelectric Focusing Signature of Protein Kinase Cδ Provides an Integrated Measure of Its Modulation in Response to Ligands

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    2015-01-01

    Protein kinase C (PKC), a validated therapeutic target for cancer chemotherapy, provides a paradigm for assessing structure–activity relations, where ligand binding has multiple consequences for a target. For PKC, ligand binding controls not only PKC activation and multiple phosphorylations but also subcellular localization, affecting subsequent signaling. Using a capillary isoelectric focusing immunoassay system, we could visualize a high resolution isoelectric focusing signature of PKCδ upon stimulation by ligands of the phorbol ester and bryostatin classes. Derivatives that possessed different physicochemical characteristics and induced different patterns of biological response generated different signatures. Consistent with different patterns of PKCδ localization as one factor linked to these different signatures, we found different signatures for activated PKCδ from the nuclear and non-nuclear fractions. We conclude that the capillary isoelectric focusing immunoassay system may provide a window into the integrated consequences of ligand binding and thus afford a powerful platform for compound development. PMID:24906106

  10. Integrated Molecular Signature of Disease: Analysis of Influenza Virus-Infected Macaques through Functional Genomics and Proteomics

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    Baas, T.; Baskin, C. R.; Diamond, Deborah L.; Garcia-Sastre, A.; Bielefeldt-Ohmann, H.; Tumpey, T. M.; Thomas, M. J.; Carter, V. S.; Teal, T. H.; Van Hoven, N.; Proll, Sean; Jacobs, Jon M.; Caldwell, Z.; Gritsenko, Marina A.; Hukkanen, R.; Camp, David G.; Smith, Richard D.; Katze, Michael G.

    2006-11-01

    Recent outbreaks of avian influenza in humans have stressed the need for an improved non-human primate model of influenza pathogenesis. In order to develop our macaque model, we expanded our in vivo and functional genomics experiments: We focused on the innate immune response at day 2 post-inoculation and on gene expression in affected lung tissue with viral genetic material present; finally, we sought to identify signature genes for early infection in whole blood. For these purposes, we infected six pigtailed macaques with 107 TCID50 of influenza A/Texas/36/91 virus and three control animals with a sham inoculate. We sacrificed one control and two experimental animals at day 2, 4, and 7 and lung tissue was harvested for pathology, gene expression profiling, and proteomics. Additionally, blood was collected for genomics every other day from each animal until its endpoint. Gross and microscopic pathology, immunohistochemistry, viral gene expression by arrays and/or quantitative real-time RT-PCR confirmed successful yet mild infection in all experimental animals. Genomic experiments were performed using second generation macaque-specific oligonucleotide arrays and high-throughput proteomics revealed host response to infection at the protein level. Our data showed dramatic differences in gene expression within the same influenza-induced lesion based on the presence or absence of viral mRNA. We also identified genes tightly co-regulated in peripheral white blood cells and in lung tissue at day 2 post-inoculation. This latter finding opens the possibility of using gene expression arrays on whole blood to detect infection after exposure but prior to onset of symptoms or shedding.

  11. Molecular Signature in HCV-Positive Lymphomas

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    Valli De Re

    2012-01-01

    Full Text Available Hepatitis C virus (HCV is a positive, single-stranded RNA virus, which has been associated to different subtypes of B-cell non-Hodgkin lymphoma (B-NHL. Cumulative evidence suggests an HCV-related antigen driven process in the B-NHL development. The underlying molecular signature associated to HCV-related B-NHL has to date remained obscure. In this review, we discuss the recent developments in this field with a special mention to different sets of genes whose expression is associated with BCR coupled to Blys signaling which in turn was found to be linked to B-cell maturation stages and NF-κb transcription factor. Even if recent progress on HCV-B-NHL signature has been made, the precise relationship between HCV and lymphoma development and phenotype signature remain to be clarified.

  12. Molecular signature in HCV-positive lymphomas.

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    De Re, Valli; Caggiari, Laura; Garziera, Marica; De Zorzi, Mariangela; Repetto, Ombretta

    2012-01-01

    Hepatitis C virus (HCV) is a positive, single-stranded RNA virus, which has been associated to different subtypes of B-cell non-Hodgkin lymphoma (B-NHL). Cumulative evidence suggests an HCV-related antigen driven process in the B-NHL development. The underlying molecular signature associated to HCV-related B-NHL has to date remained obscure. In this review, we discuss the recent developments in this field with a special mention to different sets of genes whose expression is associated with BCR coupled to Blys signaling which in turn was found to be linked to B-cell maturation stages and NF-κb transcription factor. Even if recent progress on HCV-B-NHL signature has been made, the precise relationship between HCV and lymphoma development and phenotype signature remain to be clarified.

  13. Analysis and computational dissection of molecular signature multiplicity.

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    Alexander Statnikov

    2010-05-01

    Full Text Available Molecular signatures are computational or mathematical models created to diagnose disease and other phenotypes and to predict clinical outcomes and response to treatment. It is widely recognized that molecular signatures constitute one of the most important translational and basic science developments enabled by recent high-throughput molecular assays. A perplexing phenomenon that characterizes high-throughput data analysis is the ubiquitous multiplicity of molecular signatures. Multiplicity is a special form of data analysis instability in which different analysis methods used on the same data, or different samples from the same population lead to different but apparently maximally predictive signatures. This phenomenon has far-reaching implications for biological discovery and development of next generation patient diagnostics and personalized treatments. Currently the causes and interpretation of signature multiplicity are unknown, and several, often contradictory, conjectures have been made to explain it. We present a formal characterization of signature multiplicity and a new efficient algorithm that offers theoretical guarantees for extracting the set of maximally predictive and non-redundant signatures independent of distribution. The new algorithm identifies exactly the set of optimal signatures in controlled experiments and yields signatures with significantly better predictivity and reproducibility than previous algorithms in human microarray gene expression datasets. Our results shed light on the causes of signature multiplicity, provide computational tools for studying it empirically and introduce a framework for in silico bioequivalence of this important new class of diagnostic and personalized medicine modalities.

  14. Spatio-Temporal Gene Expression Profiling during In Vivo Early Ovarian Folliculogenesis: Integrated Transcriptomic Study and Molecular Signature of Early Follicular Growth.

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    Agnes Bonnet

    Full Text Available The successful achievement of early ovarian folliculogenesis is important for fertility and reproductive life span. This complex biological process requires the appropriate expression of numerous genes at each developmental stage, in each follicular compartment. Relatively little is known at present about the molecular mechanisms that drive this process, and most gene expression studies have been performed in rodents and without considering the different follicular compartments.We used RNA-seq technology to explore the sheep transcriptome during early ovarian follicular development in the two main compartments: oocytes and granulosa cells. We documented the differential expression of 3,015 genes during this phase and described the gene expression dynamic specific to these compartments. We showed that important steps occurred during primary/secondary transition in sheep. We also described the in vivo molecular course of a number of pathways. In oocytes, these pathways documented the chronology of the acquisition of meiotic competence, migration and cellular organization, while in granulosa cells they concerned adhesion, the formation of cytoplasmic projections and steroid synthesis. This study proposes the involvement in this process of several members of the integrin and BMP families. The expression of genes such as Kruppel-like factor 9 (KLF9 and BMP binding endothelial regulator (BMPER was highlighted for the first time during early follicular development, and their proteins were also predicted to be involved in gene regulation. Finally, we selected a data set of 24 biomarkers that enabled the discrimination of early follicular stages and thus offer a molecular signature of early follicular growth. This set of biomarkers includes known genes such as SPO11 meiotic protein covalently bound to DSB (SPO11, bone morphogenetic protein 15 (BMP15 and WEE1 homolog 2 (S. pombe(WEE2 which play critical roles in follicular development but other biomarkers

  15. Integrative Metabolic Signatures for Hepatic Radiation Injury.

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    Irwin Jack Kurland

    Full Text Available Radiation-induced liver disease (RILD is a dose-limiting factor in curative radiation therapy (RT for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice.Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI and were contrasted to mice, which received 10 Gy whole body irradiation (WBI. Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry.Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate, fatty acids (lineolate, n-hexadecanoic acid and DNA damage markers (uridine.We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.

  16. Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques

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    Langley, Sarah R.; Willeit, Karin; Didangelos, Athanasios; Matic, Ljubica Perisic; Skroblin, Philipp; Barallobre-Barreiro, Javier; Lengquist, Mariette; Rungger, Gregor; Kapustin, Alexander; Kedenko, Ludmilla; Molenaar, Chris; Lu, Ruifang; Barwari, Temo; Suna, Gonca; Iglseder, Bernhard; Paulweber, Bernhard; Willeit, Peter; Pasterkamp, Gerard; Davies, Alun H.; Monaco, Claudia; Hedin, Ulf; Shanahan, Catherine M.; Willeit, Johann; Kiechl, Stefan

    2017-01-01

    BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology- and imaging-based definitions of the “vulnerable plaque,” necessitating an improved approach for predicting onset of symptoms. METHODS. We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies. RESULTS. Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction and was successfully replicated in an independent cohort, the SAPHIR study. CONCLUSION. The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery. FUNDING. UK: British Heart Foundation (BHF); King’s BHF Center; and the National Institute for Health Research Biomedical Research Center based at Guy’s and St

  17. Molecular signatures in the transport properties of molecular wire junctions: what makes a junction "molecular"?

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    Troisi, Alessandro; Ratner, Mark A

    2006-02-01

    The simplest component of molecular electronics consists of a single-molecule transport junction: a molecule sandwiched between source and drain electrodes, with or without a third gate electrode. In this Concept article, we focus on how molecules control transport in metal-electrode molecular junctions, and where the molecular signatures are to be found. In the situation where the molecule is relatively short and the gap between injection energy and molecular eigenstates is large, transport occurs largely by elastic tunneling, stochastic switching is common, and the vibronic signature can be found using inelastic electron tunneling spectroscopy (IETS). As the energy gaps for injection become smaller, one begins to see stronger molecular signatures - these include Franck-Condon-like structures in the current/voltage characteristic and strong vibronic interactions, which can lead to hopping behavior at the polaron limit. Conformational changes induced by the strong electric field lead to another strong manifestation of the molecular nature of the junction. We overview some of this mechanistic landscape, focusing on significant effects of switching (both stochastic and controlled by the electric field) and of molecular vibronic coupling.

  18. A molecular signature of proteinuria in glomerulonephritis.

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    Heather N Reich

    Full Text Available Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 "albumin-regulated genes" differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n = 25 could be distinguished from those of control subjects (n = 6 based solely upon the expression of these 231 "albumin-regulated genes." The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that all forms of primary glomerulonephritis (n = 33 can be distinguished from controls (n = 21 based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis.

  19. Molecular signatures database (MSigDB) 3.0.

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    Liberzon, Arthur; Subramanian, Aravind; Pinchback, Reid; Thorvaldsdóttir, Helga; Tamayo, Pablo; Mesirov, Jill P

    2011-06-15

    Well-annotated gene sets representing the universe of the biological processes are critical for meaningful and insightful interpretation of large-scale genomic data. The Molecular Signatures Database (MSigDB) is one of the most widely used repositories of such sets. We report the availability of a new version of the database, MSigDB 3.0, with over 6700 gene sets, a complete revision of the collection of canonical pathways and experimental signatures from publications, enhanced annotations and upgrades to the web site. MSigDB is freely available for non-commercial use at http://www.broadinstitute.org/msigdb.

  20. Transcriptional networks inferred from molecular signatures of breast cancer.

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    Tongbai, Ron; Idelman, Gila; Nordgard, Silje H; Cui, Wenwu; Jacobs, Jonathan L; Haggerty, Cynthia M; Chanock, Stephen J; Børresen-Dale, Anne-Lise; Livingston, Gary; Shaunessy, Patrick; Chiang, Chih-Hung; Kristensen, Vessela N; Bilke, Sven; Gardner, Kevin

    2008-02-01

    Global genomic approaches in cancer research have provided new and innovative strategies for the identification of signatures that differentiate various types of human cancers. Computational analysis of the promoter composition of the genes within these signatures may provide a powerful method for deducing the regulatory transcriptional networks that mediate their collective function. In this study we have systematically analyzed the promoter composition of gene classes derived from previously established genetic signatures that recently have been shown to reliably and reproducibly distinguish five molecular subtypes of breast cancer associated with distinct clinical outcomes. Inferences made from the trends of transcription factor binding site enrichment in the promoters of these gene groups led to the identification of regulatory pathways that implicate discrete transcriptional networks associated with specific molecular subtypes of breast cancer. One of these inferred pathways predicted a role for nuclear factor-kappaB in a novel feed-forward, self-amplifying, autoregulatory module regulated by the ERBB family of growth factor receptors. The existence of this pathway was verified in vivo by chromatin immunoprecipitation and shown to be deregulated in breast cancer cells overexpressing ERBB2. This analysis indicates that approaches of this type can provide unique insights into the differential regulatory molecular programs associated with breast cancer and will aid in identifying specific transcriptional networks and pathways as potential targets for tumor subtype-specific therapeutic intervention.

  1. Molecular signatures in response to Isoliquiritigenin in lymphoblastoid cell lines

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    Lee, Jae-Eun; Hong, Eun-Jung; Nam, Hye-Young [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Hwang, Meeyul [Research Center for Biomedical Resource of Oriental Medicine, Daegu Haany University (Korea, Republic of); Kim, Ji-Hyun [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Han, Bok-Ghee, E-mail: bokghee@nih.go.kr [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Jeon, Jae-Pil, E-mail: jpjeon@cdc.go.kr [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer We identified the inhibitory effect of ISL on cell proliferation of LCLs. Black-Right-Pointing-Pointer We found ISL-induced genes and miRNAs through microarray approach. Black-Right-Pointing-Pointer ISL-treated LCLs represented gene expression changes in cell cycle and p53 pathway. Black-Right-Pointing-Pointer We revealed 12 putative mRNA-miRNA functional pairs associated with ISL effect. -- Abstract: Isoliquiritigenin (ISL) has been known to induce cell cycle arrest and apoptosis of various cancer cells. However, genetic factors regulating ISL effects remain unclear. The aim of this study was to identify the molecular signatures involved in ISL-induced cell death of EBV-transformed lymphoblastoid cell lines (LCLs) using microarray analyses. For gene expression and microRNA (miRNA) microarray experiments, each of 12 LCL strains was independently treated with ISL or DMSO as a vehicle control for a day prior to total RNA extraction. ISL treatment inhibited cell proliferation of LCLs in a dose-dependent manner. Microarray analysis showed that ISL-treated LCLs represented gene expression changes in cell cycle and p53 signaling pathway, having a potential as regulators in LCL survival and sensitivity to ISL-induced cytotoxicity. In addition, 36 miRNAs including five miRNAs with unknown functions were differentially expressed in ISL-treated LCLs. The integrative analysis of miRNA and gene expression profiles revealed 12 putative mRNA-miRNA functional pairs. Among them, miR-1207-5p and miR-575 were negatively correlated with p53 pathway- and cell cycle-associated genes, respectively. In conclusion, our study suggests that miRNAs play an important role in ISL-induced cytotoxicity in LCLs by targeting signaling pathways including p53 pathway and cell cycle.

  2. Molecular signatures database (MSigDB) 3.0

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    Liberzon, Arthur; Subramanian, Aravind; Pinchback, Reid; Thorvaldsdóttir, Helga; Tamayo, Pablo; Mesirov, Jill P.

    2011-01-01

    Motivation: Well-annotated gene sets representing the universe of the biological processes are critical for meaningful and insightful interpretation of large-scale genomic data. The Molecular Signatures Database (MSigDB) is one of the most widely used repositories of such sets. Results: We report the availability of a new version of the database, MSigDB 3.0, with over 6700 gene sets, a complete revision of the collection of canonical pathways and experimental signatures from publications, enhanced annotations and upgrades to the web site. Availability and Implementation: MSigDB is freely available for non-commercial use at http://www.broadinstitute.org/msigdb. Contact: gsea@broadinstitute.org PMID:21546393

  3. The proneural molecular signature is enriched in oligodendrogliomas and predicts improved survival among diffuse gliomas.

    Directory of Open Access Journals (Sweden)

    Lee A D Cooper

    Full Text Available The Cancer Genome Atlas Project (TCGA has produced an extensive collection of '-omic' data on glioblastoma (GBM, resulting in several key insights on expression signatures. Despite the richness of TCGA GBM data, the absence of lower grade gliomas in this data set prevents analysis genes related to progression and the uncovering of predictive signatures. A complementary dataset exists in the form of the NCI Repository for Molecular Brain Neoplasia Data (Rembrandt, which contains molecular and clinical data for diffuse gliomas across the full spectrum of histologic class and grade. Here we present an investigation of the significance of the TCGA consortium's expression classification when applied to Rembrandt gliomas. We demonstrate that the proneural signature predicts improved clinical outcome among 176 Rembrandt gliomas that includes all histologies and grades, including GBMs (log rank test p = 1.16e-6, but also among 75 grade II and grade III samples (p  =  2.65e-4. This gene expression signature was enriched in tumors with oligodendroglioma histology and also predicted improved survival in this tumor type (n =  43, p  =  1.25e-4. Thus, expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for lower grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy. Integrated DNA and RNA analysis of low-grade and high-grade proneural gliomas identified increased expression and gene amplification of several genes including GLIS3, TGFB2, TNC, AURKA, and VEGFA in proneural GBMs, with corresponding loss of DLL3 and HEY2. Pathway analysis highlights the importance of the Notch and Hedgehog pathways in the proneural subtype. This demonstrates that the expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for low-grade oligodendrogliomas, and likely represent important differences in tumor

  4. Prognostic Biomarker Identification Through Integrating the Gene Signatures of Hepatocellular Carcinoma Properties

    Directory of Open Access Journals (Sweden)

    Jialin Cai

    2017-05-01

    Full Text Available Many molecular classification and prognostic gene signatures for hepatocellular carcinoma (HCC patients have been established based on genome-wide gene expression profiling; however, their generalizability is unclear. Herein, we systematically assessed the prognostic effects of these gene signatures and identified valuable prognostic biomarkers by integrating these gene signatures. With two independent HCC datasets (GSE14520, N = 242 and GSE54236, N = 78, 30 published gene signatures were evaluated, and 11 were significantly associated with the overall survival (OS of postoperative HCC patients in both datasets. The random survival forest models suggested that the gene signatures were superior to clinical characteristics for predicting the prognosis of the patients. Based on the 11 gene signatures, a functional protein-protein interaction (PPI network with 1406 nodes and 10,135 edges was established. With tissue microarrays of HCC patients (N = 60, we determined the prognostic values of the core genes in the network and found that RAD21, CDK1, and HDAC2 expression levels were negatively associated with OS for HCC patients. The multivariate Cox regression analyses suggested that CDK1 was an independent prognostic factor, which was validated in an independent case cohort (N = 78. In cellular models, inhibition of CDK1 by siRNA or a specific inhibitor, RO-3306, reduced cellular proliferation and viability for HCC cells. These results suggest that the prognostic predictive capacities of these gene signatures are reproducible and that CDK1 is a potential prognostic biomarker or therapeutic target for HCC patients.

  5. Gene Expression Signatures of Lymph Node Metastasis in Oral Cancer: Molecular Characteristics and Clinical Significances

    Science.gov (United States)

    Liu, Xiqiang; Kolokythas, Antonia; Wang, Jianguang; Huang, Hongzhang; Zhou, Xiaofeng

    2011-01-01

    Even though lymph node metastasis accounts for the vast majority of cancer death in patients with oral cancer (OC), the molecular mechanisms of lymph node metastasis remain elusive. Genome-wide microarray analyses and functional studies in vitro and in vivo, along with detailed clinical observations, have identified a number of molecules that may contribute to lymph node metastasis. These include lymphangionenic cytokines, cell adhesion molecules, basement membrane-interacting molecules, matrix enzymes and relevant downstream signaling pathways. However, defined gene signatures from different studies are highly variable, which hinders their translation to clinically relevant applications. To date, none of the identified signatures or molecular biomarkers has been successfully implemented as a diagnostic or prognostic tool applicable to routine clinical practice. In this review, we will first introduce the significance of lymph node metastasis in OC, and clinical/experimental evidences that support the underlying molecular mechanisms. We will then provide a comprehensive review and integrative analysis of the existing gene expression studies that aim to identify the metastasis-related signatures in OC. Finally, the remaining challenges will be discussed and our insights on future directions will be provided. PMID:21709736

  6. Context modulates the ERP signature of contour integration.

    Directory of Open Access Journals (Sweden)

    Bart Machilsen

    Full Text Available We investigated how the electrophysiological signature of contour integration is changed by the context in which a contour is embedded. Specifically, we manipulated the orientations of Gabor elements surrounding an embedded shape outline. The amplitudes of early visual components over posterior scalp regions were changed by the presence of a contour, and by the orientation of elements surrounding the contour. Differences in context type had an effect on the early P1 and N1 components, but not on the later P2 component. The presence of a contour had an effect on the N1 and P2 components, but not on the earlier P1 component. A modulatory effect of context on contour integration was observed on the N1 component. These results highlight the importance of the context in which contour integration takes place.

  7. Mycobacterium tuberculosis strains exhibit differential and strain-specific molecular signatures in pulmonary epithelial cells.

    Science.gov (United States)

    Mvubu, Nontobeko Eunice; Pillay, Balakrishna; Gamieldien, Junaid; Bishai, William; Pillay, Manormoney

    2016-12-01

    Although pulmonary epithelial cells are integral to innate and adaptive immune responses during Mycobacterium tuberculosis infection, global transcriptomic changes in these cells remain largely unknown. Changes in gene expression induced in pulmonary epithelial cells infected with M. tuberculosis F15/LAM4/KZN, F11, F28, Beijing and Unique genotypes were investigated by RNA sequencing (RNA-Seq). The Illumina HiSeq 2000 platform generated 50 bp reads that were mapped to the human genome (Hg19) using Tophat (2.0.10). Differential gene expression induced by the different strains in infected relative to the uninfected cells was quantified and compared using Cufflinks (2.1.0) and MeV (4.0.9), respectively. Gene expression varied among the strains with the total number of genes as follows: F15/LAM4/KZN (1187), Beijing (1252), F11 (1639), F28 (870), Unique (886) and H37Rv (1179). A subset of 292 genes was commonly induced by all strains, where 52 genes were down-regulated while 240 genes were up-regulated. Differentially expressed genes were compared among the strains and the number of induced strain-specific gene signatures were as follows: F15/LAM4/KZN (138), Beijing (52), F11 (255), F28 (55), Unique (186) and H37Rv (125). Strain-specific molecular gene signatures associated with functional pathways were observed only for the Unique and H37Rv strains while certain biological functions may be associated with other strain signatures. This study demonstrated that strains of M. tuberculosis induce differential gene expression and strain-specific molecular signatures in pulmonary epithelial cells. Specific signatures induced by clinical strains of M. tuberculosis can be further explored for novel host-associated biomarkers and adjunctive immunotherapies.

  8. A 6-gene signature identifies four molecular subgroups of neuroblastoma

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    Kogner Per

    2011-04-01

    Full Text Available Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB; Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples. Four distinct clusters were identified by Principal Components Analysis (PCA in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.

  9. Purification, Visualization, and Molecular Signature of Neural Stem Cells

    Science.gov (United States)

    Yu, Yuan Hong; Narayanan, Gunaseelan; Sankaran, Shvetha; Ramasamy, Srinivas; Chan, Shi Yu; Lin, Shuping; Chen, Jinmiao; Yang, Henry; Srivats, Hariharan

    2016-01-01

    Neural stem cells (NSCs) are isolated from primary brain tissue and propagated as a heterogeneous mix of cells, including neural progenitors. To date, NSCs have not been purified in vitro to allow study of their biology and utility in regenerative medicine. In this study, we identify C1qR1as a novel marker for NSCs and show that it can be used along with Lewis-X (LeX) to yield a highly purified population of NSCs. Using time-lapse microscopy, we are able to follow NSCs forming neurospheres, allowing their visualization. Finally, using single-cell polymerase chain reaction (PCR), we determine the molecular signature of NSCs. The single-cell PCR data suggest that along with the Notch and Shh pathways, the Hippo pathway plays an important role in NSC activity. PMID:26464067

  10. Unraveling molecular signatures of immunostimulatory adjuvants in the female genital tract through systems biology.

    Directory of Open Access Journals (Sweden)

    Madelene Lindqvist

    Full Text Available Sexually transmitted infections (STIs unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha-galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome data determined which signature pathways, processes and networks are shared by or otherwise exclusive to these 2 classes of experimental vaginal adjuvants in the mouse vagina. To our knowledge, this is the first integrated genome-wide transcriptome analysis of the effects of immunomodulatory adjuvants on the female genital tract of a mammal. These results could inform rational development of effective mucosal adjuvants for vaccination against STIs.

  11. Molecular signatures of transgenerational response to ocean acidification in a species of reef fish

    Science.gov (United States)

    Schunter, Celia; Welch, Megan J.; Ryu, Taewoo; Zhang, Huoming; Berumen, Michael L.; Nilsson, Göran E.; Munday, Philip L.; Ravasi, Timothy

    2016-11-01

    The impact of ocean acidification on marine ecosystems will depend on species capacity to adapt. Recent studies show that the behaviour of reef fishes is impaired at projected CO 2 levels; however, individual variation exists that might promote adaptation. Here, we show a clear signature of parental sensitivity to high CO 2 in the brain molecular phenotype of juvenile spiny damselfish, Acanthochromis polyacanthus, primarily driven by circadian rhythm genes. Offspring of CO 2-tolerant and CO 2-sensitive parents were reared at near-future CO 2 (754 μatm) or present-day control levels (414 μatm). By integrating 33 brain transcriptomes and proteomes with a de novo assembled genome we investigate the molecular responses of the fish brain to increased CO 2 and the expression of parental tolerance to high CO 2 in the offspring molecular phenotype. Exposure to high CO 2 resulted in differential regulation of 173 and 62 genes and 109 and 68 proteins in the tolerant and sensitive groups, respectively. Importantly, the majority of differences between offspring of tolerant and sensitive parents occurred in high CO 2 conditions. This transgenerational molecular signature suggests that individual variation in CO 2 sensitivity could facilitate adaptation of fish populations to ocean acidification.

  12. Molecular signatures of transgenerational response to ocean acidification in a species of reef fish

    KAUST Repository

    Schunter, Celia Marei

    2016-07-29

    The impact of ocean acidification on marine ecosystems will depend on species capacity to adapt. Recent studies show that the behaviour of reef fishes is impaired at projected CO levels; however, individual variation exists that might promote adaptation. Here, we show a clear signature of parental sensitivity to high CO in the brain molecular phenotype of juvenile spiny damselfish, Acanthochromis polyacanthus, primarily driven by circadian rhythm genes. Offspring of CO -tolerant and CO -sensitive parents were reared at near-future CO (754 μatm) or present-day control levels (414 μatm). By integrating 33 brain transcriptomes and proteomes with a de novo assembled genome we investigate the molecular responses of the fish brain to increased CO and the expression of parental tolerance to high CO in the offspring molecular phenotype. Exposure to high CO resulted in differential regulation of 173 and 62 genes and 109 and 68 proteins in the tolerant and sensitive groups, respectively. Importantly, the majority of differences between offspring of tolerant and sensitive parents occurred in high CO conditions. This transgenerational molecular signature suggests that individual variation in CO sensitivity could facilitate adaptation of fish populations to ocean acidification.

  13. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    LENUS (Irish Health Repository)

    Abel, Frida

    2011-04-14

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and\\/or dead of disease, p < 0.05, Fisher\\'s exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group\\'s specific characteristics.

  14. Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis.

    Science.gov (United States)

    Inkeles, Megan S; Scumpia, Philip O; Swindell, William R; Lopez, David; Teles, Rosane M B; Graeber, Thomas G; Meller, Stephan; Homey, Bernhard; Elder, James T; Gilliet, Michel; Modlin, Robert L; Pellegrini, Matteo

    2015-01-01

    The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level.

  15. A common molecular signature in ASD gene expression: following Root 66 to autism.

    Science.gov (United States)

    Diaz-Beltran, L; Esteban, F J; Wall, D P

    2016-01-05

    Several gene expression experiments on autism spectrum disorders have been conducted using both blood and brain tissue. Individually, these studies have advanced our understanding of the molecular systems involved in the molecular pathology of autism and have formed the bases of ongoing work to build autism biomarkers. In this study, we conducted an integrated systems biology analysis of 9 independent gene expression experiments covering 657 autism, 9 mental retardation and developmental delay and 566 control samples to determine if a common signature exists and to test whether regulatory patterns in the brain relevant to autism can also be detected in blood. We constructed a matrix of differentially expressed genes from these experiments and used a Jaccard coefficient to create a gene-based phylogeny, validated by bootstrap. As expected, experiments and tissue types clustered together with high statistical confidence. However, we discovered a statistically significant subgrouping of 3 blood and 2 brain data sets from 3 different experiments rooted by a highly correlated regulatory pattern of 66 genes. This Root 66 appeared to be non-random and of potential etiologic relevance to autism, given their enriched roles in neurological processes key for normal brain growth and function, learning and memory, neurodegeneration, social behavior and cognition. Our results suggest that there is a detectable autism signature in the blood that may be a molecular echo of autism-related dysregulation in the brain.

  16. Integrated Transcriptomics Establish Macrophage Polarization Signatures and have Potential Applications for Clinical Health and Disease

    Science.gov (United States)

    Becker, Matheus; De Bastiani, Marco A.; Parisi, Mariana M.; Guma, Fátima T. C. R.; Markoski, Melissa M.; Castro, Mauro A. A.; Kaplan, Mark H.; Barbé-Tuana, Florencia M.; Klamt, Fábio

    2015-01-01

    Growing evidence defines macrophages (Mφ) as plastic cells with wide-ranging states of activation and expression of different markers that are time and location dependent. Distinct from the simple M1/M2 dichotomy initially proposed, extensive diversity of macrophage phenotypes have been extensively demonstrated as characteristic features of monocyte-macrophage differentiation, highlighting the difficulty of defining complex profiles by a limited number of genes. Since the description of macrophage activation is currently contentious and confusing, the generation of a simple and reliable framework to categorize major Mφ phenotypes in the context of complex clinical conditions would be extremely relevant to unravel different roles played by these cells in pathophysiological scenarios. In the current study, we integrated transcriptome data using bioinformatics tools to generate two macrophage molecular signatures. We validated our signatures in in vitro experiments and in clinical samples. More importantly, we were able to attribute prognostic and predictive values to components of our signatures. Our study provides a framework to guide the interrogation of macrophage phenotypes in the context of health and disease. The approach described here could be used to propose new biomarkers for diagnosis in diverse clinical settings including dengue infections, asthma and sepsis resolution. PMID:26302899

  17. Dynamical signatures of molecular symmetries in nonequilibrium quantum transport

    Science.gov (United States)

    Thingna, Juzar; Manzano, Daniel; Cao, Jianshu

    2016-06-01

    Symmetries play a crucial role in ubiquitous systems found in Nature. In this work, we propose an elegant approach to detect symmetries by measuring quantum currents. Our detection scheme relies on initiating the system in an anti-symmetric initial condition, with respect to the symmetric sites, and using a probe that acts like a local noise. Depending on the position of the probe the currents exhibit unique signatures such as a quasi-stationary plateau indicating the presence of metastability and multi-exponential decays in case of multiple symmetries. The signatures are sensitive to the characteristics of the probe and vanish completely when the timescale of the coherent system dynamics is much longer than the timescale of the probe. These results are demonstrated using a 4-site model and an archetypal example of the para-benzene ring and are shown to be robust under a weak disorder.

  18. Dynamical signatures of molecular symmetries in nonequilibrium quantum transport.

    Science.gov (United States)

    Thingna, Juzar; Manzano, Daniel; Cao, Jianshu

    2016-06-17

    Symmetries play a crucial role in ubiquitous systems found in Nature. In this work, we propose an elegant approach to detect symmetries by measuring quantum currents. Our detection scheme relies on initiating the system in an anti-symmetric initial condition, with respect to the symmetric sites, and using a probe that acts like a local noise. Depending on the position of the probe the currents exhibit unique signatures such as a quasi-stationary plateau indicating the presence of metastability and multi-exponential decays in case of multiple symmetries. The signatures are sensitive to the characteristics of the probe and vanish completely when the timescale of the coherent system dynamics is much longer than the timescale of the probe. These results are demonstrated using a 4-site model and an archetypal example of the para-benzene ring and are shown to be robust under a weak disorder.

  19. Dynamical signatures of molecular symmetries in nonequilibrium quantum transport

    OpenAIRE

    2016-01-01

    Symmetries play a crucial role in ubiquitous systems found in Nature. In this work, we propose an elegant approach to detect symmetries by measuring quantum currents. Our detection scheme relies on initiating the system in an anti-symmetric initial condition, with respect to the symmetric sites, and using a probe that acts like a local noise. Depending on the position of the probe the currents exhibit unique signatures such as a quasi-stationary plateau indicating the presence of metastabilit...

  20. Uncovering the Hidden Molecular Signatures of Breast Cancer

    Science.gov (United States)

    2013-05-01

    signatures!that!are!macroenvironmental!(present! in! all! compartments!of! the! tumor)! vs ! those! that! are!microenvironmental! (present! either! in...Schreiber!GJ,!Peterse!JL,! Roberts!C,!Marton!MJ,!Parrish!M,!Atsma!D,!Witteveen!A,! Glas !A,!Delahaye!L,!van!der!Velde!T,! Bartelink!H,!Rodenhuis!S,!Rutgers...were grown on tissue culture plastic and counted every 24 h (C). Error bars, SEM. To assess any effect on cell viability, cells treated with MET

  1. Integrative radiogenomic analysis for genomic signatures in glioblastomas presenting leptomeningeal dissemination.

    Science.gov (United States)

    You, Hye Jin; Park, Ho-Young; Kim, Jinkuk; Lee, In-Hee; Seol, Ho Jun; Lee, Jung-Il; Kim, Sung Tae; Kong, Doo-Sik; Nam, Do-Hyun

    2016-07-01

    Despite therapeutic advances, the prognosis for glioblastoma (GBM) remains poor. In particular, leptomeningeal dissemination (LMD) has a dismal prognosis. The aim of this study was to identify tumor molecular phenotype, which has a great propensity to develop LMD. Between May 2004 and December 2012, a total of 145 GBM tumor samples were obtained from data registry. A total of 20 of the 145 patients with GBM were found to develop LMD. A specialized radiologist confirmed the diagnosis of LMD on magnetic resonance imaging. To clarify the genomic signatures in GBM with LMD, we performed integrative analysis of whole transcriptome sequencing and copy number alteration in the radiological features indicating LMD phenotypes in GBM. Eleven newly diagnosed patients with GBM with LMD had worse prognosis than those without LMD (median 5.55 vs. 12.94 months, P LMD group. In addition, it was demonstrated that NME2, TMEM100, and SIVA1 were downregulated with the loss of copy number. We also found that mesenchymal subtype accounted for 50% in LMD group, whereas mesenchymal subtype consisted of 29% in non-LMD group, even though there was no statistical significance (P = 0.06). Through this radiogenomic analysis, we suggested the possibility of finding candidate genes associated with LMD and highlighted the significance of integrating approach to clarify the molecular characteristics in LMD.

  2. Identification of a 5-protein biomarker molecular signature for predicting Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Martín Gómez Ravetti

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a progressive brain disease with a huge cost to human lives. The impact of the disease is also a growing concern for the governments of developing countries, in particular due to the increasingly high number of elderly citizens at risk. Alzheimer's is the most common form of dementia, a common term for memory loss and other cognitive impairments. There is no current cure for AD, but there are drug and non-drug based approaches for its treatment. In general the drug-treatments are directed at slowing the progression of symptoms. They have proved to be effective in a large group of patients but success is directly correlated with identifying the disease carriers at its early stages. This justifies the need for timely and accurate forms of diagnosis via molecular means. We report here a 5-protein biomarker molecular signature that achieves, on average, a 96% total accuracy in predicting clinical AD. The signature is composed of the abundances of IL-1alpha, IL-3, EGF, TNF-alpha and G-CSF. METHODOLOGY/PRINCIPAL FINDINGS: Our results are based on a recent molecular dataset that has attracted worldwide attention. Our paper illustrates that improved results can be obtained with the abundance of only five proteins. Our methodology consisted of the application of an integrative data analysis method. This four step process included: a abundance quantization, b feature selection, c literature analysis, d selection of a classifier algorithm which is independent of the feature selection process. These steps were performed without using any sample of the test datasets. For the first two steps, we used the application of Fayyad and Irani's discretization algorithm for selection and quantization, which in turn creates an instance of the (alpha-beta-k-Feature Set problem; a numerical solution of this problem led to the selection of only 10 proteins. CONCLUSIONS/SIGNIFICANCE: the previous study has provided an extremely

  3. Molecular signatures define alopecia areata subtypes and transcriptional biomarkers

    Directory of Open Access Journals (Sweden)

    Ali Jabbari

    2016-05-01

    Full Text Available Alopecia areata (AA is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis. Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis.

  4. Molecular subsets in the gene expression signatures of scleroderma skin.

    Directory of Open Access Journals (Sweden)

    Ausra Milano

    Full Text Available BACKGROUND: Scleroderma is a clinically heterogeneous disease with a complex phenotype. The disease is characterized by vascular dysfunction, tissue fibrosis, internal organ dysfunction, and immune dysfunction resulting in autoantibody production. METHODOLOGY AND FINDINGS: We analyzed the genome-wide patterns of gene expression with DNA microarrays in skin biopsies from distinct scleroderma subsets including 17 patients with systemic sclerosis (SSc with diffuse scleroderma (dSSc, 7 patients with SSc with limited scleroderma (lSSc, 3 patients with morphea, and 6 healthy controls. 61 skin biopsies were analyzed in a total of 75 microarray hybridizations. Analysis by hierarchical clustering demonstrates nearly identical patterns of gene expression in 17 out of 22 of the forearm and back skin pairs of SSc patients. Using this property of the gene expression, we selected a set of 'intrinsic' genes and analyzed the inherent data-driven groupings. Distinct patterns of gene expression separate patients with dSSc from those with lSSc and both are easily distinguished from normal controls. Our data show three distinct patient groups among the patients with dSSc and two groups among patients with lSSc. Each group can be distinguished by unique gene expression signatures indicative of proliferating cells, immune infiltrates and a fibrotic program. The intrinsic groups are statistically significant (p<0.001 and each has been mapped to clinical covariates of modified Rodnan skin score, interstitial lung disease, gastrointestinal involvement, digital ulcers, Raynaud's phenomenon and disease duration. We report a 177-gene signature that is associated with severity of skin disease in dSSc. CONCLUSIONS AND SIGNIFICANCE: Genome-wide gene expression profiling of skin biopsies demonstrates that the heterogeneity in scleroderma can be measured quantitatively with DNA microarrays. The diversity in gene expression demonstrates multiple distinct gene expression programs

  5. Molecular-signature analyses support the establishment of the actinobacterial genus Sphaerimonospora (Mingma et al. 2016).

    Science.gov (United States)

    Meyers, Paul R

    2017-08-18

    The genera Microbispora and Sphaerimonospora were examined for GyrB and RecA amino-acid signatures to determine whether molecular-signature analyses support the recent establishment of the genus Sphaerimonospora. The creation of Sphaerimonospora was based mainly upon morphological differences between Microbispora and Sphaerimonospora and the clustering of the type strains of the two genera in phylogenetic trees based on a multilocus sequence analysis. The molecular-signature analyses showed that all members of Sphaerimonospora can be distinguished from all members of Microbispora at 14 amino acid positions in the GyrB protein and at four positions in the shorter RecA protein. These amino acid differences can be used as signatures to differentiate the members of these genera from each other and thus provide support for the establishment of the genus Sphaerimonospora. This is the first demonstration of the use of molecular signatures to support the establishment of a new genus in the family Streptosporangiaceae. Following the transfer of Microbispora mesophila and Microbispora thailandensis from Microbispora to Sphaerimonospora, all species in the genus Microbispora are characterised by the insertion of a small, hydrophobic amino acid after position 208 in the GyrB protein. This insertion is absent from the GyrB protein of members of the genus Sphaerimonospora. Copyright © 2017 Elsevier GmbH. All rights reserved.

  6. Integrative radiogenomic analysis for genomic signatures in glioblastomas presenting leptomeningeal dissemination

    Science.gov (United States)

    You, Hye Jin; Park, Ho-Young; Kim, Jinkuk; Lee, In-Hee; Seol, Ho Jun; Lee, Jung-Il; Kim, Sung Tae; Kong, Doo-Sik; Nam, Do-Hyun

    2016-01-01

    Abstract Despite therapeutic advances, the prognosis for glioblastoma (GBM) remains poor. In particular, leptomeningeal dissemination (LMD) has a dismal prognosis. The aim of this study was to identify tumor molecular phenotype, which has a great propensity to develop LMD. Between May 2004 and December 2012, a total of 145 GBM tumor samples were obtained from data registry. A total of 20 of the 145 patients with GBM were found to develop LMD. A specialized radiologist confirmed the diagnosis of LMD on magnetic resonance imaging. To clarify the genomic signatures in GBM with LMD, we performed integrative analysis of whole transcriptome sequencing and copy number alteration in the radiological features indicating LMD phenotypes in GBM. Eleven newly diagnosed patients with GBM with LMD had worse prognosis than those without LMD (median 5.55 vs. 12.94 months, P < 0.0001). Integrating analysis using gene expression based on the change of copy number revealed that SPOCK1, EHD2, SLC2A3, and ANXA11 were highly expressed with the gain of copy number, compared with the gene expression in the non-LMD group. In addition, it was demonstrated that NME2, TMEM100, and SIVA1 were downregulated with the loss of copy number. We also found that mesenchymal subtype accounted for 50% in LMD group, whereas mesenchymal subtype consisted of 29% in non-LMD group, even though there was no statistical significance (P = 0.06). Through this radiogenomic analysis, we suggested the possibility of finding candidate genes associated with LMD and highlighted the significance of integrating approach to clarify the molecular characteristics in LMD. PMID:27399113

  7. Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy*

    Science.gov (United States)

    Turk, Rolf; Hsiao, Jordy J.; Smits, Melinda M.; Ng, Brandon H.; Pospisil, Tyler C.; Jones, Kayla S.; Campbell, Kevin P.; Wright, Michael E.

    2016-01-01

    Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of the DGC in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components. Bioinformatic analyses suggested that cell-adhesion pathways were under the transcriptional control of NFκB in DGC mutant mice, which is a finding that is supported by previous studies that showed NFκB-regulated pathways underlie the pathophysiology of DGC-related muscular dystrophies. Moreover, the bioinformatic analyses suggested that inflammatory and compensatory mechanisms were activated in skeletal muscle of DGC mutant mice. Additionally, this proteomic study provides a molecular framework to refine our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle https://www.mda.org/disease/congenital-muscular-dystrophy/research. PMID:27099343

  8. Angiogenic molecular signature in colorectal cancer: Pharmacogenomic implications for the use of antiangiogenic therapies

    OpenAIRE

    2014-01-01

    In the framework of personalized medicine in antiangiogenesis, we took a translational research approach to explore the angiogenic molecular signature of advanced CRC patients. As derived from our findings in vitro, the tumour microenvironment of CRC metastases would be different to that of primary tumours. The mCRC more aggressive molecular phenotype provides some intrinsic resistance to the hypoxic induction of VEGF expression. The distinct metastatic "secretome" emerge as potential pro...

  9. An Overview of Biomarkers and Molecular Signatures in HCC

    Directory of Open Access Journals (Sweden)

    Seon-Hee Yim

    2010-05-01

    Full Text Available Hepatocellular carcinoma (HCC is the third most common cause of cancer mortality worldwide. Although most HCCs seem to originate from the accumulation of genetic abnormalities induced by various risk factors, underlying mechanisms of hepatocarcinogenesis remain unclear. Long-term survival of HCC patients is also poor, partly due to HCC recurrence. Although serum alpha-fetoprotein (AFP level is a useful marker for the detection and monitoring of HCC, AFP levels may remain normal in the patients even with advanced HCC. To identify useful biomarkers for HCC, many studies have been conducted on molecular events such as genetic and epigenetic alterations, and gene expression. This review summarizes recent studies of potential molecular markers for diagnosis and monitoring metastasis or recurrence of HCC.

  10. An Overview of Biomarkers and Molecular Signatures in HCC

    Energy Technology Data Exchange (ETDEWEB)

    Yim, Seon-Hee [Integrated Research Center for Genome Polymorphism, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701 (Korea, Republic of); Chung, Yeun-Jun, E-mail: yejun@catholic.ac.kr [Integrated Research Center for Genome Polymorphism, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701 (Korea, Republic of); Department of Microbiology, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701 (Korea, Republic of)

    2010-05-07

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Although most HCCs seem to originate from the accumulation of genetic abnormalities induced by various risk factors, underlying mechanisms of hepatocarcinogenesis remain unclear. Long-term survival of HCC patients is also poor, partly due to HCC recurrence. Although serum alpha-fetoprotein (AFP) level is a useful marker for the detection and monitoring of HCC, AFP levels may remain normal in the patients even with advanced HCC. To identify useful biomarkers for HCC, many studies have been conducted on molecular events such as genetic and epigenetic alterations, and gene expression. This review summarizes recent studies of potential molecular markers for diagnosis and monitoring metastasis or recurrence of HCC.

  11. Quantum signatures of a molecular nanomagnet in direct magnetocaloric measurements.

    Science.gov (United States)

    Sharples, Joseph W; Collison, David; McInnes, Eric J L; Schnack, Jürgen; Palacios, Elias; Evangelisti, Marco

    2014-10-22

    Geometric spin frustration in low-dimensional materials, such as the two-dimensional kagome or triangular antiferromagnetic nets, can significantly enhance the change of the magnetic entropy and adiabatic temperature following a change in the applied magnetic field, that is, the magnetocaloric effect. In principle, an equivalent outcome should also be observable in certain high-symmetry zero-dimensional, that is, molecular, structures with frustrated topologies. Here we report experimental realization of this in a heptametallic gadolinium molecule. Adiabatic demagnetization experiments reach ~200 mK, the first sub-Kelvin cooling with any molecular nanomagnet, and reveal isentropes (the constant entropy paths followed in the temperature-field plane) with a rich structure. The latter is shown to be a direct manifestation of the trigonal antiferromagnetic net structure, allowing study of frustration-enhanced magnetocaloric effects in a finite system.

  12. A Molecular Signature of Myalgia in Myotonic Dystrophy 2.

    Science.gov (United States)

    Moshourab, Rabih; Palada, Vinko; Grunwald, Stefanie; Grieben, Ulrike; Lewin, Gary R; Spuler, Simone

    2016-05-01

    Chronic muscle pain affects close to 20% of the population and is a major health burden. The underlying mechanisms of muscle pain are difficult to investigate as pain presents in patients with very diverse histories. Treatment options are therefore limited and not tailored to underlying mechanisms. To gain insight into the pathophysiology of myalgia we investigated a homogeneous group of patients suffering from myotonic dystrophy type 2 (DM2), a monogenic disorder presenting with myalgia in at least 50% of affected patients. After IRB approval we performed an observational cross-sectional cohort study and recruited 42 patients with genetically confirmed DM2 plus 20 healthy age and gender matched control subjects. All participants were subjected to an extensive sensory-testing protocol. In addition, RNA sequencing was performed from 12 muscle biopsy specimens obtained from DM2 patients. Clinical sensory testing as well as RNA sequencing clearly separated DM2 myalgic from non-myalgia patients and also from healthy controls. In particular pressure pain thresholds were significantly lowered for all muscles tested in myalgic DM2 patients but were not significantly different between non-myalgic patients and healthy controls. The expression of fourteen muscle expressed genes in myalgic patients was significantly up or down-regulated in myalgic compared to non-myalgic DM2 patients. Our data support the idea that molecular changes in the muscles of DM2 patients are associated with muscle pain. Further studies should address whether muscle-specific molecular pathways play a significant role in myalgia in order to facilitate the development of mechanism-based therapeutic strategies to treat musculoskeletal pain. This study was funded by the German Research Society (DFG, GK1631), KAP programme of Charité Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Signatures of molecular recognition from the topography of electrostatic potential

    Indian Academy of Sciences (India)

    Dhimoy K Roy; P Balanarayan; Shridhar R Gadre

    2009-09-01

    The recognition of interaction between two molecules is analysed via the topography of their molecular electrostatic potentials (MESP). The point of recognition between two species is proposed to be the geometry at which there is a change in the nature of the set of MESP critical points of one of the molecules vis-a-vis with its MESP topography at infinite separation. These results are presented for certain model systems such as pyridine and benzene dimers, cytosine-guanine and adenine-thymine base pairs in various orientations of approach of the two species.

  14. Contraction Signatures Toward Dense Cores in the Perseus Molecular Cloud

    CERN Document Server

    Campbell, J L; Martin, P G; Caselli, P; Kauffmann, J; Pineda, J E

    2016-01-01

    We report the results of an HCO+ (3-2) and N2D+ (3-2) molecular line survey performed toward 91 dense cores in the Perseus molecular cloud using the James Clerk Maxwell Telescope, to identify the fraction of starless and protostellar cores with systematic radial motions. We quantify the HCO+ asymmetry using a dimensionless asymmetry parameter $\\delta_v$, and identify 20 cores with significant blue or red line asymmetries in optically-thick emission indicative of collapsing or expanding motions, respectively. We separately fit the HCO+ profiles with an analytic collapse model and determine contraction (expansion) speeds toward 22 cores. Comparing the $\\delta_v$ and collapse model results, we find that $\\delta_v$ is a good tracer of core contraction if the optically-thin emission is aligned with the model-derived systemic velocity. The contraction speeds range from subsonic (0.03 km/s) to supersonic (0.4 km/s), where the supersonic contraction speeds may trace global rather than local core contraction. Most cor...

  15. Reading the molecular signature of ecosystems in dissolved organic matter

    Science.gov (United States)

    Simon, Carsten; Roth, Vanessa-Nina; Dittmar, Thorsten; Gleixner, Gerd

    2017-04-01

    To make forecasts about the behavior, origin and fate of dissolved organic matter (DOM) in the environment, we need further insights into the molecular composition of this complex mixture. The development of soft ionization procedures and mass spectrometers capable of ultrahigh resolution (Fourier-Transform Mass Spectrometry, FTMS) have opened important new horizons in this regard. However, the application of such systems is restricted due to high purchase and maintenance costs. The introduction of the improved version of the Orbitrap FTMS analyzer ("Elite") in 2011 could open new perspectives for the molecular-level investigation of DOM, as it combines high performance with lower overall costs. We compared the Orbitrap with an established FT-ICR-MS (ion cyclotron resonance, 15 Tesla) to assess the potential of this analyzer on a broad set of 17 terrestrial and aquatic DOM samples prepared by solid phase extraction (SPE-DOM, Dittmar et al. 2008). The dataset included groundwater, soil water from different depths and vegetation covers (forests, grassland), as well as bog, river, lake and marine waters. We here show that the Orbitrap analyzer is able to detect hard-to-resolve nitrogen and sulfur containing compounds (triplet signal [CHO]N2O2, [CHO]C5, [CHO]C2H4S) up to a mass-to-charge ratio of 430 and well retrieves the intensity information of the FT-ICR-MS. Both points have been recently reported as major obstacles in the detailed molecular-level analyses of DOM by Orbitrap systems (Hawkes et al. 2016). In our data, slight deviations in intensity representation were only found in samples characterized by stronger aromaticity, and especially in the lower mass range (below m/z 250). A subset of > 6000 formulae detected in both sets was used to further characterize the sample set on a molecular level. The derived ecological information, as assessed by ordination and post-ordination gradient fitting, was highly consistent among both datasets. A dominating first

  16. Contraction Signatures toward Dense Cores in the Perseus Molecular Cloud

    Science.gov (United States)

    Campbell, J. L.; Friesen, R. K.; Martin, P. G.; Caselli, P.; Kauffmann, J.; Pineda, J. E.

    2016-03-01

    We report the results of an HCO+ (3-2) and N2D+ (3-2) molecular line survey performed toward 91 dense cores in the Perseus molecular cloud using the James Clerk Maxwell Telescope, to identify the fraction of starless and protostellar cores with systematic radial motions. We quantify the HCO+ asymmetry using a dimensionless asymmetry parameter δv, and identify 20 cores with significant blue or red line asymmetries in optically thick emission indicative of collapsing or expanding motions, respectively. We separately fit the HCO+ profiles with an analytic collapse model and determine contraction (expansion) speeds toward 22 cores. Comparing the δv and collapse model results, we find that δv is a good tracer of core contraction if the optically thin emission is aligned with the model-derived systemic velocity. The contraction speeds range from subsonic (0.03 km s-1) to supersonic (0.4 km s-1), where the supersonic contraction speeds may trace global rather than local core contraction. Most cores have contraction speeds significantly less than their free-fall speeds. Only 7 of 28 starless cores have spectra well-fit by the collapse model, which more than doubles (15 of 28) for protostellar cores. Starless cores with masses greater than the Jeans mass (M/MJ > 1) are somewhat more likely to show contraction motions. We find no trend of optically thin non-thermal line width with M/MJ, suggesting that any undetected contraction motions are small and subsonic. Most starless cores in Perseus are either not in a state of collapse or expansion, or are in a very early stage of collapse.

  17. CONTRACTION SIGNATURES TOWARD DENSE CORES IN THE PERSEUS MOLECULAR CLOUD

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, J. L. [Department of Astronomy and Astrophysics, University of Toronto, 50 St. George St., Toronto, Ontario, M5S 3H4 (Canada); Friesen, R. K. [Dunlap Institute for Astronomy and Astrophysics, University of Toronto, 50 St. George St., Toronto, Ontario, M5S 3H4 (Canada); Martin, P. G. [Canadian Institute for Theoretical Astrophysics, University of Toronto, 60 St. George St., Toronto, Ontario, M5S 3H8 (Canada); Caselli, P.; Pineda, J. E. [Max-Planck-Institut für extraterrestrische Physik (MPE), Gießenbachstrasse 1, D-85741 Garching (Germany); Kauffmann, J., E-mail: jessicalynn.campbell@mail.utoronto.ca [Max-Planck-Institut für Radioastronomie, Auf dem Hügel 69, D-53121 Bonn (Germany)

    2016-03-10

    We report the results of an HCO{sup +} (3–2) and N{sub 2}D{sup +} (3–2) molecular line survey performed toward 91 dense cores in the Perseus molecular cloud using the James Clerk Maxwell Telescope, to identify the fraction of starless and protostellar cores with systematic radial motions. We quantify the HCO{sup +} asymmetry using a dimensionless asymmetry parameter δ{sub v}, and identify 20 cores with significant blue or red line asymmetries in optically thick emission indicative of collapsing or expanding motions, respectively. We separately fit the HCO{sup +} profiles with an analytic collapse model and determine contraction (expansion) speeds toward 22 cores. Comparing the δ{sub v} and collapse model results, we find that δ{sub v} is a good tracer of core contraction if the optically thin emission is aligned with the model-derived systemic velocity. The contraction speeds range from subsonic (0.03 km s{sup −1}) to supersonic (0.4 km s{sup −1}), where the supersonic contraction speeds may trace global rather than local core contraction. Most cores have contraction speeds significantly less than their free-fall speeds. Only 7 of 28 starless cores have spectra well-fit by the collapse model, which more than doubles (15 of 28) for protostellar cores. Starless cores with masses greater than the Jeans mass (M/M{sub J} > 1) are somewhat more likely to show contraction motions. We find no trend of optically thin non-thermal line width with M/M{sub J}, suggesting that any undetected contraction motions are small and subsonic. Most starless cores in Perseus are either not in a state of collapse or expansion, or are in a very early stage of collapse.

  18. Molecular signature of organic nitrogen in septic-impacted groundwater

    Science.gov (United States)

    Arnold, William A.; Longnecker, Krista; Kroeger, Kevin D.; Kujawinski, Elizabeth B.

    2014-01-01

    Dissolved inorganic and organic nitrogen levels are elevated in aquatic systems due to anthropogenic activities. Dissolved organic nitrogen (DON) arises from various sources, and its impact could be more clearly constrained if specific sources were identified and if the molecular-level composition of DON were better understood. In this work, the pharmaceutical carbamazepine was used to identify septic-impacted groundwater in a coastal watershed. Using ultrahigh resolution mass spectrometry data, the nitrogen-containing features of the dissolved organic matter in septic-impacted and non-impacted samples were compared. The septic-impacted groundwater samples have a larger abundance of nitrogen-containing formulas. Impacted samples have additional DON features in the regions ascribed as ‘protein-like’ and ‘lipid-like’ in van Krevelen space and have more intense nitrogen-containing features in a specific region of a carbon versus mass plot. These features are potential indicators of dissolved organic nitrogen arising from septic effluents, and this work suggests that ultrahigh resolution mass spectrometry is a valuable tool to identify and characterize sources of DON.

  19. Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma.

    Science.gov (United States)

    Drew, Janice E; Farquharson, Andrew J; Mayer, Claus Dieter; Vase, Hollie F; Coates, Philip J; Steele, Robert J; Carey, Francis A

    2014-01-01

    Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.

  20. Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma.

    Directory of Open Access Journals (Sweden)

    Janice E Drew

    Full Text Available Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2, proliferation (PCNA, CCND1, MS4A12, differentiation (B4GANLT2, CDX1, CDX2, apoptotic (CASP3, NOX1, NTN1, fibroblast (FSP1, COL1A1, structural (ACTG2, CNN1, DES, gene transcription (HDAC1, stem cell (LGR5, endothelial (VWF and mucin production (MUC2. Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.

  1. A description of the Molecular Signatures Database (MSigDB) Web site.

    Science.gov (United States)

    Liberzon, Arthur

    2014-01-01

    Annotated lists of genes help researchers to prioritize their own lists of candidate genes and to plan follow-up studies. The Molecular Signatures Database (MSigDB) is one of the most widely used knowledge base repositories of annotated sets of genes involved in biochemical pathways, signaling cascades, expression profiles from research publications, and other biological concepts. Here we provide an overview of MSigDB and its online analytical tools.

  2. Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma.

    Science.gov (United States)

    Lin, Chin-Hsing Annie; Rhodes, Christopher T; Lin, ChenWei; Phillips, Joanna J; Berger, Mitchel S

    2017-04-18

    Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM. In the absence of IDH mutation, several genes associated with metabolism are differentially expressed in these subtypes of primary GBM, implicating metabolic reprogramming occurs in tumor microenvironment. Furthermore, histone lysine methyltransferase EZH2 was upregulated while histone lysine demethylases KDM2 and KDM4 were downregulated in both group I and II primary GBM. Lastly, we identified 9 common genes across large data sets of gene expression profiles among MRI-classified group I/II GBM, a large cohort of GBM subtypes from TCGA, and glioma stem cells by unsupervised clustering comparison. These commonly upregulated genes have known functions in cell cycle, centromere assembly, chromosome segregation, and mitotic progression. Our findings highlight altered expression of genes important in chromosome integrity across all GBM, suggesting a common mechanism of disrupted fidelity of chromosome structure in GBM.

  3. Square-root actions, metric signature, and the path-integral of quantum gravity

    CERN Document Server

    Carlini, A; Carlini, A; Greensite, J

    1995-01-01

    We consider quantization of the Baierlein-Sharp-Wheeler form of the gravitational action, in which the lapse function is determined from the Hamiltonian constraint. This action has a square root form, analogous to the actions of the relativistic particle and Nambu string. We argue that path-integral quantization of the gravitational action should be based on a path integrand \\exp[ \\sqrt{i} S ] rather than the familiar Feynman expression \\exp[ i S ], and that unitarity requires integration over manifolds of both Euclidean and Lorentzian signature. We discuss the relation of this path integral to our previous considerations regarding the problem of time, and extend our approach to include fermions.

  4. Square-root actions, metric signature, and the path integral of quantum gravity

    Science.gov (United States)

    Carlini, A.; Greensite, J.

    1995-12-01

    We consider quantization of the Baierlein-Sharp-Wheeler form of the gravitational action, in which the lapse function is determined from the Hamiltonian constraint. This action has a square root form, analogous to the actions of the relativistic particle and Nambu string. We argue that path-integral quantization of the gravitational action should be based on a path integrand exp[ √i S] rather than the familiar Feynman expression exp[iS], and that unitarity requires integration over manifolds of both Euclidean and Lorentzian signature. We discuss the relation of this path integral to our previous considerations regarding the problem of time, and extend our approach to include fermions.

  5. Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema.

    Science.gov (United States)

    Quaranta, Maria; Knapp, Bettina; Garzorz, Natalie; Mattii, Martina; Pullabhatla, Venu; Pennino, Davide; Andres, Christian; Traidl-Hoffmann, Claudia; Cavani, Andrea; Theis, Fabian J; Ring, Johannes; Schmidt-Weber, Carsten B; Eyerich, Stefanie; Eyerich, Kilian

    2014-07-09

    Previous attempts to gain insight into the pathogenesis of psoriasis and eczema by comparing their molecular signatures were hampered by the high interindividual variability of those complex diseases. In patients affected by both psoriasis and nonatopic or atopic eczema simultaneously (n = 24), an intraindividual comparison of the molecular signatures of psoriasis and eczema identified genes and signaling pathways regulated in common and exclusive for each disease across all patients. Psoriasis-specific genes were important regulators of glucose and lipid metabolism, epidermal differentiation, as well as immune mediators of T helper 17 (TH17) responses, interleukin-10 (IL-10) family cytokines, and IL-36. Genes in eczema related to epidermal barrier, reduced innate immunity, increased IL-6, and a TH2 signature. Within eczema subtypes, a mutually exclusive regulation of epidermal differentiation genes was observed. Furthermore, only contact eczema was driven by inflammasome activation, apoptosis, and cellular adhesion. On the basis of this comprehensive picture of the pathogenesis of psoriasis and eczema, a disease classifier consisting of NOS2 and CCL27 was created. In an independent cohort of eczema (n = 28) and psoriasis patients (n = 25), respectively, this classifier diagnosed all patients correctly and also identified initially misdiagnosed or clinically undifferentiated patients.

  6. Molecular signatures associated with HCV-induced hepatocellular carcinoma and liver metastasis.

    Directory of Open Access Journals (Sweden)

    Valeria De Giorgi

    Full Text Available Hepatocellular carcinomas (HCCs are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis.A diagnostic molecular signature complementing conventional pathologic assessment was identified.

  7. Optical signatures of molecular dissymmetry: combining theory with experiments to address stereochemical puzzles.

    Science.gov (United States)

    Mukhopadhyay, Parag; Wipf, Peter; Beratan, David N

    2009-06-16

    Modern chemistry emerged from the quest to describe the three-dimensional structure of molecules: van't Hoff's tetravalent carbon placed symmetry and dissymmetry at the heart of chemistry. In this Account, we explore how modern theory, synthesis, and spectroscopy can be used in concert to elucidate the symmetry and dissymmetry of molecules and their assemblies. Chiroptical spectroscopy, including optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA), measures the response of dissymmetric structures to electromagnetic radiation. This response can in turn reveal the arrangement of atoms in space, but deciphering the molecular information encoded in chiroptical spectra requires an effective theoretical approach. Although important correlations between ECD and molecular stereochemistry have existed for some time, a battery of accurate new theoretical methods that link a much wider range of chiroptical spectroscopies to structure have emerged over the past decade. The promise of this field is considerable: theory and spectroscopy can assist in assigning the relative and absolute configurations of complex products, revealing the structure of noncovalent aggregates, defining metrics for molecular diversity based on polarization response, and designing chirally imprinted nanomaterials. The physical organic chemistry of chirality is fascinating in its own right: defining atomic and group contributions to optical rotation (OR) is now possible. Although the common expectation is that chiroptical response is determined solely by a chiral solute's electronic structure in a given environment, chiral imprinting effects on the surrounding medium and molecular assembly can, in fact, dominate the chiroptical signatures. The theoretical interpretation of chiroptical markers is challenging because the optical properties are subtle, resulting from the strong electric dipole and the weaker electric

  8. Integrating Iris and Signature Traits for Personal Authentication Using User-SpecificWeighting

    Directory of Open Access Journals (Sweden)

    Serestina Viriri

    2012-03-01

    Full Text Available Biometric systems based on uni-modal traits are characterized by noisy sensor data, restricted degrees of freedom, non-universality and are susceptible to spoof attacks. Multi-modal biometric systems seek to alleviate some of these drawbacks by providing multiple evidences of the same identity. In this paper, a user-score-based weighting technique for integrating the iris and signature traits is presented. This user-specific weighting technique has proved to be an efficient and effective fusion scheme which increases the authentication accuracy rate of multi-modal biometric systems. The weights are used to indicate the importance of matching scores output by each biometrics trait. The experimental results show that our biometric system based on the integration of iris and signature traits achieve a false rejection rate (FRR of 0.08% and a false acceptance rate (FAR of 0.01%.

  9. Molecular Signature for Lymphatic Invasion Associated with Survival of Epithelial Ovarian Cancer.

    Science.gov (United States)

    Paik, E Sun; Choi, Hyun Jin; Kim, Tae-Joong; Lee, Jeong-Won; Kim, Byoung-Gie; Bae, Duk-Soo; Choi, Chel Hun

    2017-05-22

    We aimed to develop molecular classifier that can predict lymphatic invasion and their clinical significance in epithelial ovarian cancer (EOC) patients. We analyzed gene expression (mRNA, methylated DNA) in data from The Cancer Genome Atlas. To identify molecular signatures for lymphatic invasion, we found differentially expressed genes. The performance of classifier was validated by receiver operating characteristics analysis, logistic regression, linear discriminant analysis (LDA), and support vector machine (SVM). We assessed prognostic role of classifier using random survival forest (RSF) model and pathway deregulation score (PDS). For external validation, we analyzed microarray data from 26 EOC samples of Samsung Medical Center and curatedOvarianData database. We identified 21 mRNAs, and 7 methylated DNAs from primary EOC tissues that predicted lymphatic invasion, and created prognostic models. The classifier predicted lymphatic invasion well, which was validated by logistic regression, LDA, and SVM algorithm (C-index of 0.90, 0.71, and 0.74 for mRNA and C-index of 0.64, 0.68, and 0.69 for DNA methylation). Using RSF model, incorporating molecular data with clinical variables improved prediction of progression-free survival compared with using only clinical variables (P < 0.001 and P = 0.008). Similarly, PDS enabled us to classify patients into high-risk and low-risk group, which resulted in survival difference in mRNA profiles (Log rank P value = 0.011). In external validation, gene signature was well correlated with prediction of lymphatic invasion and patients' survival. Molecular signature model predicting lymphatic invasion was well performed, and also associated with survival of EOC patients.

  10. Integrated Molecular and Cellular Biophysics

    CERN Document Server

    Raicu, Valerica

    2008-01-01

    This book integrates concepts and methods from physics, biology, biochemistry and physical chemistry into a standalone, unitary text of biophysics that aims to provide a quantitative description of structures and processes occurring in living matter. The book introduces graduate physics students and physicists interested in biophysics research to 'classical' as well as emerging areas of biophysics. The advanced undergraduate physics students and the life scientists are also invited to join in, by building on their knowledge of basic physics. Essential notions of biochemistry and biology are introduced, as necessary, throughout the book, while the reader's familiarity with basic knowledge of physics is assumed. Topics covered include interactions between biological molecules, physical chemistry of phospholipids association into bilayer membranes, DNA and protein structure and folding, passive and active electrical properties of the cell membrane, classical as well as fractal aspects of reaction kinetics and di...

  11. Reexamination of molecular integrals arising from the Dirac equation. Analytical evaluation of molecular auxiliary functions integrals

    OpenAIRE

    Bagci, A.

    2016-01-01

    In this work, analytical solutions to relativistic molecular integrals are proposed for use in ab-initio molecular electronic structure calculations. They are expressed through molecular auxiliary functions integrals in prolate spheroidal coordinates. Recurrence relations and new convergent series representation formulae are derived. They involve Slater-type orbitals basis set with non-integer principal quantum numbers. The comparison is made with the benchmark results of use numerical global...

  12. Reexamination of molecular integrals arising from the Dirac equation. Analytical evaluation of molecular auxiliary functions integrals

    CERN Document Server

    Bagci, A

    2016-01-01

    The author in his previous works were presented a numerical integration method, namely, global-adaptive with the Gauss-Kronrod numerical integration extension in order to accurate calculation of molecular auxiliary functions integrals involve power functions with non-integer exponents. They are constitute elements of molecular integrals arising in Dirac equation when Slater-type orbitals with non-integer principal quantum numbers are used. Binomial series representation of power functions method, so far, is used for analytical evaluation of the molecular auxiliary function integrals however, intervals of integration cover areas beyond the condition of convergence. In the present study, analytical evaluation of these integrals is re-examined. They are expressed via prolate spheroidal coordinates. An alternative analytical approximation are derived. Slowly convergent binomial series representation formulae for power functions is investigated through nonlinear sequence transformations for the acceleration of con...

  13. Molecular trajectories provide signatures of protein clustering and crowding at the oil/water interface.

    Science.gov (United States)

    McUmber, Aaron C; Larson, Nicholas R; Randolph, Theodore W; Schwartz, Daniel K

    2015-06-02

    Using high throughput single-molecule total internal reflection fluorescence microscopy (TIRFM), we have acquired molecular trajectories of bovine serum albumin (BSA) and hen egg white lysozyme during protein layer formation at the silicone oil-water interface. These trajectories were analyzed to determine the distribution of molecular diffusion coefficients, and for signatures of molecular crowding/caging, including subdiffusive motion and temporal anticorrelation of the instantaneous velocity vector. The evolution of these properties with aging time of the interface was compared with dynamic interfacial tension measurements. For both lysozyme and BSA, we observed an overall slowing of protein objects, the onset of both subdiffusive and anticorrelated motion (associated with crowding), and a decrease in the interfacial tension with aging time. For lysozyme, all of these phenomena occurred virtually simultaneously, consistent with a homogeneous model of layer formation that involves gradual crowding of weakly interacting proteins. For BSA, however, the slowing occurred first, followed by the signatures of crowding/caging, followed by a decrease in interfacial tension, consistent with a heterogeneous model of layer formation involving the formation of protein clusters. The application of microrheological methods to single molecule trajectories described here provides an unprecedented level of mechanistic interpretation of interfacial events that occurred over a wide range of interfacial protein coverage.

  14. A candidate molecular signature associated with tamoxifen failure in primary breast cancer.

    Science.gov (United States)

    Vendrell, Julie A; Robertson, Katherine E; Ravel, Patrice; Bray, Susan E; Bajard, Agathe; Purdie, Colin A; Nguyen, Catherine; Hadad, Sirwan M; Bieche, Ivan; Chabaud, Sylvie; Bachelot, Thomas; Thompson, Alastair M; Cohen, Pascale A

    2008-01-01

    Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer. Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified. Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERalpha, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-alpha, gamma-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERalpha, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERalpha, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression

  15. A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition.

    Science.gov (United States)

    Mak, Milena P; Tong, Pan; Diao, Lixia; Cardnell, Robert J; Gibbons, Don L; William, William N; Skoulidis, Ferdinandos; Parra, Edwin R; Rodriguez-Canales, Jaime; Wistuba, Ignacio I; Heymach, John V; Weinstein, John N; Coombes, Kevin R; Wang, Jing; Byers, Lauren Averett

    2016-02-01

    We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort. This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints. ©2015 American Association for Cancer Research.

  16. A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial to mesenchymal transition

    Science.gov (United States)

    Mak, Milena P.; Tong, Pan; Diao, Lixia; Cardnell, Robert J.; Gibbons, Don L.; William, William N.; Skoulidis, Ferdinandos; Parra, Edwin R.; Rodriguez-Canales, Jaime; Wistuba, Ignacio I.; Heymach, John V.; Weinstein, John N.; Coombes, Kevin R.; Wang, Jing; Byers, Lauren Averett

    2015-01-01

    Purpose We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. Experimental Design Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. Results Compared to the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets such as PD1, PD-L1, CTLA4, OX40L, and PDL2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by immunohistochemistry in an independent lung cancer cohort. Conclusions This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints. PMID:26420858

  17. Molecular signatures of biogeochemical transformations in dissolved organic matter from ten World Rivers

    Science.gov (United States)

    Riedel, Thomas; Zark, Maren; Vähätalo, Anssi; Niggemann, Jutta; Spencer, Robert; Hernes, Peter; Dittmar, Thorsten

    2016-09-01

    Rivers carry large amounts of dissolved organic matter (DOM) to the oceans thereby connecting terrestrial and marine element cycles. Photo-degradation in conjunction with microbial turnover is considered a major pathway by which terrigenous DOM is decomposed. To reveal globally relevant patterns behind this process, we performed photo-degradation experiments and year-long bio-assays on DOM from ten of the largest world rivers that collectively account for more than one-third of the fresh water discharge to the global ocean. We furthermore tested the hypothesis that the terrigenous component in deep ocean DOM may be far higher than biomarker studies suggest, because of the selective photochemical destruction of characteristic biomolecules from vascular plants. DOM was molecularly characterized by a combination of non-targeted ultrahigh-resolution mass spectrometry and quantitative molecular tracer analyses. We show that the reactivity of DOM is globally related to broad catchment properties. Basins that are dominated by forest and grassland export more photo-degradable DOM than other rivers. Chromophoric compounds are mainly vascular plant-derived polyphenols, and partially carry a pyrogenic signature from vegetation fires. These forest and grassland dominated rivers lost up to 50% of dissolved organic carbon (DOC) during irradiation, and up to 85% of DOC was lost in total if subsequently bio-incubated for one year. Basins covered by cropland, on the other hand, export DOM with a higher proportion of photo-resistant and bio-available DOM which is enriched in nitrogen. In these rivers, 30% or less of DOC was photodegraded. Consistent with previous studies, we found that riverine DOM resembled marine DOM in its broad molecular composition after extensive degradation, mainly due to almost complete removal of aromatics. More detailed molecular fingerprinting analysis (based on the relative abundance of >4000 DOM molecular formulae), however, revealed clear differences

  18. Molecular signatures of biogeochemical transformations in dissolved organic matter from ten World Rivers

    Directory of Open Access Journals (Sweden)

    Thomas Riedel

    2016-09-01

    Full Text Available Rivers carry large amounts of dissolved organic matter (DOM to the oceans thereby connecting terrestrial and marine element cycles. Photo-degradation in conjunction with microbial turnover is considered a major pathway by which terrigenous DOM is decomposed. To reveal globally relevant patterns behind this process, we performed photo-degradation experiments and year-long bio-assays on DOM from ten of the largest world rivers that collectively account for more than one-third of the fresh water discharge to the global ocean. We furthermore tested the hypothesis that the terrigenous component in deep ocean DOM may be far higher than biomarker studies suggest, because of the selective photochemical destruction of characteristic biomolecules from vascular plants. DOM was molecularly characterized by a combination of non-targeted ultrahigh-resolution mass spectrometry and quantitative molecular tracer analyses. We show that the reactivity of DOM is globally related to broad catchment properties. Basins that are dominated by forest and grassland export more photo-degradable DOM than other rivers. Chromophoric compounds are mainly vascular plant-derived polyphenols, and partially carry a pyrogenic signature from vegetation fires. These forest and grassland dominated rivers lost up to 50% of dissolved organic carbon (DOC during irradiation, and up to 85% of DOC was lost in total if subsequently bio-incubated for one year. Basins covered by cropland, on the other hand, export DOM with a higher proportion of photo-resistant and bio-available DOM which is enriched in nitrogen. In these rivers, 30% or less of DOC was photodegraded. Consistent with previous studies, we found that riverine DOM resembled marine DOM in its broad molecular composition after extensive degradation, mainly due to almost complete removal of aromatics. More detailed molecular fingerprinting analysis (based on the relative abundance of >4000 DOM molecular formulae, however, revealed

  19. Signatures of fast and slow magnetohydrodynamic shocks in turbulent molecular clouds

    Science.gov (United States)

    Lehmann, Andrew; Wardle, Mark

    2016-01-01

    The character of star formation is intimately related to the supersonic magnetohydrodynamic (MHD) turbulent dynamics of the molecular clouds in which stars form. A significant amount of the turbulent energy dissipates in low-velocity shocks. Fast and slow MHD shocks differ in how they compress and heat the molecular gas, and so their radiative signatures reveal distinct physical conditions. We use a two-fluid model to compare one-dimensional fast and slow MHD shocks propagating at low speeds (a few km s- 1). Fast shocks are magnetically driven, forcing ion species to stream through the neutral gas ahead of the shock front. This magnetic precursor heats the gas sufficiently to create a large, warm transition zone where all the fluid variables smoothly change in the shock front. In contrast, slow shocks are driven by gas pressure, and neutral species collide with ion species in a thin hot slab that closely resembles an ordinary gas dynamic shock. We consider shocks at velocities vs = 2-4 km s- 1 and pre-shock hydrogen nuclei densities nH = 102-104 cm-3. We include a simple oxygen chemistry and cooling by CO, H2 and H2O. CO rotational lines above J = 6-5 are more strongly excited in slow shocks. These slow-shock signatures may have already been observed in infrared dark clouds in the Milky Way.

  20. Molecular and anatomical signatures of sleep deprivation in the mouse brain

    Directory of Open Access Journals (Sweden)

    Carol L Thompson

    2010-10-01

    Full Text Available Sleep deprivation (SD leads to a suite of cognitive and behavioral impairments, and yet the molecular consequences of SD in the brain are poorly understood. Using a systematic immediate-early gene mapping to detect neuronal activation, the consequences of SD were mapped primarily to forebrain regions. Sleep deprivation was found to both induce and suppress immediate early gene expression (and thus neuronal activity in subregions of neocortex, striatum, and other brain regions. Laser microdissection and cDNA microarrays were used to identify the molecular consequences of SD in 7 brain regions. In situ hybridization for 222 genes selected from the microarray data and other sources confirmed that robust molecular changes were largely restricted to the forebrain. Analysis of the ISH data for 222 genes (publicly accessible at http://sleep.alleninstitute.org provided a molecular and anatomic signature of the effects of SD on the brain. The SCN and the neocortex exhibited differential regulation of the same genes, such that in the SCN genes exhibited time-of-day effects while in the neocortex, genes exhibited only SD and W effects. In the neocortex, SD activated gene expression in areal-, layer-, and cell type-specific manner. In the forebrain, SD preferentially activated excitatory neurons, as demonstrated by double-labeling, except for striatum which consists primarily of inhibitory neurons. These data provide a characterization of the anatomical and cell-type specific signatures of SD on neuronal activity and gene expression that may account for the associated cognitive and behavioral effects.

  1. Integrated ray tracing simulation of spectral bio-signatures from full 3D earth model

    Science.gov (United States)

    Ryu, Dongok; Seong, Sehyun; Lee, Jae-Min; Hong, Jinsuk; Jeong, Soomin; Jeong, Yukyeong; Kim, Sug-Whan

    2009-08-01

    Accurate identification and understanding of spectral bio-signatures from possible extra terrestrial planets have received an ever increasing attention from both astronomy and space science communities in recent years. In pursuance of this subject, one of the most important scientific breakthroughs would be to obtain the detailed understanding on spectral biosignatures of the Earth, as it serves as a reference datum for accurate interpretation of collapsed (in temporal and spatial domains) information from the spectral measurement using TPF instruments. We report a new Integrated Ray Tracing (IRT) model capable of computing various spectral bio-signatures as they are observed from the Earth surface. The model includes the Sun, the full 3-D Earth, and an optical instrument, all combined into single ray tracing environment in real scale. In particular, the full 3-D Earth surface is constructed from high resolution coastal line data and defined with realistic reflectance and BSDF characteristics depending on wavelength, vegetation types and their distributions. We first examined the model validity by confirming the imaging and radiometric performance of the AmonRa visible channel camera, simulating the Earth observation from the L1 halo orbit. We then computed disk averaged spectra, light curves and NDVI indexes, leading to the construction of the observed disk averaged spectra at the AmonRa instrument detector plane. The model, computational procedure and the simulation results are presented. The future plan for the detailed spectral signature simulation runs for various input conditions including seasonal vegetation changes and variable cloud covers is discussed.

  2. Signatures of fast and slow magnetohydrodynamic shocks in turbulent molecular clouds

    CERN Document Server

    Lehmann, Andrew

    2015-01-01

    The character of star formation is intimately related to the supersonic magnetohydrodynamic (MHD) turbulent dynamics of the giant molecular clouds in which stars form. A significant amount of the turbulent energy dissipates in low-velocity shock waves. These shocks cause molecular line cooling of the compressed and heated gas, and so their radiative signatures probe the nature of the turbulence. In MHD fluids the three distinct families of shocks---fast, intermediate and slow---differ in how they compress and heat the molecular gas, and so observational differences between them may also distinguish driving modes of turbulent regions. Here we use a two-fluid model to compare the characteristics of one-dimensional fast and slow MHD shocks propagating at low speeds (a few km/s) in molecular clouds. Fast MHD shocks are magnetically driven, forcing ion species to stream through the neutral gas ahead of the shock front. This magnetic precursor heats the gas sufficiently to create a large, warm transition zone where...

  3. Molecular signature of differential virulence in natural isolates of Erwinia amylovora.

    Science.gov (United States)

    Wang, Dongping; Korban, Schuyler S; Zhao, Youfu

    2010-02-01

    ABSTRACT Erwinia amylovora, the causal agent of fire blight, is considered to be a genetically homogeneous species based on physiological, biochemical, phylogenetic, and genetic analysis. However, E. amylovora strains exhibiting differential virulence are isolated from nature. The exopolysaccharide amylovoran and type III secretion system (T3SS) are two major yet separate virulence factors in E. amylovora. The objective of this study was to investigate whether there is a correlation between E. amylovora virulence and levels of virulence gene expression. Four wild-type strains (Ea1189, Ea273, Ea110, and CFBP1430), widely used in studies of E. amylovora pathogenesis, have been analyzed and compared. E. amylovora strains Ea273 and Ea110 elicited higher severity of disease symptoms than those of Ea1189 and CFBP1430 on apple cv. Golden Delicious and G16 apple root stock plants but not on susceptible Gala plants. In addition, Ea273 and Ea110 elicited severe hypersensitive responses within shorter periods of time at lower inoculum concentrations than those of Ea1189 and CFBP1430 on tobacco plants. Further molecular analyses have revealed that amylovoran production and expression of both amylovoran (amsG) and T3SS (dspE and hrpL) genes were significantly higher in Ea273 and Ea110 than those in Ea1189 and CFBP1430. Other phenotypes such as swarming motility in these four strains also differed significantly. These results indicate that E. amylovora strains of different origin can be divided into subgroups based on molecular signatures of virulence gene expression. Therefore, these molecular signatures may be used to differentiate E. amylovora strains, which may have taxonomical and evolutionary implications.

  4. Bead-Fourier path integral molecular dynamics

    Science.gov (United States)

    Ivanov, Sergei D.; Lyubartsev, Alexander P.; Laaksonen, Aatto

    2003-06-01

    Molecular dynamics formulation of Bead-Fourier path integral method for simulation of quantum systems at finite temperatures is presented. Within this scheme, both the bead coordinates and Fourier coefficients, defining the path representing the quantum particle, are treated as generalized coordinates with corresponding generalized momenta and masses. Introduction of the Fourier harmonics together with the center-of-mass thermostating scheme is shown to remove the ergodicity problem, known to pose serious difficulties in standard path integral molecular dynamics simulations. The method is tested for quantum harmonic oscillator and hydrogen atom (Coulombic potential). The simulation results are compared with the exact analytical solutions available for both these systems. Convergence of the results with respect to the number of beads and Fourier harmonics is analyzed. It was shown that addition of a few Fourier harmonics already improves the simulation results substantially, even for a relatively small number of beads. The proposed Bead-Fourier path integral molecular dynamics is a reliable and efficient alternative to simulations of quantum systems.

  5. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants.

    Science.gov (United States)

    Olafsdottir, Thorunn A; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H E; Reed, Steven G; Harandi, Ali M

    2016-12-13

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

  6. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants

    Science.gov (United States)

    Olafsdottir, Thorunn A.; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H. E.; Reed, Steven G.; Harandi, Ali M.

    2016-12-01

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

  7. Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice

    Directory of Open Access Journals (Sweden)

    Choi Se

    2008-10-01

    Full Text Available Abstract Background Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2 contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes. Results To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the PSEN1/PSEN2 double knock-out mice and littermate controls at five different ages ranging from 2–8 months. Our data suggest that combined deficiencies of PSEN1 and PSEN2 results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of cathepsin and complement system transcripts. Conclusion The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of PSEN1 and PSEN2. Furthermore, our results suggest that the evaluation of inhibitors of PS/γ-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.

  8. An rpoB signature sequence provides unique resolution for the molecular typing of cyanobacteria.

    Science.gov (United States)

    Gaget, Virginie; Gribaldo, Simonetta; Tandeau de Marsac, Nicole

    2011-01-01

    The use of morphological characters for the classification of cyanobacteria has often led to ambiguous strain assignment. In the past two decades, the availability of sequences, such as those of the 16S rRNA, nif, cpc and rpoC1 genes, and the use of metagenomics, has steadily increased and has made the reconstruction of evolutionary relationships of some cyanobacterial groups possible in addition to improving strain assignment. Conserved indels (insertions/deletions) are present in all cyanobacterial RpoB (β subunit of RNA polymerase) sequences presently available in public databases. These indels are located in the Rpb2_6 domain of RpoB, which is involved in DNA binding and DNA-directed RNA polymerase activity. They are variable in length (6-44 aa) and sequence, and form part of what appears to be a longer signature sequence (43-81 aa). Indeed, a number of these sequences turn out to be distinctive among several strains of a given genus and even among strains of a given species. These signature sequences can thus be used to identify cyanobacteria at a subgenus level and can be useful molecular markers to establish the taxonomic positions of cyanobacterial isolates in laboratory cultures, and/or to assess cyanobacterial biodiversity in space and time in natural ecosystems.

  9. Human BAT possesses molecular signatures that resemble beige/brite cells.

    Directory of Open Access Journals (Sweden)

    Louis Z Sharp

    Full Text Available Brown adipose tissue (BAT dissipates chemical energy and generates heat to protect animals from cold and obesity. Rodents possess two types of UCP-1 positive brown adipocytes arising from distinct developmental lineages: "classical" brown adipocytes develop during the prenatal stage whereas "beige" or "brite" cells that reside in white adipose tissue (WAT develop during the postnatal stage in response to chronic cold or PPARγ agonists. Beige cells' inducible characteristics make them a promising therapeutic target for obesity treatment, however, the relevance of this cell type in humans remains unknown. In the present study, we determined the gene signatures that were unique to classical brown adipocytes and to beige cells induced by a specific PPARγ agonist rosiglitazone in mice. Subsequently we applied the transcriptional data to humans and examined the molecular signatures of human BAT isolated from multiple adipose depots. To our surprise, nearly all the human BAT abundantly expressed beige cell-selective genes, but the expression of classical brown fat-selective genes were nearly undetectable. Interestingly, expression of known brown fat-selective genes such as PRDM16 was strongly correlated with that of the newly identified beige cell-selective genes, but not with that of classical brown fat-selective genes. Furthermore, histological analyses showed that a new beige cell marker, CITED1, was selectively expressed in the UCP1-positive beige cells as well as in human BAT. These data indicate that human BAT may be primary composed of beige/brite cells.

  10. A novel gene signature for molecular diagnosis of human prostate cancer by RT-qPCR.

    Directory of Open Access Journals (Sweden)

    Federica Rizzi

    Full Text Available BACKGROUND: Prostate cancer (CaP is one of the most relevant causes of cancer death in Western Countries. Although detection of CaP at early curable stage is highly desirable, actual screening methods present limitations and new molecular approaches are needed. Gene expression analysis increases our knowledge about the biology of CaP and may render novel molecular tools, but the identification of accurate biomarkers for reliable molecular diagnosis is a real challenge. We describe here the diagnostic power of a novel 8-genes signature: ornithine decarboxylase (ODC, ornithine decarboxylase antizyme (OAZ, adenosylmethionine decarboxylase (AdoMetDC, spermidine/spermine N(1-acetyltransferase (SSAT, histone H3 (H3, growth arrest specific gene (GAS1, glyceraldehyde 3-phosphate dehydrogenase (GAPDH and Clusterin (CLU in tumour detection/classification of human CaP. METHODOLOGY/PRINCIPAL FINDINGS: The 8-gene signature was detected by retrotranscription real-time quantitative PCR (RT-qPCR in frozen prostate surgical specimens obtained from 41 patients diagnosed with CaP and recommended to undergo radical prostatectomy (RP. No therapy was given to patients at any time before RP. The bio-bank used for the study consisted of 66 specimens: 44 were benign-CaP paired from the same patient. Thirty-five were classified as benign and 31 as CaP after final pathological examination. Only molecular data were used for classification of specimens. The Nearest Neighbour (NN classifier was used in order to discriminate CaP from benign tissue. Validation of final results was obtained with 10-fold cross-validation procedure. CaP versus benign specimens were discriminated with (80+/-5% accuracy, (81+/-6% sensitivity and (78+/-7% specificity. The method also correctly classified 71% of patients with Gleason score or =7, an important predictor of final outcome. CONCLUSIONS/SIGNIFICANCE: The method showed high sensitivity in a collection of specimens in which a significant

  11. Molecular signatures of age-associated chronic degeneration of shoulder muscles.

    Science.gov (United States)

    Raz, Yotam; Henseler, Jan Ferdinand; Kolk, Arjen; Tatum, Zuotian; Groosjohan, Niels Kuipers; Verwey, Nisha E; Arindrarto, Wibowo; Kielbasa, Szymon M; Nagels, Jochem; 't Hoen, Peter A C; Nelissen, Rob G H H; Raz, Vered

    2016-02-23

    Chronic muscle diseases are highly prevalent in the elderly causing severe mobility limitations, pain and frailty. The intrinsic molecular mechanisms are poorly understood due to multifactorial causes, slow progression with age and variations between individuals. Understanding the underlying molecular mechanisms could lead to new treatment options which are currently limited. Shoulder complaints are highly common in the elderly, and therefore, muscles of the shoulder's rotator cuff could be considered as a model for chronic age-associated muscle degeneration. Diseased shoulder muscles were characterized by muscle atrophy and fatty infiltration compared with unaffected shoulder muscles. We confirmed fatty infiltration using histochemical analysis. Additionally, fibrosis and loss of contractile myosin expression were found in diseased muscles. Most cellular features, including proliferation rate, apoptosis and cell senescence, remained unchanged and genome-wide molecular signatures were predominantly similar between diseased and intact muscles. However, we found down-regulation of a small subset of muscle function genes, and up-regulation of extracellular region genes. Myogenesis was defected in muscle cell culture from diseased muscles but was restored by elevating MyoD levels. We suggest that impaired muscle functionality in a specific environment of thickened extra-cellular matrix is crucial for the development of chronic age-associated muscle degeneration.

  12. Molecular Signatures of Psychosocial Stress and Cognition Are Modulated by Chronic Lithium Treatment.

    Science.gov (United States)

    Brzózka, Magdalena M; Havemann-Reinecke, Ursula; Wichert, Sven P; Falkai, Peter; Rossner, Moritz J

    2016-07-01

    Chronic psychosocial stress is an important environmental risk factor of psychiatric diseases such as schizophrenia. Social defeat in rodents has been shown to be associated with maladaptive cellular and behavioral consequences including cognitive impairments. Although gene expression changes upon psychosocial stress have been described, a comprehensive transcriptome profiling study at the global level in precisely defined hippocampal subregions which are associated with learning has been lacking. In this study, we exposed adult C57Bl/6N mice for 3 weeks to "resident-intruder" paradigm and combined laser capture microdissection with microarray analyses to identify transcriptomic signatures of chronic psychosocial stress in dentate gyrus and CA3 subregion of the dorsal hippocampus. At the individual transcript level, we detected subregion specific stress responses whereas gene set enrichment analyses (GSEA) identified several common pathways upregulated upon chronic psychosocial stress related to proteasomal function and energy supply. Behavioral profiling revealed stress-associated impairments most prominent in fear memory formation which was prevented by chronic lithium treatment. Thus, we again microdissected the CA3 region and performed global transcriptome analysis to search for molecular signatures altered by lithium treatment in stressed animals. By combining GSEA with unsupervised clustering, we detected pathways that are regulated by stress and lithium in the CA3 region of the hippocampus including proteasomal components, oxidative phosphorylation, and anti-oxidative mechanisms. Our study thus provides insight into hidden molecular phenotypes of chronic psychosocial stress and lithium treatment and proves a beneficial role for lithium treatment as an agent attenuating negative effects of psychosocial stress on cognition.

  13. Integrating evolutionary and molecular genetics of aging.

    Science.gov (United States)

    Flatt, Thomas; Schmidt, Paul S

    2009-10-01

    Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.

  14. Molecular signatures discriminating the male and the female sexual pathways in the pearl oyster Pinctada margaritifera.

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    Vaihiti Teaniniuraitemoana

    Full Text Available The genomics of economically important marine bivalves is studied to provide better understanding of the molecular mechanisms underlying their different reproductive strategies. The recently available gonad transcriptome of the black-lip pearl oyster Pinctada margaritifera is a novel and powerful resource to study these mechanisms in marine mollusks displaying hermaphroditic features. In this study, RNAseq quantification data of the P. margaritifera gonad transcriptome were analyzed to identify candidate genes in histologically-characterized gonad samples to provide molecular signatures of the female and male sexual pathway in this pearl oyster. Based on the RNAseq data set, stringent expression analysis identified 1,937 contigs that were differentially expressed between the gonad histological categories. From the hierarchical clustering analysis, a new reproduction model is proposed, based on a dual histo-molecular analytical approach. Nine candidate genes were identified as markers of the sexual pathway: 7 for the female pathway and 2 for the male one. Their mRNA levels were assayed by real-time PCR on a new set of gonadic samples. A clustering method revealed four principal expression patterns based on the relative gene expression ratio. A multivariate regression tree realized on these new samples and validated on the previously analyzed RNAseq samples showed that the sexual pathway of P. margaritifera can be predicted by a 3-gene-pair expression ratio model of 4 different genes: pmarg-43476, pmarg-foxl2, pmarg-54338 and pmarg-fem1-like. This 3-gene-pair expression ratio model strongly suggests only the implication of pmarg-foxl2 and pmarg-fem1-like in the sex inversion of P. margaritifera. This work provides the first histo-molecular model of P. margaritifera reproduction and a gene expression signature of its sexual pathway discriminating the male and female pathways. These represent useful tools for understanding and studying sex inversion

  15. Integrating Advanced Molecular Technologies into Public Health.

    Science.gov (United States)

    Gwinn, Marta; MacCannell, Duncan R; Khabbaz, Rima F

    2017-03-01

    Advances in laboratory and information technologies are transforming public health microbiology. High-throughput genome sequencing and bioinformatics are enhancing our ability to investigate and control outbreaks, detect emerging infectious diseases, develop vaccines, and combat antimicrobial resistance, all with increased accuracy, timeliness, and efficiency. The Advanced Molecular Detection (AMD) initiative has allowed the Centers for Disease Control and Prevention (CDC) to provide leadership and coordination in integrating new technologies into routine practice throughout the U.S. public health laboratory system. Collaboration and partnerships are the key to navigating this transition and to leveraging the next generation of methods and tools most effectively for public health.

  16. Molecular Slater Integrals for Electronic Energy Calculations

    Science.gov (United States)

    2010-10-15

    Facultad de Ciencias . Departamento de Quı́mica Fı́sica Aplicada. C-XIV. Abstract The algorithms for computing molecular integrals with Slater functions...ζ + ζ ′) 2 ) (90) Defining α = ζ + ζ ′ and α′ = ζ − ζ ′, and taking into account that: ( − ∂ ∂ζ )n ( − ∂ ∂ζ ′ )n′ = (−1)n+n′ n+n′∑ p=0 cnn ′ p ( ∂ ∂α...p+ p′ + 1)! p! p′! ∫ 1 0 du up (1− u)p′ (ζ2 u+ ζ ′2 (1− u) + k2)p+p′+2 (116) changing the order of the integrals and taking into account that

  17. Fuzzy logic selection as a new reliable tool to identify molecular grade signatures in breast cancer--the INNODIAG study.

    Science.gov (United States)

    Kempowsky-Hamon, Tatiana; Valle, Carine; Lacroix-Triki, Magali; Hedjazi, Lyamine; Trouilh, Lidwine; Lamarre, Sophie; Labourdette, Delphine; Roger, Laurence; Mhamdi, Loubna; Dalenc, Florence; Filleron, Thomas; Favre, Gilles; François, Jean-Marie; Le Lann, Marie-Véronique; Anton-Leberre, Véronique

    2015-02-07

    Personalized medicine has become a priority in breast cancer patient management. In addition to the routinely used clinicopathological characteristics, clinicians will have to face an increasing amount of data derived from tumor molecular profiling. The aims of this study were to develop a new gene selection method based on a fuzzy logic selection and classification algorithm, and to validate the gene signatures obtained on breast cancer patient cohorts. We analyzed data from four published gene expression datasets for breast carcinomas. We identified the best discriminating genes by comparing molecular expression profiles between histologic grade 1 and 3 tumors for each of the training datasets. The most pertinent probes were selected and used to define fuzzy molecular grade 1-like (good prognosis) and fuzzy molecular grade 3-like (poor prognosis) profiles. To evaluate the prognostic performance of the fuzzy grade signatures in breast cancer tumors, a Kaplan-Meier analysis was conducted to compare the relapse-free survival deduced from histologic grade and fuzzy molecular grade classification. We applied the fuzzy logic selection on breast cancer databases and obtained four new gene signatures. Analysis in the training public sets showed good performance of these gene signatures for grade (sensitivity from 90% to 95%, specificity 67% to 93%). To validate these gene signatures, we designed probes on custom microarrays and tested them on 150 invasive breast carcinomas. Good performance was obtained with an error rate of less than 10%. For one gene signature, among 74 histologic grade 3 and 18 grade 1 tumors, 88 cases (96%) were correctly assigned. Interestingly histologic grade 2 tumors (n = 58) were split in these two molecular grade categories. We confirmed the use of fuzzy logic selection as a new tool to identify gene signatures with good reliability and increased classification power. This method based on artificial intelligence algorithms was successfully

  18. Phylogenomics and molecular signatures for species from the plant pathogen-containing order xanthomonadales.

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    Hafiz Sohail Naushad

    Full Text Available The species from the order Xanthomonadales, which harbors many important plant pathogens and some human pathogens, are currently distinguished primarily on the basis of their branching in the 16S rRNA tree. No molecular or biochemical characteristic is known that is specific for these bacteria. Phylogenetic and comparative analyses were conducted on 26 sequenced Xanthomonadales genomes to delineate their branching order and to identify molecular signatures consisting of conserved signature indels (CSIs in protein sequences that are specific for these bacteria. In a phylogenetic tree based upon sequences for 28 proteins, Xanthomonadales species formed a strongly supported clade with Rhodanobacter sp. 2APBS1 as its deepest branch. Comparative analyses of protein sequences have identified 13 CSIs in widely distributed proteins such as GlnRS, TypA, MscL, LysRS, LipA, Tgt, LpxA, TolQ, ParE, PolA and TyrB that are unique to all species/strains from this order, but not found in any other bacteria. Fifteen additional CSIs in proteins (viz. CoxD, DnaE, PolA, SucA, AsnB, RecA, PyrG, LigA, MutS and TrmD are uniquely shared by different Xanthomonadales except Rhodanobacter and in a few cases by Pseudoxanthomonas species, providing further support for the deep branching of these two genera. Five other CSIs are commonly shared by Xanthomonadales and 1-3 species from the orders Chromatiales, Methylococcales and Cardiobacteriales suggesting that these deep branching orders of Gammaproteobacteria might be specifically related. Lastly, 7 CSIs in ValRS, CarB, PyrE, GlyS, RnhB, MinD and X001065 are commonly shared by Xanthomonadales and a limited number of Beta- or Gamma-proteobacteria. Our analysis indicates that these CSIs have likely originated independently and they are not due to lateral gene transfers. The Xanthomonadales-specific CSIs reported here provide novel molecular markers for the identification of these important plant and human pathogens and also as

  19. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression.

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    Byungwoo Ryu

    Full Text Available BACKGROUND: Gene expression profiling has revolutionized our ability to molecularly classify primary human tumors and significantly enhanced the development of novel tumor markers and therapies; however, progress in the diagnosis and treatment of melanoma over the past 3 decades has been limited, and there is currently no approved therapy that significantly extends lifespan in patients with advanced disease. Profiling studies of melanoma to date have been inconsistent due to the heterogeneous nature of this malignancy and the limited availability of informative tissue specimens from early stages of disease. METHODOLOGY/PRINCIPLE FINDINGS: In order to gain an improved understanding of the molecular basis of melanoma progression, we have compared gene expression profiles from a series of melanoma cell lines representing discrete stages of malignant progression that recapitulate critical characteristics of the primary lesions from which they were derived. Here we describe the unsupervised hierarchical clustering of profiling data from melanoma cell lines and melanocytes. This clustering identifies two distinctive molecular subclasses of melanoma segregating aggressive metastatic tumor cell lines from less-aggressive primary tumor cell lines. Further analysis of expression signatures associated with melanoma progression using functional annotations categorized these transcripts into three classes of genes: 1 Upregulation of activators of cell cycle progression, DNA replication and repair (CDCA2, NCAPH, NCAPG, NCAPG2, PBK, NUSAP1, BIRC5, ESCO2, HELLS, MELK, GINS1, GINS4, RAD54L, TYMS, and DHFR, 2 Loss of genes associated with cellular adhesion and melanocyte differentiation (CDH3, CDH1, c-KIT, PAX3, CITED1/MSG-1, TYR, MELANA, MC1R, and OCA2, 3 Upregulation of genes associated with resistance to apoptosis (BIRC5/survivin. While these broad classes of transcripts have previously been implicated in the progression of melanoma and other malignancies, the

  20. Multi-tissue microarray analysis identifies a molecular signature of regeneration.

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    Sarah E Mercer

    Full Text Available The inability to functionally repair tissues that are lost as a consequence of disease or injury remains a significant challenge for regenerative medicine. The molecular and cellular processes involved in complete restoration of tissue architecture and function are expected to be complex and remain largely unknown. Unlike humans, certain salamanders can completely regenerate injured tissues and lost appendages without scar formation. A parsimonious hypothesis would predict that all of these regenerative activities are regulated, at least in part, by a common set of genes. To test this hypothesis and identify genes that might control conserved regenerative processes, we performed a comprehensive microarray analysis of the early regenerative response in five regeneration-competent tissues from the newt Notophthalmus viridescens. Consistent with this hypothesis, we established a molecular signature for regeneration that consists of common genes or gene family members that exhibit dynamic differential regulation during regeneration in multiple tissue types. These genes include members of the matrix metalloproteinase family and its regulators, extracellular matrix components, genes involved in controlling cytoskeleton dynamics, and a variety of immune response factors. Gene Ontology term enrichment analysis validated and supported their functional activities in conserved regenerative processes. Surprisingly, dendrogram clustering and RadViz classification also revealed that each regenerative tissue had its own unique temporal expression profile, pointing to an inherent tissue-specific regenerative gene program. These new findings demand a reconsideration of how we conceptualize regenerative processes and how we devise new strategies for regenerative medicine.

  1. Multi-Tissue Microarray Analysis Identifies a Molecular Signature of Regeneration

    Science.gov (United States)

    Mercer, Sarah E.; Cheng, Chia-Ho; Atkinson, Donald L.; Krcmery, Jennifer; Guzman, Claudia E.; Kent, David T.; Zukor, Katherine; Marx, Kenneth A.; Odelberg, Shannon J.; Simon, Hans-Georg

    2012-01-01

    The inability to functionally repair tissues that are lost as a consequence of disease or injury remains a significant challenge for regenerative medicine. The molecular and cellular processes involved in complete restoration of tissue architecture and function are expected to be complex and remain largely unknown. Unlike humans, certain salamanders can completely regenerate injured tissues and lost appendages without scar formation. A parsimonious hypothesis would predict that all of these regenerative activities are regulated, at least in part, by a common set of genes. To test this hypothesis and identify genes that might control conserved regenerative processes, we performed a comprehensive microarray analysis of the early regenerative response in five regeneration-competent tissues from the newt Notophthalmus viridescens. Consistent with this hypothesis, we established a molecular signature for regeneration that consists of common genes or gene family members that exhibit dynamic differential regulation during regeneration in multiple tissue types. These genes include members of the matrix metalloproteinase family and its regulators, extracellular matrix components, genes involved in controlling cytoskeleton dynamics, and a variety of immune response factors. Gene Ontology term enrichment analysis validated and supported their functional activities in conserved regenerative processes. Surprisingly, dendrogram clustering and RadViz classification also revealed that each regenerative tissue had its own unique temporal expression profile, pointing to an inherent tissue-specific regenerative gene program. These new findings demand a reconsideration of how we conceptualize regenerative processes and how we devise new strategies for regenerative medicine. PMID:23300656

  2. Nuclear signature effect on spatial distribution of molecular harmonic in the presence of spatial inhomogeneous field

    Science.gov (United States)

    Feng, Liqiang; Li, Wenliang

    2017-01-01

    Spatial distribution of the molecular harmonic spectra from \\text{H}\\text{2}+ in the presence of inhomogeneous field has been theoretically investigated. It shows that (i) the harmonic intensities from the negative-H nucleus play the dominating role in harmonic emission spectra. (ii) Through the investigations of the nuclear signature effect on the spatial distribution of the molecular harmonic spectra, the differences of the harmonic intensities between the negative-H nucleus and the positive-H nucleus can be enhanced and reduced with the introduction of the higher vibrational state and the heavy nucleus (i.e. \\text{D}2+ ), respectively. The time-frequency analyses of the harmonic spectra, the time-dependent wave function and the electron localization have been shown to explain the harmonic spatial distribution and the electron motion. (iii) Due to the plasmon-resonance-enhancement near the metallic nanostructure, the harmonic cutoff can be remarkably enhanced as the spatial position of the inhomogeneous field moving away from the gap center. The ionization probabilities have been shown to explain the harmonic cutoff extension.

  3. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia.

    Science.gov (United States)

    Giustacchini, Alice; Thongjuea, Supat; Barkas, Nikolaos; Woll, Petter S; Povinelli, Benjamin J; Booth, Christopher A G; Sopp, Paul; Norfo, Ruggiero; Rodriguez-Meira, Alba; Ashley, Neil; Jamieson, Lauren; Vyas, Paresh; Anderson, Kristina; Segerstolpe, Åsa; Qian, Hong; Olsson-Strömberg, Ulla; Mustjoki, Satu; Sandberg, Rickard; Jacobsen, Sten Eirik W; Mead, Adam J

    2017-06-01

    Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

  4. Low-variance RNAs identify Parkinson's disease molecular signature in blood.

    Science.gov (United States)

    Chikina, Maria D; Gerald, Christophe P; Li, Xianting; Ge, Yongchao; Pincas, Hanna; Nair, Venugopalan D; Wong, Aaron K; Krishnan, Arjun; Troyanskaya, Olga G; Raymond, Deborah; Saunders-Pullman, Rachel; Bressman, Susan B; Yue, Zhenyu; Sealfon, Stuart C

    2015-05-01

    The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.

  5. Microelectromechanical systems integrating molecular spin crossover actuators

    Science.gov (United States)

    Manrique-Juarez, Maria D.; Rat, Sylvain; Mathieu, Fabrice; Saya, Daisuke; Séguy, Isabelle; Leïchlé, Thierry; Nicu, Liviu; Salmon, Lionel; Molnár, Gábor; Bousseksou, Azzedine

    2016-08-01

    Silicon MEMS cantilevers coated with a 200 nm thin layer of the molecular spin crossover complex [Fe(H2B(pz)2)2(phen)] (H2B(pz)2 = dihydrobis(pyrazolyl)borate and phen = 1,10-phenantroline) were actuated using an external magnetic field and their resonance frequency was tracked by means of integrated piezoresistive detection. The light-induced spin-state switching of the molecules from the ground low spin to the metastable high spin state at 10 K led to a well-reproducible shift of the cantilever's resonance frequency (Δfr = -0.52 Hz). Control experiments at different temperatures using coated as well as uncoated devices along with simple calculations support the assignment of this effect to the spin transition. This latter translates into changes in mechanical behavior of the cantilever due to the strong spin-state/lattice coupling. A guideline for the optimization of device parameters is proposed so as to efficiently harness molecular scale movements for large-scale mechanical work, thus paving the road for nanoelectromechanical systems (NEMS) actuators based on molecular materials.

  6. Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease.

    Directory of Open Access Journals (Sweden)

    Alison R Erickson

    Full Text Available Crohn's disease (CD is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD or colon (CCD. Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers.

  7. Integrated Metagenomics/Metaproteomics Reveals Human Host-Microbiota Signatures of Crohn's Disease

    Science.gov (United States)

    Darzi, Youssef; Mongodin, Emmanuel F.; Pan, Chongle; Shah, Manesh; Halfvarson, Jonas; Tysk, Curt; Henrissat, Bernard; Raes, Jeroen; Verberkmoes, Nathan C.; Jansson, Janet K.

    2012-01-01

    Crohn's disease (CD) is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD) or colon (CCD). Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers. PMID:23209564

  8. Integrated Metagenomics/Metaproteomics Reveals Human Host-Microbiota Signatures of Crohn's Disease

    Energy Technology Data Exchange (ETDEWEB)

    Erickson, Alison L [ORNL; Cantarel, Brandi [University of Maryland School of Medicine, The, Baltimore, MD; Lamendella, Regina [Lawrence Berkeley National Laboratory (LBNL); Darzi, Youssef [Vrije Universiteit Brussel, Brussels, Belgium; Mongodin, Emmanuel [University of Maryland School of Medicine, The, Baltimore, MD; Pan, Chongle [ORNL; Shah, Manesh B [ORNL; Halfvarsson, J [Orebro University Hospital, Orebro, Sweden; Tysk, C [Orebro University Hospital, Orebro, Sweden; Henrissat, Bernard [Universite d' Aix-Marseille I & II; Raes, Jeroen [Vrije Universiteit Brussel, Brussels, Belgium; Verberkmoes, Nathan C [ORNL; Fraser-Liggett, C [University of Maryland; Hettich, Robert {Bob} L [ORNL; Jansson, Janet [Lawrence Berkeley National Laboratory (LBNL)

    2012-01-01

    Crohn's disease (CD) is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD) or colon (CCD). Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers.

  9. Scattering signatures of suspended particles: an integrated system for combining digital holography and laser diffraction.

    Science.gov (United States)

    Davies, Emlyn J; Nimmo-Smith, W Alex M; Agrawal, Yogesh C; Souza, Alejandro J

    2011-12-05

    The use of laser diffraction is now common practice for the determination of an in situ particle size distribution in the marine environment. However, various imaging techniques have shown that particles vary greatly in shape, leading to uncertainty in the response of laser diffraction instruments when subjected to this diverse range of complex particles. Here we present a novel integrated system which combines both digital in-line holography and a LISST-100 type C, to simultaneously record in-focus images of artificial and natural particles with their small-angle forward scattering signature. The system will allow for further development of a reliable alternative to Mie Theory when using laser diffraction for the in situ measurement of complex suspended particles. A more detailed knowledge of the performance of laser diffraction when subjected to the wide variety of complex particles found in the marine environment will then be possible.

  10. Integration of molecular pathology, epidemiology and social science for global precision medicine.

    Science.gov (United States)

    Nishi, Akihiro; Milner, Danny A; Giovannucci, Edward L; Nishihara, Reiko; Tan, Andy S; Kawachi, Ichiro; Ogino, Shuji

    2016-01-01

    The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science.

  11. How to Make a Dolphin: Molecular Signature of Positive Selection in Cetacean Genome.

    Directory of Open Access Journals (Sweden)

    Mariana F Nery

    Full Text Available Cetaceans are unique in being the only mammals completely adapted to an aquatic environment. This adaptation has required complex changes and sometimes a complete restructuring of physiology, behavior and morphology. Identifying genes that have been subjected to selection pressure during cetacean evolution would greatly enhance our knowledge of the ways in which genetic variation in this mammalian order has been shaped by natural selection. Here, we performed a genome-wide scan for positive selection in the dolphin lineage. We employed models of codon substitution that account for variation of selective pressure over branches on the tree and across sites in a sequence. We analyzed 7,859 nuclear-coding ortholog genes and using a series of likelihood ratio tests (LRTs, we identified 376 genes (4.8% with molecular signatures of positive selection in the dolphin lineage. We used the cow as the sister group and compared estimates of selection in the cetacean genome to this using the same methods. This allowed us to define which genes have been exclusively under positive selection in the dolphin lineage. The enrichment analysis found that the identified positively selected genes are significantly over-represented for three exclusive functional categories only in the dolphin lineage: segment specification, mesoderm development and system development. Of particular interest for cetacean adaptation to an aquatic life are the following GeneOntology targets under positive selection: genes related to kidney, heart, lung, eye, ear and nervous system development.

  12. In vivo epigenomic profiling of germ cells reveals germ cell molecular signatures.

    Science.gov (United States)

    Ng, Jia-Hui; Kumar, Vibhor; Muratani, Masafumi; Kraus, Petra; Yeo, Jia-Chi; Yaw, Lai-Ping; Xue, Kun; Lufkin, Thomas; Prabhakar, Shyam; Ng, Huck-Hui

    2013-02-11

    The limited number of in vivo germ cells poses an impediment to genome-wide studies. Here, we applied a small-scale chromatin immunoprecipitation sequencing (ChIP-seq) method on purified mouse fetal germ cells to generate genome-wide maps of four histone modifications (H3K4me3, H3K27me3, H3K27ac, and H2BK20ac). Comparison of active chromatin state between somatic, embryonic stem, and germ cells revealed promoters and enhancers needed for stem cell maintenance and germ cell development. We found the nuclear receptor Nr5a2 motif to be enriched at a subset of germ cell cis-regulatory regions, and our results implicate Nr5a2 in germ cell biology. Interestingly, in germ cells, the H3K27me3 histone modification occurs more frequently at regions that are enriched for retrotransposons and MHC genes, indicating that these loci are specifically silenced in germ cells. Together, our study provides genome-wide histone modification maps of in vivo germ cells and reveals the molecular chromatin signatures of germ cells.

  13. Th17 cells are long lived and retain a stem cell-like molecular signature.

    Science.gov (United States)

    Muranski, Pawel; Borman, Zachary A; Kerkar, Sid P; Klebanoff, Christopher A; Ji, Yun; Sanchez-Perez, Luis; Sukumar, Madhusudhanan; Reger, Robert N; Yu, Zhiya; Kern, Steven J; Roychoudhuri, Rahul; Ferreyra, Gabriela A; Shen, Wei; Durum, Scott K; Feigenbaum, Lionel; Palmer, Douglas C; Antony, Paul A; Chan, Chi-Chao; Laurence, Arian; Danner, Robert L; Gattinoni, Luca; Restifo, Nicholas P

    2011-12-23

    Th17 cells have been described as short lived, but this view is at odds with their capacity to trigger protracted damage to normal and transformed tissues. We report that Th17 cells, despite displaying low expression of CD27 and other phenotypic markers of terminal differentiation, efficiently eradicated tumors and caused autoimmunity, were long lived, and maintained a core molecular signature resembling early memory CD8(+) cells with stem cell-like properties. In addition, we found that Th17 cells had high expression of Tcf7, a direct target of the Wnt and β-catenin signaling axis, and accumulated β-catenin, a feature observed in stem cells. In vivo, Th17 cells gave rise to Th1-like effector cell progeny and also self-renewed and persisted as IL-17A-secreting cells. Multipotency was required for Th17 cell-mediated tumor eradication because effector cells deficient in IFN-γ or IL-17A had impaired activity. Thus, Th17 cells are not always short lived and are a less-differentiated subset capable of superior persistence and functionality.

  14. Ontology based molecular signatures for immune cell types via gene expression analysis

    Science.gov (United States)

    2013-01-01

    Background New technologies are focusing on characterizing cell types to better understand their heterogeneity. With large volumes of cellular data being generated, innovative methods are needed to structure the resulting data analyses. Here, we describe an ‘Ontologically BAsed Molecular Signature’ (OBAMS) method that identifies novel cellular biomarkers and infers biological functions as characteristics of particular cell types. This method finds molecular signatures for immune cell types based on mapping biological samples to the Cell Ontology (CL) and navigating the space of all possible pairwise comparisons between cell types to find genes whose expression is core to a particular cell type’s identity. Results We illustrate this ontological approach by evaluating expression data available from the Immunological Genome project (IGP) to identify unique biomarkers of mature B cell subtypes. We find that using OBAMS, candidate biomarkers can be identified at every strata of cellular identity from broad classifications to very granular. Furthermore, we show that Gene Ontology can be used to cluster cell types by shared biological processes in order to find candidate genes responsible for somatic hypermutation in germinal center B cells. Moreover, through in silico experiments based on this approach, we have identified genes sets that represent genes overexpressed in germinal center B cells and identify genes uniquely expressed in these B cells compared to other B cell types. Conclusions This work demonstrates the utility of incorporating structured ontological knowledge into biological data analysis – providing a new method for defining novel biomarkers and providing an opportunity for new biological insights. PMID:24004649

  15. Molecular signatures to define spermatogenic cells in common marmoset (Callithrix jacchus).

    Science.gov (United States)

    Lin, Zachary Yu-Ching; Imamura, Masanori; Sano, Chiaki; Nakajima, Ryusuke; Suzuki, Tomoko; Yamadera, Rie; Takehara, Yuji; Okano, Hirotaka James; Sasaki, Erika; Okano, Hideyuki

    2012-05-01

    Germ cell development is a fundamental process required to produce offspring. The developmental program of spermatogenesis has been assumed to be similar among mammals. However, recent studies have revealed differences in the molecular properties of primate germ cells compared with the well-characterized mouse germ cells. This may prevent simple application of rodent insights into higher primates. Therefore, thorough investigation of primate germ cells is necessary, as this may lead to the development of more appropriate animal models. The aim of this study is to define molecular signatures of spermatogenic cells in the common marmoset, Callithrix jacchus. Interestingly, NANOG, PRDM1, DPPA3 (STELLA), IFITM3, and ZP1 transcripts, but no POU5F1 (OCT4), were detected in adult marmoset testis. Conversely, mouse testis expressed Pou5f1 but not Nanog, Prdm1, Dppa3, Ifitm3, and Zp1. Other previously described mouse germ cell markers were conserved in marmoset and mouse testes. Intriguingly, marmoset spermatogenic cells underwent dynamic protein expression in a developmental stage-specific manner; DDX4 (VASA) protein was present in gonocytes, diminished in spermatogonial cells, and reexpressed in spermatocytes. To investigate epigenetic differences between adult marmoset and mice, DNA methylation analyses identified unique epigenetic profiles to marmoset and mice. Marmoset NANOG and POU5F1 promoters in spermatogenic cells exhibited a methylation status opposite to that in mice, while the DDX4 and LEFTY1 loci, as well as imprinted genes, displayed an evolutionarily conserved methylation pattern. Marmosets have great advantages as models for human reproductive biology and are also valuable as experimental nonhuman primates; thus, the current study provides an important platform for primate reproductive biology, including possible applications to humans.

  16. Aqueous Cation-Amide Binding: Free Energies and IR Spectral Signatures by Ab Initio Molecular Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Pluharova, Eva; Baer, Marcel D.; Mundy, Christopher J.; Schmidt, Burkhard; Jungwirth, Pavel

    2014-07-03

    Understanding specific ion effects on proteins remains a considerable challenge. N-methylacetamide serves as a useful proxy for the protein backbone that can be well characterized both experimentally and theoretically. The spectroscopic signatures in the amide I band reflecting the strength of the interaction of alkali cations and alkali earth dications with the carbonyl group remain difficult to assign and controversial to interpret. Herein, we directly compute the IR shifts corresponding to the binding of either sodium or calcium to aqueous N-methylacetamide using ab initio molecular dynamics simulations. We show that the two cations interact with aqueous N-methylacetamide with different affinities and in different geometries. Since sodium exhibits a weak interaction with the carbonyl group, the resulting amide I band is similar to an unperturbed carbonyl group undergoing aqueous solvation. In contrast, the stronger calcium binding results in a clear IR shift with respect to N-methylacetamide in pure water. Support from the Czech Ministry of Education (grant LH12001) is gratefully acknowledged. EP thanks the International Max-Planck Research School for support and the Alternative Sponsored Fellowship program at Pacific Northwest National Laboratory (PNNL). PJ acknowledges the Praemium Academie award from the Academy of Sciences. Calculations of the free energy profiles were made possible through generous allocation of computer time from the North-German Supercomputing Alliance (HLRN). Calculations of vibrational spectra were performed in part using the computational resources in the National Energy Research Supercomputing Center (NERSC) at Lawrence Berkeley National Laboratory. This work was supported by National Science Foundation grant CHE-0431312. CJM is supported by the U.S. Department of Energy`s (DOE) Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences. PNNL is operated for the Department of Energy by Battelle. MDB is

  17. Signatures of Hot Molecular Hydrogen Absorption from Protoplanetary Disks. I. Non-thermal Populations

    Science.gov (United States)

    Hoadley, Keri; France, Kevin; Arulanantham, Nicole; Parke Loyd, R. O.; Kruczek, Nicholas

    2017-09-01

    The environment around protoplanetary disks (PPDs) regulates processes that drive the chemical and structural evolution of circumstellar material. We perform a detailed empirical survey of warm molecular hydrogen (H2) absorption observed against H i-Lyα (Lyα: λ1215.67) emission profiles for 22 PPDs, using archival Hubble Space Telescope ultraviolet (UV) spectra to identify H2 absorption signatures and quantify the column densities of H2 ground states in each sightline. We compare thermal equilibrium models of H2 to the observed H2 rovibrational level distributions. We find that, for the majority of targets, there is a clear deviation in high-energy states (T exc ≳ 20,000 K) away from thermal equilibrium populations (T(H2) ≳ 3500 K). We create a metric to estimate the total column density of non-thermal H2 (N(H2)nLTE) and find that the total column densities of thermal (N(H2)) and N(H2)nLTE correlate for transition disks and targets with detectable C iv-pumped H2 fluorescence. We compare N(H2) and N(H2)nLTE to circumstellar observables and find that N(H2)nLTE correlates with X-ray and far-UV luminosities, but no correlations are observed with the luminosities of discrete emission features (e.g., Lyα, C iv). Additionally, N(H2) and N(H2)nLTE are too low to account for the H2 fluorescence observed in PPDs, so we speculate that this H2 may instead be associated with a diffuse, hot, atomic halo surrounding the planet-forming disk. We create a simple photon-pumping model for each target to test this hypothesis and find that Lyα efficiently pumps H2 levels with T exc ≥ 10,000 K out of thermal equilibrium.

  18. Detecting robust gene signature through integrated analysis of multiple types of high-throughput data in liver cancer

    Institute of Scientific and Technical Information of China (English)

    Xin-yu ZHANG; Tian-tian LI; Xiang-jun LIU

    2007-01-01

    Aim: To investigate the robust gene signature in liver cancer, we applied an integrated approach to perform a joint analysis of a highly diverse collection of liver cancer genome-wide datasets, including genomic alterations and transcrip- tion profiles. Methods: 1-class Significance Analysis of Microarrays coupled with ranking score method were used to identify the robust gene signature in liver tumor tissue. Results: In total, 1 625 051 gene expression measurements from 16 public microarrays, 2 pairs of serial analyses of gene expression experiments, and 252 loss of heterozygosity reports obtained from 568 publications were used in this integrated study. The resulting robust gene signatures included 90 genes, which may be of great importance to liver cancer research. A system assessment analysis revealed that our integrative method had an accuracy of 92% and a correlation coefficient value of 0.88. Conclusion: The system assessment results indicated that our method had the ability of integrating the datasets from various types of sources, and eliciting more accurate results, as can be very useful in the study of liver cancer.

  19. The stable isotopic signature of biologically produced molecular hydrogen (H2

    Directory of Open Access Journals (Sweden)

    T. Röckmann

    2012-10-01

    Full Text Available Biologically produced molecular hydrogen (H2 is characterised by a very strong depletion in deuterium. Although the biological source to the atmosphere is small compared to photochemical or combustion sources, it makes an important contribution to the global isotope budget of H2. Large uncertainties exist in the quantification of the individual production and degradation processes that contribute to the atmospheric budget, and isotope measurements are a tool to distinguish the contributions from the different sources. Measurements of δ D from the various H2 sources are scarce and for biologically produced H2 only very few measurements exist. Here the first systematic study of the isotopic composition of biologically produced H2 is presented. In a first set of experiments, we investigated δ D of H2 produced in a biogas plant, covering different treatments of biogas production. In a second set of experiments, we investigated pure cultures of several H2 producing microorganisms such as bacteria or green algae. A Keeling plot analysis provides a robust overall source signature of δ D = −712‰ (±13‰ for the samples from the biogas reactor (at 38 °C, δ DH2O= +73.4‰, with a fractionation constant ϵH2-H2O of −689‰ (±20‰ between H2 and the water. The five experiments using pure culture samples from different microorganisms give a mean source signature of δ D = −728‰ (±28‰, and a fractionation constant ϵH2-H2O of −711‰ (±34‰ between H2 and the water. The results confirm the massive deuterium depletion of biologically produced H2 as was predicted by the calculation of the thermodynamic fractionation factors for hydrogen exchange between H2 and water vapour. Systematic errors in the isotope scale are difficult to assess in the absence of international standards for δ D of H2. As expected for a thermodynamic equilibrium, the fractionation factor is temperature dependent, but largely independent of the

  20. Xmrk, kras and myc transgenic zebrafish liver cancer models share molecular signatures with subsets of human hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Weiling Zheng

    Full Text Available Previously three oncogene transgenic zebrafish lines with inducible expression of xmrk, kras or Myc in the liver have been generated and these transgenic lines develop oncogene-addicted liver tumors upon chemical induction. In the current study, comparative transcriptomic approaches were used to examine the correlation of the three induced transgenic liver cancers with human liver cancers. RNA profiles from the three zebrafish tumors indicated relatively small overlaps of significantly deregulated genes and biological pathways. Nevertheless, the three transgenic tumor signatures all showed significant correlation with advanced or very advanced human hepatocellular carcinoma (HCC. Interestingly, molecular signature from each oncogene-induced zebrafish liver tumor correlated with only a small subset of human HCC samples (24-29% and there were conserved up-regulated pathways between the zebrafish and correlated human HCC subgroup. The three zebrafish liver cancer models together represented nearly half (47.2% of human HCCs while some human HCCs showed significant correlation with more than one signature defined from the three oncogene-addicted zebrafish tumors. In contrast, commonly deregulated genes (21 up and 16 down in the three zebrafish tumor models generally showed accordant deregulation in the majority of human HCCs, suggesting that these genes might be more consistently deregulated in a broad range of human HCCs with different molecular mechanisms and thus serve as common diagnosis markers and therapeutic targets. Thus, these transgenic zebrafish models with well-defined oncogene-induced tumors are valuable tools for molecular classification of human HCCs and for understanding of molecular drivers in hepatocarcinogenesis in each human HCC subgroup.

  1. Molecular signature of high yield (growth influenza a virus reassortants prepared as candidate vaccine seeds.

    Directory of Open Access Journals (Sweden)

    Manojkumar Ramanunninair

    Full Text Available BACKGROUND: Human influenza virus isolates generally grow poorly in embryonated chicken eggs. Hence, gene reassortment of influenza A wild type (wt viruses is performed with a highly egg adapted donor virus, A/Puerto Rico/8/1934 (PR8, to provide the high yield reassortant (HYR viral 'seeds' for vaccine production. HYR must contain the hemagglutinin (HA and neuraminidase (NA genes of wt virus and one to six 'internal' genes from PR8. Most studies of influenza wt and HYRs have focused on the HA gene. The main objective of this study is the identification of the molecular signature in all eight gene segments of influenza A HYR candidate vaccine seeds associated with high growth in ovo. METHODOLOGY: The genomes of 14 wt parental viruses, 23 HYRs (5 H1N1; 2, 1976 H1N1-SOIV; 2, 2009 H1N1pdm; 2 H2N2 and 12 H3N2 and PR8 were sequenced using the high-throughput sequencing pipeline with big dye terminator chemistry. RESULTS: Silent and coding mutations were found in all internal genes derived from PR8 with the exception of the M gene. The M gene derived from PR8 was invariant in all 23 HYRs underlining the critical role of PR8 M in high yield phenotype. None of the wt virus derived internal genes had any silent change(s except the PB1 gene in X-157. The highest number of recurrent silent and coding mutations was found in NS. With respect to the surface antigens, the majority of HYRs had coding mutations in HA; only 2 HYRs had coding mutations in NA. SIGNIFICANCE: In the era of application of reverse genetics to alter influenza A virus genomes, the mutations identified in the HYR gene segments associated with high growth in ovo may be of great practical benefit to modify PR8 and/or wt virus gene sequences for improved growth of vaccine 'seed' viruses.

  2. Conserved signature indels and signature proteins as novel tools for understanding microbial phylogeny and systematics: identification of molecular signatures that are specific for the phytopathogenic genera Dickeya, Pectobacterium and Brenneria.

    Science.gov (United States)

    Naushad, Hafiz Sohail; Lee, Brian; Gupta, Radhey S

    2014-02-01

    Genome sequences are enabling applications of different approaches to more clearly understand microbial phylogeny and systematics. Two of these approaches involve identification of conserved signature indels (CSIs) and conserved signature proteins (CSPs) that are specific for different lineages. These molecular markers provide novel and more definitive means for demarcation of prokaryotic taxa and for identification of species from these groups. Genome sequences are also enabling determination of phylogenetic relationships among species based upon sequences for multiple proteins. In this work, we have used all of these approaches for studying the phytopathogenic bacteria belonging to the genera Dickeya, Pectobacterium and Brenneria. Members of these genera, which cause numerous diseases in important food crops and ornamental plants, are presently distinguished mainly on the basis of their branching in phylogenetic trees. No biochemical or molecular characteristic is known that is uniquely shared by species from these genera. Hence, detailed studies using the above approaches were carried out on proteins from the genomes of these bacteria to identify molecular markers that are specific for them. In phylogenetic trees based upon concatenated sequences for 23 conserved proteins, members of the genera Dickeya, Pectobacterium and Brenneria formed a strongly supported clade within the other Enterobacteriales. Comparative analysis of protein sequences from the Dickeya, Pectobacterium and Brenneria genomes has identified 10 CSIs and five CSPs that are either uniquely or largely found in all genome-sequenced species from these genera, but not present in any other bacteria in the database. In addition, our analyses have identified 10 CSIs and 17 CSPs that are specifically present in either all or most sequenced Dickeya species/strains, and six CSIs and 19 CSPs that are uniquely found in the sequenced Pectobacterium genomes. Finally, our analysis also identified three CSIs

  3. Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology.

    Science.gov (United States)

    Velasco, Guillaume; Walton, Emma L; Sterlin, Delphine; Hédouin, Sabrine; Nitta, Hirohisa; Ito, Yuya; Fouyssac, Fanny; Mégarbané, André; Sasaki, Hiroyuki; Picard, Capucine; Francastel, Claire

    2014-04-17

    Immunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease. We used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients. We report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease. Early diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust

  4. Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance.

    Science.gov (United States)

    Shi, Ke-Qing; Lin, Zhuo; Chen, Xiang-Jian; Song, Mei; Wang, Yu-Qun; Cai, Yi-Jing; Yang, Nai-Bing; Zheng, Ming-Hua; Dong, Jin-Zhong; Zhang, Lei; Chen, Yong-Ping

    2015-09-22

    microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated-signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR-145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR-221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR-221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079-2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057-1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC.

  5. Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis.

    Directory of Open Access Journals (Sweden)

    Ang Cui

    Full Text Available Gene expression-based signatures help identify pathways relevant to diseases and treatments, but are challenging to construct when there is a diversity of disease mechanisms and treatments in patients with complex diseases. To overcome this challenge, we present a new application of an in silico gene expression deconvolution method, ISOpure-S1, and apply it to identify a common gene expression signature corresponding to response to treatment in 33 juvenile idiopathic arthritis (JIA patients. Using pre- and post-treatment gene expression profiles only, we found a gene expression signature that significantly correlated with a reduction in the number of joints with active arthritis, a measure of clinical outcome (Spearman rho = 0.44, p = 0.040, Bonferroni correction. This signature may be associated with a decrease in T-cells, monocytes, neutrophils and platelets. The products of most differentially expressed genes include known biomarkers for JIA such as major histocompatibility complexes and interleukins, as well as novel biomarkers including α-defensins. This method is readily applicable to expression datasets of other complex diseases to uncover shared mechanistic patterns in heterogeneous samples.

  6. Integrated molecular landscape of Parkinson's disease

    NARCIS (Netherlands)

    Klemann, C.J.H.M.; Martens, G.J.; Sharma, M.; Martens, M.B.; Isacson, O.; Gasser, T.; Visser, J.E.; Poelmans, G.J.V.

    2017-01-01

    Parkinson's disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson's disease, a common mechanism underlying especially sporadic Parkinson's disease is still largely

  7. A watermarking-based medical image integrity control system and an image moment signature for tampering characterization.

    Science.gov (United States)

    Coatrieux, Gouenou; Huang, Hui; Shu, Huazhong; Luo, Limin; Roux, Christian

    2013-11-01

    In this paper, we present a medical image integrity verification system to detect and approximate local malevolent image alterations (e.g., removal or addition of lesions) as well as identifying the nature of a global processing an image may have undergone (e.g., lossy compression, filtering, etc.). The proposed integrity analysis process is based on nonsignificant region watermarking with signatures extracted from different pixel blocks of interest, which are compared with the recomputed ones at the verification stage. A set of three signatures is proposed. The first two devoted to detection and modification location are cryptographic hashes and checksums, while the last one is issued from the image moment theory. In this paper, we first show how geometric moments can be used to approximate any local modification by its nearest generalized 2-D Gaussian. We then demonstrate how ratios between original and recomputed geometric moments can be used as image features in a classifier-based strategy in order to determine the nature of a global image processing. Experimental results considering both local and global modifications in MRI and retina images illustrate the overall performances of our approach. With a pixel block signature of about 200 bit long, it is possible to detect, to roughly localize, and to get an idea about the image tamper.

  8. New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies.

    Science.gov (United States)

    Scott, David W; Abrisqueta, Pau; Wright, George W; Slack, Graham W; Mottok, Anja; Villa, Diego; Jares, Pedro; Rauert-Wunderlich, Hilka; Royo, Cristina; Clot, Guillem; Pinyol, Magda; Boyle, Merrill; Chan, Fong Chun; Braziel, Rita M; Chan, Wing C; Weisenburger, Dennis D; Cook, James R; Greiner, Timothy C; Fu, Kai; Ott, German; Delabie, Jan; Smeland, Erlend B; Holte, Harald; Jaffe, Elaine S; Steidl, Christian; Connors, Joseph M; Gascoyne, Randy D; Rosenwald, Andreas; Staudt, Louis M; Campo, Elias; Rimsza, Lisa M

    2017-05-20

    Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to

  9. Integrated Cellular and Plasma Proteomics of Contrasting B-cell Cancers Reveals Common, Unique and Systemic Signatures.

    Science.gov (United States)

    Johnston, Harvey E; Carter, Matthew J; Cox, Kerry L; Dunscombe, Melanie; Manousopoulou, Antigoni; Townsend, Paul A; Garbis, Spiros D; Cragg, Mark S

    2017-03-01

    Approximately 800,000 leukemia and lymphoma cases are diagnosed worldwide each year. Burkitt's lymphoma (BL) and chronic lymphocytic leukemia (CLL) are examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumor, frequently affecting children, whereas CLL typically presents as an indolent, slow-progressing leukemia affecting the elderly. The B-cell-specific overexpression of the myc and TCL1 oncogenes in mice induce spontaneous malignancies modeling BL and CLL, respectively. Quantitative mass spectrometry proteomics and isobaric labeling were employed to examine the biology underpinning contrasting Eμ-myc and Eμ-TCL1 B-cell tumors. Additionally, the plasma proteome was evaluated using subproteome enrichment to interrogate biomarker emergence and the systemic effects of tumor burden. Over 10,000 proteins were identified (qIL5) receptor. IL5 treatment promoted Eμ-TCL1 tumor proliferation, suggesting an amplification of IL5-induced AKT signaling by TCL1. Tumor plasma contained a substantial tumor lysis signature, most prominent in Eμ-myc plasma, whereas Eμ-TCL1 plasma contained signatures of immune-response, inflammation and microenvironment interactions, with putative biomarkers in early-stage cancer. These findings provide a detailed characterization of contrasting B-cell tumor models, identifying common and specific tumor mechanisms. Integrated plasma proteomics allowed the dissection of a systemic response and a tumor lysis signature present in early- and late-stage cancers, respectively. Overall, this study suggests common B-cell cancer signatures exist and illustrates the potential of the further evaluation of B-cell cancer subtypes by integrative proteomics.

  10. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures

    Science.gov (United States)

    Zeng, Hongkui; Shen, Elaine H.; Hohmann, John G.; Oh, Wook Seung; Bernard, Amy; Royall, Joshua J.; Glattfelder, Katie J.; Sunkin, Susan M.; Morris, John A.; Guillozet-Bongaarts, Angela L.; Smith, Kimberly A.; Ebbert, Amanda J.; Swanson, Beryl; Kuan, Leonard; Page, Damon T.; Overly, Caroline C.; Lein, Ed S.; Hawrylycz, Michael J.; Hof, Patrick R.; Hyde, Thomas M.; Kleinman, Joel E.; Jones, Allan R.

    2012-01-01

    Summary Although there have been major advances in elucidating the functional biology of the human brain, relatively little is known of its cellular and molecular organization. Here we report a large-scale characterization of the expression of ~1,000 genes important for neural functions, by in situ hybridization with cellular resolution in visual and temporal cortices of adult human brains. These data reveal diverse gene expression patterns and remarkable conservation of each individual gene’s expression among individuals (95%), cortical areas (84%), and between human and mouse (79%). A small but substantial number of genes (21%) exhibited species-differential expression. Distinct molecular signatures, comprised of genes both common between species and unique to each, were identified for each major cortical cell type. The data suggest that gene expression profile changes may contribute to differential cortical function across species, in particular, a shift from corticosubcortical to more predominant corticocortical communications in the human brain. PMID:22500809

  11. Accurate Kirkwood-Buff Integrals from Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Wedberg, Nils Hejle Rasmus Ingemar; O'Connell, John P.; Peters, Günther H.J.

    2010-01-01

    A method is proposed for obtaining thermodynamic properties via Kirkwood–Buff (KB) integrals from molecular simulations. In order to ensure that the KB integration converges, the pair distribution function is extrapolated to large distances using the extension method of Verlet, which enforces...

  12. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

    NARCIS (Netherlands)

    M. Smid (Marcel); F.G. Rodriguez-Gonzalez (F. German); A.M. Sieuwerts (Anieta); R. Salgado (Roberto); W.J.C. Prager-van der Smissen (Wendy); Vlugt-Daane, M.V.D. (Michelle Van Der); A. van Galen (Anne); S. Nik-Zainal (Serena); J. Staaf (Johan); A.B. Brinkman (Arie B.); M.J. Vijver (Marc ); A.L. Richardson (Andrea); A. Fatima (Aquila); Berentsen, K. (Kim); A. Butler (Adam); S. Martin (Sandra); H. Davies (Helen); J.E.M.A. Debets (Reno); M.E.M.-V. Gelder (Marion E. Meijer-Van); C.H.M. van Deurzen (Carolien); Macgrogan, G. (Gaëtan); Van Den Eynden, G.G.G.M. (Gert G. G. M.); C.A. Purdie (Colin A.); A.M. Thompson (Alastair M.); C. Caldas (Carlos); P.N. Span (Paul); Simpson, P.T. (Peter T.); S. Lakhani (Sunil); S.J. van Laere (Steven); C. Desmedt (Christine); Ringnér, M. (Markus); Tommasi, S. (Stefania); Eyford, J. (Jorunn); A. Broeks (Annegien); A. Vincent-Salomon (Anne); Futreal, P.A. (P. Andrew); S. Knappskog (Stian); King, T. (Tari); G. Thomas (Gilles); Viari, A. (Alain); Langerød, A. (Anita); A.-L. Borresen-Dale (Anne-Lise); E. Birney (Ewan); H. Stunnenberg (Henk); M.R. Stratton (Michael); J.A. Foekens (John); J.W.M. Martens (John)

    2016-01-01

    textabstractA recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP

  13. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

    NARCIS (Netherlands)

    Smid, M.; Rodriguez-Gonzalez, F.G.; Sieuwerts, A.M.; Salgado, R.; Smissen, W.J. Prager-Van der; Vlugt-Daane, M.V.; Galen, A. van; Nik-Zainal, S.; Staaf, J.; Brinkman, A.B.; Vijver, M.J. van de; Richardson, A.L.; Fatima, A.; Berentsen, K.; Butler, A.; Martin, S.; Davies, H.R.; Debets, R.; Gelder, M.E. Meijer-van; Deurzen, C.H. van; MacGrogan, G.; Eynden, G.G. Van den; Purdie, C.; Thompson, A.M.; Caldas, C.; Span, P.N; Simpson, P.T.; Lakhani, S.R.; Laere, S. van; Desmedt, C.; Ringner, M.; Tommasi, S.; Eyford, J.; Broeks, A.; Vincent-Salomon, A.; Futreal, P.A.; Knappskog, S.; King, T.; Thomas, G; Viari, A.; Langerod, A.; Borresen-Dale, A.L.; Birney, E.; Stunnenberg, H.G.; Stratton, M.; Foekens, J.A.; Martens, J.W.M.

    2016-01-01

    A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA,

  14. Integrative Molecular Analysis of Intrahepatic Cholangiocarcinoma Reveals 2 Classes That Have Different Outcomes

    Science.gov (United States)

    SIA, DANIELA; HOSHIDA, YUJIN; VILLANUEVA, AUGUSTO; ROAYAIE, SASAN; FERRER, JOANA; TABAK, BARBARA; PEIX, JUDIT; SOLE, MANEL; TOVAR, VICTORIA; ALSINET, CLARA; CORNELLA, HELENA; KLOTZLE, BRANDY; FAN, JIAN–BING; COTSOGLOU, CHRISTIAN; THUNG, SWAN N.; FUSTER, JOSEP; WAXMAN, SAMUEL; GARCIA–VALDECASAS, JUAN CARLOS; BRUIX, JORDI; SCHWARTZ, MYRON E.; BEROUKHIM, RAMEEN; MAZZAFERRO, VINCENZO; LLOVET, JOSEP M.

    2013-01-01

    BACKGROUND & AIMS Cholangiocarcinoma, the second most common liver cancer, can be classified as intra-hepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation– based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001). CONCLUSIONS We used an integrative genomic analysis to identify 2 classes

  15. Exploring RNA structure by integrative molecular modelling

    DEFF Research Database (Denmark)

    Masquida, Benoît; Beckert, Bertrand; Jossinet, Fabrice

    2010-01-01

    RNA molecular modelling is adequate to rapidly tackle the structure of RNA molecules. With new structured RNAs constituting a central class of cellular regulators discovered every year, the need for swift and reliable modelling methods is more crucial than ever. The pragmatic method based...... on interactive all-atom molecular modelling relies on the observation that specific structural motifs are recurrently found in RNA sequences. Once identified by a combination of comparative sequence analysis and biochemical data, the motifs composing the secondary structure of a given RNA can be extruded...... in three dimensions (3D) and used as building blocks assembled manually during a bioinformatic interactive process. Comparing the models to the corresponding crystal structures has validated the method as being powerful to predict the RNA topology and architecture while being less accurate regarding...

  16. Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes.

    Science.gov (United States)

    Ackermann, Amanda M; Wang, Zhiping; Schug, Jonathan; Naji, Ali; Kaestner, Klaus H

    2016-03-01

    Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity. We sorted human α- and β-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to α-cells, while CHODL (chondrolectin) immunoreactivity was only present in β-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. We have determined the genetic landscape of

  17. The stable isotopic signature of biologically produced molecular hydrogen (H2)

    NARCIS (Netherlands)

    Walter, S.; Laukenmann, S.; Stams, A.J.M.; Vollmer, M.K.; Gleixner, G.; Roeckmann, T.|info:eu-repo/dai/nl/304838233

    2011-01-01

    Biologically produced molecular hydrogen (H2) is characterized by a very strong depletion in deuterium. Although the biological source to the atmosphere is small compared to photochemical or combustion sources, it makes an important contribution to the global isotope budget of molecular hydrogen

  18. A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Alakesh Bera

    Full Text Available In this study a microRNA (miRNA signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC cell line model (BxPC3-GZR and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13. Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.

  19. A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

    Science.gov (United States)

    Bera, Alakesh; VenkataSubbaRao, Kolaparthi; Manoharan, Muthu Saravanan; Hill, Ping; Freeman, James W

    2014-01-01

    In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.

  20. Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Jerzy Bernholc

    2011-02-03

    photolithography will some day reach a miniaturization limit, forcing designers of Si-based electronics to pursue increased performance by other means. Any other alternative approach would have the unenviable task of matching the ability of Si technology to pack more than a billion interconnected and addressable devices on a chip the size of a thumbnail. Nevertheless, the prospects of developing alternative approaches to fabricate electronic devices have spurred an ever-increasing pace of fundamental research. One of the promising possibilities is molecular electronics (ME), self-assembled molecular-based electronic systems composed of single-molecule devices in ultra dense, ultra fast molecular-sized components. This project focused on developing accurate, reliable theoretical modeling capabilities for describing molecular electronics devices. The participants in the project are given in Table 1. The primary outcomes of this fundamental computational science grant are publications in the open scientific literature. As listed below, 62 papers have been published from this project. In addition, the research has also been the subject of more than 100 invited talks at conferences, including several plenary or keynote lectures. Many of the goals of the original proposal were completed. Specifically, the multi-disciplinary group developed a unique set of capabilities and tools for investigating electron transport in fabricated and self-assembled nanostructures at multiple length and time scales.

  1. Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Weinan E

    2012-03-29

    The main bottleneck in modeling transport in molecular devices is to develop the correct formulation of the problem and efficient algorithms for analyzing the electronic structure and dynamics using, for example, the time-dependent density functional theory. We have divided this task into several steps. The first step is to developing the right mathematical formulation and numerical algorithms for analyzing the electronic structure using density functional theory. The second step is to study time-dependent density functional theory, particularly the far-field boundary conditions. The third step is to study electronic transport in molecular devices. We are now at the end of the first step. Under DOE support, we have made subtantial progress in developing linear scaling and sub-linear scaling algorithms for electronic structure analysis. Although there has been a huge amount of effort in the past on developing linear scaling algorithms, most of the algorithms developed suffer from the lack of robustness and controllable accuracy. We have made the following progress: (1) We have analyzed thoroughly the localization properties of the wave-functions. We have developed a clear understanding of the physical as well as mathematical origin of the decay properties. One important conclusion is that even for metals, one can choose wavefunctions that decay faster than any algebraic power. (2) We have developed algorithms that make use of these localization properties. Our algorithms are based on non-orthogonal formulations of the density functional theory. Our key contribution is to add a localization step into the algorithm. The addition of this localization step makes the algorithm quite robust and much more accurate. Moreover, we can control the accuracy of these algorithms by changing the numerical parameters. (3) We have considerably improved the Fermi operator expansion (FOE) approach. Through pole expansion, we have developed the optimal scaling FOE algorithm.

  2. Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Weinan E

    2012-03-29

    The main bottleneck in modeling transport in molecular devices is to develop the correct formulation of the problem and efficient algorithms for analyzing the electronic structure and dynamics using, for example, the time-dependent density functional theory. We have divided this task into several steps. The first step is to developing the right mathematical formulation and numerical algorithms for analyzing the electronic structure using density functional theory. The second step is to study time-dependent density functional theory, particularly the far-field boundary conditions. The third step is to study electronic transport in molecular devices. We are now at the end of the first step. Under DOE support, we have made subtantial progress in developing linear scaling and sub-linear scaling algorithms for electronic structure analysis. Although there has been a huge amount of effort in the past on developing linear scaling algorithms, most of the algorithms developed suffer from the lack of robustness and controllable accuracy. We have made the following progress: (1) We have analyzed thoroughly the localization properties of the wave-functions. We have developed a clear understanding of the physical as well as mathematical origin of the decay properties. One important conclusion is that even for metals, one can choose wavefunctions that decay faster than any algebraic power. (2) We have developed algorithms that make use of these localization properties. Our algorithms are based on non-orthogonal formulations of the density functional theory. Our key contribution is to add a localization step into the algorithm. The addition of this localization step makes the algorithm quite robust and much more accurate. Moreover, we can control the accuracy of these algorithms by changing the numerical parameters. (3) We have considerably improved the Fermi operator expansion (FOE) approach. Through pole expansion, we have developed the optimal scaling FOE algorithm.

  3. Molecular signatures that are distinctive characteristics of the vertebrates and chordates and supporting a grouping of vertebrates with the tunicates.

    Science.gov (United States)

    Gupta, Radhey S

    2016-01-01

    Members of the phylum Chordata and the subphylum Vertebrata are presently distinguished solely on the basis of morphological characteristics. The relationship of the vertebrates to the two non-vertebrate chordate subphyla is also a subject of debate. Analyses of protein sequences have identified multiple conserved signature indels (CSIs) that are specific for Chordata or for Vertebrata. Five CSIs in 4 important proteins are specific for the Vertebrata, whereas two other CSIs are uniquely found in all sequenced chordate species including Ciona intestinalis and Oikapleura dioica (Tunicates) as well as Branchiostoma floridae (Cephalochordates). The shared presence of these molecular signatures by all vertebrates/chordate species, but in no other animal taxa, strongly indicates that the genetic changes represented by the identified CSIs diagnose monophyletic groups. Two other discovered CSIs are uniquely shared by different vertebrate species and by either one (Ciona intestinalis) or both tunicate (Ciona and Oikapleura) species, but they are not found in Branchiostoma or other animal species. Specific presence of these CSIs in different vertebrates and either one or both tunicate species provides strong independent evidence that the vertebrate species are more closely related to the urochordates (tunicates) than to the cephalochordates.

  4. Optical signatures of molecular particles via mass-selected cluster spectroscopy

    Science.gov (United States)

    Duncan, Michael A.

    1990-01-01

    A new molecular beam apparatus was developed to study optical absorption in cold (less than 100 K) atomic clusters and complexes produced by their condensation with simple molecular gases. In this instrument, ionized clusters produced in a laser vaporization nozzle source are mass selected and studied with photodissociation spectroscopy at visible and ultraviolet wavelengths. This new approach can be applied to synthesize and characterize numerous particulates and weakly bound complexes expected in planetary atmospheres and in comets.

  5. Significance analysis of prognostic signatures.

    Directory of Open Access Journals (Sweden)

    Andrew H Beck

    Full Text Available A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically

  6. Quantum tunneling splittings from path-integral molecular dynamics

    Science.gov (United States)

    Mátyus, Edit; Wales, David J.; Althorpe, Stuart C.

    2016-03-01

    We illustrate how path-integral molecular dynamics can be used to calculate ground-state tunnelling splittings in molecules or clusters. The method obtains the splittings from ratios of density matrix elements between the degenerate wells connected by the tunnelling. We propose a simple thermodynamic integration scheme for evaluating these elements. Numerical tests on fully dimensional malonaldehyde yield tunnelling splittings in good overall agreement with the results of diffusion Monte Carlo calculations.

  7. Variational path integral molecular dynamics study of a water molecule

    Science.gov (United States)

    Miura, Shinichi

    2013-08-01

    In the present study, a variational path integral molecular dynamics method developed by the author [Chem. Phys. Lett. 482, 165 (2009)] is applied to a water molecule on the adiabatic potential energy surface. The method numerically generates an exact wavefunction using a trial wavefunction of the target system. It has been shown that even if a poor trial wavefunction is employed, the exact quantum distribution is numerically extracted, demonstrating the robustness of the variational path integral method.

  8. Phylogenetic analysis and molecular signatures defining a monophyletic clade of heterocystous cyanobacteria and identifying its closest relatives.

    Science.gov (United States)

    Howard-Azzeh, Mohammad; Shamseer, Larissa; Schellhorn, Herb E; Gupta, Radhey S

    2014-11-01

    Detailed phylogenetic and comparative genomic analyses are reported on 140 genome sequenced cyanobacteria with the main focus on the heterocyst-differentiating cyanobacteria. In a phylogenetic tree for cyanobacteria based upon concatenated sequences for 32 conserved proteins, the available cyanobacteria formed 8-9 strongly supported clades at the highest level, which may correspond to the higher taxonomic clades of this phylum. One of these clades contained all heterocystous cyanobacteria; within this clade, the members exhibiting either true (Nostocales) or false (Stigonematales) branching of filaments were intermixed indicating that the division of the heterocysts-forming cyanobacteria into these two groups is not supported by phylogenetic considerations. However, in both the protein tree as well as in the 16S rRNA gene tree, the akinete-forming heterocystous cyanobacteria formed a distinct clade. Within this clade, the members which differentiate into hormogonia or those which lack this ability were also separated into distinct groups. A novel molecular signature identified in this work that is uniquely shared by the akinete-forming heterocystous cyanobacteria provides further evidence that the members of this group are specifically related and they shared a common ancestor exclusive of the other cyanobacteria. Detailed comparative analyses on protein sequences from the genomes of heterocystous cyanobacteria reported here have also identified eight conserved signature indels (CSIs) in proteins involved in a broad range of functions, and three conserved signature proteins, that are either uniquely or mainly found in all heterocysts-forming cyanobacteria, but generally not found in other cyanobacteria. These molecular markers provide novel means for the identification of heterocystous cyanobacteria, and they provide evidence of their monophyletic origin. Additionally, this work has also identified seven CSIs in other proteins which in addition to the heterocystous

  9. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration.

    Science.gov (United States)

    Smid, Marcel; Rodríguez-González, F Germán; Sieuwerts, Anieta M; Salgado, Roberto; Prager-Van der Smissen, Wendy J C; Vlugt-Daane, Michelle van der; van Galen, Anne; Nik-Zainal, Serena; Staaf, Johan; Brinkman, Arie B; van de Vijver, Marc J; Richardson, Andrea L; Fatima, Aquila; Berentsen, Kim; Butler, Adam; Martin, Sancha; Davies, Helen R; Debets, Reno; Gelder, Marion E Meijer-Van; van Deurzen, Carolien H M; MacGrogan, Gaëtan; Van den Eynden, Gert G G M; Purdie, Colin; Thompson, Alastair M; Caldas, Carlos; Span, Paul N; Simpson, Peter T; Lakhani, Sunil R; Van Laere, Steven; Desmedt, Christine; Ringnér, Markus; Tommasi, Stefania; Eyford, Jorunn; Broeks, Annegien; Vincent-Salomon, Anne; Futreal, P Andrew; Knappskog, Stian; King, Tari; Thomas, Gilles; Viari, Alain; Langerød, Anita; Børresen-Dale, Anne-Lise; Birney, Ewan; Stunnenberg, Hendrik G; Stratton, Mike; Foekens, John A; Martens, John W M

    2016-09-26

    A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.

  10. The nanomechanical signature of liver cancer tissues and its molecular origin

    Science.gov (United States)

    Tian, Mengxin; Li, Yiran; Liu, Weiren; Jin, Lei; Jiang, Xifei; Wang, Xinyan; Ding, Zhenbin; Peng, Yuanfei; Zhou, Jian; Fan, Jia; Cao, Yi; Wang, Wei; Shi, Yinghong

    2015-07-01

    Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the ``gold standard'' in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus distribution of surgically removed liver cancer tissues can serve as a mechanical fingerprint to evaluate the malignancy of liver cancer. Cirrhotic tissues shared the same LEP as normal tissues. However, a noticeable downward shift in the LEP was detected when the cirrhotic tissues progressed to a malignant state, making the tumor tissues more prone to microvascular invasion. Cell-level mechanistic studies revealed that the expression level of a Rho-family effector (mDia1) was consistent with the mechanical trend exhibited by the tissue. Our findings indicate that the mechanical profiles of liver cancer tissues directly varied with tumor progression, providing an additional platform for the future diagnosis of HCC.Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the ``gold standard'' in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus

  11. HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events.

    Directory of Open Access Journals (Sweden)

    Stéphane Buhler

    Full Text Available Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies.Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model. However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used

  12. An Integrated Biochemistry Laboratory, Including Molecular Modeling

    Science.gov (United States)

    Hall, Adele J. Wolfson Mona L.; Branham, Thomas R.

    1996-11-01

    ) experience with methods of protein purification; (iii) incorporation of appropriate controls into experiments; (iv) use of basic statistics in data analysis; (v) writing papers and grant proposals in accepted scientific style; (vi) peer review; (vii) oral presentation of results and proposals; and (viii) introduction to molecular modeling. Figure 1 illustrates the modular nature of the lab curriculum. Elements from each of the exercises can be separated and treated as stand-alone exercises, or combined into short or long projects. We have been able to offer the opportunity to use sophisticated molecular modeling in the final module through funding from an NSF-ILI grant. However, many of the benefits of the research proposal can be achieved with other computer programs, or even by literature survey alone. Figure 1.Design of project-based biochemistry laboratory. Modules (projects, or portions of projects) are indicated as boxes. Each of these can be treated independently, or used as part of a larger project. Solid lines indicate some suggested paths from one module to the next. The skills and knowledge required for protein purification and design are developed in three units: (i) an introduction to critical assays needed to monitor degree of purification, including an evaluation of assay parameters; (ii) partial purification by ion-exchange techniques; and (iii) preparation of a grant proposal on protein design by mutagenesis. Brief descriptions of each of these units follow, with experimental details of each project at the end of this paper. Assays for Lysozyme Activity and Protein Concentration (4 weeks) The assays mastered during the first unit are a necessary tool for determining the purity of the enzyme during the second unit on purification by ion exchange. These assays allow an introduction to the concept of specific activity (units of enzyme activity per milligram of total protein) as a measure of purity. In this first sequence, students learn a turbidimetric assay

  13. Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells

    Directory of Open Access Journals (Sweden)

    Kim Han

    2012-07-01

    Full Text Available Abstract Background In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related signaling pathways, four different microarray experiments were reanalyzed before radiotherapy. Results Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1 was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2. Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway. Conclusions Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that

  14. The nanomechanical signature of liver cancer tissues and its molecular origin.

    Science.gov (United States)

    Tian, Mengxin; Li, Yiran; Liu, Weiren; Jin, Lei; Jiang, Xifei; Wang, Xinyan; Ding, Zhenbin; Peng, Yuanfei; Zhou, Jian; Fan, Jia; Cao, Yi; Wang, Wei; Shi, Yinghong

    2015-08-14

    Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the "gold standard" in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus distribution of surgically removed liver cancer tissues can serve as a mechanical fingerprint to evaluate the malignancy of liver cancer. Cirrhotic tissues shared the same LEP as normal tissues. However, a noticeable downward shift in the LEP was detected when the cirrhotic tissues progressed to a malignant state, making the tumor tissues more prone to microvascular invasion. Cell-level mechanistic studies revealed that the expression level of a Rho-family effector (mDia1) was consistent with the mechanical trend exhibited by the tissue. Our findings indicate that the mechanical profiles of liver cancer tissues directly varied with tumor progression, providing an additional platform for the future diagnosis of HCC.

  15. Effect of heparin on the biological properties and molecular signature of human mesenchymal stem cells.

    Science.gov (United States)

    Ling, Ling; Camilleri, Emily T; Helledie, Torben; Samsonraj, Rebekah M; Titmarsh, Drew M; Chua, Ren Jie; Dreesen, Oliver; Dombrowski, Christian; Rider, David A; Galindo, Mario; Lee, Ian; Hong, Wanjin; Hui, James H; Nurcombe, Victor; van Wijnen, Andre J; Cool, Simon M

    2016-01-15

    Chronic use of heparin as an anti-coagulant for the treatment of thrombosis or embolism invokes many adverse systemic events including thrombocytopenia, vascular reactions and osteoporosis. Here, we addressed whether adverse effects might also be directed to mesenchymal stem cells that reside in the bone marrow compartment. Harvested human bone marrow-derived mesenchymal stem cells (hMSCs) were exposed to varying doses of heparin and their responses profiled. At low doses (heparin exerted a variable effect on hMSC proliferation and multipotentiality across multiple donors, while at higher doses (≥ 100 μg/ml), heparin supplementation inhibited cell growth and increased both senescence and cell size. Gene expression profiling using cDNA arrays and RNA-seq analysis revealed pleiotropic effects of low-dose heparin on signaling pathways essential to hMSC growth and differentiation (including the TGFβ/BMP superfamily, FGFs, and Wnts). Cells serially passaged in low-dose heparin possess a donor-dependent gene signature that reflects their altered phenotype. Our data indicate that heparin supplementation during the culturing of hMSCs can alter their biological properties, even at low doses. This warrants caution in the application of heparin as a culture supplement for the ex vivo expansion of hMSCs. It also highlights the need for careful evaluation of the bone marrow compartment in patients receiving chronic heparin treatment.

  16. Current and Emerging Technologies for Probing Molecular Signatures of Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Ari Ercole

    2017-08-01

    Full Text Available Traumatic brain injury (TBI is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available techniques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype.

  17. Microbe-associated molecular pattern (MAMP) signatures, synergy, size and charge

    DEFF Research Database (Denmark)

    Aslam, Shazia N.; Erbs, Gitte; Morrissey, Kate L.

    2009-01-01

    Triggering of defences by microbes has mainly been investigated using single elicitors or microbe-associated molecular patterns (MAMPs), but MAMPs are released in planta as complex mixtures together with endogenous oligogalacturonan (OGA) elicitor. We investigated the early responses in Arabidopsis...

  18. The stable isotopic signature of biologically produced molecular hydrogen (H2)

    NARCIS (Netherlands)

    Walter, S.; Laukenmann, S.; Stams, A.J.M.; Vollmer, M.K.; Gleixner, G.; Roeckmann, T.

    2012-01-01

    Biologically produced molecular hydrogen (H2) is characterised by a very strong depletion in deuterium. Although the biological source to the atmosphere is small compared to photochemical or combustion sources, it makes an important contribution to the global isotope budget of H2. Large

  19. Fast Electron Repulsion Integrals for Molecular Coulomb Sturmians

    DEFF Research Database (Denmark)

    Avery, James Emil

    2013-01-01

    of hyperspherical harmonics. A rudimentary software library has been implemented and preliminary benchmarks indicate very good performance: On average 40 ns, or approximately 80 clock cycles, per electron repulsion integral. This makes molecular Coulomb Sturmians competitive with Gaussian type orbitals in terms...

  20. Molecular hydrogen (H2) combustion emissions and their isotope (D/H) signatures from domestic heaters, diesel vehicle engines, waste incinerator plants, and biomass burning

    NARCIS (Netherlands)

    Vollmer, M.K.; Walter, S.; Mohn, J.; Steinbacher, M.; Bond, S.W.; Röckmann, T.; Reimann, S.

    2012-01-01

    Molecular hydrogen (H2), its stable isotope signature ( D), and the key combustion parameters carbon monoxide (CO), carbon dioxide (CO2), and methane (CH4) were measured from various combustion processes. H2 in the exhaust of gas and oil-fired heaters and of waste incinerator plants was generally de

  1. Molecular hydrogen (H2) combustion emissions and their isotope (D/H) signatures from domestic heaters, diesel vehicle engines, waste incinerator plants, and biomass burning

    NARCIS (Netherlands)

    Vollmer, M.K.; Walter, S.; Mohn, J.; Steinbacher, M.; Bond, S.W.; Röckmann, T.; Reimann, S.

    2012-01-01

    Molecular hydrogen (H2), its stable isotope signature ( D), and the key combustion parameters carbon monoxide (CO), carbon dioxide (CO2), and methane (CH4) were measured from various combustion processes. H2 in the exhaust of gas and oil-fired heaters and of waste incinerator plants was generally

  2. Molecular hydrogen (H2) emissions and their isotopic signatures (H/D) from a motor vehicle : implications on atmospheric H2

    NARCIS (Netherlands)

    Vollmer, M.K.; Walter, S.; Bond, S.W.; Soltic, P.; Röckmann, T.

    2010-01-01

    Molecular hydrogen (H2), its isotopic signature (deuterium/hydrogen, δD), carbon monoxide (CO) and other compounds were studied in the exhaust of a passenger car engine fuelled with gasoline or methane and run under variable air-fuel ratios and operating modes. H2 and CO concentrations were largely

  3. Molecular hydrogen (H2) emissions and their isotopic signatures (H/D) from a motor vehicle : implications on atmospheric H2

    NARCIS (Netherlands)

    Vollmer, M.K.; Walter, S.; Bond, S.W.; Soltic, P.; Röckmann, T.

    2010-01-01

    Molecular hydrogen (H2), its isotopic signature (deuterium/hydrogen, δD), carbon monoxide (CO) and other compounds were studied in the exhaust of a passenger car engine fuelled with gasoline or methane and run under variable air-fuel ratios and operating modes. H2 and CO concentrations were largely

  4. Integrative network analysis unveils convergent molecular pathways in Parkinson's disease and diabetes.

    Directory of Open Access Journals (Sweden)

    Jose A Santiago

    Full Text Available BACKGROUND: Shared dysregulated pathways may contribute to Parkinson's disease and type 2 diabetes, chronic diseases that afflict millions of people worldwide. Despite the evidence provided by epidemiological and gene profiling studies, the molecular and functional networks implicated in both diseases, have not been fully explored. In this study, we used an integrated network approach to investigate the extent to which Parkinson's disease and type 2 diabetes are linked at the molecular level. METHODS AND FINDINGS: Using a random walk algorithm within the human functional linkage network we identified a molecular cluster of 478 neighboring genes closely associated with confirmed Parkinson's disease and type 2 diabetes genes. Biological and functional analysis identified the protein serine-threonine kinase activity, MAPK cascade, activation of the immune response, and insulin receptor and lipid signaling as convergent pathways. Integration of results from microarrays studies identified a blood signature comprising seven genes whose expression is dysregulated in Parkinson's disease and type 2 diabetes. Among this group of genes, is the amyloid precursor protein (APP, previously associated with neurodegeneration and insulin regulation. Quantification of RNA from whole blood of 192 samples from two independent clinical trials, the Harvard Biomarker Study (HBS and the Prognostic Biomarker Study (PROBE, revealed that expression of APP is significantly upregulated in Parkinson's disease patients compared to healthy controls. Assessment of biomarker performance revealed that expression of APP could distinguish Parkinson's disease from healthy individuals with a diagnostic accuracy of 80% in both cohorts of patients. CONCLUSIONS: These results provide the first evidence that Parkinson's disease and diabetes are strongly linked at the molecular level and that shared molecular networks provide an additional source for identifying highly sensitive biomarkers

  5. EVALUATING THE ECOLOGICAL RESILIENT DRIVEN PERFORMANCE OF A TROPICAL WASTE STABILIZATION POND SYSTEM USING ECOLOGICAL SIGNATURE OF BIOLOGICAL INTEGRITY

    Directory of Open Access Journals (Sweden)

    Susmita Lahiri Ganguly

    2015-06-01

    Full Text Available Using ecological signature of biological integrity as a measure of performance, the reclamation efficiency of waste stabilization ponds was evaluated over a period of four years in a tropical sewage treatment plant – cum fish culture consisting of two anaerobic, two facultative and four maturation ponds located serially across the sewage effluent gradient. The four maturation ponds were used for batch culture of fish. Samples of surface and bottom water as well as surface sediment were collected twice a month from different ponds of the system and examined for some nutrient cycling bacteria, primary production, chlorophyll content of micro-algae, phytoplankton, zooplankton abundance, fish growth and water quality parameters. Computation of ecological signature using aerobic mineralization index for heterotrophic and ammonifying bacteria revealed steady increase across the sewage effluent gradient. The heterotrophic and ammonifying bacterial populations appeared to have a direct function with the concentrations of chemical oxygen demand of water. The sum of total scores for different optimal conditions for fish growth increased as a function of the distance from the source of effluent implying that ecological resilience of the waste stabilization ponds has been accomplished by the sedimentation, chelation, and biological functional attributes mediated through redundancy of different subsystems, self- purification capacity of the system as a whole.

  6. Integrating molecular diagnostics into histopathology training: the Belfast model.

    Science.gov (United States)

    Flynn, C; James, J; Maxwell, P; McQuaid, S; Ervine, A; Catherwood, M; Loughrey, M B; McGibben, D; Somerville, J; McManus, D T; Gray, M; Herron, B; Salto-Tellez, M

    2014-07-01

    Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information.

  7. Using biomarker signature patterns for an mRNA molecular diagnostic of mouse embryonic stem cell differentiation state

    Directory of Open Access Journals (Sweden)

    Zhang Xue W

    2007-07-01

    Full Text Available Abstract Background The pluripotency and self-renewal capabilities, which define the "stemness" state, of mouse embryonic stem (ES cells, are usually investigated by functional assays or quantitative measurements of the expression levels of known ES cell markers. Strong correlations between these expression levels and functional assays, particularly at the early stage of cell differentiation, have usually not been observed. An effective molecular diagnostic to properly identify the differentiation state of mouse ES cells, prior to further experimentation, is needed. Results A novel molecular pattern recognition procedure has been developed to diagnose the differentiation state of ES cells. This is based on mRNA transcript levels of genes differentially expressed between ES cells and their differentiating progeny. Large publicly available ES cell data sets from various platforms were used to develop and test the diagnostic model. Signature patterns consisting of five gene expression levels achieved high accuracy at determining the cell state (sensitivity and specificity > 97%. Conclusion The effective ES cell state diagnostic scheme described here can be implemented easily to assist researchers in identifying the differentiation state of their cultures. It also provides a step towards standardization of experiments relying on cells being in the stem cell or differentiating state.

  8. Kinematic Results From a Systematic Search for Infall Signatures Towards the Starless Core Population in the Perseus Molecular Cloud

    Science.gov (United States)

    Walker-LaFollette, Amanda; Shirley, Y. L.; Amaya, H.; Becker, S. L.; Biddle, L. I.; Lichtenberger, M.; Nieberding, M. N.; Raphael, B. A.; Romine, J. M.; Small, L.; Stanford-Jones, C.; Smith, C.; Thompson, R.; Towner, A. P.; Turner, J.; Watson, Z.; Cates, I.; McGraw, A. M.; Pearson, K.; Robertson, A.; Tombleson, R.

    2014-01-01

    We present the results of a survey searching for infall signatures toward 72 starless cores in the Perseus molecular cloud. Observations of the ground state rotational transitions of HCN, HNC, and H13CN were carried out using the 12-m radio telescope on Kitt Peak operated by the Arizona Radio Observatory. All three molecules are tracers of dense molecular gas. HCN 1-0 is an excellent infall tracer, with its three hyperfine lines probing different optical depths. We examined the spectra for signs of infall by comparing observed line asymmetries with the velocity peak of the optically thin isotopologue H13CN. We find that there is an excess of blue asymmetries, but clearly self-absorbed profiles are rare (blue asymmetric and blue skewed profiles to the number of class II protostars, we find a range for the observable collapse lifetime of 6x10^4-2x10^5yrs, which is commensurate with the gravitational free-fall time (5x10^4yrs) for the observed central densities of Perseus starless cores. The best infall candidates all have observed masses that are above the Jeans mass. We calculate the infall speeds for the best collapse candidates and compare their dynamics to other known collapsing starless cores. This project was observed by The University of Arizona Undergraduate Astronomy Club.

  9. Molecular Signatures of Hepatitis C Virus (HCV-Induced Type II Mixed Cryoglobulinemia (MCII

    Directory of Open Access Journals (Sweden)

    Roberto Burioni

    2012-11-01

    Full Text Available The role of hepatitis C virus (HCV infection in the induction of type II mixed cryoglobulinemia (MCII and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL, is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated.

  10. The molecular signature and cis-regulatory architecture of a C. elegans gustatory neuron

    Science.gov (United States)

    Etchberger, John F.; Lorch, Adam; Sleumer, Monica C.; Zapf, Richard; Jones, Steven J.; Marra, Marco A.; Holt, Robert A.; Moerman, Donald G.; Hobert, Oliver

    2007-01-01

    Taste receptor cells constitute a highly specialized cell type that perceives and conveys specific sensory information to the brain. The detailed molecular composition of these cells and the mechanisms that program their fate are, in general, poorly understood. We have generated serial analysis of gene expression (SAGE) libraries from two distinct populations of single, isolated sensory neuron classes, the gustatory neuron class ASE and the thermosensory neuron class AFD, from the nematode Caenorhabditis elegans. By comparing these two libraries, we have identified >1000 genes that define the ASE gustatory neuron class on a molecular level. This set of genes contains determinants of the differentiated state of the ASE neuron, such as a surprisingly complex repertoire of transcription factors (TFs), ion channels, neurotransmitters, and receptors, as well as seven-transmembrane receptor (7TMR)-type putative gustatory receptor genes. Through the in vivo dissection of the cis-regulatory regions of several ASE-expressed genes, we identified a small cis-regulatory motif, the “ASE motif,” that is required for the expression of many ASE-expressed genes. We demonstrate that the ASE motif is a binding site for the C2H2 zinc finger TF CHE-1, which is essential for the correct differentiation of the ASE gustatory neuron. Taken together, our results provide a unique view of the molecular landscape of a single neuron type and reveal an important aspect of the regulatory logic for gustatory neuron specification in C. elegans. PMID:17606643

  11. Signatures of chaos and non-integrability in two-dimensional gravity with dynamical boundary

    Directory of Open Access Journals (Sweden)

    Fitkevich Maxim

    2016-01-01

    Full Text Available We propose a model of two-dimensional dilaton gravity with a boundary. In the bulk our model coincides with the classically integrable CGHS model; the dynamical boundary cuts of the CGHS strong-coupling region. As a result, classical dynamics in our model reminds that in the spherically-symmetric gravity: wave packets of matter fields either reflect from the boundary or form black holes. We find large integrable sector of multisoliton solutions in this model. At the same time, we argue that the model is globally non-integrable because solutions at the verge of black hole formation display chaotic properties.

  12. A molecular signature in blood identifies early Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Molochnikov Leonid

    2012-05-01

    Full Text Available Abstract Background The search for biomarkers in Parkinson’s disease (PD is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. Results The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60–0.90, huntingtin interacting protein-2 (OR 1.32; CI 1.08–1.61, aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75–0.99, 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60–0.89 and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14–1.70. At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38, resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity. Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09 in this cohort was higher than that of the early PD group (0.83 (SD = 0.22, suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully

  13. Molecular signature of the radioinduction in the thyroid tumors developed after radiotherapy; Signature moleculaire de la radio-induction dans des tumeurs de la thyroide developpees apres radiotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Mallard, Ch.

    2005-10-15

    Several epidemiological studies enlightens an increase of the number of thyroid cancers among children and adolescents exposed to ionizing radiation after an internal exposure ( Chernobylsk accident) or external one as a radiotherapy. No increase arose for adults.The analysis of the transcriptome was realised with micro arrays prepared on the genomic platform of the Cea at Evry that allow to study simultaneously the expression of 6000 genes. this study allows to enlighten a signature of radioinduction constituted by series of genes specifically expressed in one or other type of cancer in function of its etiology. This signature includes 59 genes expressed differentially between the sporadic carcinomas and 45 genes in the case of adenomas. with this signature an analysis in principal components allowed to determine correctly the etiology of 12 tumors among 13, the etiology of a sporadic adenoma was not determined. Besides, the study of the expression of genes specific to thyroid (TSHR, TG, TPO, TTF1, TTF2, PAX8) in relation with the presence of arrangements RET/PTC or mutations of BRAF was made. It allowed to enlighten the loss of TPO expression in the cancers changed for BRAF as well as a new mechanism of BRAF activation. (N.C.)

  14. Genome-wide transcriptional profiling reveals molecular signatures of secondary xylem differentiation in Populus tomentosa.

    Science.gov (United States)

    Yang, X H; Li, X G; Li, B L; Zhang, D Q

    2014-11-11

    Wood formation occurs via cell division, primary cell wall and secondary wall formation, and programmed cell death in the vascular cambium. Transcriptional profiling of secondary xylem differentiation is essential for understanding the molecular mechanisms underlying wood formation. Differential gene expression in secondary xylem differentiation of Populus has been previously investigated using cDNA microarray analysis. However, little is known about the molecular mechanisms from a genome-wide perspective. In this study, the Affymetrix poplar genome chips containing 61,413 probes were used to investigate the changes in the transcriptome during secondary xylem differentiation in Chinese white poplar (Populus tomentosa). Two xylem tissues (newly formed and lignified) were sampled for genome-wide transcriptional profiling. In total, 6843 genes (~11%) were identified with differential expression in the two xylem tissues. Many genes involved in cell division, primary wall modification, and cellulose synthesis were preferentially expressed in the newly formed xylem. In contrast, many genes, including 4-coumarate:cinnamate-4-hydroxylase (C4H), 4-coumarate:CoA ligase (4CL), cinnamyl alcohol dehydrogenase (CAD), and caffeoyl CoA 3-O-methyltransferase (CCoAOMT), associated with lignin biosynthesis were more transcribed in the lignified xylem. The two xylem tissues also showed differential expression of genes related to various hormones; thus, the secondary xylem differentiation could be regulated by hormone signaling. Furthermore, many transcription factor genes were preferentially expressed in the lignified xylem, suggesting that wood lignification involves extensive transcription regulation. The genome-wide transcriptional profiling of secondary xylem differentiation could provide additional insights into the molecular basis of wood formation in poplar species.

  15. Imaging Molecular Signatures of Breast Cancer With X-ray Activated Nano-Phosphors

    Science.gov (United States)

    2011-09-01

    shot-noise limited detection" was assumed to be too low to detect. To calculate the molar concentration, we assumed a spherical 10 nm diameter...Kandarakis et al. !a" Minimum weight concentration !in mg/ml" vs dose !Gy". !b" Minimum molar concentration !in M" vs dose !Gy". a b c d FIG. 5. Agar imaging...Contrast agents: X-ray contrast agents and molecular imaging—A contradiction ?,” Handb Exp Pharmacol 185, 167–175 񓟸#. 3R. Weissleder and M. J. Pittet

  16. Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold.

    Science.gov (United States)

    Johnson, Natalie M; Egner, Patricia A; Baxter, Victoria K; Sporn, Michael B; Wible, Ryan S; Sutter, Thomas R; Groopman, John D; Kensler, Thomas W; Roebuck, Bill D

    2014-07-01

    In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P-positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200 μg/kg rat/day) for four weeks and receiving either vehicle or CDDO-Im (three times weekly), one week before and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared with a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N(7)-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P-positive foci increased substantially (0%-13.8%) over the four weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im-treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development.

  17. Signature of an Intermediate-Mass Black Hole in the Central Molecular Zone of Our Galaxy

    CERN Document Server

    Oka, Tomoharu; Miura, Kodai; Takekawa, Shunya

    2015-01-01

    We mapped the high-velocity compact cloud CO-0.40-0.22 in 21 molecular lines in the 3 mm band using the Nobeyama Radio Observatory 45 m radio telescope. Eighteen lines were detected from CO-0.40-0.22. The map of each detected line shows that this cloud has a compact appearance (d=~3 pc) and extremely broad velocity width (DV=~100 km/s). The mass and kinetic energy of CO-0.40-0.22 are estimated to be 10^{3.6} M_sun and 10^{49.7} erg, respectively. The representative position-velocity map along the major axis shows that CO-0.40-0.22 consists of an intense region with a shallow velocity gradient and a less intense high-velocity wing. Here, we show that this kinematical structure can be attributed to a gravitational kick to the molecular cloud caused by an invisible compact object with a mass of ~10^5 M_sun. Its compactness and the absence of counterparts at other wavelengths suggest that this massive object is an intermediate-mass black hole.

  18. Signature of an Intermediate-mass Black Hole in the Central Molecular Zone of Our Galaxy

    Science.gov (United States)

    Oka, Tomoharu; Mizuno, Reiko; Miura, Kodai; Takekawa, Shunya

    2016-01-01

    We mapped the high-velocity compact cloud CO-0.40-0.22 in 21 molecular lines in the 3 mm band using the Nobeyama Radio Observatory 45 m radio telescope. Eighteen lines were detected from CO-0.40-0.22. The map of each detected line shows that this cloud has a compact appearance (d ≃ 3 pc) and extremely broad velocity width (ΔV ≃ 100 km s-1). The mass and kinetic energy of CO-0.40-0.22 are estimated to be 103.6 M⊙ and 1049.7 erg, respectively. The representative position-velocity map along the major axis shows that CO-0.40-0.22 consists of an intense region with a shallow velocity gradient and a less intense high-velocity wing. Here, we show that this kinematical structure can be attributed to a gravitational kick to the molecular cloud caused by an invisible compact object with a mass of ˜105 M⊙. Its compactness and the absence of counterparts at other wavelengths suggest that this massive object is an intermediate-mass black hole.

  19. Atypical scrapie isolates involve a uniform prion species with a complex molecular signature.

    Directory of Open Access Journals (Sweden)

    Dorothea R Götte

    Full Text Available The pathobiology of atypical scrapie, a prion disease affecting sheep and goats, is still poorly understood. In a previous study, we demonstrated that atypical scrapie affecting small ruminants in Switzerland differs in the neuroanatomical distribution of the pathological prion protein (PrP(d. To investigate whether these differences depend on host-related vs. pathogen-related factors, we transmitted atypical scrapie to transgenic mice over-expressing the ovine prion protein (tg338. The clinical, neuropathological, and molecular phenotype of tg338 mice is similar between mice carrying the Swiss atypical scrapie isolates and the Nor98, an atypical scrapie isolate from Norway. Together with published data, our results suggest that atypical scrapie is caused by a uniform type of prion, and that the observed phenotypic differences in small ruminants are likely host-dependant. Strikingly, by using a refined SDS-PAGE technique, we established that the prominent proteinase K-resistant prion protein fragment in atypical scrapie consists of two separate, unglycosylated peptides with molecular masses of roughly 5 and 8 kDa. These findings show similarities to those for other prion diseases in animals and humans, and lay the groundwork for future comparative research.

  20. Atypical scrapie isolates involve a uniform prion species with a complex molecular signature.

    Science.gov (United States)

    Götte, Dorothea R; Benestad, Sylvie L; Laude, Hubert; Zurbriggen, Andreas; Oevermann, Anna; Seuberlich, Torsten

    2011-01-01

    The pathobiology of atypical scrapie, a prion disease affecting sheep and goats, is still poorly understood. In a previous study, we demonstrated that atypical scrapie affecting small ruminants in Switzerland differs in the neuroanatomical distribution of the pathological prion protein (PrP(d)). To investigate whether these differences depend on host-related vs. pathogen-related factors, we transmitted atypical scrapie to transgenic mice over-expressing the ovine prion protein (tg338). The clinical, neuropathological, and molecular phenotype of tg338 mice is similar between mice carrying the Swiss atypical scrapie isolates and the Nor98, an atypical scrapie isolate from Norway. Together with published data, our results suggest that atypical scrapie is caused by a uniform type of prion, and that the observed phenotypic differences in small ruminants are likely host-dependant. Strikingly, by using a refined SDS-PAGE technique, we established that the prominent proteinase K-resistant prion protein fragment in atypical scrapie consists of two separate, unglycosylated peptides with molecular masses of roughly 5 and 8 kDa. These findings show similarities to those for other prion diseases in animals and humans, and lay the groundwork for future comparative research.

  1. Integrating ontogenetic shift, growth and mortality to determine a species' ecological role from isotopic signatures.

    Directory of Open Access Journals (Sweden)

    Nelson F Fontoura

    Full Text Available Understanding species linkages and energy transfer is a basic goal underlying any attempt at ecosystem analysis. Although the first food-web studies were based on gut contents of captured specimens, the assessment of stable isotopes, mainly δ13C and δ15N, has become a standard methodology for wide-range analyses in the last 30 years. Stable isotopes provide information on the trophic level of species, food-web length, and origin of organic matter ingested by consumers. In this study, we analyzed the ontogenetic variability of δ13C and δ15N obtained from samples of three Neotropical fish species: silver sardine (Lycengraulis grossidens, n=46, white lambari (Cyanocharax alburnus, n= 26, and the red-tail lambari (Astyanax fasciatus, n=23 in Pinguela Lagoon, southern Brazil. We developed a new metric, called the Weighted Isotopic Signature (φ 15N or φ 13C, ‰, that incorporates ontogenetic variability, body growth, and natural mortality into a single number.

  2. The molecular signatures of Taxodiaceae / Cupressaceae / Taxaceae (TCT) leaf waxes in modern and ancient samples

    Science.gov (United States)

    Ho, M.; Zinniker, D.; Green Nylen, N.; Moldowan, J. M.; Denisevich, P.

    2005-12-01

    optimized for the synthesis of C34 and C36 fatty acids. The bimodal distribution of n-alkanes (abundant C25 and C27 and abundant C33 and C35) in some Cupressus species indicates that the expression of this VLCFA elongase may be spatially or temporally limited in some taxa. Examples of fossil TCT leaf waxes have been observed in Pleistocene coastal sediments from California and Washington and in Jurassic coals from the Turpan basin in western China. These wax contributions can be identified by their unique n-alkane and diterpenoid signatures and their relationship with macrofossil and/or microfossil remains tied to members of the TCT complex. The carbon isotopic composition of Pleistocene waxes is consistent with a rainforest or marsh adapted TCT taxon (possibly Thuja plicata), while the isotopic composition of the Jurassic waxes is indicative of a highly water stressed taxon. Unique enzymes for very long chain n-alkane biosynthesis in the core group of TCT taxa listed above may have arisen during the early Mesozoic in a desert or salt marsh adapted species in response to extreme temperatures or water stress.

  3. Signi fi cance of Neural Crest in Tooth Development: The Molecular Signature

    Directory of Open Access Journals (Sweden)

    VP Jayasekharan

    2014-07-01

    Full Text Available The neural crest originates from cells located along the lateral margins of the neural plate. Neural crest cells arise as the result of an inductive action by the non-neural ectoderm adjacent to the neural plate and possibly by nearby mesoderm as well. As the neural tube forms, a group of cells separate from the neuro- ectoderm. These cells have the capacity to migrate and differen- tiate extensively within the developing embryo and they are the basis of structures such as spinal sensory ganglia, sympathetic neurons, Schwann cells, pigment cells and meninges. Speci fi c interactions occur during the development of tooth and recent research has concentrated more on the molecular aspects of these interactions. Thus, it is highly imperative to understand and digress the complex mechanisms involved in these processes

  4. Molecular Signatures in the Near Infrared Dayside Spectrum of HD 189733b

    CERN Document Server

    Swain, M R; Tinetti, G; Bouwman, J; Chen, Pin; Yung, Y; Deming, D; Deroo, P

    2008-01-01

    We have measured the dayside spectrum of HD 189733b between 1.5 and 2.5 microns using the NICMOS instrument on the Hubble Space Telescope. The emergent spectrum contains significant modulation, which we attribute to the presence of molecular bands seen in absorption. We find that water (H2O), carbon monoxide (CO), and carbon dioxide (CO2) are needed to explain the observations, and we are able to estimate the mixing ratios for these molecules. We also find temperature decreases with altitude in the ~0.01 < P < ~1 bar region of the dayside near-infrared photosphere and set an upper limit to the dayside abundance of methane (CH4) at these pressures.

  5. Ab initio Path Integral Molecular Dynamics Based on Fragment Molecular Orbital Method

    Science.gov (United States)

    Fujita, Takatoshi; Watanabe, Hirofumi; Tanaka, Shigenori

    2009-10-01

    We have developed an ab initio path integral molecular dynamics method based on the fragment molecular orbital method. This “FMO-PIMD” method can treat both nuclei and electrons quantum mechanically, and is useful to simulate large hydrogen-bonded systems with high accuracy. After a benchmark calculation for water monomer, water trimer and glycine pentamer have been studied using the FMO-PIMD method to investigate nuclear quantum effects on structure and molecular interactions. The applicability of the present approach is demonstrated through a number of test calculations.

  6. Total Correlation Function Integrals and Isothermal Compressibilities from Molecular Simulations

    DEFF Research Database (Denmark)

    Wedberg, Rasmus; Peters, Günther H.j.; Abildskov, Jens

    2008-01-01

    Generation of thermodynamic data, here compressed liquid density and isothermal compressibility data, using molecular dynamics simulations is investigated. Five normal alkane systems are simulated at three different state points. We compare two main approaches to isothermal compressibilities: (1...... in approximately the same amount of time. This suggests that computation of total correlation function integrals is a route to isothermal compressibility, as accurate and fast as well-established benchmark techniques. A crucial step is the integration of the radial distribution function. To obtain sensible results...

  7. The signature of 44Ti in Cassiopeia a Revealed by IBIS/ISGRI on INTEGRAL

    NARCIS (Netherlands)

    Renaud, M.; Vink, J.|info:eu-repo/dai/nl/182880559; Decourchelle, A.; Lebrun, F.; den Hartog, P.R.; Terrier, R.; Couvreur, C.; Knödlseder, J.; Martin, P; Prantzos, N.; Bykov, A.M.; Bloemen, H.

    2006-01-01

    We report the detection of both the 67.9 and 78.4 keV 44Sc g-ray lines in Cassiopeia A with the INTEGRAL IBIS/ISGRI instrument. Besides the robustness provided by spectroimaging observations, the main improvements compared to previous measurements are a clear separation of the two 44Sc lines

  8. Integrative radiogenomic analysis for genomic signatures in glioblastomas presenting leptomeningeal dissemination

    OpenAIRE

    2016-01-01

    Abstract Despite therapeutic advances, the prognosis for glioblastoma (GBM) remains poor. In particular, leptomeningeal dissemination (LMD) has a dismal prognosis. The aim of this study was to identify tumor molecular phenotype, which has a great propensity to develop LMD. Between May 2004 and December 2012, a total of 145 GBM tumor samples were obtained from data registry. A total of 20 of the 145 patients with GBM were found to develop LMD. A specialized radiologist confirmed the diagnosis ...

  9. Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways.

    Directory of Open Access Journals (Sweden)

    Roy Blum

    Full Text Available BACKGROUND: Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system. METHODOLOGY/PRINCIPAL FINDINGS: We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2, lipid metabolism (e.g., Srebp1 and cell migration (e.g., Areb6 and Rreb1. Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche. CONCLUSIONS/SIGNIFICANCE: We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may

  10. Quantitative Proteomic Profiling the Molecular Signatures of Annexin A5 in Lung Squamous Carcinoma Cells

    Science.gov (United States)

    Zhang, Liyuan; Gong, Linlin; Qi, Xiaoyu; Li, Huizhen; Wang, Faming; Chi, Xinming; Jiang, Yulin; Shao, Shujuan

    2016-01-01

    Lung cancer remains the leading cancer killer around the world. It’s crucial to identify newer mechanism-based targets to effectively manage lung cancer. Annexin A5 (ANXA5) is a protein kinase C inhibitory protein and calcium dependent phospholipid-binding protein, which may act as an endogenous regulator of various pathophysiological processes. However, its molecular mechanism in lung cancer remains poorly understood. This study was designed to determine the mechanism of ANXA5 in lung cancer with a hope to obtain useful information to provide a new therapeutic target. We used a stable isotope dimethyl labeling based quantitative proteomic method to identify differentially expressed proteins in NSCLC cell lines after ANXA5 transfection. Out of 314 proteins, we identified 26 and 44 proteins that were down- and up-regulated upon ANXA5 modulation, respectively. The IPA analysis revealed that glycolysis and gluconeogenesis were the predominant pathways modulated by ANXA5. Multiple central nodes, namely HSPA5, FN1, PDIA6, ENO1, ALDOA, JUP and KRT6A appeared to occupy regulatory nodes in the protein-protein networks upon ANXA5 modulation. Taken together, ANXA5 appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of ANXA5 as a potential target in lung cancer. This study might provide a new insight into the mechanism of ANXA5 in lung cancer. PMID:27684953

  11. Molecular signatures of nicotinoid-pathogen synergy in the termite gut.

    Directory of Open Access Journals (Sweden)

    Ruchira Sen

    Full Text Available Previous studies in lower termites revealed unexpected synergies between nicotinoid insecticides and fungal entomopathogens. The present study investigated molecular mechanisms of nicotinoid-pathogen synergy in the lower termite Reticulitermes flavipes, using the nicotinoid, imidacloprid, in combination with fungal and bacterial entomopathogens. Particular focus was placed on metatranscriptome composition and microbial dynamics in the symbiont-rich termite gut, which houses diverse mixes of protists and bacteria. cDNA microarrays containing a mix of host and protist symbiont oligonucleotides were used to simultaneously assess termite and protist gene expression. Five treatments were compared that included single challenges with sublethal doses of fungi (Metharizium anisopliae, bacteria (Serratia marcescens or imidacloprid, and dual challenges with fungi + imidacloprid or bacteria + imidacloprid. Our findings point towards protist dysbiosis and compromised social behavior, rather than suppression of stereotypical immune defense mechanisms, as the dominant factors underlying nicotinoid-pathogen synergy in termites. Also, greater impacts observed for the fungal pathogen than for the bacterial pathogen suggest that the rich bacterial symbiont community in the R. flavipes gut (>5000 species-level phylotypes exists in an ecological balance that effectively excludes exogenous bacterial pathogens. These findings significantly advance our understanding of antimicrobial defenses in this important eusocial insect group, as well as provide novel insights into how nicotinoids can exert deleterious effects on social insect colonies.

  12. Molecular signature of anastasis for reversal of apoptosis [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Ho Man Tang

    2017-02-01

    Full Text Available Anastasis (Greek for "rising to life" is a cell recovery phenomenon that rescues dying cells from the brink of cell death. We recently discovered anastasis to occur after the execution-stage of apoptosis in vitro and in vivo. Promoting anastasis could in principle preserve injured cells that are difficult to replace, such as cardiomyocytes and neurons. Conversely, arresting anastasis in dying cancer cells after cancer therapies could improve treatment efficacy. To develop new therapies that promote or inhibit anastasis, it is essential to identify the key regulators and mediators of anastasis – the therapeutic targets. Therefore, we performed time-course microarray analysis to explore the molecular mechanisms of anastasis during reversal of ethanol-induced apoptosis in mouse primary liver cells. We found striking changes in transcription of genes involved in multiple pathways, including early activation of pro-cell survival, anti-oxidation, cell cycle arrest, histone modification, DNA-damage and stress-inducible responses, and at delayed times, angiogenesis and cell migration. Validation with RT-PCR confirmed similar changes in the human liver cancer cell line, HepG2, during anastasis. Here, we present the time-course whole-genome gene expression dataset revealing gene expression profiles during the reversal of apoptosis. This dataset provides important insights into the physiological, pathological, and therapeutic implications of anastasis.

  13. The Biophysical Probes 2-fluorohistidine and 4-fluorohistidine: Spectroscopic Signatures and Molecular Properties

    Science.gov (United States)

    Kasireddy, Chandana; Ellis, Jonathan M.; Bann, James G.; Mitchell-Koch, Katie R.

    2017-02-01

    Fluorinated amino acids serve as valuable biological probes, by reporting on local protein structure and dynamics through 19F NMR chemical shifts. 2-fluorohistidine and 4-fluorohistidine, studied here with DFT methods, have even more capabilities for biophysical studies, as their altered pKa values, relative to histidine, allow for studies of the role of proton transfer and tautomeric state in enzymatic mechanisms. Considering the two tautomeric forms of histidine, it was found that 2-fluorohistidine primarily forms the common (for histidine) τ-tautomer at neutral pH, while 4-fluorohistidine exclusively forms the less common π-tautomer. This suggests the two isomers of fluorohistidine can also serve as probes of tautomeric form within biomolecules, both by monitoring NMR chemical shifts and by potential perturbation of the tautomeric equilibrium within biomolecules. Fluorine also enables assignment of tautomeric states in crystal structures. The differences in experimental pKa values between the isomers was found to arise from solvation effects, providing insight into the polarization and molecular properties of each isomer. Results also encompass 13C and 19F NMR chemical shifts, from both tautomers of 2-fluorohistidine and 4-fluorohistidine in a number of different environments. This work can serve as a guide for interpretation of spectroscopic results in biophysical studies employing 2-fluorohistidine and 4-fluorohistidine.

  14. Molecular modeling, spectroscopic signature and NBO analysis of some building blocks of organic conductors.

    Science.gov (United States)

    Mukherjee, V

    2014-11-11

    Vibrational spectra with IR and Raman intensities in optimum state have been calculated for 2,2'-Bi-1,3-diselenole (commonly known as tetraselenafulvalene) and its halogen derivatives. All these calculations have been done by employing density functional theory (DFT) and second order Moller-Plesset perturbation theory (MP2) methods incorporated with suitable functionals and basis sets. Normal coordinate analysis has also been performed to calculate potential energy distributions (PEDs) to make a conspicuous assignment. The vibrational frequencies of all the four molecules have been assigned using PEDs and the results are compared with available values for the most similar molecules like tetrathiafulvalene. The molecular stability and bond strength have investigated by applying the Natural Bond Orbital (NBO) analysis. The energy gap between HOMO and LUMO is 2.041 eV for tetraselenafulvalene and it is slightly less than 2eV for halogen derivatives which implies that these molecules fall in the wide band gap semiconductor groups.

  15. Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy.

    Science.gov (United States)

    Scotton, Chiara; Bovolenta, Matteo; Schwartz, Elena; Falzarano, Maria Sofia; Martoni, Elena; Passarelli, Chiara; Armaroli, Annarita; Osman, Hana; Rodolico, Carmelo; Messina, Sonia; Pegoraro, Elena; D'Amico, Adele; Bertini, Enrico; Gualandi, Francesca; Neri, Marcella; Selvatici, Rita; Boffi, Patrizia; Maioli, Maria Antonietta; Lochmüller, Hanns; Straub, Volker; Bushby, Katherine; Castrignanò, Tiziana; Pesole, Graziano; Sabatelli, Patrizia; Merlini, Luciano; Braghetta, Paola; Bonaldo, Paolo; Bernardi, Paolo; Foley, Reghan; Cirak, Sebahattin; Zaharieva, Irina; Muntoni, Francesco; Capitanio, Daniele; Gelfi, Cecilia; Kotelnikova, Ekaterina; Yuryev, Anton; Lebowitz, Michael; Zhang, Xiping; Hodge, Brian A; Esser, Karyn A; Ferlini, Alessandra

    2016-04-15

    Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI-null (Col6a1(-/-)) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1(-/-)mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1(-/-)(also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis.

  16. Molecular signatures associated with Mx1-mediated resistance to highly pathogenic influenza virus infection: mechanisms of survival.

    Science.gov (United States)

    Cilloniz, Cristian; Pantin-Jackwood, Mary J; Ni, Chester; Carter, Victoria S; Korth, Marcus J; Swayne, David E; Tumpey, Terrence M; Katze, Michael G

    2012-03-01

    Understanding the role of host factors during lethal influenza virus infection is critical to deciphering the events that determine the fate of the host. One such factor is encoded by the Mx1 gene, which confers resistance to influenza virus infection. Here, we compared pathology and global gene expression profiles in lung tissue from BALB/c (Mx1(-)) and BALB · A2G-Mx1 mice (Mx1(+/+)) infected with the fully reconstructed 1918 pandemic influenza virus. Mx1(+/+) mice showed less tissue damage than Mx(-) animals, and pathology and mortality were further reduced by treating the mice with interferon prior to infection. Using global transcriptional profiling, we identified distinct molecular signatures associated with partial protection, complete protection, and the contribution of interferon to the host response. In the absence of interferon treatment, partial protection was characterized by the generation of an acute response with the upregulation of genes associated with apoptosis, reactive oxygen species, and cell migration. Complete protection was characterized by the downregulation of cytokine and chemokine genes previously associated with influenza virus pathogenesis. The contribution of interferon treatment to total protection in virus-infected Mx1(+/+) mice was characterized by the altered regulation of cell cycle genes. These genes were upregulated in Mx1(+/+) mice treated with interferon but downregulated in the absence of interferon treatment. Our results suggest that Mx1(+/+) mice generate a protective antiviral response by controlling the expression of key modulator molecules associated with influenza virus lethality.

  17. Mining the mouse transcriptome of receptive endometrium reveals distinct molecular signatures for the luminal and glandular epithelium.

    Science.gov (United States)

    Niklaus, Andrea L; Pollard, Jeffrey W

    2006-07-01

    Epithelia coat most tissues where they sense and respond to the environment and participate in innate immune responses. In the adult mouse uterus, columnar epithelium lines the central lumen and the glands that penetrate the underlying stroma. A nidatory surge of estrogen causes differentiation of the luminal epithelium to the receptive state that permits blastocyst attachment and allows subsequent implantation. Here, using laser-capture microdissection to isolate the luminal and glandular epithelia separately, we have profiled gene expression 2 h before embryo attachment to determine whether there are unique roles for these two epithelial structures in this process. Although most genes were expressed in both compartments, there was greater expression of 153 and 118 genes in the lumen and glands, respectively. In the luminal epithelium, there is enrichment in lipid, metal-ion binding, and carbohydrate-metabolizing enzymes, whereas in the glands, immune response genes are emphasized. In situ hybridization to uterine sections obtained from mice during the preimplantation period validated these data and indicated an array of previously undocumented genes expressed with unique patterns in these epithelia. The data show that each epithelial compartment has a distinct molecular signature and that they act differentially and synergistically to permit blastocyst implantation.

  18. Distinct molecular signature of human skin Langerhans cells denotes critical differences in cutaneous dendritic cell immune regulation.

    Science.gov (United States)

    Polak, Marta E; Thirdborough, Stephen M; Ung, Chuin Y; Elliott, Tim; Healy, Eugene; Freeman, Tom C; Ardern-Jones, Michael R

    2014-03-01

    Langerhans cells (LCs) are professional antigen-presenting cells (APCs) residing in the epidermis. Despite their high potential to activate T lymphocytes, current understanding of human LC biology is limited. Genome-wide comparison of the transcriptional profiles of human skin migratory CD1a+ LCs and CD11c+ dermal dendritic cells (DDCs) demonstrated significant differences between these "dendritic cell (DC)" types, including preferential expression of 625 genes (Pmolecular networks activated after stimulation with tumor necrosis factor-α (TNF-α) confirmed the unique molecular signature of LCs. Although LCs conformed to the phenotype of professional APC, inflammatory signaling activated primarily genes associated with cellular metabolism and mitochondrial activation (e.g., CYB561 and MRPS35), cell membrane re-organization, and antigen acquisition and degradation (CAV1 and PSMD14; P<0.05-P<0.0001). Conversely, TNF-α induced classical activation in DDCs with early downregulation of surface receptors (mannose receptor-1 (MRC1) and C-type lectins), and subsequent upregulation of cytokines, chemokines (IL1a, IL1b, and CCL18), and matrix metalloproteinases (MMP1, MMP3, and MMP9; P<0.05-P<0.0001). Functional interference of caveolin abrogated LCs superior ability to cross-present antigens to CD8+ T lymphocytes, highlighting the importance of these networks to biological function. Taken together, these observations support the idea of distinct biological roles of cutaneous DC types.

  19. Molecular signature of response and potential pathways related to resistance to the HSP90 inhibitor, 17AAG, in breast cancer

    Directory of Open Access Journals (Sweden)

    Benitez Javier

    2010-10-01

    Full Text Available Abstract Background HSP90 may be a favorable target for investigational therapy in breast cancer. In fact, the HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer. Methods Gene expression profiling using Whole Human Genome Agilent array technology was applied to a total of six sensitive and two resistant breast cancer cell lines pre-treatment and treated with the 17AAG for 24 and 48 hours. Results We have identified a common molecular signature of response to 17AAG composed of 35 genes which include novel pharmacodynamic markers of this drug. In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness. Finally, we have found differentially expressed pathways associated to resistance to 17AAG. We observed significant activation of NF-κB and MAPK pathways in resistant cells upon treatment, indicating that these pathways could be potentially targeted to overcome resistance. Conclusions Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance.

  20. Molecularly imprinted Ru complex catalysts integrated on oxide surfaces.

    Science.gov (United States)

    Muratsugu, Satoshi; Tada, Mizuki

    2013-02-19

    Selective catalysis is critical for the development of green chemical processes, and natural enzymes that possess specialized three-dimensional reaction pockets with catalytically active sites represent the most sophisticated systems for selective catalysis. A reaction space in an enzyme consists of an active metal center, functional groups for molecular recognition (such as amino acids), and a surrounding protein matrix to prepare the reaction pocket. The artificial design of such an integrated catalytic unit in a non-enzymatic system remains challenging. Molecular imprinting of a supported metal complex provides a promising approach for shape-selective catalysis. In this process, an imprinted cavity with a shape matched to a template molecule is created in a polymer matrix with a catalytically active metal site. In this Account, we review our studies on molecularly imprinted metal complex catalysts, focusing on Ru complexes, on oxide surfaces for shape-selective catalysis. Oxide surface-attached transition metal complex catalysts not only improve thermal stability and catalyst dispersion but also provide unique catalytic performance not observed in homogeneous precursors. We designed molecularly imprinted Ru complexes by using surface-attached Ru complexes with template ligands and inorganic/organic surface matrix overlayers to control the chemical environment around the active metal complex catalysts on oxide surfaces. We prepared the designed, molecularly imprinted Ru complexes on SiO(2) surfaces in a step-by-step manner and characterized them with solid-state (SS) NMR, diffuse-reflectance (DR) UV-vis, X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller isotherm (BET), X-ray fluorescence (XRF), and Ru K-edge extended X-ray absorption fine structure (EXAFS). The catalytic performances of these Ru complexes suggest that this process of molecular imprinting facilitates the artificial integration of catalytic functions at surfaces. Further advances such

  1. Distinct molecular signatures in pediatric infratentorial glioblastomas defined by aCGH.

    Science.gov (United States)

    Sharma, S; Free, A; Mei, Y; Peiper, S C; Wang, Z; Cowell, J K

    2010-10-01

    Glioblastomas (GBM) are rare in children, but reportedly have more varied outcome which suggests differences in tumor etiology compared to typical GBM of adults. To investigate this we performed high resolution array comparative genomic hybridization (aCGH) analysis on three pediatric infratentorial GBM, ages 3.5, 7 and 14 years. Two of these tumors occurred in the brainstem and one in the spinal cord. While histologically typical, one brainstem tumor showed mainly pleomorphic astrocytic cells, whereas the other brainstem and spinal tumors showed a GFAP positive small cell component. Whole chromosomal gains (#1 and #2) and loss (#20) were seen only in the pleomorphic brainstem GBM, which also showed a high level of segmental genomic copy number changes. Segmental loss involving chromosome 8 was seen in all three tumors (Chr8;133039446-136869494, Chr8;pter-3581577, and Chr8;pter-30480019 respectively), whereas loss involving chromosome 16 was seen in only 2 cases with small cell components (Chr16;31827239-qter and Chr16;pter-29754532). Segmental gain of chromosome 7 was shared only between the 2 brainstem cases (Chr7;17187166-qter and Chr7;69824947-qter). Chromosome 17 showed segmental gain of 17q in the backdrop of loss of 17p only in case 1. Segmental gain of chromosome 1q was seen only in case 2. The spinal GBM showed a relatively stable karyotype with a unique loss of Chr19;32848902-qter. None of the frequent losses, gains and amplifications known to occur in adult GBM were identified, suggesting that pediatric infratentorial glioblastomas show a molecular karyotype that was more characteristic of pediatric embryonal tumors than adult GBM.

  2. Different molecular signatures in magnetic resonance imaging-staged facioscapulohumeral muscular dystrophy muscles.

    Directory of Open Access Journals (Sweden)

    Giorgio Tasca

    Full Text Available BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD is one of the most common muscular dystrophies and is characterized by a non-conventional genetic mechanism activated by pathogenic D4Z4 repeat contractions. By muscle Magnetic Resonance Imaging (MRI we observed that T2-short tau inversion recovery (T2-STIR sequences identify two different conditions in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity, takes place. We studied these conditions in order to obtain further information on the molecular mechanisms involved in the selective wasting of single muscles or muscle groups in this disease. METHODS: Histopathology, gene expression profiling and real time PCR were performed on biopsies from FSHD muscles with different MRI pattern (T1-weighted normal/T2-STIR normal and T1-weighted normal/T2-STIR hyperintense. Data were compared with those from inflammatory myopathies, dysferlinopathies and normal controls. In order to validate obtained results, two additional FSHD samples with different MRI pattern were analyzed. RESULTS: Myopathic and inflammatory changes characterized T2-STIR hyperintense FSHD muscles, at variance with T2-STIR normal muscles. These two states could be easily distinguished from each other by their transcriptional profile. The comparison between T2-STIR hyperintense FSHD muscles and inflammatory myopathy muscles showed peculiar changes, although many alterations were shared among these conditions. CONCLUSIONS: At the single muscle level, different stages of the disease correspond to the two MRI patterns. T2-STIR hyperintense FSHD muscles are more similar to inflammatory myopathies than to T2-STIR normal FSHD muscles or other muscular dystrophies, and share with them upregulation of genes involved in innate and adaptive immunity. Our data suggest that selective inflammation, together with perturbation in biological processes such as neoangiogenesis

  3. The roles of integration in molecular systems biology.

    Science.gov (United States)

    O'Malley, Maureen A; Soyer, Orkun S

    2012-03-01

    A common way to think about scientific practice involves classifying it as hypothesis- or data-driven. We argue that although such distinctions might illuminate scientific practice very generally, they are not sufficient to understand the day-to-day dynamics of scientific activity and the development of programmes of research. One aspect of everyday scientific practice that is beginning to gain more attention is integration. This paper outlines what is meant by this term and how it has been discussed from scientific and philosophical points of view. We focus on methodological, data and explanatory integration, and show how they are connected. Then, using some examples from molecular systems biology, we will show how integration works in a range of inquiries to generate surprising insights and even new fields of research. From these examples we try to gain a broader perspective on integration in relation to the contexts of inquiry in which it is implemented. In today's environment of data-intensive large-scale science, integration has become both a practical and normative requirement with corresponding implications for meta-methodological accounts of scientific practice. We conclude with a discussion of why an understanding of integration and its dynamics is useful for philosophy of science and scientific practice in general.

  4. Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers.

    Science.gov (United States)

    Verma, Gaurav; Vishnoi, Kanchan; Tyagi, Abhishek; Jadli, Mohit; Singh, Tejveer; Goel, Ankit; Sharma, Ankita; Agarwal, Kiran; Prasad, Subhash Chandra; Pandey, Durgatosh; Sharma, Shashi; Mehrotra, Ravi; Singh, Sukh Mahendra; Bharti, Alok Chandra

    2017-02-03

    Prior studies established constitutively active AP-1, NF-κB, and STAT3 signaling in oral cancer. Differential expression/activation of specific members of these transcription factors has been documented in HPV-positive oral lesions that respond better to therapy. We performed a comprehensive analysis of differentially expressed, transcriptionally active members of these pivotal signaling mediators to develop specific signatures of HPV-positive and HPV-negative oral lesions by immunohistochemical method that is applicable in low-resource settings. We examined a total of 31 prospective and 30 formalin-fixed, paraffin-embedded tissues from treatment-naïve, histopathologically and clinically confirmed cases diagnosed as oral or oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Following determination of their HPV status by GP5 + /GP6 +  PCR, the sequential sections of the tissues were evaluated for expression of JunB, JunD, c-Fos, p50, p65, STAT3, and pSTAT3(Y705), along with two key regulatory proteins pEGFR and p16 by IHC. Independent analysis of JunB and p65 showed direct correlation with HPV positivity, whereas STAT3 and pSTAT3 were inversely correlated. A combined analysis of transcription factors revealed a more restrictive combination, characterized by the presence of AP-1 and NF-κB lacking involvement of STAT3 that strongly correlated with HPV-positive tumors. Presence of STAT3/pSTAT3 with NF-κB irrespective of the presence or absence of AP-1 members was present in HPV-negative lesions. Expression of pSTAT3 strongly correlated with all the AP-1/NF-κB members (except JunD), its upstream activator pEGFR(Y)(1092) , and HPV infection-related negative regulator p16. Overall, we show a simple combination of AP-1, NF-κB, and STAT3 members' expression that may serve as molecular signature of HPV-positive lesions or more broadly the tumors that show better prognosis.

  5. Technology of Electronic Signatur

    OpenAIRE

    2004-01-01

    An electronic signature uses a hash of message and an asymetrical algorithm of encryption for its generation. During verification of message on receiver side the hash of original message must be identical with the hash of received message. Electronic message is secured autentization of author and integrity of transmission date. By electronic signature it is possible to sign everything what is in digital form.

  6. Stage-dependent prognostic impact of molecular signatures in clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Weber T

    2014-05-01

    Full Text Available Thomas Weber,1,2 Matthias Meinhardt,3 Stefan Zastrow,1 Andreas Wienke,4 Kati Erdmann,1 Jörg Hofmann,1 Susanne Fuessel,1 Manfred P Wirth11Department of Urology, Technische Universität Dresden, Dresden, Germany; 2Department of Oncology and Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale, Germany; 3Institute of Pathology, Technische Universität Dresden, Dresden, Germany; 4Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale, GermanyPurpose: To enhance prognostic information of protein biomarkers for clear cell renal cell carcinomas (ccRCCs, we analyzed them within prognostic groups of ccRCC harboring different tumor characteristics of this clinically and molecularly heterogeneous tumor entity.Methods: Tissue microarrays from 145 patients with primary ccRCC were immunohistochemically analyzed for VHL (von Hippel-Lindau tumor suppressor, Ki67 (marker of proliferation 1, p53 (tumor protein p53, p21 (cyclin-dependent kinase inhibitor 1A, survivin (baculoviral IAP repeat containing 5, and UEA-1 (ulex europaeus agglutinin I to assess microvessel-density.Results: When analyzing all patients, nuclear staining of Ki67 (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.04–1.12 and nuclear survivin (nS; HR 1.04, 95% CI 1.01–1.08 were significantly associated with disease-specific survival (DSS. In the cohort of patients with advanced localized or metastasized ccRCC, high staining of Ki67, p53 and nS predicted shorter DSS (Ki67: HR 1.07, 95% CI 1.02–1.11; p53: HR 1.05, 95% CI 1.01–1.09; nS: HR 1.08, 95% CI 1.02–1.14. In organ-confined ccRCC, patients with high p21-staining had a longer DSS (HR 0.96, 95% CI 0.92–0.99. In a multivariate model with stepwise backward elimination, tumor size and p21-staining showed a significant association with DSS in patients with "organ-confined" ccRCCs. The p21-staining increased the concordance index of tumor size from

  7. Integration of molecular functions into Si device for nanoscale molecular devices

    Energy Technology Data Exchange (ETDEWEB)

    Wakayama, Yutaka, E-mail: WAKAYAMA.Yutaka@nims.go.jp; Hayakawa, Ryoma

    2014-03-03

    Recent progress on nanoscale molecular devices is reviewed. The advantages of organic molecules are highlighted in terms of their unique features such as quantum effects based on their nanometer size, optical properties originating from photochromism and chemical syntheses for various structural designs. This review covers three topics: a scanning probe microscope-based evaluation of individual molecules, nano-gap electrodes for electrical current through single-molecules and the incorporation of molecular functions into Si-based devices. In particular, the importance of the incorporation of organic molecules into Si-device architecture is emphasized with a view to realizing the large-scale integration of nanoscale molecular devices. - Highlights: • Scanning probe microscope-based evaluation of individual molecules; • Nano-gap electrodes for electrical current through single-molecules; • Incorporation of molecular functions into Si-based devices.

  8. Coupling molecular spin centers to microwave planar resonators: towards integration of molecular qubits in quantum circuits.

    Science.gov (United States)

    Bonizzoni, C; Ghirri, A; Bader, K; van Slageren, J; Perfetti, M; Sorace, L; Lan, Y; Fuhr, O; Ruben, M; Affronte, M

    2016-11-14

    We present spectroscopic measurements looking for the coherent coupling between molecular magnetic centers and microwave photons. The aim is to find the optimal conditions and the best molecular features to achieve the quantum strong coupling regime, for which coherent dynamics of hybrid photon-spin states take place. To this end, we used a high critical temperature YBCO superconducting planar resonator working at 7.7 GHz and at low temperatures to investigate three molecular mononuclear coordination compounds, namely (PPh4)2[Cu(mnt)2] (where mnt(2-) = maleonitriledithiolate), [ErPc2](-)TBA(+) (where pc(2-) is the phtalocyaninato and TBA(+) is the tetra-n-butylammonium cation) and Dy(trensal) (where H3trensal = 2,2',2''-tris(salicylideneimino)triethylamine). Although the strong coupling regime was not achieved in these preliminary experiments, the results provided several hints on how to design molecular magnetic centers to be integrated into hybrid quantum circuits.

  9. Cold and heat pattern of rheumatoid arthritis in traditional Chinese medicine: distinct molecular signatures indentified by microarray expression profiles in CD4-positive T cell

    OpenAIRE

    Lu, Cheng; Xiao, Cheng; Chen, Gao; Jiang, Miao; Zha, Qinglin; Yan, Xiaoping; Kong, Weiping; Lu, Aiping

    2010-01-01

    The research is aimed to explore the distinct molecular signatures in discriminating the rheumatoid arthritis patients with traditional Chinese medicine (TCM) cold pattern and heat pattern. Twenty patients with typical TCM cold pattern and heat pattern were included. Microarray technology was used to reveal gene expression profiles in CD4+ T cells. The signal intensity of each expressed gene was globally normalized using the R statistics program. The ratio of cold pattern to heat pattern in p...

  10. PathSys: integrating molecular interaction graphs for systems biology

    Directory of Open Access Journals (Sweden)

    Raval Alpan

    2006-02-01

    Full Text Available Abstract Background The goal of information integration in systems biology is to combine information from a number of databases and data sets, which are obtained from both high and low throughput experiments, under one data management scheme such that the cumulative information provides greater biological insight than is possible with individual information sources considered separately. Results Here we present PathSys, a graph-based system for creating a combined database of networks of interaction for generating integrated view of biological mechanisms. We used PathSys to integrate over 14 curated and publicly contributed data sources for the budding yeast (S. cerevisiae and Gene Ontology. A number of exploratory questions were formulated as a combination of relational and graph-based queries to the integrated database. Thus, PathSys is a general-purpose, scalable, graph-data warehouse of biological information, complete with a graph manipulation and a query language, a storage mechanism and a generic data-importing mechanism through schema-mapping. Conclusion Results from several test studies demonstrate the effectiveness of the approach in retrieving biologically interesting relations between genes and proteins, the networks connecting them, and of the utility of PathSys as a scalable graph-based warehouse for interaction-network integration and a hypothesis generator system. The PathSys's client software, named BiologicalNetworks, developed for navigation and analyses of molecular networks, is available as a Java Web Start application at http://brak.sdsc.edu/pub/BiologicalNetworks.

  11. Integrating atomistic molecular dynamics simulations, experiments, and network analysis to study protein dynamics: strength in unity.

    Science.gov (United States)

    Papaleo, Elena

    2015-01-01

    In the last years, we have been observing remarkable improvements in the field of protein dynamics. Indeed, we can now study protein dynamics in atomistic details over several timescales with a rich portfolio of experimental and computational techniques. On one side, this provides us with the possibility to validate simulation methods and physical models against a broad range of experimental observables. On the other side, it also allows a complementary and comprehensive view on protein structure and dynamics. What is needed now is a better understanding of the link between the dynamic properties that we observe and the functional properties of these important cellular machines. To make progresses in this direction, we need to improve the physical models used to describe proteins and solvent in molecular dynamics, as well as to strengthen the integration of experiments and simulations to overcome their own limitations. Moreover, now that we have the means to study protein dynamics in great details, we need new tools to understand the information embedded in the protein ensembles and in their dynamic signature. With this aim in mind, we should enrich the current tools for analysis of biomolecular simulations with attention to the effects that can be propagated over long distances and are often associated to important biological functions. In this context, approaches inspired by network analysis can make an important contribution to the analysis of molecular dynamics simulations.

  12. Identification of a gene expression core signature for Duchenne Muscular Dystrophy (DMD) via integrative analysis reveals novel potential compounds for treatment

    KAUST Repository

    Ichim-Moreno, Norú

    2010-05-01

    Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy and one of the most prevalent genetic disorders of childhood. DMD is characterized by rapid progression of muscle degeneration, and ultimately death. Currently, glucocorticoids are the only available treatment for DMD, but they have been shown to result in serious side effects. The purpose of this research was to define a core signature of gene expression related to DMD via integrative analysis of mouse and human datasets. This core signature was subsequently used to screen for novel potential compounds that antagonistically affect the expression of signature genes. With this approach we were able to identify compounds that are 1) already used to treat DMD, 2) currently under investigation for treatment, and 3) so far unknown but promising candidates. Our study highlights the potential of meta-analyses through the combination of datasets to unravel previously unrecognized associations and reveal new relationships. © IEEE.

  13. ID3 contributes to the acquisition of molecular stem cell-like signature in microvascular endothelial cells: its implication for understanding microvascular diseases.

    Science.gov (United States)

    Das, Jayanta K; Voelkel, Norbert F; Felty, Quentin

    2015-03-01

    While significant progress has been made to advance our knowledge of microvascular lesion formation, yet the investigation of how stem-like cells may contribute to the pathogenesis of microvascular diseases is still in its infancy. We assessed whether the inhibitor of DNA binding and differentiation 3 (ID3) contributes to the acquisition of a molecular stem cell-like signature in microvascular endothelial cells. The effects of stable ID3 overexpression and SU5416 treatment - a chemical inducer of microvascular lesions, had on the stemness signature were determined by flow cytometry, immunoblot, and immunohistochemistry. Continuous ID3 expression produced a molecular stemness signature consisting of CD133(+) VEGFR3(+) CD34(+) cells. Cells exposed to SU5416 showed positive protein expression of ID3, VEGFR3, CD34 and increased expression of pluripotent transcription factors Oct-4 and Sox-2. ID3 overexpressing cells supported the formation of a 3-D microvascular lesion co-cultured with smooth muscle cells. In addition, in vivo microvascular lesions from SuHx rodent model showed an increased expression of ID3, VEGFR3, and Pyk2 similar to SU5416 treated human endothelial cells. Further investigations into how normal and stem-like cells utilize ID3 may open up new avenues for a better understanding of the molecular mechanisms which are underlying the pathological development of microvascular diseases.

  14. Integrating molecular markers into the World Health Organization classification of CNS tumors: a survey of the neuro-oncology community.

    Science.gov (United States)

    Aldape, Kenneth; Nejad, Romina; Louis, David N; Zadeh, Gelareh

    2017-03-01

    Molecular markers provide important biological and clinical information related to the classification of brain tumors, and the integration of relevant molecular parameters into brain tumor classification systems has been a widely discussed topic in neuro-oncology over the past decade. With recent advances in the development of clinically relevant molecular signatures and the 2016 World Health Organization (WHO) update, the views of the neuro-oncology community on such changes would be informative for implementing this process. A survey with 8 questions regarding molecular markers in tumor classification was sent to an email list of Society for Neuro-Oncology members and attendees of prior meetings (n=5065). There were 403 respondents. Analysis was performed using whole group response, based on self-reported subspecialty. The survey results show overall strong support for incorporating molecular knowledge into the classification and clinical management of brain tumors. Across all 7 subspecialty groups, ≥70% of respondents agreed to this integration. Interestingly, some variability is seen among subspecialties, notably with lowest support from neuropathologists, which may reflect their roles in implementing such diagnostic technologies. Based on a survey provided to the neuro-oncology community, we report strong support for the integration of molecular markers into the WHO classification of brain tumors, as well as for using an integrated "layered" diagnostic format. While membership from each specialty showed support, there was variation by specialty in enthusiasm regarding proposed changes. The initial results of this survey influenced the deliberations underlying the 2016 WHO classification of tumors of the central nervous system.

  15. The signature of 44Ti in Cassiopeia A revealed by IBIS/ISGRI on INTEGRAL

    CERN Document Server

    Renaud, M; Decourchelle, A; Lebrun, F; Den Hartog, P R; Terrier, R; Couvreur, C; Knödlseder, J; Martin, P; Prantzos, N; Bykov, A M; Blömen, H

    2006-01-01

    We report the detection of both the 67.9 and 78.4 keV 44Sc gamma-ray lines in Cassiopeia A with the INTEGRAL IBIS/ISGRI instrument. Besides the robustness provided by spectro-imaging observations, the main improvements compared to previous measurements are a clear separation of the two 44Sc lines together with an improved significance of the detection of the hard X-ray continuum up to 100 keV. These allow us to refine the determination of the 44Ti yield and to constrain the nature of the nonthermal continuum emission. By combining COMPTEL, BeppoSAX/PDS and ISGRI measurements, we find a line flux of (2.5 +/- 0.3)*10(-5) cm(-2) s(-1) leading to a synthesized 44Ti mass of 1.6 (+0.6-0.3)*10(-4) solar mass. This high value suggests that Cas A is peculiar in comparison to other young supernova remnants, from which so far no line emission from 44Ti decay has been unambiguously detected.

  16. Evaluation and Integration of Genetic Signature for Prediction Risk of Nasopharyngeal Carcinoma in Southern China

    Directory of Open Access Journals (Sweden)

    Xiuchan Guo

    2014-01-01

    Full Text Available Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC. A number of single nucleotide polymorphisms (SNPs have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC. Results. The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1, HLA-F, HLA-A, and HCG9 were statistically significant in both cohorts (Pcombined range from 5.96 × 10−17 to 0.02. We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC.

  17. Ectomycorrhizal fungi increase soil carbon storage: molecular signatures of mycorrhizal competition driving soil C storage at global scale

    Science.gov (United States)

    Averill, C.; Barry, B. K.; Hawkes, C.

    2015-12-01

    Soil carbon storage and decay is regulated by the activity of free-living decomposer microbes, which can be limited by nitrogen availability. Many plants associate with symbiotic ectomycorrhizal fungi on their roots, which produce nitrogen-degrading enzymes and may be able to compete with free-living decomposers for soil organic nitrogen. By doing so, ectomycorrhizal fungi may able to induce nitrogen limitation and reduce activity of free-living microbial decomposition by mining soil organic nitrogen. The implication is that ectomycorrhizal-dominated systems should have increased soil carbon storage relative to non-ectomycorrhizal systems, which has been confirmed at a global scale. To investigate these effects, we analyzed 364 globally distributed observations of soil fungal communities using 454 sequencing of the ITS region, along with soil C and N concentrations, climate and chemical data. We assigned operational taxonomic units using the QIIME pipeline and UNITE fungal database and assigned fungal reads as ectomycorrhizal or non-mycorrhizal based on current taxonomic knowledge. We tested for associations between ectomycorrhizal abundance, climate, and soil carbon and nitrogen. Sites with greater soil carbon had quantitatively more ectomycorrhizal fungi within the soil microbial community based on fungal sequence abundance, after accounting for soil nitrogen availability. This is consistent with our hypothesis that ectomycorrhizal fungi induce nitrogen-limitation of free-living decomposers and thereby increase soil carbon storage. The strength of the mycorrhizal effect increased non-linearly with ectomycorrhizal abundance: the greater the abundance, the greater the effect size. Mean annual temperature, potential evapotranspiration, soil moisture and soil pH were also significant predictors in the final AIC selected model. This analysis suggests that molecular data on soil microbial communities can be used to make quantitative biogeochemical predictions. The

  18. Phylogeny and molecular signatures (conserved proteins and indels that are specific for the Bacteroidetes and Chlorobi species

    Directory of Open Access Journals (Sweden)

    Lorenzini Emily

    2007-05-01

    reported based on concatenated sequences for 12 conserved proteins by different methods including the character compatibility (or clique approach. The placement of Salinibacter ruber with other Bacteroidetes species was not resolved by other phylogenetic methods, but this affiliation was strongly supported by the character compatibility approach. Conclusion The molecular signatures described here provide novel tools for identifying and circumscribing species from the Bacteroidetes and Chlorobi phyla as well as some of their main groups in clear terms. These results also provide strong evidence that species from these two phyla (and also possibly Fibrobacteres are specifically related to each other and they form a single superphylum. Functional studies on these proteins and indels should aid in the discovery of novel biochemical and physiological characteristics that are unique to these groups of bacteria.

  19. A unified scheme for ab initio molecular orbital theory and path integral molecular dynamics

    Science.gov (United States)

    Shiga, Motoyuki; Tachikawa, Masanori; Miura, Shinichi

    2001-11-01

    We present a general approach for accurate calculation of chemical substances which treats both nuclei and electrons quantum mechanically, adopting ab initio molecular orbital theory for the electronic structure and path integral molecular dynamics for the nuclei. The present approach enables the evaluation of physical quantities dependent on the nuclear configuration as well as the electronic structure, within the framework of Born-Oppenheimer adiabatic approximation. As an application, we give the path integral formulation of electric response properties—dipole moment and polarizability, which characterize the changes both in electronic structure and nuclear configuration at a given temperature when uniform electrostatic field is present. We also demonstrate the calculation of a water molecule using the present approach and the result of temperature and isotope effects is discussed.

  20. VitisNet: "Omics" integration through grapevine molecular networks.

    Directory of Open Access Journals (Sweden)

    Jérôme Grimplet

    Full Text Available BACKGROUND: Genomic data release for the grapevine has increased exponentially in the last five years. The Vitis vinifera genome has been sequenced and Vitis EST, transcriptomic, proteomic, and metabolomic tools and data sets continue to be developed. The next critical challenge is to provide biological meaning to this tremendous amount of data by annotating genes and integrating them within their biological context. We have developed and validated a system of Grapevine Molecular Networks (VitisNet. METHODOLOGY/PRINCIPAL FINDINGS: The sequences from the Vitis vinifera (cv. Pinot Noir PN40024 genome sequencing project and ESTs from the Vitis genus have been paired and the 39,424 resulting unique sequences have been manually annotated. Among these, 13,145 genes have been assigned to 219 networks. The pathway sets include 88 "Metabolic", 15 "Genetic Information Processing", 12 "Environmental Information Processing", 3 "Cellular Processes", 21 "Transport", and 80 "Transcription Factors". The quantitative data is loaded onto molecular networks, allowing the simultaneous visualization of changes in the transcriptome, proteome, and metabolome for a given experiment. CONCLUSIONS/SIGNIFICANCE: VitisNet uses manually annotated networks in SBML or XML format, enabling the integration of large datasets, streamlining biological functional processing, and improving the understanding of dynamic processes in systems biology experiments. VitisNet is grounded in the Vitis vinifera genome (currently at 8x coverage and can be readily updated with subsequent updates of the genome or biochemical discoveries. The molecular network files can be dynamically searched by pathway name or individual genes, proteins, or metabolites through the MetNet Pathway database and web-portal at http://metnet3.vrac.iastate.edu/. All VitisNet files including the manual annotation of the grape genome encompassing pathway names, individual genes, their genome identifier, and chromosome

  1. Molecular structure and elastic properties of thermotropic liquid crystals: Integrated molecular dynamics—Statistical mechanical theory vs molecular field approach

    Science.gov (United States)

    Capar, M. Ilk; Nar, A.; Ferrarini, A.; Frezza, E.; Greco, C.; Zakharov, A. V.; Vakulenko, A. A.

    2013-03-01

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio.

  2. Efficient stochastic thermostatting of path integral molecular dynamics

    Science.gov (United States)

    Ceriotti, Michele; Parrinello, Michele; Markland, Thomas E.; Manolopoulos, David E.

    2010-09-01

    The path integral molecular dynamics (PIMD) method provides a convenient way to compute the quantum mechanical structural and thermodynamic properties of condensed phase systems at the expense of introducing an additional set of high frequency normal modes on top of the physical vibrations of the system. Efficiently sampling such a wide range of frequencies provides a considerable thermostatting challenge. Here we introduce a simple stochastic path integral Langevin equation (PILE) thermostat which exploits an analytic knowledge of the free path integral normal mode frequencies. We also apply a recently developed colored noise thermostat based on a generalized Langevin equation (GLE), which automatically achieves a similar, frequency-optimized sampling. The sampling efficiencies of these thermostats are compared with that of the more conventional Nosé-Hoover chain (NHC) thermostat for a number of physically relevant properties of the liquid water and hydrogen-in-palladium systems. In nearly every case, the new PILE thermostat is found to perform just as well as the NHC thermostat while allowing for a computationally more efficient implementation. The GLE thermostat also proves to be very robust delivering a near-optimum sampling efficiency in all of the cases considered. We suspect that these simple stochastic thermostats will therefore find useful application in many future PIMD simulations.

  3. A systems biology pipeline identifies new immune and disease related molecular signatures and networks in human cells during microgravity exposure

    Science.gov (United States)

    Mukhopadhyay, Sayak; Saha, Rohini; Palanisamy, Anbarasi; Ghosh, Madhurima; Biswas, Anupriya; Roy, Saheli; Pal, Arijit; Sarkar, Kathakali; Bagh, Sangram

    2016-05-01

    Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions.

  4. Integrative ChIP-seq/microarray analysis identifies a CTNNB1 target signature enriched in intestinal stem cells and colon cancer.

    Directory of Open Access Journals (Sweden)

    Kazuhide Watanabe

    Full Text Available BACKGROUND: Deregulation of canonical Wnt/CTNNB1 (beta-catenin pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 are highly frequent in colon cancer and cause aberrant stabilization of CTNNB1, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of CTNNB1 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of CTNNB1 in colon cancer cells. RESULTS: We observed 3629 CTNNB1 binding peaks across the genome and a significant correlation between CTNNB1 binding and knockdown-induced gene expression change. Our integrative analysis led to the discovery of a direct Wnt target signature composed of 162 genes. Gene ontology analysis of this signature revealed a significant enrichment of Wnt pathway genes, suggesting multiple feedback regulations of the pathway. We provide evidence that this gene signature partially overlaps with the Lgr5+ intestinal stem cell signature, and is significantly enriched in normal intestinal stem cells as well as in clinical colorectal cancer samples. Interestingly, while the expression of the CTNNB1 target gene set does not correlate with survival, elevated expression of negative feedback regulators within the signature predicts better prognosis. CONCLUSION: Our data provide a genome-wide view of chromatin occupancy and gene regulation of Wnt/CTNNB1 signaling in colon cancer cells.

  5. Growth, modification and integration of carbon nanotubes into molecular electronics

    Science.gov (United States)

    Moscatello, Jason P.

    Molecules are the smallest possible elements for electronic devices, with active elements for such devices typically a few Angstroms in footprint area. Owing to the possibility of producing ultra-high density devices, tremendous effort has been invested in producing electronic junctions by using various types of molecules. The major issues for molecular electronics include (1) developing an effective scheme to connect molecules with the present micro- and nano-technology, (2) increasing the lifetime and stabilities of the devices, and (3) increasing their performance in comparison to the state-of-the-art devices. In this work, we attempt to use carbon nanotubes (CNTs) as the interconnecting nanoelectrodes between molecules and microelectrodes. The ultimate goal is to use two individual CNTs to sandwich molecules in a cross-bar configuration while having these CNTs connected with microelectrodes such that the junction displays the electronic character of the molecule chosen. We have successfully developed an effective scheme to connect molecules with CNTs, which is scalable to arrays of molecular electronic devices. To realize this far reaching goal, the following technical topics have been investigated. (1) Synthesis of multi-walled carbon nanotubes (MWCNTs) by thermal chemical vapor deposition (T-CVD) and plasma-enhanced chemical vapor deposition (PECVD) techniques (Chapter 3). We have evaluated the potential use of tubular and bamboo-like MWCNTs grown by T-CVD and PE-CVD in terms of their structural properties. (2) Horizontal dispersion of MWCNTs with and without surfactants, and the integration of MWCNTs to microelectrodes using deposition by dielectrophoresis (DEP) (Chapter 4). We have systematically studied the use of surfactant molecules to disperse and horizontally align MWCNTs on substrates. In addition, DEP is shown to produce impurityfree placement of MWCNTs, forming connections between microelectrodes. We demonstrate the deposition density is tunable by

  6. Signature Balancing

    NARCIS (Netherlands)

    Noordkamp, H.W.; Brink, M. van den

    2006-01-01

    Signatures are an important part of the design of a ship. In an ideal situation, signatures must be as low as possible. However, due to budget constraints it is most unlikely to reach this ideal situation. The arising question is which levels of signatures are optimal given the different scenarios i

  7. Path-integral Monte Carlo simulations for electronic dynamics on molecular chains. II. Transport across impurities

    Science.gov (United States)

    Mühlbacher, Lothar; Ankerhold, Joachim

    2005-05-01

    Electron transfer (ET) across molecular chains including an impurity is studied based on a recently improved real-time path-integral Monte Carlo (PIMC) approach [L. Mühlbacher, J. Ankerhold, and C. Escher, J. Chem. Phys. 121 12696 (2004)]. The reduced electronic dynamics is studied for various bridge lengths and defect site energies. By determining intersite hopping rates from PIMC simulations up to moderate times, the relaxation process in the extreme long-time limit is captured within a sequential transfer model. The total transfer rate is extracted and shown to be enhanced for certain defect site energies. Superexchange turns out to be relevant for extreme gap energies only and then gives rise to different dynamical signatures for high- and low-lying defects. Further, it is revealed that the entire bridge compound approaches a steady state on a much shorter time scale than that related to the total transfer. This allows for a simplified description of ET along donor-bridge-acceptor systems in the long-time range.

  8. Molecular signatures of amyotrophic lateral sclerosis disease progression in hind and forelimb muscles of an SOD1(G93A) mouse model.

    Science.gov (United States)

    Capitanio, Daniele; Vasso, Michele; Ratti, Antonia; Grignaschi, Giuliano; Volta, Manuela; Moriggi, Manuela; Daleno, Cristina; Bendotti, Caterina; Silani, Vincenzo; Gelfi, Cecilia

    2012-11-15

    This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1(G93A)) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD(+), and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as

  9. Integrating fossils with molecular phylogenies improves inference of trait evolution.

    Science.gov (United States)

    Slater, Graham J; Harmon, Luke J; Alfaro, Michael E

    2012-12-01

    Comparative biologists often attempt to draw inferences about tempo and mode in evolution by comparing the fit of evolutionary models to phylogenetic comparative data consisting of a molecular phylogeny with branch lengths and trait measurements from extant taxa. These kinds of approaches ignore historical evidence for evolutionary pattern and process contained in the fossil record. In this article, we show through simulation that incorporation of fossil information dramatically improves our ability to distinguish among models of quantitative trait evolution using comparative data. We further suggest a novel Bayesian approach that allows fossil information to be integrated even when explicit phylogenetic hypotheses are lacking for extinct representatives of extant clades. By applying this approach to a comparative dataset comprising body sizes for caniform carnivorans, we show that incorporation of fossil information not only improves ancestral state estimates relative to those derived from extant taxa alone, but also results in preference of a model of evolution with trend toward large body size over alternative models such as Brownian motion or Ornstein-Uhlenbeck processes. Our approach highlights the importance of considering fossil information when making macroevolutionary inference, and provides a way to integrate the kind of sparse fossil information that is available to most evolutionary biologists. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

  10. Path-integral molecular dynamics simulation of diamond

    Science.gov (United States)

    Ramírez, Rafael; Herrero, Carlos P.; Hernández, Eduardo R.

    2006-06-01

    Diamond is studied by path-integral molecular dynamics simulations of the atomic nuclei in combination with a tight-binding Hamiltonian to describe its electronic structure and total energy. This approach allows us to quantify the influence of quantum zero-point vibrations and finite temperatures on both the electronic and vibrational properties of diamond. The electron-phonon coupling mediated by the zero-point vibration reduces the direct electronic gap of diamond by 10%. The calculated decrease of the direct gap with temperature shows good agreement with the experimental data available up to 700K . Anharmonic vibrational frequencies of the crystal have been obtained from a linear-response approach based on the path integral formalism. In particular, the temperature dependence of the zone-center optical phonon has been derived from the simulations. The anharmonicity of the interatomic potential produces a red shift of this phonon frequency. At temperatures above 500K , this shift is overestimated in comparison to available experimental data. The predicted temperature shift of the elastic constant c44 displays reasonable agreement with the available experimental results.

  11. Technology of Electronic Signatur

    Directory of Open Access Journals (Sweden)

    Jaroslav Sadovsky

    2004-01-01

    Full Text Available An electronic signature uses a hash of message and an asymetrical algorithm of encryption for its generation. During verification of message on receiver side the hash of original message must be identical with the hash of received message. Electronic message is secured autentization of author and integrity of transmission date. By electronic signature it is possible to sign everything what is in digital form.

  12. Molecular hydrogen (H2 emissions and their isotopic signatures (H/D from a motor vehicle: implications on atmospheric H2

    Directory of Open Access Journals (Sweden)

    T. Röckmann

    2010-06-01

    Full Text Available Molecular hydrogen (H2, its isotopic signature (deuterium/hydrogen, δD, carbon monoxide (CO, and other compounds were studied in the exhaust of a passenger car engine fuelled with gasoline or methane and run under variable air-fuel ratios and operating modes. H2 and CO concentrations were largely reduced downstream of the three-way catalytic converter (TWC compared to levels upstream, and showed a strong dependence on the air-fuel ratio (expressed as lambda, λ. The isotopic composition of H2 ranged from δD = −140‰ to δD = −195‰ upstream of the TWC but these values decreased to −270‰ to −370‰ after passing through the TWC. Post-TWC δD values for the fuel-rich range showed a strong dependence on TWC temperature with more negative δD for lower temperatures. These effects are attributed to a rapid temperature-dependent H-D isotope equilibration between H2 and water (H2O. In addition, post TWC δD in H2 showed a strong dependence on the fraction of removed H2, suggesting isotopic enrichment during catalytic removal of H2 with enrichment factors (ε ranging from −39.8‰ to −15.5‰ depending on the operating mode. Our results imply that there may be considerable variability in real-world δD emissions from vehicle exhaust, which may mainly depend on TWC technology and exhaust temperature regime. This variability is suggestive of a δD from traffic that varies over time, by season, and by geographical location. An earlier-derived integrated pure (end-member δD from anthropogenic activities of −270‰ (Rahn et al., 2002 can be explained as a mixture of mainly vehicle emissions from cold starts and fully functional TWCs, but enhanced δD values by >50‰ are likely for regions where TWC technology is not fully implemented. Our results also suggest that a full hydrogen isotope analysis on fuel and exhaust gas may greatly aid at understanding process-level reactions in the exhaust gas, in particular in the TWC.

  13. Molecular hydrogen (H2 emissions and their isotopic signatures (H/D from a motor vehicle: implications on atmospheric H2

    Directory of Open Access Journals (Sweden)

    T. Röckmann

    2010-02-01

    Full Text Available Molecular hydrogen (H2, its isotopic signature (deuterium/hydrogen, δD, carbon monoxide (CO and other compounds were studied in the exhaust of a passenger car engine fuelled with gasoline or methane and run under variable air-fuel ratios and operating modes. H2 and CO concentrations were largely reduced downstream of the three-way catalytic converter (TWC compared to levels upstream, and showed a strong dependence on the air-fuel ratio (expressed as lambda, λ. The isotopic composition of H2 ranged from δD=–140‰ to δD=–195‰ upstream of the TWC but these values decreased to –270‰ to –370‰ after passing through the TWC. Post-TWC δD values for the fuel-rich range showed a strong dependence on TWC temperature with more negative δD for lower temperatures. These effects are attributed to a rapid temperature-dependent H-D isotope equilibration between H2 and water (H2O. In addition, post TWC δD in H2 showed a strong dependence on the fraction of removed H2, suggesting isotopic enrichment during catalytic removal of H2 with enrichment factors (ε ranging from –39.8‰ to –15.5‰ depending on the operating mode. Our results imply that there may be considerable variability in real-world δD emissions from vehicle exhaust, which may mainly depend on TWC technology and exhaust temperature regime. This variability is suggestive of a δD from traffic that varies over time, by season, and by geographical location. An earlier-derived integrated pure (end-member δD from anthropogenic activities of –270‰ (Rahn et al., 2002 can be explained as a mixture of mainly vehicle emissions from cold starts and fully functional TWCs, but enhanced δD values by >50‰ are likely for regions where TWC technology is not fully implemented. Our results also suggest that a full hydrogen isotope analysis on fuel and exhaust gas may greatly aid at understanding process-level reactions in the exhaust gas, in particular in the TWC.

  14. Ab initio molecular orbital calculation considering the quantum mechanical effect of nuclei by path integral molecular dynamics

    Science.gov (United States)

    Shiga, Motoyuki; Tachikawa, Masanori; Miura, Shinichi

    2000-12-01

    We present an accurate calculational scheme for many-body systems composed of electrons and nuclei, by path integral molecular dynamics technique combined with the ab initio molecular orbital theory. Based upon the scheme, the simulation of a water molecule at room temperature is demonstrated, applying all-electron calculation at the Hartree-Fock level of theory.

  15. Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes

    Directory of Open Access Journals (Sweden)

    Amanda M. Ackermann

    2016-03-01

    Conclusions: We have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.

  16. Towards a "Lyon molecular signature" to individualize the treatment of rectal cancer. Prognostic analysis of a prospective cohort of 94 rectal cancers T1-2-3 Nx MO to be the basis of a molecular signature.

    Science.gov (United States)

    Gérard, J-P; Baulieux, J; Doyen, J; Gal, J; Letouze, E; Olschwang, S; Chapet, O; Romestaing, P

    2012-12-01

    In 1998 a translational research was initiated in Lyon aiming at identifying a prognostic "biomolecular signature" in rectal cancer. This paper presents the clinical outcome of the patients included in this study. A total of 94 patients were included between 1998 and 2001. A staging with rectoscopy and biopsies was performed before treatment. In case of surgery, the operative specimen was analysed to evaluate the pathological response. There were two types of treatment: neoadjuvant radiotherapy (with or without concurrent chemotherapy) followed by surgery (76 cases) and radiotherapy alone with 'contactherapy' often associated with external beam radiotherapy (18 patients). The patients had a mean age of 63years. Stage was T1: 4, T2: 24, T3: 65 and T4: 1. The overall survival of the 94 patients was 62% at 8years with a rate of distant metastases of 29%. Rate of local recurrence at 8years was 6% in the neoadjuvant group and 16% in the radiotherapy group with an overall 8years survival in both groups respectively: 64% and 53%. There was a trend towards more metastases in cT3, tumour diameter above 4cm, circumferential extension. There was a significant increase in the risk of metastases for ypT3, ypN1-2 and Dworak score 1-2-3. In multivariate analysis ypT3 was significantly associated with a high rate of metastases (55%; P=0.0003). The rate of distant metastases is a major prognostic factor. These clinical results will serve as the base line to identify a "biomolecular signature" which could complement the TN(M) classification. Copyright © 2012 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  17. Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas

    Science.gov (United States)

    Duregon, Eleonora; Bertero, Luca; Pittaro, Alessandra; Soffietti, Riccardo; Rudà, Roberta; Trevisan, Morena; Papotti, Mauro; Ventura, Laura; Senetta, Rebecca; Cassoni, Paola

    2016-01-01

    Despite several molecular signatures for “lower grade diffuse gliomas” (LGG) have been identified, WHO grade still remains a cornerstone of treatment guidelines. Mitotic count bears a crucial role in its definition, although limited by the poor reproducibility of standard Hematoxylin & Eosin (H&E) evaluation. Phospho-histone-H3 (PHH3) and Ki-67 have been proposed as alternative assays of cellular proliferation. Therefore in the present series of 141 LGG, the molecular characterization (namely IDH status, 1p/19q co-deletion and MGMT promoter methylation) was integrated with the tumor “proliferative trait” (conventional H&E or PHH3-guided mitotic count and Ki-67 index) in term of prognosis definition. Exclusively high PHH3 and Ki-67 values were predictor of poor prognosis (log rank test, P = 0.0281 for PHH3 and P = 0.032 for Ki-67), unlike standard mitotic count. Based on Cox proportional hazard regression analyses, among all clinical (age), pathological (PHH3 and Ki-67) and molecular variables (IDH, 1p/19q codeletion and MGMT methylation) with a prognostic relevance at univariate survival analysis, only IDH expression (P = 0.001) and Ki-67 proliferation index (P = 0.027) proved to be independent prognostic factors. In addition, stratifying by IDH expression status, high Ki-67 retained its prognostic relevance uniquely in the IDH negative patient (P = 0.029) doubling their risk of death (hazard ratio = 2.27). Overall, PHH3 immunostaining is the sole reliable method with a prognostic value to highlight mitotic figures in LGG. Ki-67 proliferation index exceeds PHH3 mitotic count as a predictor of patient's prognosis, and should be integrated with molecular markers in a comprehensive grading system for LGG. PMID:27049832

  18. SignS: a parallelized, open-source, freely available, web-based tool for gene selection and molecular signatures for survival and censored data

    Directory of Open Access Journals (Sweden)

    Diaz-Uriarte Ramon

    2008-01-01

    Full Text Available Abstract Background Censored data are increasingly common in many microarray studies that attempt to relate gene expression to patient survival. Several new methods have been proposed in the last two years. Most of these methods, however, are not available to biomedical researchers, leading to many re-implementations from scratch of ad-hoc, and suboptimal, approaches with survival data. Results We have developed SignS (Signatures for Survival data, an open-source, freely-available, web-based tool and R package for gene selection, building molecular signatures, and prediction with survival data. SignS implements four methods which, according to existing reviews, perform well and, by being of a very different nature, offer complementary approaches. We use parallel computing via MPI, leading to large decreases in user waiting time. Cross-validation is used to asses predictive performance and stability of solutions, the latter an issue of increasing concern given that there are often several solutions with similar predictive performance. Biological interpretation of results is enhanced because genes and signatures in models can be sent to other freely-available on-line tools for examination of PubMed references, GO terms, and KEGG and Reactome pathways of selected genes. Conclusion SignS is the first web-based tool for survival analysis of expression data, and one of the very few with biomedical researchers as target users. SignS is also one of the few bioinformatics web-based applications to extensively use parallelization, including fault tolerance and crash recovery. Because of its combination of methods implemented, usage of parallel computing, code availability, and links to additional data bases, SignS is a unique tool, and will be of immediate relevance to biomedical researchers, biostatisticians and bioinformaticians.

  19. Strategy to find molecular signatures in a small series of rare cancers: validation for radiation-induced breast and thyroid tumors.

    Directory of Open Access Journals (Sweden)

    Nicolas Ugolin

    Full Text Available Methods of classification using transcriptome analysis for case-by-case tumor diagnosis could be limited by tumor heterogeneity and masked information in the gene expression profiles, especially as the number of tumors is small. We propose a new strategy, EMts_2PCA, based on: 1 The identification of a gene expression signature with a great potential for discriminating subgroups of tumors (EMts stage, which includes: a a learning step, based on an expectation-maximization (EM algorithm, to select sets of candidate genes whose expressions discriminate two subgroups, b a training step to select from the sets of candidate genes those with the highest potential to classify training tumors, c the compilation of genes selected during the training step, and standardization of their levels of expression to finalize the signature. 2 The predictive classification of independent prospective tumors, according to the two subgroups of interest, by the definition of a validation space based on a two-step principal component analysis (2PCA. The present method was evaluated by classifying three series of tumors and its robustness, in terms of tumor clustering and prediction, was further compared with that of three classification methods (Gene expression bar code, Top-scoring pair(s and a PCA-based method. Results showed that EMts_2PCA was very efficient in tumor classification and prediction, with scores always better that those obtained by the most common methods of tumor clustering. Specifically, EMts_2PCA permitted identification of highly discriminating molecular signatures to differentiate post-Chernobyl thyroid or post-radiotherapy breast tumors from their sporadic counterparts that were previously unsuccessfully classified or classified with errors.

  20. Benchmark values for molecular three-center integrals arising in the Dirac equation

    OpenAIRE

    Bagci, A.; Hoggan, P. E.

    2015-01-01

    The authors in their previous papers obtained compact, arbitrarily accurate expressions for two-center one- and two-electron relativistic molecular integrals expressed over Slater-type orbitals. In this present study, the accuracy limits of given expressions is examined for three-center nuclear attraction integrals, which are the first integral set do not have analytically closed form relations. They are expressed through new molecular auxiliary functions obtained via Neumann expansion of Cou...

  1. A hybrid approach to survival model building using integration of clinical and molecular information in censored data.

    Science.gov (United States)

    Choi, Ickwon; Kattan, Michael W; Wells, Brian J; Yu, Changhong

    2012-01-01

    In medical society, the prognostic models, which use clinicopathologic features and predict prognosis after a certain treatment, have been externally validated and used in practice. In recent years, most research has focused on high dimensional genomic data and small sample sizes. Since clinically similar but molecularly heterogeneous tumors may produce different clinical outcomes, the combination of clinical and genomic information, which may be complementary, is crucial to improve the quality of prognostic predictions. However, there is a lack of an integrating scheme for clinic-genomic models due to the P ≥ N problem, in particular, for a parsimonious model. We propose a methodology to build a reduced yet accurate integrative model using a hybrid approach based on the Cox regression model, which uses several dimension reduction techniques, L₂ penalized maximum likelihood estimation (PMLE), and resampling methods to tackle the problem. The predictive accuracy of the modeling approach is assessed by several metrics via an independent and thorough scheme to compare competing methods. In breast cancer data studies on a metastasis and death event, we show that the proposed methodology can improve prediction accuracy and build a final model with a hybrid signature that is parsimonious when integrating both types of variables.

  2. Final Report for Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Glotzer, Sharon C.

    2013-08-28

    In collaboration with researchers at Vanderbilt University, North Carolina State University, Princeton and Oakridge National Laboratory we developed multiscale modeling and simulation methods capable of modeling the synthesis, assembly, and operation of molecular electronics devices. Our role in this project included the development of coarse-grained molecular and mesoscale models and simulation methods capable of simulating the assembly of millions of organic conducting molecules and other molecular components into nanowires, crossbars, and other organized patterns.

  3. Molecular signature of clinical severity in recovering patients with severe acute respiratory syndrome coronavirus (SARS-CoV

    Directory of Open Access Journals (Sweden)

    Wu Ting-Shu

    2005-09-01

    Full Text Available Abstract Background Severe acute respiratory syndrome (SARS, a recent epidemic human disease, is caused by a novel coronavirus (SARS-CoV. First reported in Asia, SARS quickly spread worldwide through international travelling. As of July 2003, the World Health Organization reported a total of 8,437 people afflicted with SARS with a 9.6% mortality rate. Although immunopathological damages may account for the severity of respiratory distress, little is known about how the genome-wide gene expression of the host changes under the attack of SARS-CoV. Results Based on changes in gene expression of peripheral blood, we identified 52 signature genes that accurately discriminated acute SARS patients from non-SARS controls. While a general suppression of gene expression predominated in SARS-infected blood, several genes including those involved in innate immunity, such as defensins and eosinophil-derived neurotoxin, were upregulated. Instead of employing clustering methods, we ranked the severity of recovering SARS patients by generalized associate plots (GAP according to the expression profiles of 52 signature genes. Through this method, we discovered a smooth transition pattern of severity from normal controls to acute SARS patients. The rank of SARS severity was significantly correlated with the recovery period (in days and with the clinical pulmonary infection score. Conclusion The use of the GAP approach has proved useful in analyzing the complexity and continuity of biological systems. The severity rank derived from the global expression profile of significantly regulated genes in patients may be useful for further elucidating the pathophysiology of their disease.

  4. Epidemic and Maintenance of Rabies in Chinese Ferret Badgers (Melogale moschata) indicated by Epidemiology and the Molecular Signatures of Rabies Viruses

    Institute of Scientific and Technical Information of China (English)

    Shoufeng Zhang; Ye Liu; Yanli Hou; Jinghui Zhao; Fei Zhang; Ying Wang; Rongliang Hu

    2013-01-01

    An epidemic of Chinese ferret badger-associated human rabies was investigated in Wuyuan county,Jiangxi province and rabies viruses isolates from ferret badgers in different districts in Jiangxi and Zhejiang provinces were sequenced with their nucleotides and amino acids and aligned for epidemiological analysis.The results showed that the human rabies in Wuyuan are only associated with ferret badger bites; the rabies virus can be isolated in a high percentage of ferret badgers in the epidemic areas in Jiangxi and Zhejiang provinces; the isolates share the same molecular features in nucleotides and have characteristic amino acid signatures,i.e.,2 sites in the nucleoprotein and 3 sites in the glycoprotein,that are distinct from virus isolates from dogs in the same region.We conclude that rabies in Chinese ferret badgers has formed an independent transmission cycle and ferret badgers may serve as another important rabies reservoir independent of dog rabies in China.

  5. Molecular Assemblies, Genes and Genomics Integrated Efficiently (MAGGIE)

    Energy Technology Data Exchange (ETDEWEB)

    Baliga, Nitin S

    2011-05-26

    Final report on MAGGIE. We set ambitious goals to model the functions of individual organisms and their community from molecular to systems scale. These scientific goals are driving the development of sophisticated algorithms to analyze large amounts of experimental measurements made using high throughput technologies to explain and predict how the environment influences biological function at multiple scales and how the microbial systems in turn modify the environment. By experimentally evaluating predictions made using these models we will test the degree to which our quantitative multiscale understanding wilt help to rationally steer individual microbes and their communities towards specific tasks. Towards this end we have made substantial progress towards understanding evolution of gene families, transcriptional structures, detailed structures of keystone molecular assemblies (proteins and complexes), protein interactions, biological networks, microbial interactions, and community structure. Using comparative analysis we have tracked the evolutionary history of gene functions to understand how novel functions evolve. One level up, we have used proteomics data, high-resolution genome tiling microarrays, and 5' RNA sequencing to revise genome annotations, discover new genes including ncRNAs, and map dynamically changing operon structures of five model organisms: For Desulfovibrio vulgaris Hildenborough, Pyrococcus furiosis, Sulfolobus solfataricus, Methanococcus maripaludis and Haiobacterium salinarum NROL We have developed machine learning algorithms to accurately identify protein interactions at a near-zero false positive rate from noisy data generated using tagfess complex purification, TAP purification, and analysis of membrane complexes. Combining other genome-scale datasets produced by ENIGMA (in particular, microarray data) and available from literature we have been able to achieve a true positive rate as high as 65% at almost zero false positives

  6. Integrating Molecular Computation and Material Production in an Artificial Subcellular Matrix

    DEFF Research Database (Denmark)

    Fellermann, Harold; Hadorn, Maik; Bönzli, Eva

    Living systems are unique in that they integrate molecular recognition and information processing with material production on the molecular scale. Pre- dominant locus of this integration is the cellular matrix, where a multitude of biochemical reactions proceed simultaneously in highly compartmen......Living systems are unique in that they integrate molecular recognition and information processing with material production on the molecular scale. Pre- dominant locus of this integration is the cellular matrix, where a multitude of biochemical reactions proceed simultaneously in highly...... compartmentalized re- action compartments that interact and get delivered through vesicle trafficking. The European Commission funded project MatchIT (Matrix for Chemical IT) aims at creating an artificial cellular matrix that seamlessly integrates infor- mation processing and material production in much the same...... way as its biological counterpart: the project employs addressable chemical containers (chemtainers) interfaced with electronic computers via mechano-electronic microfluidics....

  7. ELECTRONIC SIGNATURES

    African Journals Online (AJOL)

    10332324

    'electronic signature' means data attached to, incorporated in, or logically ... See Cwele v S 2012 4 All SA 497 (SCA); Mohlabeng v Minister of Safety and Security ... ZAKZPHC 51 (2 September 2010); Delta Finance, a Division of Wesbank, ...

  8. Molecular integrals for exponential-type orbitals using hyperspherical harmonics

    DEFF Research Database (Denmark)

    Avery, James Emil; Avery, John Scales

    2015-01-01

    Exponential-type orbitals are better suited to calculations of molecular electronic structure than are Gaussians, since ETO's can accurately represent the behavior of molecular orbitals near to atomic nuclei, as well as their long-distance exponential decay. Orbitals based on Gaussians fail in bo...

  9. Integrating Geo-Spatial Data for Regional Landslide Susceptibility Modeling in Consideration of Run-Out Signature

    Science.gov (United States)

    Lai, J.-S.; Tsai, F.; Chiang, S.-H.

    2016-06-01

    This study implements a data mining-based algorithm, the random forests classifier, with geo-spatial data to construct a regional and rainfall-induced landslide susceptibility model. The developed model also takes account of landslide regions (source, non-occurrence and run-out signatures) from the original landslide inventory in order to increase the reliability of the susceptibility modelling. A total of ten causative factors were collected and used in this study, including aspect, curvature, elevation, slope, faults, geology, NDVI (Normalized Difference Vegetation Index), rivers, roads and soil data. Consequently, this study transforms the landslide inventory and vector-based causative factors into the pixel-based format in order to overlay with other raster data for constructing the random forests based model. This study also uses original and edited topographic data in the analysis to understand their impacts to the susceptibility modeling. Experimental results demonstrate that after identifying the run-out signatures, the overall accuracy and Kappa coefficient have been reached to be become more than 85 % and 0.8, respectively. In addition, correcting unreasonable topographic feature of the digital terrain model also produces more reliable modelling results.

  10. CERTIFICATELESS SIGNATURE AND BLIND SIGNATURE

    Institute of Scientific and Technical Information of China (English)

    Zhang Lei; Zhang Futai

    2008-01-01

    Certificateless public key cryptography is a new paradigm introduced by AI-Riyami and Paterson. It eliminates the need of the certificates in traditional public key cryptosystems and the key escrow problem in IDentity-based Public Key Cryptography (ID-PKC). Due to the advantages of the certificateless public key cryptography,a new efficient certificateless pairing-based signature scheme is presented,which has some advantages over previous constructions in computational cost. Based on this new signature scheme,a certificateless blind signature scheme is proposed. The security of our schemes is proven based on the hardness of computational Diffie-Hellman problem.

  11. Solution of multi-center molecular integrals of Slater-type orbitals

    Science.gov (United States)

    Tai, H.

    1989-01-01

    The troublesome multi-center molecular integrals of Slater-type orbitals (STO) in molecular physics calculations can be evaluated by using the Fourier transform and proper coupling of the two center exchange integrals. A numerical integration procedure is then readily rendered to the final expression in which the integrand consists of well known special functions of arguments containing the geometrical arrangement of the nuclear centers and the exponents of the atomic orbitals. A practical procedure was devised for the calculation of a general multi-center molecular integrals coupling arbitrary Slater-type orbitals. Symmetry relations and asymptotic conditions are discussed. Explicit expressions of three-center one-electron nuclear-attraction integrals and four-center two-electron repulsion integrals for STO of principal quantum number n=2 are listed. A few numerical results are given for the purpose of comparison.

  12. Report of the Integrative Molecular Cancer Epidemiology International Symposium, Lyon, France.

    Science.gov (United States)

    Raimondi, S

    2008-01-01

    An International Symposium on Integrative Molecular Cancer Epidemiology took place in Lyon, France, on 3-5 July 2008. The Symposium focused on aetiological and mechanistic aspects of molecular and genetic cancer epidemiology research and was divided into the following three sections: Molecular epidemiology-application of novel molecular markers to cancer epidemiology.Genomic epidemiology in the era of whole genome scan.INTEGRATIVE MOLECULAR EPIDEMIOLOGY: visions for the future.Participants included epidemiologists, geneticists, biochemical and molecular biologists, pharmacologists, pathologists and all researchers interested in this field. The Symposium provided a complete and clear overview of the present and future programmes in molecular cancer epidemiology. It also served to encourage international scientific collaboration between investigators working in this specific research field, and to stimulate transdisciplinary research with experts of other research areas. Highlights of each of the scientific presentations are summarized below.

  13. A Novel Molecular and Functional Stemness Signature Assessing Human Cord Blood-Derived Endothelial Progenitor Cell Immaturity.

    Directory of Open Access Journals (Sweden)

    Oriane Guillevic

    Full Text Available Endothelial Colony Forming Cells (ECFCs, a distinct population of Endothelial Progenitor Cells (EPCs progeny, display phenotypic and functional characteristics of endothelial cells while retaining features of stem/progenitor cells. Cord blood-derived ECFCs (CB-ECFCs have a high clonogenic and proliferative potentials and they can acquire different endothelial phenotypes, this requiring some plasticity. These properties provide angiogenic and vascular repair capabilities to CB-ECFCs for ischemic cell therapies. However, the degree of immaturity retained by EPCs is still confused and poorly defined. Consequently, to better characterize CB-ECFC stemness, we quantified their clonogenic potential and demonstrated that they were reprogrammed into induced pluripotent stem cells (iPSCs more efficiently and rapidly than adult endothelial cells. Moreover, we analyzed the transcriptional profile of a broad gene panel known to be related to stem cells. We showed that, unlike mature endothelial cells, CB-ECFCs expressed genes involved in the maintenance of embryonic stem cell properties such as DNMT3B, GDF3 or SOX2. Thus, these results provide further evidence and tools to appreciate EPC-derived cell stemness. Moreover this novel stem cell transcriptional signature of ECFCs could help better characterizing and ranging EPCs according to their immaturity profile.

  14. Comparison of molecular signatures in large scale protein interaction networks in normal and cancer conditions of brain, cervix, lung, ovary and prostate

    Directory of Open Access Journals (Sweden)

    Rajat Suvra Banik

    2016-04-01

    Full Text Available Background Cancer, the disease of intricateness, has remained beyond our complete perception so far. Network systems biology (termed NSB is one of the most recent approaches to understand the unsolved problems of cancer development. From this perspective, differential protein networks (PINs have been developed based on the expression and interaction data of brain, cervix, lung, ovary and prostate for normal and cancer conditions. Methods Differential expression database GeneHub-GEPIS and interaction database STRING were applied for primary data retrieval. Cytoscape platform and related plugins named network analyzer; MCODE and ModuLand were used for visualization of complex networks and subsequent analysis. Results Significant differences were observedamong different common network parameters between normal and cancer states. Moreover, molecular complex numbers and overlapping modularization found to be varying significantly between normal and cancerous tissues. The number of the ranked molecular complex and the nodes involved in the overlapping modules were meaningfully higher in cancer condition.We identified79 commonly up regulated and 6 down regulated proteins in all five tissues. Number of nodes, edges; multi edge node pair, and average number of neighbor are found with significant fluctuations in case of cervix and ovarian tissues.Cluster analysis showed that the association of Myc and Cdk4 proteins is very close with other proteins within the network.Cervix and ovarian tissue showed higher increment of the molecular complex number and overlapping module network during cancer in comparison to normal state. Conclusions The differential molecular signatures identified from the work can be studied further to understand the cancer signaling process, and potential therapeutic and detection approach. [Biomed Res Ther 2016; 3(4.000: 605-615

  15. Final technical report for DOE Computational Nanoscience Project: Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Cummings, P. T.

    2010-02-08

    This document reports the outcomes of the Computational Nanoscience Project, "Integrated Multiscale Modeling of Molecular Computing Devices". It includes a list of participants and publications arising from the research supported.

  16. A variational path integral molecular dynamics study of a solid helium-4

    Science.gov (United States)

    Miura, Shinichi

    2011-01-01

    In the present study, a variational path integral molecular dynamics method developed by the author [Chem. Phys. Lett. 482 (2009) 165] is applied to a solid helium-4 in the ground state. The method is a molecular dynamics algorithm for a variational path integral method which can be used to generate the exact ground state numerically. The solid state is shown to successfully be realized by the method, although a poor trial wavefunction that cannot describe the solid state is used.

  17. 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

  18. Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis

    Directory of Open Access Journals (Sweden)

    Nurul-Syakima Ab Mutalib

    2016-06-01

    Full Text Available Background. Papillary thyroid carcinoma (PTC is the commonest thyroid malignancy originating from the follicle cells in the thyroid. Despite a good overall prognosis, certain high-risk cases as in those with lymph node metastasis (LNM have progressive disease and poorer prognosis. MicroRNAs are a class of non-protein-coding, 19–24 nucleotides single-stranded RNAs which regulate gene expression and these molecules have been shown to play a role in LNM. The integrated analysis of miRNAs and gene expression profiles together with transcription factors (TFs has been shown to improve the identification of functional miRNA-target gene-TF relationships, providing a more complete view of molecular events underlying metastasis process. Objectives. We reanalyzed The Cancer Genome Atlas (TCGA datasets on PTC to identify differentially expressed miRNAs/genes in PTC patients with LNM-positive (LNM-P versus lymph node negative (LNN PTC patients and to investigate the miRNA-gene-TF regulatory circuit that regulate LNM in PTC. Results. PTC patients with LNM (PTC LNM-P have a significantly shorter disease-free survival rate compared to PTC patients without LNM (PTC LNN (Log-rank Mantel Cox test, p = 0.0049. We identified 181 significantly differentially expressed miRNAs in PTC LNM-P versus PTC LNN; 110 were upregulated and 71 were downregulated. The five topmost deregulated miRNAs were hsa-miR-146b, hsa-miR-375, hsa-miR-31, hsa-miR-7-2 and hsa-miR-204. In addition, 395 miRNAs were differentially expressed between PTC LNM-P and normal thyroid while 400 miRNAs were differentially expressed between PTC LNN and normal thyroid. We found four significant enrichment pathways potentially involved in metastasis to the lymph nodes, namely oxidative phosphorylation (OxPhos, cell adhesion molecules (CAMs, leukocyte transendothelial migration and cytokine–cytokine receptor interaction. OxPhos was the most significantly perturbed pathway (p = 4.70E−06 involving

  19. Unique molecular signatures influencing the biological function and fate of post-natal stem cells isolated from different sources.

    Science.gov (United States)

    Abu Kasim, Noor Hayaty; Govindasamy, Vijayendran; Gnanasegaran, Nareshwaran; Musa, Sabri; Pradeep, Padmaja Jayaprasad; Srijaya, Thekkeparambil Chandrabose; Aziz, Zeti Adura Che Ab

    2015-12-01

    The discovery of mesenchymal stem cells (MSCs) from a myriad of tissues has triggered the initiative of establishing tailor-made stem cells for disease-specific therapy. Nevertheless, lack of understanding on the inherent differential propensities of these cells may restrict their clinical outcome. Therefore, a comprehensive study was done to compare the proliferation, differentiation, expression of cell surface markers and gene profiling of stem cells isolated from different sources, viz. bone marrow, Wharton's jelly, adipose tissue and dental pulp. We found that although all MSCs were phenotypically similar to each other, Wharton's jelly (WJ) MSCs and dental pulp stem cells (DPSCs) were highly proliferative as compared to bone marrow (BM) MSCs and adipose tissue (AD) MSCs. Moreover, indistinguishable cell surface characteristics and differentiation capacity were confirmed to be similar among all cell types. Based on gene expression profiling, we postulate that BM-MSCs constitutively expressed genes related to inflammation and immunodulation, whereas genes implicated in tissue development were highly expressed in AD-MSCs. Furthermore, the transcriptome profiling of WJ-MSCs and DPSCs revealed an inherent bias towards the neuro-ectoderm lineage. Based on our findings, we believe that there is no unique master mesenchymal stem cell that is appropriate to treat all target diseases. More precisely, MSCs from different sources exhibit distinct and unique gene expression signatures that make them competent to give rise to specific lineages rather than others. Therefore, stem cells should be subjected to rigorous characterization and utmost vigilance needs to be adopted in order to choose the best cellular source for a particular disease.

  20. Membrane curvature in cell biology: An integration of molecular mechanisms.

    Science.gov (United States)

    Jarsch, Iris K; Daste, Frederic; Gallop, Jennifer L

    2016-08-15

    Curving biological membranes establishes the complex architecture of the cell and mediates membrane traffic to control flux through subcellular compartments. Common molecular mechanisms for bending membranes are evident in different cell biological contexts across eukaryotic phyla. These mechanisms can be intrinsic to the membrane bilayer (either the lipid or protein components) or can be brought about by extrinsic factors, including the cytoskeleton. Here, we review examples of membrane curvature generation in animals, fungi, and plants. We showcase the molecular mechanisms involved and how they collaborate and go on to highlight contexts of curvature that are exciting areas of future research. Lessons from how membranes are bent in yeast and mammals give hints as to the molecular mechanisms we expect to see used by plants and protists.

  1. Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts.

    Directory of Open Access Journals (Sweden)

    Michael E Johnson

    Full Text Available Genome-wide expression profiling in systemic sclerosis (SSc has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like, each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.

  2. Molecular signatures of trauma-hemorrhagic shock-induced lung injury: hemorrhage- and injury-associated genes.

    Science.gov (United States)

    Feinman, Rena; Deitch, Edwin A; Aris, Virginie; Chu, Hung B; Abungu, Billy; Caputo, Francis J; Galante, Anthony; Xu, DaZhong; Lu, Qi; Colorado, Iriana; Streck, Deanna; Dermody, James; Soteropoulos, Patricia

    2007-09-01

    The etiology of trauma-hemorrhagic shock (T/HS)-induced acute lung injury has been difficult to elucidate because of, at least in part, the inability of in vivo studies to separate the noninjurious pulmonary effects of trauma-hemorrhage from the tissue-injurious ones. To circumvent this in vivo limitation, we used a model of T/HS in which T/HS lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the noninjurious systemic response to T/HS by comparing the pulmonary molecular responses of rats subjected to T/HS, which did and did not develop lung injury, with those of nonshocked rats. Using high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 h after the end of the shock or sham-shock period, 139 of 8,799 assessed genes were identified by significant analysis of microarrays. Hemorrhage without the secondary effects of lung injury modulated the expression of 21 genes such as interleukin 1beta, metallothionein-2, and myeloctomatosis oncogene (c-myc). In response to injury, 42 genes were identified to be differentially expressed. Upregulated genes included the L1 retroposon and guanine deaminase, whereas downregulated genes included catalase and superoxide dismutase 1. Real-time polymerase chain reaction confirmed the differential expression for selected genes. PathwayAssist analysis identified interleukin 1beta as a central regulator of two subpathways of stress response-related genes (c-myc and superoxide dismutase 1/catalase) as well as several unrelated genes such as lipoprotein lipase. Our model system provided a unique opportunity to distinguish the molecular changes associated with T/HS-induced acute lung injury from the systemic molecular response to T/HS.

  3. Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression?

    Directory of Open Access Journals (Sweden)

    Barreto Rafael A

    2012-10-01

    Full Text Available Abstract Background Psychological stress, particularly in chronic form, can lead to mood and cognitive dysfunction and is a major risk factor in the development of depressive states. How stress affects the brain to cause psychopathologies is incompletely understood. We sought to characterise potential depression related mechanisms by analysing gene expression and molecular pathways in the infralimbic medial prefrontal cortex (ILmPFC, following a repeated psychological stress paradigm. The ILmPFC is thought to be involved in the processing of emotionally contextual information and in orchestrating the related autonomic responses, and it is one of the brain regions implicated in both stress responses and depression. Results Genome-wide microarray analysis of gene expression showed sub-chronic restraint stress resulted predominantly in a reduction in transcripts 24 hours after the last stress episode, with 239 genes significantly decreased, while just 24 genes had increased transcript abundance. Molecular pathway analysis using DAVID identified 8 pathways that were significantly enriched in the differentially expressed gene list, with genes belonging to the brain-derived neurotrophic factor – neurotrophin receptor tyrosine kinase 2 (BDNF-Ntrk2 pathway most enriched. Of the three intracellular signalling pathways that are downstream of Ntrk2, real-time quantitative PCR confirmed that only the PI3K-AKT-GSK3B and MAPK/ERK pathways were affected by sub-chronic stress, with the PLCγ pathway unaffected. Interestingly, chronic antidepressant treatment with the selective serotonin reuptake inhibitor, fluoxetine, prevented the stress-induced Ntrk2 and PI3K pathway changes, but it had no effect on the MAPK/ERK pathway. Conclusions These findings indicate that abnormal BDNF-Ntrk2 signalling may manifest at a relatively early time point, and is consistent with a molecular signature of depression developing well before depression-like behaviours occur

  4. Benchmark values for molecular three-center integrals arising in the Dirac equation

    Science.gov (United States)

    Baǧcı, A.; Hoggan, P. E.

    2015-10-01

    Previous papers by the authors report that they obtained compact, arbitrarily accurate expressions for two-center, one- and two-electron relativistic molecular integrals expressed over Slater-type orbitals. In the present study, accuracy limits of expressions given are examined for three-center nuclear attraction integrals, which are one-electron, three-center integrals with no analytically closed-form expression. In this work new molecular auxiliary functions are used. They are obtained via Neumann expansion of the Coulomb interaction. The numerical global adaptive method is used to evaluate these integrals for arbitrary values of orbital parameters and quantum numbers. Several methods, such as Laplace expansion of Coulomb interaction, single-center expansion, and the Fourier transformation method, have previously been used to evaluate these integrals considering the values of principal quantum numbers in the set of positive integer numbers. This study of three-center integrals places no restrictions on quantum numbers in all ranges of orbital parameters.

  5. Benchmark values for molecular three-center integrals arising in the Dirac equation.

    Science.gov (United States)

    Bağcı, A; Hoggan, P E

    2015-10-01

    Previous papers by the authors report that they obtained compact, arbitrarily accurate expressions for two-center, one- and two-electron relativistic molecular integrals expressed over Slater-type orbitals. In the present study, accuracy limits of expressions given are examined for three-center nuclear attraction integrals, which are one-electron, three-center integrals with no analytically closed-form expression. In this work new molecular auxiliary functions are used. They are obtained via Neumann expansion of the Coulomb interaction. The numerical global adaptive method is used to evaluate these integrals for arbitrary values of orbital parameters and quantum numbers. Several methods, such as Laplace expansion of Coulomb interaction, single-center expansion, and the Fourier transformation method, have previously been used to evaluate these integrals considering the values of principal quantum numbers in the set of positive integer numbers. This study of three-center integrals places no restrictions on quantum numbers in all ranges of orbital parameters.

  6. Ab initio path integral ring polymer molecular dynamics: Vibrational spectra of molecules

    Science.gov (United States)

    Shiga, Motoyuki; Nakayama, Akira

    2008-01-01

    The path integral ring polymer molecular dynamics method is combined with 'on-the-fly' ab initio electronic structure calculations and applied to vibrational spectra of small molecules, LiH and H 2O, at the room temperature. The results are compared with those of the numerically exact solution and ab initio path integral centroid molecular dynamics calculation. The peak positions in the calculated spectra are found to be reasonable, showing the red-shift due to potential anharmonicity. This unification enables the investigation of real-time quantum dynamics of chemically complex molecular systems on the ab initio Born-Oppenheimer potential energy surface.

  7. Post-quantum signatures for today

    OpenAIRE

    Dahmen, Erik

    2009-01-01

    Digital signatures are essential for the security of computer networks such as the Internet. For example, digital signatures are widely used to ensure the authenticity and integrity of updates for operating systems and other software applications. The security of the few practically used signature schemes is threatened by quantum computers. When large quantum computers are built, all currently used signature schemes will become insecure. It is therefore of extreme importance to develop altern...

  8. Multicenter molecular integrals for Slater orbitals of higher principal quantum numbers

    Science.gov (United States)

    Tai, H.

    1989-01-01

    As was shown earlier by Tai (1979), by using the Fourier-transform technique and properly coupling a pair of two-center exchange integrals, the multicenter molecular integrals can be cast into a simple expression upon which numerical procedures can be directly applied. In this paper, the procedure of Tai is extended to integrals involving orbitals with arbitrarily higher principal quantum number. The derivation is outlined, and the explicit expressions are presented for a three-center nuclear attraction integral and a four-center two-electron Coulomb repulsion integral of arbitrary higher states.

  9. Signature of coexistence of superconductivity and ferromagnetism in two-dimensional NbSe2 triggered by surface molecular adsorption

    Science.gov (United States)

    Zhu, Xiaojiao; Guo, Yuqiao; Cheng, Hao; Dai, Jun; An, Xingda; Zhao, Jiyin; Tian, Kangzhen; Wei, Shiqiang; Cheng Zeng, Xiao; Wu, Changzheng; Xie, Yi

    2016-04-01

    Ferromagnetism is usually deemed incompatible with superconductivity. Consequently, the coexistence of superconductivity and ferromagnetism is usually observed only in elegantly designed multi-ingredient structures in which the two competing electronic states originate from separate structural components. Here we report the use of surface molecular adsorption to induce ferromagnetism in two-dimensional superconducting NbSe2, representing the freestanding case of the coexistence of superconductivity and ferromagnetism in one two-dimensional nanomaterial. Surface-structural modulation of the ultrathin superconducting NbSe2 by polar reductive hydrazine molecules triggers a slight elongation of the covalent Nb-Se bond, which weakens the covalent interaction and enhances the ionicity of the tetravalent Nb with unpaired electrons, yielding ferromagnetic ordering. The induced ferromagnetic momentum couples with conduction electrons generating unique correlated effects of intrinsic negative magnetoresistance and the Kondo effect. We anticipate that the surface molecular adsorption will be a powerful tool to regulate spin ordering in the two-dimensional paradigm.

  10. Signature of coexistence of superconductivity and ferromagnetism in two-dimensional NbSe2 triggered by surface molecular adsorption.

    Science.gov (United States)

    Zhu, Xiaojiao; Guo, Yuqiao; Cheng, Hao; Dai, Jun; An, Xingda; Zhao, Jiyin; Tian, Kangzhen; Wei, Shiqiang; Cheng Zeng, Xiao; Wu, Changzheng; Xie, Yi

    2016-04-04

    Ferromagnetism is usually deemed incompatible with superconductivity. Consequently, the coexistence of superconductivity and ferromagnetism is usually observed only in elegantly designed multi-ingredient structures in which the two competing electronic states originate from separate structural components. Here we report the use of surface molecular adsorption to induce ferromagnetism in two-dimensional superconducting NbSe2, representing the freestanding case of the coexistence of superconductivity and ferromagnetism in one two-dimensional nanomaterial. Surface-structural modulation of the ultrathin superconducting NbSe2 by polar reductive hydrazine molecules triggers a slight elongation of the covalent Nb-Se bond, which weakens the covalent interaction and enhances the ionicity of the tetravalent Nb with unpaired electrons, yielding ferromagnetic ordering. The induced ferromagnetic momentum couples with conduction electrons generating unique correlated effects of intrinsic negative magnetoresistance and the Kondo effect. We anticipate that the surface molecular adsorption will be a powerful tool to regulate spin ordering in the two-dimensional paradigm.

  11. On the applicability of centroid and ring polymer path integral molecular dynamics for vibrational spectroscopy

    Science.gov (United States)

    Witt, Alexander; Ivanov, Sergei D.; Shiga, Motoyuki; Forbert, Harald; Marx, Dominik

    2009-05-01

    Centroid molecular dynamics (CMD) and ring polymer molecular dynamics (RPMD) are two conceptually distinct extensions of path integral molecular dynamics that are able to generate approximate quantum dynamics of complex molecular systems. Both methods can be used to compute quasiclassical time correlation functions which have direct application in molecular spectroscopy; in particular, to infrared spectroscopy via dipole autocorrelation functions. The performance of both methods for computing vibrational spectra of several simple but representative molecular model systems is investigated systematically as a function of temperature and isotopic substitution. In this context both CMD and RPMD feature intrinsic problems which are quantified and investigated in detail. Based on the obtained results guidelines for using CMD and RPMD to compute infrared spectra of molecular systems are provided.

  12. A theoretical molecular network for dyslexia: integrating available genetic findings

    NARCIS (Netherlands)

    Poelmans, G.J.V.; Buitelaar, J.K.; Pauls, D.L.; Franke, B.

    2011-01-01

    Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslex

  13. Deterministic Entanglement via Molecular Dissociation in Integrated Atom Optics

    OpenAIRE

    Zhao, Bo; Chen, Zeng-Bing; Pan, Jian-Wei; Schmiedmayer, J.; Recati, Alessio; Astrakharchik, Grigory E.; Calarco, Tommaso

    2005-01-01

    Deterministic entanglement of neutral cold atoms can be achieved by combining several already available techniques like the creation/dissociation of neutral diatomic molecules, manipulating atoms with micro fabricated structures (atom chips) and detecting single atoms with almost 100% efficiency. Manipulating this entanglement with integrated/linear atom optics will open a new perspective for quantum information processing with neutral atoms.

  14. Integrated Multiscale Modeling of Molecular Computing Devices. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Schulze, Tim [Univ. of Tennessee, Knoxville, TN (United States)

    2012-11-01

    The general theme of this research has been to expand the capabilities of a simulation technique, Kinetic Monte Carlo (KMC) and apply it to study self-assembled nano-structures on epitaxial thin films. KMC simulates thin film growth and evolution by replacing the detailed dynamics of the system's evolution, which might otherwise be studied using molecular dynamics, with an appropriate stochastic process.

  15. Integrated Multiscale Modeling of Molecular Computing Devices. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Schulze, Tim [Univ. of Tennessee, Knoxville, TN (United States)

    2012-11-01

    The general theme of this research has been to expand the capabilities of a simulation technique, Kinetic Monte Carlo (KMC) and apply it to study self-assembled nano-structures on epitaxial thin films. KMC simulates thin film growth and evolution by replacing the detailed dynamics of the system's evolution, which might otherwise be studied using molecular dynamics, with an appropriate stochastic process.

  16. Stress inducible heat shock protein 70: a potent molecular and toxicological signature in arsenic exposed broiler chickens.

    Science.gov (United States)

    Das, S; Pan, D; Bera, A K; Rana, T; Bandyopadhyay, S; De, S; Das, S K; Bhattacharya, D; Bandyopadhyay, S K

    2010-10-01

    This communication reports about heat shock protein response after arsenic exposure in broiler chickens in vivo and in vitro both. Splenocytes harvested in presence of sodium arsenite expressed Heat shock protein 70 (HSP 70) which could be identified on the basis of relative migration pattern and western blot analysis. Serum levels of HSP 70 in broiler chicken also increased after continuous feeding of sodium arsenite in drinking water. This particular observation may be attributed towards systematic inflammation, oxidative stress and hepatocellular injury. In vitro relative quantification of transcription level of HSP 70 revealed that splenocytes harvested in presence of sodium arsenite expressed (final concentration 3 and 7 μM/ml) more HSP 70 in comparison to cells harvested without sodium arsenite and the values were statistically significant (P < 0.001) when compared to untreated control. Collectively this result indicated that, HSP 70 level increased both in vivo and in vitro trials and may be used as potential molecular and toxicological biomarker.

  17. Understanding Complex Spectral Signatures of Embedded Excess Protons in Molecular Scaffolds with Third Order Corrections to the Harmonic Potential Surface

    Science.gov (United States)

    Deblase, Andrew F.; Johnson, Mark A.; Lectka, Thomas; Wang, Xun; Jordan, Kenneth D.; McCoy, Anne B.

    2013-06-01

    Overtones and combination bands observed in vibrational predissociation spectra of cold ions can often be anticipated by expanding the potential energy surface to third order. This is achieved by relating the third derivatives to the matrix elements that couple the allowed and forbidden states in the harmonic basis. Such a strategy has been successful in predicting Fermi resonances in formic acid clusters and some charged H-bonded complexes. Furthermore, third order couplings have been used to develop a vibrational adiabatic model in which excitation of a bright state is distributed over a Franck-Condon envelop of a lower energy mode, such as a water rocking against triatomic domains of molecular anions. Previous applications include the analysis of long vibrational progressions of soft modes in the OH stretching region of the actetate-water binary complex. Here we explore to extent to which this order of correction captures the irregular patterns associated with intramolecular proton bonds.

  18. Cardio-chemical exchange saturation transfer magnetic resonance imaging reveals molecular signatures of endogenous fibrosis and exogenous contrast media.

    Science.gov (United States)

    Vandsburger, Moriel; Vandoorne, Katrien; Oren, Roni; Leftin, Avigdor; Mpofu, Senzeni; Delli Castelli, Daniela; Aime, Silvio; Neeman, Michal

    2015-01-01

    Application of emerging molecular MRI techniques, including chemical exchange saturation transfer (CEST)-MRI, to cardiac imaging is desirable; however, conventional methods are poorly suited for cardiac imaging, particularly in small animals with rapid heart rates. We developed a CEST-encoded steady state and retrospectively gated cardiac cine imaging sequence in which the presence of fibrosis or paraCEST contrast agents was directly encoded into the steady-state myocardial signal intensity (cardioCEST). Development of cardioCEST: A CEST-encoded cardiac cine MRI sequence was implemented on a 9.4T small animal scanner. CardioCEST of fibrosis was serially performed by acquisition of a series of CEST-encoded cine images at multiple offset frequencies in mice (n=7) after surgically induced myocardial infarction. Scar formation was quantified using a spectral modeling approach and confirmed with histological staining. Separately, circulatory redistribution kinetics of the paramagnetic CEST agent Eu-HPDO3A were probed in mice using cardioCEST imaging, revealing rapid myocardial redistribution, and washout within 30 minutes (n=6). Manipulation of vascular tone resulted in heightened peak CEST contrast in the heart, but did not alter redistribution kinetics (n=6). At 28 days after myocardial infarction (n=3), CEST contrast kinetics in infarct zone tissue were altered, demonstrating gradual accumulation of Eu-HPDO3A in the increased extracellular space. cardioCEST MRI enables in vivo imaging of myocardial fibrosis using endogenous contrast mechanisms, and of exogenously delivered paraCEST agents, and can enable multiplexed imaging of multiple molecular targets at high-resolution coupled with conventional cardiac MRI scans. © 2013 American Heart Association, Inc.

  19. CD34(-) cells at the apex of the human hematopoietic stem cell hierarchy have distinctive cellular and molecular signatures.

    Science.gov (United States)

    Anjos-Afonso, Fernando; Currie, Erin; Palmer, Hector G; Foster, Katie E; Taussig, David C; Bonnet, Dominique

    2013-08-01

    In addition to well-characterized CD34(+) hematopoietic stem and progenitor cells (HSPCs), the human hematopoietic stem cell (HSC) hierarchy contains a rare CD34(-) population with severe combined immunodeficiency-repopulating capacity. However, little is known about the molecular characteristics of these CD34(-) cells or their relationship to the CD34(+) populations. Here, we show that the self-renewing Lin(-)CD34(-)CD38(-)CD93(hi) population contains cells that not only function as HSCs, but can also be placed above the CD34(+) populations in the hematopoietic hierarchy. These cells have an active Notch pathway, in which signaling through Delta4 is crucial for maintenance of the primitive state, and combined signals from Jagged1 and TGF-β are important in controlling its quiescence. They are also refractory to proliferative signals and show a repressed canonical Wnt pathway, in part regulated by Notch. Overall, therefore, CD34(-) cells represent an immature and quiescent human HSC population maintained through a distinctive network of cellular signaling interactions.

  20. Use of geochemical signatures, including rare earth elements, in mosses and lichens to assess spatial integration and the influence of forest environment

    Science.gov (United States)

    Gandois, L.; Agnan, Y.; Leblond, S.; Séjalon-Delmas, N.; Le Roux, G.; Probst, A.

    2014-10-01

    In order to assess the influence of local environment and spatial integration of Trace Metals (TM) by biomonitors, Al, As, Cd, Cr, Cs, Cu, Fe, Mn, Ni, Pb, Sb, Sn, V and Zn and some rare earth element (REE) concentrations have been measured in lichens and mosses collected in three French forest sites located in three distinct mountainous areas, as well as in the local soil and bedrock, and in both bulk deposition (BD) and throughfall (TF). Similar enrichment factors (EF) were calculated using lichens and mosses and local bedrock for most elements, except for Cs, Mn, Ni, Pb, and Cu which were significantly (KW, p lichens and mosses at each study sites, indicating a regional integration of atmospheric deposition by both biomonitors. Both TM signature and REE composition of mosses revealed that this biomonitor is highly influenced by throughfall composition, and reflect atmospheric deposition interaction with the forest canopy. This explained the higher enrichment measured in mosses for elements which concentration in deposition were influenced by the canopy, either due to leaching (Mn), direct uptake (Ni), or dry deposition dissolution (Pb, Cu, Cs).

  1. Plasma Molecular Signatures in Hypertensive Patients With Renin-Angiotensin System Suppression: New Predictors of Renal Damage and De Novo Albuminuria Indicators.

    Science.gov (United States)

    Baldan-Martin, Montserrat; Mourino-Alvarez, Laura; Gonzalez-Calero, Laura; Moreno-Luna, Rafael; Sastre-Oliva, Tamara; Ruiz-Hurtado, Gema; Segura, Julian; Lopez, Juan Antonio; Vazquez, Jesus; Vivanco, Fernando; Alvarez-Llamas, Gloria; Ruilope, Luis M; de la Cuesta, Fernando; Barderas, Maria G

    2016-07-01

    Albuminuria is a risk factor strongly associated with cardiovascular disease, the first cause of death in the general population. It is well established that renin-angiotensin system suppressors prevent the development of new-onset albuminuria in naïf hypertensive patients and diminish its excretion, but we cannot forget the percentage of hypertensive patients who develop de novo albuminuria. Here, we applied multiple proteomic strategy with the purpose to elucidate specific molecular pathways involved in the pathogenesis and provide predictors and chronic organ damage indicators. Briefly, 1143 patients were followed up for a minimum period of 3 years. One hundred and twenty-nine hypertensive patients chronically renin-angiotensin system suppressed were recruited, classified in 3 different groups depending on their albuminuria levels (normoalbuminuria, de novo albuminuria, and sustained albuminuria), and investigated by multiple proteomic strategies. Our strategy allowed us to perform one of the deepest plasma proteomic analysis to date, which has shown 2 proteomic signatures: (1) with predictive value of de novo albuminuria and (2) sustained albuminuria indicator proteins. These proteins are involved in inflammation, immune as well as in the proteasome activation occurring in situations of endoplasmic reticulum stress. Furthermore, these results open the possibility of a future strategy based on anti-immune therapy to treat hypertension which could help to prevent the development of albuminuria and, hence, the progression of kidney damage.

  2. Emergence of canine distemper virus strains with modified molecular signature and enhanced neuronal tropism leading to high mortality in wild carnivores.

    Science.gov (United States)

    Origgi, F C; Plattet, P; Sattler, U; Robert, N; Casaubon, J; Mavrot, F; Pewsner, M; Wu, N; Giovannini, S; Oevermann, A; Stoffel, M H; Gaschen, V; Segner, H; Ryser-Degiorgis, M-P

    2012-11-01

    An ongoing canine distemper epidemic was first detected in Switzerland in the spring of 2009. Compared to previous local canine distemper outbreaks, it was characterized by unusually high morbidity and mortality, rapid spread over the country, and susceptibility of several wild carnivore species. Here, the authors describe the associated pathologic changes and phylogenetic and biological features of a multiple highly virulent canine distemper virus (CDV) strain detected in and/or isolated from red foxes (Vulpes vulpes), Eurasian badgers (Meles meles), stone (Martes foina) and pine (Martes martes) martens, from a Eurasian lynx (Lynx lynx), and a domestic dog. The main lesions included interstitial to bronchointerstitial pneumonia and meningopolioencephalitis, whereas demyelination--the classic presentation of CDV infection--was observed in few cases only. In the brain lesions, viral inclusions were mainly in the nuclei of the neurons. Some significant differences in brain and lung lesions were observed between foxes and mustelids. Swiss CDV isolates shared together with a Hungarian CDV strain detected in 2004. In vitro analysis of the hemagglutinin protein from one of the Swiss CDV strains revealed functional and structural differences from that of the reference strain A75/17, with the Swiss strain showing increased surface expression and binding efficiency to the signaling lymphocyte activation molecule (SLAM). These features might be part of a novel molecular signature, which might have contributed to an increase in virus pathogenicity, partially explaining the high morbidity and mortality, the rapid spread, and the large host spectrum observed in this outbreak.

  3. Molecular Signature of Pseudomonas aeruginosa with Simultaneous Nanomolar Detection of Quorum Sensing Signaling Molecules at a Boron-Doped Diamond Electrode

    Science.gov (United States)

    Buzid, Alyah; Shang, Fengjun; Reen, F. Jerry; Muimhneacháin, Eoin Ó.; Clarke, Sarah L.; Zhou, Lin; Luong, John H. T.; O’Gara, Fergal; McGlacken, Gerard P.; Glennon, Jeremy D.

    2016-07-01

    Electroanalysis was performed using a boron-doped diamond (BDD) electrode for the simultaneous detection of 2-heptyl-3-hydroxy-4-quinolone (PQS), 2-heptyl-4-hydroxyquinoline (HHQ) and pyocyanin (PYO). PQS and its precursor HHQ are two important signal molecules produced by Pseudomonas aeruginosa, while PYO is a redox active toxin involved in virulence and pathogenesis. This Gram-negative and opportunistic human pathogen is associated with a hospital-acquired infection particularly in patients with compromised immunity and is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. Early detection is crucial in the clinical management of this pathogen, with established infections entering a biofilm lifestyle that is refractory to conventional antibiotic therapies. Herein, a detection procedure was optimized and proven for the simultaneous detection of PYO, HHQ and PQS in standard mixtures, biological samples, and P. aeruginosa spiked CF sputum samples with remarkable sensitivity, down to nanomolar levels. Differential pulse voltammetry (DPV) scans were also applicable for monitoring the production of PYO, HHQ and PQS in P. aeruginosa PA14 over 8 h of cultivation. The simultaneous detection of these three compounds represents a molecular signature specific to this pathogen.

  4. Meta-Analysis of Pulmonary Transcriptomes from Differently Primed Mice Identifies Molecular Signatures to Differentiate Immune Responses following Bordetella pertussis Challenge

    Directory of Open Access Journals (Sweden)

    René H. M. Raeven

    2017-01-01

    Full Text Available Respiratory infection with Bordetella pertussis leads to severe effects in the lungs. The resulting immunity and also immunization with pertussis vaccines protect against disease, but the induced type of immunity and longevity of the response are distinct. In this study the effects of priming, by either vaccination or infection, on a subsequent pathogen encounter were studied. To that end, three postchallenge transcriptome datasets of previously primed mice were combined and compared to the responses in unprimed control mice. In total, 205 genes showed different transcription activity. A coexpression network analysis assembled these genes into 27 clusters, combined into six groups with overlapping biological function. Local pulmonary immunity was only present in mice with infection-induced immunity. Complement-mediated responses were more prominent in mice immunized with an outer membrane vesicle pertussis vaccine than in mice that received a whole-cell pertussis vaccine. Additionally, 46 genes encoding for secreted proteins may serve as markers in blood for the degree of protection (Cxcl9, Gp2, and Pla2g2d, intensity of infection (Retnla, Saa3, Il6, and Il1b, or adaptive recall responses (Ighg, C1qb. The molecular signatures elucidated in this study contribute to better understanding of functional interactions in challenge-induced responses in relation to pertussis immunity.

  5. Molecular Signature of Pseudomonas aeruginosa with Simultaneous Nanomolar Detection of Quorum Sensing Signaling Molecules at a Boron-Doped Diamond Electrode

    Science.gov (United States)

    Buzid, Alyah; Shang, Fengjun; Reen, F. Jerry; Muimhneacháin, Eoin Ó; Clarke, Sarah L.; Zhou, Lin; Luong, John H. T.; O’Gara, Fergal; McGlacken, Gerard P.; Glennon, Jeremy D.

    2016-01-01

    Electroanalysis was performed using a boron-doped diamond (BDD) electrode for the simultaneous detection of 2-heptyl-3-hydroxy-4-quinolone (PQS), 2-heptyl-4-hydroxyquinoline (HHQ) and pyocyanin (PYO). PQS and its precursor HHQ are two important signal molecules produced by Pseudomonas aeruginosa, while PYO is a redox active toxin involved in virulence and pathogenesis. This Gram-negative and opportunistic human pathogen is associated with a hospital-acquired infection particularly in patients with compromised immunity and is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. Early detection is crucial in the clinical management of this pathogen, with established infections entering a biofilm lifestyle that is refractory to conventional antibiotic therapies. Herein, a detection procedure was optimized and proven for the simultaneous detection of PYO, HHQ and PQS in standard mixtures, biological samples, and P. aeruginosa spiked CF sputum samples with remarkable sensitivity, down to nanomolar levels. Differential pulse voltammetry (DPV) scans were also applicable for monitoring the production of PYO, HHQ and PQS in P. aeruginosa PA14 over 8 h of cultivation. The simultaneous detection of these three compounds represents a molecular signature specific to this pathogen. PMID:27427496

  6. Benchmark values for molecular two-electron integrals arising from the Dirac equation

    Science.gov (United States)

    Baǧcı, A.; Hoggan, P. E.

    2015-02-01

    The two-center two-electron Coulomb and hybrid integrals arising in relativistic and nonrelativistic ab initio calculations on molecules are evaluated. Compact, arbitrarily accurate expressions are obtained. They are expressed through molecular auxiliary functions and evaluated with the numerical Global-adaptive method for arbitrary values of parameters in the noninteger Slater-type orbitals. Highly accurate benchmark values are presented for these integrals. The convergence properties of new molecular auxiliary functions are investigated. The comparison for two-center two-electron integrals is made with results obtained from single center expansions by translation of the wave function to a single center with integer principal quantum numbers and results obtained from the Cuba numerical integration algorithm, respectively. The procedures discussed in this work are capable of yielding highly accurate two-center two-electron integrals for all ranges of orbital parameters.

  7. Benchmark values for molecular two-electron integrals arising from the Dirac equation.

    Science.gov (United States)

    Bağcı, A; Hoggan, P E

    2015-02-01

    The two-center two-electron Coulomb and hybrid integrals arising in relativistic and nonrelativistic ab initio calculations on molecules are evaluated. Compact, arbitrarily accurate expressions are obtained. They are expressed through molecular auxiliary functions and evaluated with the numerical Global-adaptive method for arbitrary values of parameters in the noninteger Slater-type orbitals. Highly accurate benchmark values are presented for these integrals. The convergence properties of new molecular auxiliary functions are investigated. The comparison for two-center two-electron integrals is made with results obtained from single center expansions by translation of the wave function to a single center with integer principal quantum numbers and results obtained from the Cuba numerical integration algorithm, respectively. The procedures discussed in this work are capable of yielding highly accurate two-center two-electron integrals for all ranges of orbital parameters.

  8. Classification of signature-only signature models

    Institute of Scientific and Technical Information of China (English)

    CAO ZhengJun; LIU MuLan

    2008-01-01

    We introduce a set of criterions for classifying signature-only signature models. By the criterions, we classify signature models into 5 basic types and 69 general classes. Theoretically, 21141 kinds of signature models can be derived by appro-priately combining different general classes. The result comprises almost existing signature models. It will be helpful for exploring new signature models. To the best of our knowledge, it is the first time for investigation of the problem of classifica-tion of signature-only signature models.

  9. Molecular Signature and In Vivo Behavior of Bone Marrow Endosteal and Subendosteal Stromal Cell Populations and their Relevance to Hematopoiesis

    Science.gov (United States)

    Balduino, Alex; Coelho, Valeria Mello; Wang, Zhou; Taichman, Russell S.; Krebsbach, Paul H.; Weeraratna, Ashani T.; Becker, Kevin G.; de Mello, Wallace; Taub, Dennis D.; Borojevic, Radovan

    2012-01-01

    In the bone marrow cavity, hematopoietic stem cells (HSC) have been shown to reside in the endosteal and subendosteal perivascular niches, which play specific roles on HSC maintenance. Although cells with long-term ability to reconstitute full hematopoietic system can be isolated from both niches, several data support a heterogenous distribution regarding the cycling behavior of HSC. Whether this distinct behavior depends upon the role played by the stromal populations which distinctly create these two niches is a question that remains open. In the present report, we used our previously described in vivo assay to demonstrate that endosteal and subendosteal stromal populations are very distinct regarding skeletal lineage differentiation potential. This was further supported by a microarray-based analysis, which also demonstrated that these two stromal populations play distinct, albeit complementary, roles in HSC niche. Both stromal populations were preferentially isolated from the trabecular region and behave distinctly in vitro, as previously reported. Even though these two niches are organized in a very close range, in vivo assays and molecular analyses allowed us to identify endosteal stroma (F-OST) cells as fully committed osteoblasts and subendosteal stroma (F-RET) cells as uncommitted mesenchymal cells mainly represented by perivascular reticular cells expressing high levels of chemokine ligand, CXCL12. Interestingly, a number of cytokines and growth factors including interleukin-6 (IL-6), IL-7, IL-15, Hepatocyte growth factor (HGF) and stem cell factor (SCF) matrix metalloproteases (MMPs) were also found to be differentially expressed by F-OST and F-RET cells. Further microarray analyses indicated important mechanisms used by the two stromal compartments in order to create and coordinate the “quiescent” and “proliferative” niches in which hematopoietic stem cells and progenitors reside. PMID:22841688

  10. The signature of seeds in resurrection plants: a molecular and physiological comparison of desiccation tolerance in seeds and vegetative tissues.

    Science.gov (United States)

    Illing, Nicola; Denby, Katherine J; Collett, Helen; Shen, Arthur; Farrant, Jill M

    2005-11-01

    Desiccation-tolerance in vegetative tissues of angiosperms has a polyphyletic origin and could be due to 1) appropriation of the seed-specific program of gene expression that protects orthodox seeds against desiccation, and/or 2) a sustainable version of the abiotic stress response. We tested these hypotheses by comparing molecular and physiological data from the development of orthodox seeds, the response of desiccation-sensitive plants to abiotic stress, and the response of desiccation-tolerant plants to extreme water loss. Analysis of publicly-available gene expression data of 35 LEA proteins and 68 anti-oxidant enzymes in the desiccation-sensitive Arabidopsis thaliana identified 13 LEAs and 4 anti-oxidants exclusively expressed in seeds. Two (a LEA6 and 1-cys-peroxiredoxin) are not expressed in vegetative tissues in A. thaliana, but have orthologues that are specifically activated in desiccating leaves of Xerophyta humilis. A comparison of antioxidant enzyme activity in two desiccation-sensitive species of Eragrostis with the desiccation-tolerant E. nindensis showed equivalent responses upon initial dehydration, but activity was retained at low water content in E. nindensis only. We propose that these antioxidants are housekeeping enzymes and that they are protected from damage in the desiccation-tolerant species. Sucrose is considered an important protectant against desiccation in orthodox seeds, and we show that sucrose accumulates in drying leaves of E. nindensis, but not in the desiccation-sensitive Eragrostis species. The activation of "seed-specific" desiccation protection mechanisms (sucrose accumulation and expression of LEA6 and 1-cys-peroxiredoxin genes) in the vegetative tissues of desiccation-tolerant plants points towards acquisition of desiccation tolerance from seeds.

  11. Molecular population genetics of human CYP3A locus: signatures of positive selection and implications for evolutionary environmental medicine.

    Science.gov (United States)

    Chen, Xiaoping; Wang, Haijian; Zhou, Gangqiao; Zhang, Xiumei; Dong, Xiaojia; Zhi, Lianteng; Jin, Li; He, Fuchu

    2009-10-01

    The human CYP3A gene cluster codes for cytochrome P450 (CYP) subfamily enzymes that catalyze the metabolism of various exogenous and endogenous chemicals and is an obvious candidate for evolutionary and environmental genomic study. Functional variants in the CYP3A locus may have undergone a selective sweep in response to various environmental conditions. The goal of this study was to profile the allelic structure across the human CYP3A locus and investigate natural selection on that locus. From the CYP3A locus spanning 231 kb, we resequenced 54 genomic DNA fragments (a total of 43,675 bases) spanning four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) and two pseudogenes (CYP3AP1 and CYP3AP2), and randomly selected intergenic regions at the CYP3A locus in Africans (24 individuals), Caucasians (24 individuals), and Chinese (29 individuals). We comprehensively investigated the nucleotide diversity and haplotype structure and examined the possible role of natural selection in shaping the sequence variation throughout the gene cluster. Neutrality tests with Tajima's D, Fu and Li's D* and F*, and Fay and Wu's H indicated possible roles of positive selection on the entire CYP3A locus in non-Africans. Sliding-window analyses of nucleotide diversity and frequency spectrum, as well as haplotype diversity and phylogenetically inferred haplotype structure, revealed that CYP3A4 and CYP3A7 had recently undergone or were undergoing a selective sweep in all three populations, whereas CYP3A43 and CYP3A5 were undergoing a selective sweep in non-Africans and Caucasians, respectively. The refined allelic architecture and selection spectrum for the human CYP3A locus highlight that evolutionary dynamics of molecular adaptation may underlie the phenotypic variation of the xenobiotic disposition system and varied predisposition to complex disorders in which xenobiotics play a role.

  12. Molecular signature and in vivo behavior of bone marrow endosteal and subendosteal stromal cell populations and their relevance to hematopoiesis

    Energy Technology Data Exchange (ETDEWEB)

    Balduino, Alex, E-mail: balduino@uva.edu.br [School of Dentistry, Veiga de Almeida University, Rio de Janeiro, RJ (Brazil); Mello-Coelho, Valeria [Biomedical Science Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ (Brazil); National Institute on Aging, National Institute of Health, Baltimore, MD (United States); Wang, Zhou; Taichman, Russell S.; Krebsbach, Paul H. [Department of Periodontics, Prevention and Geriatrics, University of Michigan School of Dentistry, Ann Arbor, MI (United States); Weeraratna, Ashani T.; Becker, Kevin G. [National Institute on Aging, National Institute of Health, Baltimore, MD (United States); Mello, Wallace de [Instituto Oswaldo Cruz, Rio de Janeiro, RJ (Brazil); Taub, Dennis D. [National Institute on Aging, National Institute of Health, Baltimore, MD (United States); Borojevic, Radovan [Biomedical Science Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ (Brazil)

    2012-11-15

    In the bone marrow cavity, hematopoietic stem cells (HSC) have been shown to reside in the endosteal and subendosteal perivascular niches, which play specific roles on HSC maintenance. Although cells with long-term ability to reconstitute full hematopoietic system can be isolated from both niches, several data support a heterogenous distribution regarding the cycling behavior of HSC. Whether this distinct behavior depends upon the role played by the stromal populations which distinctly create these two niches is a question that remains open. In the present report, we used our previously described in vivo assay to demonstrate that endosteal and subendosteal stromal populations are very distinct regarding skeletal lineage differentiation potential. This was further supported by a microarray-based analysis, which also demonstrated that these two stromal populations play distinct, albeit complementary, roles in HSC niche. Both stromal populations were preferentially isolated from the trabecular region and behave distinctly in vitro, as previously reported. Even though these two niches are organized in a very close range, in vivo assays and molecular analyses allowed us to identify endosteal stroma (F-OST) cells as fully committed osteoblasts and subendosteal stroma (F-RET) cells as uncommitted mesenchymal cells mainly represented by perivascular reticular cells expressing high levels of chemokine ligand, CXCL12. Interestingly, a number of cytokines and growth factors including interleukin-6 (IL-6), IL-7, IL-15, Hepatocyte growth factor (HGF) and stem cell factor (SCF) matrix metalloproteases (MMPs) were also found to be differentially expressed by F-OST and F-RET cells. Further microarray analyses indicated important mechanisms used by the two stromal compartments in order to create and coordinate the 'quiescent' and 'proliferative' niches in which hematopoietic stem cells and progenitors reside.

  13. New hybrid method for reactive systems from integrating molecular orbital or molecular mechanics methods with analytical potential energy surfaces.

    Science.gov (United States)

    Espinosa-Garciá, Joaquín; Rangel, Cipriano; Navarrete, Marta; Corchado, José C

    2004-09-15

    A computational approach to calculating potential energy surfaces for reactive systems is presented and tested. This hybrid approach is based on integrated methods where calculations for a small model system are performed by using analytical potential energy surfaces, and for the real system by using molecular orbital or molecular mechanics methods. The method is tested on a hydrogen abstraction reaction by using the variational transition-state theory with multidimensional tunneling corrections. The agreement between the calculated and experimental information depends on the quality of the method chosen for the real system. When the real system is treated by accurate quantum mechanics methods, the rate constants are in excellent agreement with the experimental measurements over a wide temperature range. When the real system is treated by molecular mechanics methods, the results are still good, which is very encouraging since molecular mechanics itself is not at all capable of describing this reactive system. Since no experimental information or additional fits are required to apply this method, it can be used to improve the accuracy of molecular orbital methods or to extend the molecular mechanics method to treat any reactive system with the single constraint of the availability of an analytical potential energy surface that describes the model system.

  14. Variational path integral molecular dynamics and hybrid Monte Carlo algorithms using a fourth order propagator with applications to molecular systems

    Science.gov (United States)

    Kamibayashi, Yuki; Miura, Shinichi

    2016-08-01

    In the present study, variational path integral molecular dynamics and associated hybrid Monte Carlo (HMC) methods have been developed on the basis of a fourth order approximation of a density operator. To reveal various parameter dependence of physical quantities, we analytically solve one dimensional harmonic oscillators by the variational path integral; as a byproduct, we obtain the analytical expression of the discretized density matrix using the fourth order approximation for the oscillators. Then, we apply our methods to realistic systems like a water molecule and a para-hydrogen cluster. In the HMC, we adopt two level description to avoid the time consuming Hessian evaluation. For the systems examined in this paper, the HMC method is found to be about three times more efficient than the molecular dynamics method if appropriate HMC parameters are adopted; the advantage of the HMC method is suggested to be more evident for systems described by many body interaction.

  15. Communication: Kirkwood-Buff integrals in the thermodynamic limit from small-sized molecular dynamics simulations

    Science.gov (United States)

    Cortes-Huerto, R.; Kremer, K.; Potestio, R.

    2016-10-01

    We present an accurate and efficient method to obtain Kirkwood-Buff (KB) integrals in the thermodynamic limit from small-sized molecular dynamics simulations. By introducing finite size effects into integral equations of statistical mechanics, we derive an analytical expression connecting the KB integrals of the bulk system with the fluctuations of the number of molecules in the corresponding closed system. We validate the method by calculating the activity coefficients of aqueous urea mixtures and the KB integrals of Lennard-Jones fluids. Moreover, our results demonstrate how to identify simulation conditions under which computer simulations reach the thermodynamic limit.

  16. Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators.

    Directory of Open Access Journals (Sweden)

    Sonia Paco

    Full Text Available Collagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts.In order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays.We found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases.

  17. Unraveling signatures of biogeochemical processes and the depositional setting in the molecular composition of pore water DOM across different marine environments

    Science.gov (United States)

    Schmidt, Frauke; Koch, Boris P.; Goldhammer, Tobias; Elvert, Marcus; Witt, Matthias; Lin, Yu-Shih; Wendt, Jenny; Zabel, Matthias; Heuer, Verena B.; Hinrichs, Kai-Uwe

    2017-06-01

    consistent with elevated HS- concentrations reflecting the incorporation of sulfur into biomolecules during early diagenesis. Sulfurization resulted in an increased average molecular mass of DOM and higher formula richness (up to 5899 formulas per sample). In sediments from the methanogenic zone in the Black Sea, the DOM pool was distinctly more reduced than overlying sediments from the sulfate-reducing zone. Bottom and pore water DOM from the Discovery Basin contained the highest abundances of aliphatic compounds in the entire dataset; a large fraction of abundant N-bearing formulas possibly represented peptide and nucleotide formulas suggesting preservation of these molecules in the life inhibiting environment of the Discovery Basin. Our unique data set provides the basis for a comprehensive understanding of the molecular signatures in pore water DOM and the turnover of sedimentary organic matter in marine sediments.

  18. The Molecular Signature of HIV-1-Associated Lipomatosis Reveals Differential Involvement of Brown and Beige/Brite Adipocyte Cell Lineages.

    Directory of Open Access Journals (Sweden)

    Rubén Cereijo

    Full Text Available Highly active antiretroviral therapy has remarkably improved quality of life of HIV-1-infected patients. However, this treatment has been associated with the so-called lipodystrophic syndrome, which conveys a number of adverse metabolic effects and morphological alterations. Among them, lipoatrophy of subcutaneous fat in certain anatomical areas and hypertrophy of visceral depots are the most common. Less frequently, lipomatous enlargements of subcutaneous fat at distinct anatomic areas occur. Lipomatous adipose tissue in the dorso-cervical area ("buffalo hump" has been associated with a partial white-to-brown phenotype transition and with increased cell proliferation, but, to date, lipomatous enlargements arising in other parts of the body have not been characterized. In order to establish the main molecular events associated with the appearance of lipomatosis in HIV-1 patients, we analyzed biopsies of lipomatous tissue from "buffalo hump" and from other anatomical areas in patients, in comparison with healthy subcutaneous adipose tissue, using a marker gene expression approach. Both buffalo-hump and non-buffalo-hump lipomatous adipose tissues exhibited similar patterns of non-compromised adipogenesis, unaltered inflammation, non-fibrotic phenotype and proliferative activity. Shorter telomere length, prelamin A accumulation and SA-β-Gal induction, reminiscent of adipocyte senescence, were also common to both types of lipomatous tissues. Buffalo hump biopsies showed expression of marker genes of brown adipose tissue (e.g. UCP1 and, specifically, of "classical" brown adipocytes (e.g. ZIC1 but not of beige/brite adipocytes. No such brown fat-related gene expression occurred in lipomatous tissues at other anatomical sites. In conclusion, buffalo hump and other subcutaneous adipose tissue enlargements from HIV-1-infected patients share a similar lipomatous character. However, a distorted induction of white-to-"classical brown adipocyte" phenotype

  19. i-PI: A Python interface for ab initio path integral molecular dynamics simulations

    CERN Document Server

    Ceriotti, Michele; Manolopoulos, David E

    2014-01-01

    Recent developments in path integral methodology have significantly reduced the computational expense of including quantum mechanical effects in the nuclear motion in ab initio molecular dynamics simulations. However, the implementation of these developments requires a considerable programming effort, which has hindered their adoption. Here we describe i-PI, an interface written in Python that has been designed to minimise the effort required to bring state-of-the-art path integral techniques to an electronic structure program. While it is best suited to first principles calculations and path integral molecular dynamics, i-PI can also be used to perform classical molecular dynamics simulations, and can just as easily be interfaced with an empirical forcefield code. To give just one example of the many potential applications of the interface, we use it in conjunction with the CP2K electronic structure package to showcase the importance of nuclear quantum effects in high pressure water.

  20. Ab initio centroid path integral molecular dynamics: Application to vibrational dynamics of diatomic molecular systems

    Science.gov (United States)

    Ohta, Yasuhito; Ohta, Koji; Kinugawa, Kenichi

    2004-01-01

    An ab initio centroid molecular dynamics (CMD) method is developed by combining the CMD method with the ab initio molecular orbital method. The ab initio CMD method is applied to vibrational dynamics of diatomic molecules, H2 and HF. For the H2 molecule, the temperature dependence of the peak frequency of the vibrational spectral density is investigated. The results are compared with those obtained by the ab initio classical molecular dynamics method and exact quantum mechanical treatment. It is shown that the vibrational frequency obtained from the ab initio CMD approaches the exact first excitation frequency as the temperature lowers. For the HF molecule, the position autocorrelation function is also analyzed in detail. The present CMD method is shown to well reproduce the exact quantum result for the information on the vibrational properties of the system.

  1. DNA-enabled integrated molecular systems for computation and sensing.

    Science.gov (United States)

    LaBoda, Craig; Duschl, Heather; Dwyer, Chris L

    2014-06-17

    CONSPECTUS: Nucleic acids have become powerful building blocks for creating supramolecular nanostructures with a variety of new and interesting behaviors. The predictable and guided folding of DNA, inspired by nature, allows designs to manipulate molecular-scale processes unlike any other material system. Thus, DNA can be co-opted for engineered and purposeful ends. This Account details a small portion of what can be engineered using DNA within the context of computer architectures and systems. Over a decade of work at the intersection of DNA nanotechnology and computer system design has shown several key elements and properties of how to harness the massive parallelism created by DNA self-assembly. This work is presented, naturally, from the bottom-up beginning with early work on strand sequence design for deterministic, finite DNA nanostructure synthesis. The key features of DNA nanostructures are explored, including how the use of small DNA motifs assembled in a hierarchical manner enables full-addressability of the final nanostructure, an important property for building dense and complicated systems. A full computer system also requires devices that are compatible with DNA self-assembly and cooperate at a higher level as circuits patterned over many, many replicated units. Described here is some work in this area investigating nanowire and nanoparticle devices, as well as chromophore-based circuits called resonance energy transfer (RET) logic. The former is an example of a new way to bring traditional silicon transistor technology to the nanoscale, which is increasingly problematic with current fabrication methods. RET logic, on the other hand, introduces a framework for optical computing at the molecular level. This Account also highlights several architectural system studies that demonstrate that even with low-level devices that are inferior to their silicon counterparts and a substrate that harbors abundant defects, self-assembled systems can still

  2. Molecular clock integration of brown adipose tissue formation and function.

    Science.gov (United States)

    Nam, Deokhwa; Yechoor, Vijay K; Ma, Ke

    2016-01-01

    The circadian clock is an essential time-keeping mechanism that entrains internal physiology to environmental cues. Despite the well-established link between the molecular clock and metabolic homeostasis, an intimate interplay between the clock machinery and the metabolically active brown adipose tissue (BAT) is only emerging. Recently, we came to appreciate that the formation and metabolic functions of BAT, a key organ for body temperature maintenance, are under an orchestrated circadian clock regulation. Two complementary studies from our group uncover that the cell-intrinsic clock machinery exerts concerted control of brown adipogenesis with consequent impacts on adaptive thermogenesis, which adds a previously unappreciated temporal dimension to the regulatory mechanisms governing BAT development and function. The essential clock transcriptional activator, Bmal1, suppresses adipocyte lineage commitment and differentiation, whereas the clock repressor, Rev-erbα, promotes these processes. This newly discovered temporal mechanism in fine-tuning BAT thermogenic capacity may enable energy utilization and body temperature regulation in accordance with external timing signals during development and functional recruitment. Given the important role of BAT in whole-body metabolic homeostasis, pharmacological interventions targeting the BAT-modulatory activities of the clock circuit may offer new avenues for the prevention and treatment of metabolic disorders, particularly those associated with circadian dysregulation.

  3. Integrating molecular dynamics simulations with chemical probing experiments using SHAPE-FIT

    Science.gov (United States)

    Kirmizialtin, Serdal; Hennelly, Scott P.; Schug, Alexander; Onuchic, Jose N.; Sanbonmatsu, Karissa Y.

    2016-01-01

    Integration and calibration of molecular dynamics simulations with experimental data remains a challenging endeavor. We have developed a novel method to integrate chemical probing experiments with molecular simulations of RNA molecules by using a native structure-based model. Selective 2’-hydroxyl acylation by primer extension (SHAPE) characterizes the mobility of each residue in the RNA. Our method, SHAPE-FIT, automatically optimizes the potential parameters of the forcefield according to measured reactivities from SHAPE. The optimized parameter set allows simulations of dynamics highly consistent with SHAPE probing experiments. Such atomistic simulations, thoroughly grounded in experiment, can open a new window on RNA structure-function relations. PMID:25726467

  4. Algorithms and novel applications based on the isokinetic ensemble. I. Biophysical and path integral molecular dynamics

    Science.gov (United States)

    Minary, Peter; Martyna, Glenn J.; Tuckerman, Mark E.

    2003-02-01

    In this paper (Paper I) and a companion paper (Paper II), novel new algorithms and applications of the isokinetic ensemble as generated by Gauss' principle of least constraint, pioneered for use with molecular dynamics 20 years ago, are presented for biophysical, path integral, and Car-Parrinello based ab initio molecular dynamics. In Paper I, a new "extended system" version of the isokinetic equations of motion that overcomes the ergodicity problems inherent in the standard approach, is developed using a new theory of non-Hamiltonian phase space analysis [M. E. Tuckerman et al., Europhys. Lett. 45, 149 (1999); J. Chem. Phys. 115, 1678 (2001)]. Reversible multiple time step integrations schemes for the isokinetic methods, first presented by Zhang [J. Chem. Phys. 106, 6102 (1997)] are reviewed. Next, holonomic constraints are incorporated into the isokinetic methodology for use in fast efficient biomolecular simulation studies. Model and realistic examples are presented in order to evaluate, critically, the performance of the new isokinetic molecular dynamic schemes. Comparisons are made to the, now standard, canonical dynamics method, Nosé-Hoover chain dynamics [G. J. Martyna et al., J. Chem. Phys. 97, 2635 (1992)]. The new isokinetic techniques are found to yield more efficient sampling than the Nosé-Hoover chain method in both path integral molecular dynamics and biophysical molecular dynamics calculations. In Paper II, the use of isokinetic methods in Car-Parrinello based ab initio molecular dynamics calculations is presented.

  5. Benchmark values for molecular three-center integrals arising in Dirac equation

    CERN Document Server

    Bagci, A

    2015-01-01

    The authors in their previous papers obtained compact, arbitrarily accurate expressions for two center one and two electron Dirac integrals expressed over Slater orbitals with noninteger principal quantum numbers. In this present study, the accuracy limits of given expressions is examined for three-center nuclear attraction integrals, which are the first integral set do not have analytically closed form relations. They are expressed through new molecular auxiliary functions obtained via Neumann expansion of Coulomb interaction. The numerical global adaptive method is used to evaluate these integrals for arbitrarily values of orbital parameters, principal quantum numbers in Slater orbitals. Several methods, such as Laplace expansion of Coulomb interaction, single center expansions, Fourier transformation methods, have been developed for evaluation of three-center integrals when integer principal quantum number is used. This is the first attempts to study the three-center integrals with noninteger Slater orbita...

  6. Plasma DNA integrity index as a potential molecular diagnostic marker for breast cancer.

    Science.gov (United States)

    Kamel, Azza M; Teama, Salwa; Fawzy, Amal; El Deftar, Mervat

    2016-06-01

    Plasma DNA integrity index is increased in various malignancies including breast cancer, the most common cancer in women worldwide; early detection is crucial for successful treatment. Current screening methods fail to detect many cases of breast cancer at an early stage. In this study, we evaluated the level of plasma DNA integrity index in 260 females (95 with breast cancer, 95 with benign breast lesions, and 70 healthy controls) to verify its potential value in discriminating malignant from benign breast lesions. The criteria of the American Joint Committee on Cancer were used for staging of breast cancer patients. DNA integrity index was measured by real-time PCR. DNA integrity index was significantly higher in breast cancer than in benign breast patients and healthy subjects (P = cancer group was 85.3 % at 0.55 DNA integrity index cutoff. In conclusion, the plasma DNA integrity index may be a promising molecular diagnostic marker of malignancy in breast lesions.

  7. Isotope effects in water as investigated by neutron diffraction and path integral molecular dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Zeidler, Anita [University of Bath; Salmon, Phil [University of Bath; Fischer, Henry E [Institut Laue-Langevin (ILL); Neuefeind, Joerg C [ORNL; Simonson, J Michael {Mike} [ORNL; Markland, Thomas [Columbia University

    2012-01-01

    The structure of heavy and light water at 300 K was investigated by using a joint approach in which the method of neutron di raction with oxygen isotope substitution was combined with path integral molecular dynamics simulations. The di raction results, which give intra-molecular O-D and O-H bond distances of 0.985(5) and 0.990(5) A, were found to be in best agreement with those obtained by using the exible anharmonic TTM3-F water model. Both techniques show a di erence of '0.5% between the O-D and O-H intra-molecular bond lengths and the results support a competing quantum e ects model for water in which its structural and dynamical properties are governed by an o set between intra-molecular and inter-molecular quantum contributions. Further consideration of the O-O correlations is needed in order to improve agreement with experiment.

  8. Isotope effects in water as investigated by neutron diffraction and path integral molecular dynamics

    Science.gov (United States)

    Zeidler, Anita; Salmon, Philip S.; Fischer, Henry E.; Neuefeind, Jörg C.; Simonson, J. Mike; Markland, Thomas E.

    2012-07-01

    The structures of heavy and light water at 300 K were investigated by using a joint approach in which the method of neutron diffraction with oxygen isotope substitution was complemented by path integral molecular dynamics simulations. The diffraction results, which give intra-molecular O-D and O-H bond distances of 0.985(5) and 0.990(5) Å, were found to be in best agreement with those obtained by using the flexible anharmonic TTM3-F water model. Both techniques show a difference of ≃ 0.5% between the O-D and O-H intra-molecular bond lengths, and the results support a competing quantum effects model for water in which its structural and dynamical properties are governed by an offset between intra-molecular and inter-molecular quantum contributions. Further consideration of the O-O correlations is needed in order to improve agreement with experiment.

  9. Simulating signatures of two-dimensional electronic spectra of the Fenna-Matthews-Olson complex: By using a numerical path integral.

    Science.gov (United States)

    Liang, Xian-Ting

    2014-07-28

    A framework for simulating electronic spectra from photon-echo experiments is constructed by using a numerical path integral technique. This method is non-Markovian and nonperturbative and, more importantly, is not limited by a fixed form of the spectral density functions of the environment. Next, a two-dimensional (2D) third-order electronic spectrum of a dimer system is simulated. The spectrum is in agreement with the experimental and theoretical results previously reported [for example, M. Khalil, N. Demirdöven, and A. Tokmakoff, Phys. Rev. Lett. 90, 047401 (2003)]. Finally, a 2D third-order electronic spectrum of the Fenna-Matthews-Olson (FMO) complex is simulated by using the Debye, Ohmic, and Adolphs and Renger spectral density functions. It is shown that this method can clearly produce the spectral signatures of the FMO complex by using only the Adolphs and Renger spectral density function. Plots of the evolution of the diagonal and cross-peaks show that they are oscillating with the population time.

  10. A unified scheme for the calculation of differentiated and undifferentiated molecular integrals over solid-harmonic Gaussians.

    Science.gov (United States)

    Reine, Simen; Tellgren, Erik; Helgaker, Trygve

    2007-09-14

    Utilizing the fact that solid-harmonic combinations of Cartesian and Hermite Gaussian atomic orbitals are identical, a new scheme for the evaluation of molecular integrals over solid-harmonic atomic orbitals is presented, where the integration is carried out over Hermite rather than Cartesian atomic orbitals. Since Hermite Gaussians are defined as derivatives of spherical Gaussians, the corresponding molecular integrals become the derivatives of integrals over spherical Gaussians, whose transformation to the solid-harmonic basis is performed in the same manner as for integrals over Cartesian Gaussians, using the same expansion coefficients. The presented solid-harmonic Hermite scheme simplifies the evaluation of derivative molecular integrals, since differentiation by nuclear coordinates merely increments the Hermite quantum numbers, thereby providing a unified scheme for undifferentiated and differentiated four-center molecular integrals. For two- and three-center two-electron integrals, the solid-harmonic Hermite scheme is particularly efficient, significantly reducing the cost relative to the Cartesian scheme.

  11. Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures

    Directory of Open Access Journals (Sweden)

    Williams Robert W

    2011-05-01

    Full Text Available Abstract Background The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics. Methods Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org. Results Expression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P

  12. An integrated molecular cytogenetic map of Cucumis sativus L. chromosome 2

    Directory of Open Access Journals (Sweden)

    Huang Sanwen

    2011-01-01

    Full Text Available Abstract Background Integration of molecular, genetic and cytological maps is still a challenge for most plant species. Recent progress in molecular and cytogenetic studies created a basis for developing integrated maps in cucumber (Cucumis sativus L.. Results In this study, eleven fosmid clones and three plasmids containing 45S rDNA, the centromeric satellite repeat Type III and the pericentriomeric repeat CsRP1 sequences respectively were hybridized to cucumber metaphase chromosomes to assign their cytological location on chromosome 2. Moreover, an integrated molecular cytogenetic map of cucumber chromosomes 2 was constructed by fluorescence in situ hybridization (FISH mapping of 11 fosmid clones together with the cucumber centromere-specific Type III sequence on meiotic pachytene chromosomes. The cytogenetic map was fully integrated with genetic linkage map since each fosmid clone was anchored by a genetically mapped simple sequence repeat marker (SSR. The relationship between the genetic and physical distances along chromosome was analyzed. Conclusions Recombination was not evenly distributed along the physical length of chromosome 2. Suppression of recombination was found in centromeric and pericentromeric regions. Our results also indicated that the molecular markers composing the linkage map for chromosome 2 provided excellent coverage of the chromosome.

  13. IVSPlat 1.0: an integrated virtual screening platform with a molecular graphical interface.

    Science.gov (United States)

    Sun, Yin Xue; Huang, Yan Xin; Li, Feng Li; Wang, Hong Yan; Fan, Cong; Bao, Yong Li; Sun, Lu Guo; Ma, Zhi Qiang; Kong, Jun; Li, Yu Xin

    2012-01-05

    The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed. A free open-source platform, IVSPlat 1.0, was developed in this study for the management and automation of VS tasks. We integrated several VS-related programs into a molecular graphics system to provide a comprehensive platform for the solution of VS tasks based on molecular docking, pharmacophore detection, and a combination of both methods. This tool can be used to visualize intermediate and final results of the VS execution, while also providing a clustering tool for the analysis of VS results. A case study was conducted to demonstrate the applicability of this platform. IVSPlat 1.0 provides a plug-in-based solution for the management, automation, and visualization of VS tasks. IVSPlat 1.0 is an open framework that allows the integration of extra software to extend its functionality and modified versions can be freely distributed. The open source code and documentation are available at http://kyc.nenu.edu.cn/IVSPlat/.

  14. The vanilloid receptor family of calcium-permeable channels: molecular integrators of microenvironmental stimuli.

    Science.gov (United States)

    O'Neil, Roger G; Brown, Rachel C

    2003-12-01

    The TRPV subfamily of calcium-permeable channels is widely distributed in sensory and nonsensory cells from nematodes to mammals. These channels can be variably activated by a diverse range of stimuli (osmotic/mechanical stress, noxious chemicals and heat, endogenous mediators) that often converge on the same channel. Evidence is presented that TRPV channels function as novel "molecular integrators" of diverse microenvironmental stimuli.

  15. Molecular Signatures of Natural Selection

    DEFF Research Database (Denmark)

    Nielsen, Rasmus

    2005-01-01

    There is an increasing interest in detecting genes, or genomic regions, that have been targeted by natural selection. The interest stems from a basic desire to learn more about evolutionary processes in humans and other organisms, and from the realization that inferences regarding selection may...... provide important functional information. This review provides a nonmathematical description of the issues involved in detecting selection from DNA sequences and SNP data and is intended for readers who are not familiar with population genetic theory. Particular attention is placed on issues relating...

  16. Molecular characterization of transgene integration by next-generation sequencing in transgenic cattle.

    Directory of Open Access Journals (Sweden)

    Ran Zhang

    Full Text Available As the number of transgenic livestock increases, reliable detection and molecular characterization of transgene integration sites and copy number are crucial not only for interpreting the relationship between the integration site and the specific phenotype but also for commercial and economic demands. However, the ability of conventional PCR techniques to detect incomplete and multiple integration events is limited, making it technically challenging to characterize transgenes. Next-generation sequencing has enabled cost-effective, routine and widespread high-throughput genomic analysis. Here, we demonstrate the use of next-generation sequencing to extensively characterize cattle harboring a 150-kb human lactoferrin transgene that was initially analyzed by chromosome walking without success. Using this approach, the sites upstream and downstream of the target gene integration site in the host genome were identified at the single nucleotide level. The sequencing result was verified by event-specific PCR for the integration sites and FISH for the chromosomal location. Sequencing depth analysis revealed that multiple copies of the incomplete target gene and the vector backbone were present in the host genome. Upon integration, complex recombination was also observed between the target gene and the vector backbone. These findings indicate that next-generation sequencing is a reliable and accurate approach for the molecular characterization of the transgene sequence, integration sites and copy number in transgenic species.

  17. Improving the convergence of closed and open path integral molecular dynamics via higher order Trotter factorization schemes

    Science.gov (United States)

    Pérez, Alejandro; Tuckerman, Mark E.

    2011-08-01

    Higher order factorization schemes are developed for path integral molecular dynamics in order to improve the convergence of estimators for physical observables as a function of the Trotter number. The methods are based on the Takahashi-Imada and Susuki decompositions of the Boltzmann operator. The methods introduced improve the averages of the estimators by using the classical forces needed to carry out the dynamics to construct a posteriori weighting factors for standard path integral molecular dynamics. The new approaches are straightforward to implement in existing path integral codes and carry no significant overhead. The Suzuki higher order factorization was also used to improve the end-to-end distance estimator in open path integral molecular dynamics. The new schemes are tested in various model systems, including an ab initio path integral molecular dynamics calculation on the hydrogen molecule and a quantum water model. The proposed algorithms have potential utility for reducing the cost of path integral molecular dynamics calculations of bulk systems.

  18. Simulations of one- and two-electron systems by Bead-Fourier path integral molecular dynamics

    Science.gov (United States)

    Ivanov, Sergei D.; Lyubartsev, Alexander P.

    2005-07-01

    The Bead-Fourier path integral molecular dynamics technique introduced earlier [S. D. Ivanov, A. P. Lyubartsev, and A. Laaksonen, Phys. Rev. E 67 066710 (2003)] is applied for simulation of electrons in the simplest molecules: molecular hydrogen, helium atom, and their ions. Special attention is paid to the correct description of electrons in the core region of a nucleus. In an attempt to smooth the Coulomb potential at small distances, a recipe is suggested. The simulation results are in excellent agreement with the analytical solution for the "harmonic helium atom", as well as with the vibrational potential of the H2 molecule and He ionization energies. It is demonstrated, that the Bead-Fourier path integral molecular dynamics technique is able to provide the accuracy required for the description of electron structure and chemical bonds in cases when electron exchange effects need not be taken into account.

  19. Interdisciplinary education to integrate pathology and epidemiology: towards molecular and population-level health science.

    Science.gov (United States)

    Ogino, Shuji; King, Emily E; Beck, Andrew H; Sherman, Mark E; Milner, Danny A; Giovannucci, Edward

    2012-10-15

    In recent decades, epidemiology, public health, and medical sciences have been increasingly compartmentalized into narrower disciplines. The authors recognize the value of integration of divergent scientific fields in order to create new methods, concepts, paradigms, and knowledge. Herein they describe the recent emergence of molecular pathological epidemiology (MPE), which represents an integration of population and molecular biologic science to gain insights into the etiologies, pathogenesis, evolution, and outcomes of complex multifactorial diseases. Most human diseases, including common cancers (such as breast, lung, prostate, and colorectal cancers, leukemia, and lymphoma) and other chronic diseases (such as diabetes mellitus, cardiovascular diseases, hypertension, autoimmune diseases, psychiatric diseases, and some infectious diseases), are caused by alterations in the genome, epigenome, transcriptome, proteome, metabolome, microbiome, and interactome of all of the above components. In this era of personalized medicine and personalized prevention, we need integrated science (such as MPE) which can decipher diseases at the molecular, genetic, cellular, and population levels simultaneously. The authors believe that convergence and integration of multiple disciplines should be commonplace in research and education. We need to be open-minded and flexible in designing integrated education curricula and training programs for future students, clinicians, practitioners, and investigators.

  20. Total and Direct Correlation Function Integrals from Molecular Simulation of Binary Systems

    DEFF Research Database (Denmark)

    Wedberg, Nils Hejle Rasmus Ingemar; O’Connell, John P.; Peters, Günther H.J.

    2011-01-01

    The possibility for obtaining derivative properties for mixtures from integrals of spatial total and direct correlation functions obtained from molecular dynamics simulations is explored. Theoretically well-supported methods are examined to extend simulation radial distribution functions to long...... range so the integrals can converge. A previously published method developed for pure atomic fluids is here extended to handle simulations of molecular mixtures using all-atom force fields. We first test the method on simulations of Lennard-Jones/Stockmayer mixtures and show that that the results...... are consistent with an excess Helmholtz energy model fitted to available simulations. In addition, simulations of water/methanol and water/t-butanol mixtures have been carried out. The method yields results for partial molar volumes, activity coefficient derivatives, and individual correlation function integrals...

  1. RING PROXY SIGNATURES

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Proxy signatures have been used to enable the transfer of digital signing power within some context and ring signatures can be used to provide the anonymity of a signer. By combining the functionalities of proxy signatures and ring signatures, this paper introduces a new concept, named ring proxy signature, which is a proxy signature generated by an anonymous member from a set of potential signers. The paper also constructs the first concrete ring proxy signature scheme based on the provably secure Schnorr's signatures and two ID-based ring proxy signature schemes. The security analysis is provided as well.

  2. Signatures of nonthermal melting

    Directory of Open Access Journals (Sweden)

    Tobias Zier

    2015-09-01

    Full Text Available Intense ultrashort laser pulses can melt crystals in less than a picosecond but, in spite of over thirty years of active research, for many materials it is not known to what extent thermal and nonthermal microscopic processes cause this ultrafast phenomenon. Here, we perform ab-initio molecular-dynamics simulations of silicon on a laser-excited potential-energy surface, exclusively revealing nonthermal signatures of laser-induced melting. From our simulated atomic trajectories, we compute the decay of five structure factors and the time-dependent structure function. We demonstrate how these quantities provide criteria to distinguish predominantly nonthermal from thermal melting.

  3. Determination of the experimental equilibrium structure of solid nitromethane using path-integral molecular dynamics simulations

    Science.gov (United States)

    Reilly, Anthony M.; Habershon, Scott; Morrison, Carole A.; Rankin, David W. H.

    2010-03-01

    Path-integral molecular dynamics (PIMD) simulations with an empirical interaction potential have been used to determine the experimental equilibrium structure of solid nitromethane at 4.2 and 15 K. By comparing the time-averaged molecular structure determined in a PIMD simulation to the calculated minimum-energy (zero-temperature) molecular structure, we have derived structural corrections that describe the effects of thermal motion. These corrections were subsequently used to determine the equilibrium structure of nitromethane from the experimental time-averaged structure. We find that the corrections to the intramolecular and intermolecular bond distances, as well as to the torsion angles, are quite significant, particularly for those atoms participating in the anharmonic motion of the methyl group. Our results demonstrate that simple harmonic models of thermal motion may not be sufficiently accurate, even at low temperatures, while molecular simulations employing more realistic potential-energy surfaces can provide important insight into the role and magnitude of anharmonic atomic motions.

  4. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

    Directory of Open Access Journals (Sweden)

    Farshad Farshidfar

    2017-03-01

    Full Text Available Cholangiocarcinoma (CCA is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

  5. Calculation of heat capacities of light and heavy water by path-integral molecular dynamics

    Science.gov (United States)

    Shiga, Motoyuki; Shinoda, Wataru

    2005-10-01

    As an application of atomistic simulation methods to heat capacities, path-integral molecular dynamics has been used to calculate the constant-volume heat capacities of light and heavy water in the gas, liquid, and solid phases. While the classical simulation based on conventional molecular dynamics has estimated the heat capacities too high, the quantum simulation based on path-integral molecular dynamics has given reasonable results based on the simple point-charge/flexible potential model. The calculated heat capacities (divided by the Boltzmann constant) in the quantum simulation are 3.1 in the vapor H2O at 300 K, 6.9 in the liquid H2O at 300 K, and 4.1 in the ice IhH2O at 250 K, respectively, which are comparable to the experimental data of 3.04, 8.9, and 4.1, respectively. The quantum simulation also reproduces the isotope effect. The heat capacity in the liquid D2O has been calculated to be 10% higher than that of H2O, while it is 13% higher in the experiment. The results demonstrate that the path-integral simulation is a promising approach to quantitatively evaluate the heat capacities for molecular systems, taking account of quantum-mechanical vibrations as well as strongly anharmonic motions.

  6. About group digital signatures

    National Research Council Canada - National Science Library

    Adriana Cristina Enache

    2012-01-01

    ...).A group digital signature is a digital signature with enhanced privacy features that allows members of a given group to anonymously sign messages on behalf of the group, producing a group signature...

  7. Macroscopic contraction of a gel induced by the integrated motion of light-driven molecular motors.

    Science.gov (United States)

    Li, Quan; Fuks, Gad; Moulin, Emilie; Maaloum, Mounir; Rawiso, Michel; Kulic, Igor; Foy, Justin T; Giuseppone, Nicolas

    2015-02-01

    Making molecular machines that can be useful in the macroscopic world is a challenging long-term goal of nanoscience. Inspired by the protein machinery found in biological systems, and based on the theoretical understanding of the physics of motion at the nanoscale, organic chemists have developed a number of molecules that can produce work by contraction or rotation when triggered by various external chemical or physical stimuli. In particular, basic molecular switches that commute between at least two thermodynamic minima and more advanced molecular motors that behave as dissipative units working far from equilibrium when fuelled with external energy have been reported. However, despite recent progress, the ultimate challenge of coordinating individual molecular motors in a continuous mechanical process that can have a measurable effect at the macroscale has remained elusive. Here, we show that by integrating light-driven unidirectional molecular rotors as reticulating units in a polymer gel, it is possible to amplify their individual motions to achieve macroscopic contraction of the material. Our system uses the incoming light to operate under far-from-equilibrium conditions, and the work produced by the motor in the photostationary state is used to twist the entangled polymer chains up to the collapse of the gel. Our design could be a starting point to integrate nanomotors in metastable materials to store energy and eventually to convert it.

  8. Macroscopic contraction of a gel induced by the integrated motion of light-driven molecular motors

    Science.gov (United States)

    Li, Quan; Fuks, Gad; Moulin, Emilie; Maaloum, Mounir; Rawiso, Michel; Kulic, Igor; Foy, Justin T.; Giuseppone, Nicolas

    2015-02-01

    Making molecular machines that can be useful in the macroscopic world is a challenging long-term goal of nanoscience. Inspired by the protein machinery found in biological systems, and based on the theoretical understanding of the physics of motion at the nanoscale, organic chemists have developed a number of molecules that can produce work by contraction or rotation when triggered by various external chemical or physical stimuli. In particular, basic molecular switches that commute between at least two thermodynamic minima and more advanced molecular motors that behave as dissipative units working far from equilibrium when fuelled with external energy have been reported. However, despite recent progress, the ultimate challenge of coordinating individual molecular motors in a continuous mechanical process that can have a measurable effect at the macroscale has remained elusive. Here, we show that by integrating light-driven unidirectional molecular rotors as reticulating units in a polymer gel, it is possible to amplify their individual motions to achieve macroscopic contraction of the material. Our system uses the incoming light to operate under far-from-equilibrium conditions, and the work produced by the motor in the photostationary state is used to twist the entangled polymer chains up to the collapse of the gel. Our design could be a starting point to integrate nanomotors in metastable materials to store energy and eventually to convert it.

  9. Molecular hydrogen (H2 combustion emissions and their isotope (D/H signatures from domestic heaters, diesel vehicle engines, waste incinerator plants, and biomass burning

    Directory of Open Access Journals (Sweden)

    T. Röckmann

    2012-03-01

    Full Text Available Molecular hydrogen (H2, its stable isotope signature (δD, and the key combustion parameters carbon monoxide (CO, carbon dioxide (CO2, and methane (CH4 were measured from various combustion processes. H2 in the exhaust of gas and oil-fired heaters and of waste incinerator plants was generally depleted compared to ambient intake air, while CO was significantly elevated. These findings contradict the often assumed co-occurring net H2 and CO emissions in combustion processes and suggest that previous H2 emissions from combustion may have been overestimated when scaled to CO emissions. For the heater exhausts, H2 and δD generally decrease with increasing fuel-to-air ratio, from ambient values of ∼0.5 ppm and +130‰ to 0.2 ppm and −206‰, respectively. These results are interpreted as a combination of an isotopically light H2 source from fossil fuel combustion and a D/H kinetic isotope fractionation of hydrogen in the advected ambient air during its partial removal during combustion. Diesel exhaust measurements from dynamometer test stand driving cycles show elevated H2 and CO emissions during cold-start and some acceleration phases. Their molar H2/CO ratios are 2/CO emission ratios, along with CO global emission inventories, we estimate global H2 emissions for 2000, 2005, and 2010. For road transportation (gasoline and diesel, we calculate 8.6 ± 2.1 Tg, 6.3 ± 1.5 Tg, and 4.1 ± 1.0 Tg, respectively, whereas the contribution from diesel vehicles has increased from 5% to 8% over this time. Other fossil fuel emissions are believed to be negligible but H2 emissions from coal combustion are unknown. For residential (domestic emissions, which are likely dominated by biofuel combustion, emissions for the same years are estimated at 2.7 ± 0.7 Tg, 2.8 ± 0.7 Tg, and 3.0 ± 0.8 Tg, respectively. Our wood combustion measurements are combined with results from the literature to calculate biomass burning emissions. For these estimates, we propose a

  10. Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: gene expression signatures indicative of novel molecular signaling pathways

    Directory of Open Access Journals (Sweden)

    Schmitz Alexander

    2007-07-01

    Full Text Available Abstract Background Human natural killer (NK cells are the key contributors of innate immune response and the effector functions of these cells are enhanced by cytokines such as interleukine 2 (IL2. We utilized genome-wide transcriptional profiling to identify gene expression signatures and pathways in resting and IL2 activated NK cell isolated from peripheral blood of healthy donors. Results Gene expression profiling of resting NK cells showed high expression of a number of cytotoxic factors, cytokines, chemokines and inhibitory and activating surface NK receptors. Resting NK cells expressed many genes associated with cellular quiescence and also appeared to have an active TGFβ (TGFB1 signaling pathway. IL2 stimulation induced rapid downregulation of quiescence associated genes and upregulation of genes associated with cell cycle progression and proliferation. Numerous genes that may enhance immune function and responsiveness including activating receptors (DNAM1, KLRC1 and KLRC3, death receptor ligand (TNFSF6 (FASL and TRAIL, chemokine receptors (CX3CR1, CCR5 and CCR7, interleukin receptors (IL2RG, IL18RAB and IL27RA and members of secretory pathways (DEGS1, FKBP11, SSR3, SEC61G and SLC3A2 were upregulated. The expression profile suggested PI3K/AKT activation and NF-κB activation through multiple pathways (TLR/IL1R, TNF receptor induced and TCR-like possibly involving BCL10. Activation of NFAT signaling was supported by increased expression of many pathway members and downstream target genes. The transcription factor GATA3 was expressed in resting cells while T-BET was upregulated on activation concurrent with the change in cytokine expression profile. The importance of NK cells in innate immune response was also reflected by late increased expression of inflammatory chemotactic factors and receptors and molecules involved in adhesion and lymphocyte trafficking or migration. Conclusion This analysis allowed us to identify genes implicated in

  11. Parallel Higher-order Boundary Integral Electrostatics Computation on Molecular Surfaces with Curved Triangulation

    CERN Document Server

    Geng, Weihua

    2013-01-01

    In this paper, we present a parallel higher-order boundary integral method to solve the linear Poisson-Boltzmann (PB) equation. In our method, a well-posed boundary integral formulation is used to ensure the fast convergence of Krylov subspace linear solver such as GMRES. The molecular surfaces are first discretized with flat triangles and then converted to curved triangles with the assistance of normal information at vertices. To maintain the desired accuracy, four-point Gauss-Radau quadratures are used on regular triangles and sixteen-point Gauss-Legendre quadratures together with regularization transformations are applied on singular triangles. To speed up our method, we take advantage of the embarrassingly parallel feature of boundary integral formulation, and parallelize the schemes with the message passing interface (MPI) implementation. Numerical tests show significantly improved accuracy and convergence of the proposed higher-order boundary integral Poisson-Boltzmann (HOBI-PB) solver compared with bou...

  12. A simple and accurate algorithm for path integral molecular dynamics with the Langevin thermostat

    Science.gov (United States)

    Liu, Jian; Li, Dezhang; Liu, Xinzijian

    2016-07-01

    We introduce a novel simple algorithm for thermostatting path integral molecular dynamics (PIMD) with the Langevin equation. The staging transformation of path integral beads is employed for demonstration. The optimum friction coefficients for the staging modes in the free particle limit are used for all systems. In comparison to the path integral Langevin equation thermostat, the new algorithm exploits a different order of splitting for the phase space propagator associated to the Langevin equation. While the error analysis is made for both algorithms, they are also employed in the PIMD simulations of three realistic systems (the H2O molecule, liquid para-hydrogen, and liquid water) for comparison. It is shown that the new thermostat increases the time interval of PIMD by a factor of 4-6 or more for achieving the same accuracy. In addition, the supplementary material shows the error analysis made for the algorithms when the normal-mode transformation of path integral beads is used.

  13. A simple and accurate algorithm for path integral molecular dynamics with the Langevin thermostat.

    Science.gov (United States)

    Liu, Jian; Li, Dezhang; Liu, Xinzijian

    2016-07-14

    We introduce a novel simple algorithm for thermostatting path integral molecular dynamics (PIMD) with the Langevin equation. The staging transformation of path integral beads is employed for demonstration. The optimum friction coefficients for the staging modes in the free particle limit are used for all systems. In comparison to the path integral Langevin equation thermostat, the new algorithm exploits a different order of splitting for the phase space propagator associated to the Langevin equation. While the error analysis is made for both algorithms, they are also employed in the PIMD simulations of three realistic systems (the H2O molecule, liquid para-hydrogen, and liquid water) for comparison. It is shown that the new thermostat increases the time interval of PIMD by a factor of 4-6 or more for achieving the same accuracy. In addition, the supplementary material shows the error analysis made for the algorithms when the normal-mode transformation of path integral beads is used.

  14. Integrable, molecular-type solutions of the extended Skyrme-Faddeev model

    CERN Document Server

    Sawado, Nobuyuki

    2013-01-01

    We construct molecular type vortex solutions in the integrable sector of the extended Skyrme-Faddeev (ESF) model.The solutions are a holomorphic type which satisfies the zero curvature condition.For some constrained values of the coupling constants, special vortex solutions exist.For other values, special forms of the potential are employed for the stability of the molecular type solution.The solutions satisfy the zero curvature condition, and then they necessarily have an infinite number of conserved current. We numerically check their existence in terms of the simulated annealing method.

  15. Direct evaluation of phase coexistence by molecular simulation via integration along the saturation line

    Science.gov (United States)

    Kofke, David A.

    1993-03-01

    Thermodynamic integration along a path that coincides with the saturation line is proposed as an efficient means for evaluation of phase equilibria by molecular simulation. The technique allows coexistence to be determined by just one simulation, without ever attempting or performing particle insertions. Prior knowledge of one coexistence point is required to start the procedure. Integration then advances from this state according to the Clapeyron formula—a first-order ordinary differential equation that prescribes how the pressure must change with temperature to maintain coexistence. The method is unusual in the context of thermodynamic integration in that the path is not known at the outset of the process; results from each simulation determine the course that the integration subsequently takes. Predictor-corrector methods among standard numerical techniques are shown to be particularly well suited for this type of integration. A typical integration step along the saturation line proceeds as follows: An increment in the temperature is chosen, and the saturation pressure at the new temperature is ``predicted'' from previous data (the initial coexistence datum and/or previous simulations). Simultaneous but independent NPT simulations of the coexisting phases are initiated at the said conditions. Averages taken throughout the simulations are repeatedly used to ``correct'' the estimate of the pressure to convergence. Thus strictly the pressure is not fixed during the simulation. Vapor-liquid coexistence of the van der Waals model is first used to study the numerical integration method without the complications of molecular simulation. In a second application the phase envelope of the Lennard-Jones model fluid is computed, and many variations of the technique are examined. Overall, the results are remarkably consistent and in agreement with previous simulation studies. Difficulty is encountered upon approach of the critical point, but, by artificially coupling the

  16. Adaptive multi-stage integrators for optimal energy conservation in molecular simulations

    CERN Document Server

    Fernández-Pendás, Mario; Sanz-Serna, J M

    2015-01-01

    We introduce a new Adaptive Integration Approach (AIA) to be used in a wide range of molecular simulations. Given a simulation problem and a step size, the method automatically chooses the optimal scheme out of an available family of numerical integrators. Although we focus on two-stage splitting integrators, the idea may be used with more general families. In each instance, the system-specific integrating scheme identified by our approach is optimal in the sense that it provides the best conservation of energy for harmonic forces. The AIA method has been implemented in the BCAM-modified GROMACS software package. Numerical tests in molecular dynamics and hybrid Monte Carlo simulations of constrained and unconstrained physical systems show that the method successfully realises the fail-safe strategy. In all experiments, and for each of the criteria employed, the AIA is at least as good as, and often significantly outperforms the standard Verlet scheme, as well as fixed parameter, optimized two-stage integrator...

  17. Adaptive multi-stage integrators for optimal energy conservation in molecular simulations

    Science.gov (United States)

    Fernández-Pendás, Mario; Akhmatskaya, Elena; Sanz-Serna, J. M.

    2016-12-01

    We introduce a new Adaptive Integration Approach (AIA) to be used in a wide range of molecular simulations. Given a simulation problem and a step size, the method automatically chooses the optimal scheme out of an available family of numerical integrators. Although we focus on two-stage splitting integrators, the idea may be used with more general families. In each instance, the system-specific integrating scheme identified by our approach is optimal in the sense that it provides the best conservation of energy for harmonic forces. The AIA method has been implemented in the BCAM-modified GROMACS software package. Numerical tests in molecular dynamics and hybrid Monte Carlo simulations of constrained and unconstrained physical systems show that the method successfully realizes the fail-safe strategy. In all experiments, and for each of the criteria employed, the AIA is at least as good as, and often significantly outperforms the standard Verlet scheme, as well as fixed parameter, optimized two-stage integrators. In particular, for the systems where harmonic forces play an important role, the sampling efficiency found in simulations using the AIA is up to 5 times better than the one achieved with other tested schemes.

  18. Transport coefficients of normal liquid helium-4 calculated by path integral centroid molecular dynamics simulation

    Science.gov (United States)

    Imaoka, Haruna; Kinugawa, Kenichi

    2017-03-01

    Thermal conductivity, shear viscosity, and bulk viscosity of normal liquid 4He at 1.7-4.0 K are calculated using path integral centroid molecular dynamics (CMD) simulations. The calculated thermal conductivity and shear viscosity above lambda transition temperature are on the same order of magnitude as experimental values, while the agreement of shear viscosity is better. Above 2.3 K the CMD well reproduces the temperature dependences of isochoric shear viscosity and of the time integral of the energy current and off-diagonal stress tensor correlation functions. The calculated bulk viscosity, not known in experiments, is several times larger than shear viscosity.

  19. Potential molecular consequences of transgene integration: The R6/2 mouse example

    Science.gov (United States)

    Jacobsen, Jessie C.; Erdin, Serkan; Chiang, Colby; Hanscom, Carrie; Handley, Renee R.; Barker, Douglas D.; Stortchevoi, Alex; Blumenthal, Ian; Reid, Suzanne J.; Snell, Russell G.; MacDonald, Marcy E.; Morton, A. Jennifer; Ernst, Carl; Gusella, James F.; Talkowski, Michael E.

    2017-01-01

    Integration of exogenous DNA into a host genome represents an important route to generate animal and cellular models for exploration into human disease and therapeutic development. In most models, little is known concerning structural integrity of the transgene, precise site of integration, or its impact on the host genome. We previously used whole-genome and targeted sequencing approaches to reconstruct transgene structure and integration sites in models of Huntington’s disease, revealing complex structural rearrangements that can result from transgenesis. Here, we demonstrate in the R6/2 mouse, a widely used Huntington’s disease model, that integration of a rearranged transgene with coincident deletion of 5,444 bp of host genome within the gene Gm12695 has striking molecular consequences. Gm12695, the function of which is unknown, is normally expressed at negligible levels in mouse brain, but transgene integration has resulted in cortical expression of a partial fragment (exons 8–11) 3’ to the transgene integration site in R6/2. This transcript shows significant expression among the extensive network of differentially expressed genes associated with this model, including synaptic transmission, cell signalling and transcription. These data illustrate the value of sequence-level resolution of transgene insertions and transcription analysis to inform phenotypic characterization of transgenic models utilized in therapeutic research. PMID:28120936

  20. i-PI: A Python interface for ab initio path integral molecular dynamics simulations

    Science.gov (United States)

    Ceriotti, Michele; More, Joshua; Manolopoulos, David E.

    2014-03-01

    Recent developments in path integral methodology have significantly reduced the computational expense of including quantum mechanical effects in the nuclear motion in ab initio molecular dynamics simulations. However, the implementation of these developments requires a considerable programming effort, which has hindered their adoption. Here we describe i-PI, an interface written in Python that has been designed to minimise the effort required to bring state-of-the-art path integral techniques to an electronic structure program. While it is best suited to first principles calculations and path integral molecular dynamics, i-PI can also be used to perform classical molecular dynamics simulations, and can just as easily be interfaced with an empirical forcefield code. To give just one example of the many potential applications of the interface, we use it in conjunction with the CP2K electronic structure package to showcase the importance of nuclear quantum effects in high-pressure water. Catalogue identifier: AERN_v1_0 Program summary URL: http://cpc.cs.qub.ac.uk/summaries/AERN_v1_0.html Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland Licensing provisions: GNU General Public License, version 3 No. of lines in distributed program, including test data, etc.: 138626 No. of bytes in distributed program, including test data, etc.: 3128618 Distribution format: tar.gz Programming language: Python. Computer: Multiple architectures. Operating system: Linux, Mac OSX, Windows. RAM: Less than 256 Mb Classification: 7.7. External routines: NumPy Nature of problem: Bringing the latest developments in the modelling of nuclear quantum effects with path integral molecular dynamics to ab initio electronic structure programs with minimal implementational effort. Solution method: State-of-the-art path integral molecular dynamics techniques are implemented in a Python interface. Any electronic structure code can be patched to receive the atomic

  1. Spatiotemporal integration of molecular and anatomical data in virtual reality using semantic mapping

    OpenAIRE

    Soh, Jung

    2009-01-01

    Jung Soh1, Andrei L Turinsky1, Quang M Trinh1, Jasmine Chang1, Ajay Sabhaney1, et al1Sun Center of Excellence for Visual Genomics, University of Calgary, Calgary, AB, Canada; 2Department of Biological Sciences, University of Alberta, Edmonton, AB, CanadaAbstract: We have developed a computational framework for spatiotemporal integration of molecular and anatomical datasets in a virtual reality environment. Using two case studies involving gene expression data and pharmacokinetic data, respect...

  2. The microRNA molecular signature of atypic and common acquired melanocytic nevi: differential expression of miR-125b and let-7c

    DEFF Research Database (Denmark)

    Holst, Line Marie Broksø; Kaczkowski, Bogumil; Glud, Martin

    2011-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression through base pairing with mRNA and which are crucially involved in carcinogenesis (the so-called oncomiRs). We compared the miRNA signature between acquired melanocytic nevi showing clinical atypia (atypic nevi, AN...

  3. Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR

    DEFF Research Database (Denmark)

    Andersen, Lars Dyrskjøt; Reinert, Thomas; Novoradovsky, A;

    2012-01-01

    Background: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. Meth...

  4. Molecular signatures for Bacillus species: demarcation of the Bacillus subtilis and Bacillus cereus clades in molecular terms and proposal to limit the placement of new species into the genus Bacillus.

    Science.gov (United States)

    Bhandari, Vaibhav; Ahmod, Nadia Z; Shah, Haroun N; Gupta, Radhey S

    2013-07-01

    The genus Bacillus is a phylogenetically incoherent taxon with members of the group lacking a common evolutionary history. Comprising aerobic and anaerobic spore-forming bacteria, no characteristics are known that can distinguish species of this genus from other similar endospore-forming genera. With the availability of complete genomic data from over 30 different species from this group, we have constructed detailed phylogenetic trees to determine the relationships among Bacillus and other closely related taxa. Additionally, we have performed comparative genomic analysis for the determination of molecular markers, in the form of conserved signature indels (CSIs), to assist in the understanding of relationships among species of the genus Bacillus in molecular terms. Based on the analysis, we report here the identification of 11 and 6 CSIs that clearly differentiate a 'Bacillus subtilis clade' and a 'Bacillus cereus clade', respectively, from all other species of the genus Bacillus. No molecular markers were identified that supported a larger clade within this genus. The subtilis and the cereus clades were also the largest observed monophyletic groupings among species from the genus Bacillus in the phylogenetic trees based on 16S rRNA gene sequences and those based upon concatenated sequences for 20 conserved proteins. Thus, the relationships observed among these groups of species through CSIs are independently well supported by phylogenetic analysis. The molecular markers identified in this study provide a reliable means for the reorganization of the currently polyphyletic genus Bacillus into a more evolutionarily consistent set of groups. It is recommended that the genus Bacillus sensu stricto should comprise only the monophyletic subtilis clade that is demarcated by the identified CSIs, with B. subtilis as its type species. Members of the adjoining cereus clade (referred to as the Cereus clade of bacilli), although they are distinct from the subtilis clade, will

  5. Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination.

    Science.gov (United States)

    Kurashige, Junji; Hasegawa, Takanori; Niida, Atsushi; Sugimachi, Keishi; Deng, Niantao; Mima, Kosuke; Uchi, Ryutaro; Sawada, Genta; Takahashi, Yusuke; Eguchi, Hidetoshi; Inomata, Masashi; Kitano, Seigo; Fukagawa, Takeo; Sasako, Mitsuru; Sasaki, Hiroki; Sasaki, Shin; Mori, Masaki; Yanagihara, Kazuyoshi; Baba, Hideo; Miyano, Satoru; Tan, Patrick; Mimori, Koshi

    2016-03-03

    Peritoneal dissemination is the most frequent, incurable metastasis occurring in patients with advanced gastric cancer (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to provide novel insights into the molecular mechanisms that drive the peritoneal dissemination of GC. We performed combined expression analysis with in vivo-selected metastatic cell lines and samples from 200 GC patients to identify driver genes of peritoneal dissemination. The driver-gene functions associated with GC dissemination were examined using a mouse xenograft model. We identified a peritoneal dissemination-associated expression signature, whose profile correlated with those of genes related to development, focal adhesion, and the extracellular matrix. Among the genes comprising the expression signature, we identified that discoidin-domain receptor 2 (DDR2) as a potential regulator of peritoneal dissemination. The DDR2 was upregulated by the loss of DNA methylation and that DDR2 knockdown reduced peritoneal metastasis in a xenograft model. Dasatinib, an inhibitor of the DDR2 signaling pathway, effectively suppressed peritoneal dissemination. DDR2 was identified as a driver gene for GC dissemination from the combined expression signature and can potentially serve as a novel therapeutic target for inhibiting GC peritoneal dissemination.

  6. Calculation of the molecular integrals with the range-separated correlation factor

    CERN Document Server

    Silkowski, Michał; Moszynski, Robert

    2014-01-01

    Explicitly correlated quantum chemical calculations require calculations of five types of molecular integrals beyond the standard electron repulsion integrals. We present a novel scheme, which utilises general ideas of the McMurchie-Davidson technique, to compute these integrals when the so-called \\range-separated" correlation factor is used. This correlation factor combines the well-known short range behaviour, resulting from the electronic cusp condition, with the exact long-range asymptotics found for the helium atom [M. Lesiuk, B. Jeziorski, and R. Moszynski, J. Chem. Phys. $\\textbf{139}$, 134102 (2013)]. Almost all steps of the presented procedure are formulated recursively, so that an efficient implementation and control of the precision are possible. Additionally, the present formulation is very flexible and general, and it allows for use of an arbitrary correlation factor in the electronic structure calculations with minor or no changes.

  7. Integrated genomics and molecular breeding approaches for dissecting the complex quantitative traits in crop plants.

    Science.gov (United States)

    Kujur, Alice; Saxena, Maneesha S; Bajaj, Deepak; Laxmi; Parida, Swarup K

    2013-12-01

    The enormous population growth, climate change and global warming are now considered major threats to agriculture and world's food security. To improve the productivity and sustainability of agriculture, the development of highyielding and durable abiotic and biotic stress-tolerant cultivars and/climate resilient crops is essential. Henceforth, understanding the molecular mechanism and dissection of complex quantitative yield and stress tolerance traits is the prime objective in current agricultural biotechnology research. In recent years, tremendous progress has been made in plant genomics and molecular breeding research pertaining to conventional and next-generation whole genome, transcriptome and epigenome sequencing efforts, generation of huge genomic, transcriptomic and epigenomic resources and development of modern genomics-assisted breeding approaches in diverse crop genotypes with contrasting yield and abiotic stress tolerance traits. Unfortunately, the detailed molecular mechanism and gene regulatory networks controlling such complex quantitative traits is not yet well understood in crop plants. Therefore, we propose an integrated strategies involving available enormous and diverse traditional and modern -omics (structural, functional, comparative and epigenomics) approaches/resources and genomics-assisted breeding methods which agricultural biotechnologist can adopt/utilize to dissect and decode the molecular and gene regulatory networks involved in the complex quantitative yield and stress tolerance traits in crop plants. This would provide clues and much needed inputs for rapid selection of novel functionally relevant molecular tags regulating such complex traits to expedite traditional and modern marker-assisted genetic enhancement studies in target crop species for developing high-yielding stress-tolerant varieties.

  8. Massively Parallel, Molecular Analysis Platform Developed Using a CMOS Integrated Circuit With Biological Nanopores

    Science.gov (United States)

    Roever, Stefan

    2012-01-01

    A massively parallel, low cost molecular analysis platform will dramatically change the nature of protein, molecular and genomics research, DNA sequencing, and ultimately, molecular diagnostics. An integrated circuit (IC) with 264 sensors was fabricated using standard CMOS semiconductor processing technology. Each of these sensors is individually controlled with precision analog circuitry and is capable of single molecule measurements. Under electronic and software control, the IC was used to demonstrate the feasibility of creating and detecting lipid bilayers and biological nanopores using wild type α-hemolysin. The ability to dynamically create bilayers over each of the sensors will greatly accelerate pore development and pore mutation analysis. In addition, the noise performance of the IC was measured to be 30fA(rms). With this noise performance, single base detection of DNA was demonstrated using α-hemolysin. The data shows that a single molecule, electrical detection platform using biological nanopores can be operationalized and can ultimately scale to millions of sensors. Such a massively parallel platform will revolutionize molecular analysis and will completely change the field of molecular diagnostics in the future.

  9. Molecular hydrogen (H2) combustion emissions and their isotope (D/H) signatures from domestic heaters, diesel vehicle engines, waste incinerator plants, and biomass burning

    Science.gov (United States)

    Vollmer, M. K.; Walter, S.; Mohn, J.; Steinbacher, M.; Bond, S. W.; Röckmann, T.; Reimann, S.

    2012-07-01

    Molecular hydrogen (H2), its stable isotope signature (δD), and the key combustion parameters carbon monoxide (CO), carbon dioxide (CO2), and methane (CH4) were measured from various combustion processes. H2 in the exhaust of gas and oil-fired heaters and of waste incinerator plants was generally depleted compared to ambient intake air, while CO was significantly elevated. These findings contradict the often assumed co-occurring net H2 and CO emissions in combustion processes and suggest that previous H2 emissions from combustion may have been overestimated when scaled to CO emissions. For the gas and oil-fired heater exhausts, H2 and δD generally decrease with increasing CO2, from ambient values of ~0.5 ppm and +130‰ to 0.2 ppm and -206‰, respectively. These results are interpreted as a combination of an isotopically light H2 source from fossil fuel combustion and a D/H kinetic isotope fractionation of hydrogen in the advected ambient air during its partial removal during combustion. Diesel exhaust measurements from dynamometer test stand driving cycles show elevated H2 and CO emissions during cold-start and some acceleration phases. While H2 and CO emissions from diesel vehicles are known to be significantly less than those from gasoline vehicles (on a fuel-energy base), we find that their molar H2/CO ratios (median 0.026, interpercentile range 0.12) are also significantly less compared to gasoline vehicle exhaust. Using H2/CO emission ratios, along with CO global emission inventories, we estimate global H2 emissions for 2000, 2005, and 2010. For road transportation (gasoline and diesel), we calculate 8.3 ± 2.2 Tg, 6.0 ± 1.5 Tg, and 3.8 ± 0.94 Tg, respectively, whereas the contribution from diesel vehicles is low (0.9-1.4%). Other fossil fuel emissions are believed to be negligible but H2 emissions from coal combustion are unknown. For residential (domestic) emissions, which are likely dominated by biofuel combustion, emissions for the same years are

  10. An integrative genomic approach to uncover molecular mechanisms of prokaryotic traits.

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2006-11-01

    Full Text Available With mounting availability of genomic and phenotypic databases, data integration and mining become increasingly challenging. While efforts have been put forward to analyze prokaryotic phenotypes, current computational technologies either lack high throughput capacity for genomic scale analysis, or are limited in their capability to integrate and mine data across different scales of biology. Consequently, simultaneous analysis of associations among genomes, phenotypes, and gene functions is prohibited. Here, we developed a high throughput computational approach, and demonstrated for the first time the feasibility of integrating large quantities of prokaryotic phenotypes along with genomic datasets for mining across multiple scales of biology (protein domains, pathways, molecular functions, and cellular processes. Applying this method over 59 fully sequenced prokaryotic species, we identified genetic basis and molecular mechanisms underlying the phenotypes in bacteria. We identified 3,711 significant correlations between 1,499 distinct Pfam and 63 phenotypes, with 2,650 correlations and 1,061 anti-correlations. Manual evaluation of a random sample of these significant correlations showed a minimal precision of 30% (95% confidence interval: 20%-42%; n = 50. We stratified the most significant 478 predictions and subjected 100 to manual evaluation, of which 60 were corroborated in the literature. We furthermore unveiled 10 significant correlations between phenotypes and KEGG pathways, eight of which were corroborated in the evaluation, and 309 significant correlations between phenotypes and 166 GO concepts evaluated using a random sample (minimal precision = 72%; 95% confidence interval: 60%-80%; n = 50. Additionally, we conducted a novel large-scale phenomic visualization analysis to provide insight into the modular nature of common molecular mechanisms spanning multiple biological scales and reused by related phenotypes (metaphenotypes. We propose

  11. An integrated microfluidic platform for rapid tumor cell isolation, counting and molecular diagnosis.

    Science.gov (United States)

    Hung, Lien-Yu; Chuang, Ying-Hsin; Kuo, Hsin-Tzu; Wang, Chih-Hung; Hsu, Keng-Fu; Chou, Cheng-Yang; Lee, Gwo-Bin

    2013-04-01

    Ovarian cancer is the second most common of the gynecological cancers in Taiwan. It is challenging to diagnose at an early stage when proper treatment is the most effective. It is well recognized that the detection of tumor cells (TCs) is critical for determining cancer growth stages and may provide important information for accurate diagnosis and even prognosis. In this study, a new microfluidic platform integrated with a moving-wall micro-incubator, a micro flow cytometer and a molecular diagnosis module performed automated identification of ovarian cancer cells. By efficiently mixing the cells and immunomagnetic beads coated with specific antibodies, the target TCs were successfully isolated from the clinical samples. Then counting of the target cells was achieved by a combination of the micro flow cytometer and an optical detection module and showed a counting accuracy as high as 92.5 %. Finally, cancer-associated genes were amplified and detected by the downstream molecular diagnosis module. The fluorescence intensity of specific genes (CD24 and HE4) associated with ovarian cancer was amplified by the molecular diagnosis module and the results were comparable to traditional slab-gel electrophoresis analysis, with a limit of detection around 10 TCs. This integrated microfluidic platform realized the concept of a "lab-on-a-chip" and had advantages which included automation, disposability, lower cost and rapid diagnosis and, therefore, may provide a promising approach for the fast and accurate detection of cancer cells.

  12. Optimized acoustic biochip integrated with microfluidics for biomarkers detection in molecular diagnostics.

    Science.gov (United States)

    Papadakis, G; Friedt, J M; Eck, M; Rabus, D; Jobst, G; Gizeli, E

    2017-09-01

    The development of integrated platforms incorporating an acoustic device as the detection element requires addressing simultaneously several challenges of technological and scientific nature. The present work was focused on the design of a microfluidic module, which, combined with a dual or array type Love wave acoustic chip could be applied to biomedical applications and molecular diagnostics. Based on a systematic study we optimized the mechanics of the flow cell attachment and the sealing material so that fluidic interfacing/encapsulation would impose minimal losses to the acoustic wave. We have also investigated combinations of operating frequencies with waveguide materials and thicknesses for maximum sensitivity during the detection of protein and DNA biomarkers. Within our investigations neutravidin was used as a model protein biomarker and unpurified PCR amplified Salmonella DNA as the model genetic target. Our results clearly indicate the need for experimental verification of the optimum engineering and analytical parameters, in order to develop commercially viable systems for integrated analysis. The good reproducibility of the signal together with the ability of the array biochip to detect multiple samples hold promise for the future use of the integrated system in a Lab-on-a-Chip platform for application to molecular diagnostics.

  13. Molecular radiotherapy: The NUKFIT software for calculating the time-integrated activity coefficient

    Energy Technology Data Exchange (ETDEWEB)

    Kletting, P.; Schimmel, S.; Luster, M. [Klinik für Nuklearmedizin, Universität Ulm, Ulm 89081 (Germany); Kestler, H. A. [Research Group Bioinformatics and Systems Biology, Institut für Neuroinformatik, Universität Ulm, Ulm 89081 (Germany); Hänscheid, H.; Fernández, M.; Lassmann, M. [Klinik für Nuklearmedizin, Universität Würzburg, Würzburg 97080 (Germany); Bröer, J. H.; Nosske, D. [Bundesamt für Strahlenschutz, Fachbereich Strahlenschutz und Gesundheit, Oberschleißheim 85764 (Germany); Glatting, G. [Medical Radiation Physics/Radiation Protection, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167 (Germany)

    2013-10-15

    Purpose: Calculation of the time-integrated activity coefficient (residence time) is a crucial step in dosimetry for molecular radiotherapy. However, available software is deficient in that it is either not tailored for the use in molecular radiotherapy and/or does not include all required estimation methods. The aim of this work was therefore the development and programming of an algorithm which allows for an objective and reproducible determination of the time-integrated activity coefficient and its standard error.Methods: The algorithm includes the selection of a set of fitting functions from predefined sums of exponentials and the choice of an error model for the used data. To estimate the values of the adjustable parameters an objective function, depending on the data, the parameters of the error model, the fitting function and (if required and available) Bayesian information, is minimized. To increase reproducibility and user-friendliness the starting values are automatically determined using a combination of curve stripping and random search. Visual inspection, the coefficient of determination, the standard error of the fitted parameters, and the correlation matrix are provided to evaluate the quality of the fit. The functions which are most supported by the data are determined using the corrected Akaike information criterion. The time-integrated activity coefficient is estimated by analytically integrating the fitted functions. Its standard error is determined assuming Gaussian error propagation. The software was implemented using MATLAB.Results: To validate the proper implementation of the objective function and the fit functions, the results of NUKFIT and SAAM numerical, a commercially available software tool, were compared. The automatic search for starting values was successfully tested for reproducibility. The quality criteria applied in conjunction with the Akaike information criterion allowed the selection of suitable functions. Function fit

  14. Threshold Signature Scheme Based on Discrete Logarithm and Quadratic Residue

    Institute of Scientific and Technical Information of China (English)

    FEI Ru-chun; WANG Li-na

    2004-01-01

    Digital signature scheme is a very important research field in computer security and modern cryptography.A(k,n) threshold digital signature scheme is proposed by integrating digital signature scheme with Shamir secret sharing scheme.It can realize group-oriented digital signature, and its security is based on the difficulty in computing discrete logarithm and quadratic residue on some special conditions.In this scheme, effective digital signature can not be generated by any k-1 or fewer legal users, or only by signature executive.In addition, this scheme can identify any legal user who presents incorrect partial digital signature to disrupt correct signature, or any illegal user who forges digital signature.A method of extending this scheme to an Abelian group such as elliptical curve group is also discussed.The extended scheme can provide rapider computing speed and stronger security in the case of using shorter key.

  15. Logic integration of mRNA signals by an RNAi-based molecular computer.

    Science.gov (United States)

    Xie, Zhen; Liu, Siyuan John; Bleris, Leonidas; Benenson, Yaakov

    2010-05-01

    Synthetic in vivo molecular 'computers' could rewire biological processes by establishing programmable, non-native pathways between molecular signals and biological responses. Multiple molecular computer prototypes have been shown to work in simple buffered solutions. Many of those prototypes were made of DNA strands and performed computations using cycles of annealing-digestion or strand displacement. We have previously introduced RNA interference (RNAi)-based computing as a way of implementing complex molecular logic in vivo. Because it also relies on nucleic acids for its operation, RNAi computing could benefit from the tools developed for DNA systems. However, these tools must be harnessed to produce bioactive components and be adapted for harsh operating environments that reflect in vivo conditions. In a step toward this goal, we report the construction and implementation of biosensors that 'transduce' mRNA levels into bioactive, small interfering RNA molecules via RNA strand exchange in a cell-free Drosophila embryo lysate, a step beyond simple buffered environments. We further integrate the sensors with our RNAi 'computational' module to evaluate two-input logic functions on mRNA concentrations. Our results show how RNA strand exchange can expand the utility of RNAi computing and point toward the possibility of using strand exchange in a native biological setting.

  16. Integration of Chinese medicine with Western medicine could lead to future medicine: molecular module medicine.

    Science.gov (United States)

    Zhang, Chi; Zhang, Ge; Chen, Ke-ji; Lu, Ai-ping

    2016-04-01

    The development of an effective classification method for human health conditions is essential for precise diagnosis and delivery of tailored therapy to individuals. Contemporary classification of disease systems has properties that limit its information content and usability. Chinese medicine pattern classification has been incorporated with disease classification, and this integrated classification method became more precise because of the increased understanding of the molecular mechanisms. However, we are still facing the complexity of diseases and patterns in the classification of health conditions. With continuing advances in omics methodologies and instrumentation, we are proposing a new classification approach: molecular module classification, which is applying molecular modules to classifying human health status. The initiative would be precisely defining the health status, providing accurate diagnoses, optimizing the therapeutics and improving new drug discovery strategy. Therefore, there would be no current disease diagnosis, no disease pattern classification, and in the future, a new medicine based on this classification, molecular module medicine, could redefine health statuses and reshape the clinical practice.

  17. Molecular physiopathology of obesity-related diseases: multi-organ integration by GRK2.

    Science.gov (United States)

    Lucas, Elisa; Cruces-Sande, Marta; Briones, Ana M; Salaices, Mercedes; Mayor, Federico; Murga, Cristina; Vila-Bedmar, Rocio

    2015-01-01

    Obesity is a worldwide problem that has reached epidemic proportions both in developed and developing countries. The excessive accumulation of fat poses a risk to health since it favours the development of metabolic alterations including insulin resistance and tissue inflammation, which further contribute to the progress of the complex pathological scenario observed in the obese. In this review we put together the different outcomes of fat accumulation and insulin resistance in the main insulin-responsive tissues, and discuss the role of some of the key molecular routes that control disease progression both in an organ-specific and also in a more systemic manner. In particular, we focus on the importance of studying the integrated regulation of different organs and pathways that contribute to the global pathophysiology of this condition with a specific emphasis on the role of emerging key molecular nodes such as the G protein-coupled receptor kinase 2 (GRK2) signalling hub.

  18. Path integral centroid molecular dynamics simulations of semiinfinite slab and bulk liquid of para-hydrogen

    Energy Technology Data Exchange (ETDEWEB)

    Kinugawa, Kenichi [Nara Women`s Univ., Nara (Japan). Dept. of Chemistry

    1998-10-01

    It has been unsuccessful to solve a set of time-dependent Schroedinger equations numerically for many-body quantum systems which involve, e.g., a number of hydrogen molecules, protons, and excess electrons at a low temperature, where quantum effect evidently appears. This undesirable situation is fatal for the investigation of real low-temperature chemical systems because they are essentially composed of many quantum degrees of freedom. However, if we use a new technique called `path integral centroid molecular dynamics (CMD) simulation` proposed by Cao and Voth in 1994, the real-time semi-classical dynamics of many degrees of freedom can be computed by utilizing the techniques already developed in the traditional classical molecular dynamics (MD) simulations. Therefore, the CMD simulation is expected to be very powerful tool for the quantum dynamics studies or real substances. (J.P.N.)

  19. Low-temperature metallic liquid hydrogen: an ab-initio path-integral molecular dynamics perspective

    Science.gov (United States)

    Chen, Ji; Li, Xin-Zheng; Zhang, Qianfan; Probert, Matthew; Pickard, Chris; Needs, Richard; Michaelides, Angelos; Wang, Enge

    2013-03-01

    Experiments and computer simulations have shown that the melting temperature of solid hydrogen drops with pressure above about 65 GPa, suggesting that a low temperature liquid state might exist. It has also been suggested that this liquid state might be non-molecular and metallic, although evidence for such behaviour is lacking. Using a combination of ab initio path-integral molecular dynamics and the two-phase methods, we have simulated the melting of solid hydrogen under finite temperatures. We found an atomic solid phase from 500 to 800 GPa which melts at < 200 K. Beyond this and up to pressures of 1,200 GPa a metallic atomic liquid is stable at temperatures as low as 50 K. The quantum motion of the protons is critical to the low melting temperature in this system as ab initio simulations with classical nuclei lead to a considerably higher melting temperature of ~300 K across the entire pressure range considered.

  20. A novel protein refolding method integrating ion exchange chromatography with artificial molecular chaperone

    Institute of Scientific and Technical Information of China (English)

    Qin Ming Zhang; Chao Zhan Wang; Jiang Feng Liu; Li Li Wang

    2008-01-01

    Artificial molecular chaperone (AMC) and ion exchange chromatography (IEC) were integrated, thus a new refolding method,artificial molecular chaperone-ion exchange chromatography (AMC-IEC) was developed. Compared with AMC and IEC, theactivity recovery of lysozyme obtained by AMC-IEC was much higher in the investigated range of initial protein concentrations,and the results show that AMC-IEC is very efficient for protein refolding at high concentrations. When the initial concentration oflysozyme is 180 mg/mL, its activity recovery obtained by AMC-IEC is still as high as 76.6%, while the activity recoveries obtainedby AMC and IEC are 45.6% and 42.4%, respectively.2008 Chao Zhan Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

  1. Spatiotemporal integration of molecular and anatomical data in virtual reality using semantic mapping.

    Science.gov (United States)

    Soh, Jung; Turinsky, Andrei L; Trinh, Quang M; Chang, Jasmine; Sabhaney, Ajay; Dong, Xiaoli; Gordon, Paul Mk; Janzen, Ryan Pw; Hau, David; Xia, Jianguo; Wishart, David S; Sensen, Christoph W

    2009-01-01

    We have developed a computational framework for spatiotemporal integration of molecular and anatomical datasets in a virtual reality environment. Using two case studies involving gene expression data and pharmacokinetic data, respectively, we demonstrate how existing knowledge bases for molecular data can be semantically mapped onto a standardized anatomical context of human body. Our data mapping methodology uses ontological representations of heterogeneous biomedical datasets and an ontology reasoner to create complex semantic descriptions of biomedical processes. This framework provides a means to systematically combine an increasing amount of biomedical imaging and numerical data into spatiotemporally coherent graphical representations. Our work enables medical researchers with different expertise to simulate complex phenomena visually and to develop insights through the use of shared data, thus paving the way for pathological inference, developmental pattern discovery and biomedical hypothesis testing.

  2. Many-body quantum dynamics by adiabatic path-integral molecular dynamics: Disordered Frenkel Kontorova models

    Science.gov (United States)

    Krajewski, Florian R.; Müser, Martin H.

    2005-07-01

    The spectral density of quantum mechanical Frenkel Kontorova chains moving in disordered, external potentials is investigated by means of path-integral molecular dynamics. If the second moment of the embedding potential is well defined (roughness exponent H=0), there is one regime in which the chain is pinned (large masses m of chain particles) and one in which it is unpinned (small m). If the embedding potential can be classified as a random walk on large length scales ( H=1/2), then the chain is always pinned irrespective of the value of m. For H=1/2, two phonon-like branches appear in the spectra.

  3. Formation of bound states in expanded metal studied via path integral molecular dynamics

    Science.gov (United States)

    Deymier, P. A.; Oh, Ki-Dong

    2004-03-01

    The usefulness of the restricted path integral molecular dynamics method for the study of strongly correlated electrons is demonstrated by studying the formation of bound electronic states in a half-filled expanded three-dimensional hydrogenoid body-centred cubic lattice at finite temperature. Starting from a metallic state with one-component plasma character, we find that bound electrons form upon expansion of the lattice. The bound electrons are spatially localized with their centre for the motion of gyration located at ionic positions. The number of bound electrons increases monotonically with decreasing density.

  4. Path Integral Molecular Dynamics for Hydrogen with Orbital-Free Density Functional Theory

    Science.gov (United States)

    Runge, Keith; Karasiev, Valentin; Deymier, Pierre

    2014-03-01

    The computational bottleneck for performing path-integral molecular dynamics (PIMD) for nuclei on a first principles electronic potential energy surface has been the speed with which forces from the electrons can be generated. Recent advances in orbital-free density functional theory (OF-DFT) not only allow for faster generation of first principles forces but also include the effects of temperature on the electron density. We will present results of calculations on hydrogen in warm dense matter conditions where the protons are described by PIMD and the electrons by OF-DFT. Work supported by U.S. Dept. of Energy, grant DE-SC0002139.

  5. Restricted Path-Integral Molecular Dynamics for Simulating the Correlated Electron Plasma in Warm Dense Matter

    Science.gov (United States)

    Kapila, Vivek; Deymier, Pierre; Runge, Keith

    2011-10-01

    Several areas of study including heavy ion beam, large scale laser, and high pressure or Thomson scattering studies necessitate a fundamental understanding of warm dense matter (WDM) i.e. matter at high temperature and high density. The WDM regime, however, lacks any adequate highly developed class of simulation methods. Recent progress to address this deficit has been the development of orbital-free Density Functional Theory (ofDFT). However, scant benchmark information is available on temperature and pressure dependence of simple but realistic models in WDM regime. The present work aims to fill this critical gap using the restricted path-integral molecular dynamics (rPIMD) method. Within the discrete path integral representation, electrons are described as harmonic necklaces. Quantum exchange takes the form of cross linking between electron necklaces. The fermion sign problem is addressed by restricting the density matrix to positive values. The molecular dynamics algorithm is employed to sample phase space. Here, we focus on the behavior of strongly correlated electron plasmas under WDM conditions. We compute the kinetic and potential energies and compare them to those obtained with the ofDFT method. Several areas of study including heavy ion beam, large scale laser, and high pressure or Thomson scattering studies necessitate a fundamental understanding of warm dense matter (WDM) i.e. matter at high temperature and high density. The WDM regime, however, lacks any adequate highly developed class of simulation methods. Recent progress to address this deficit has been the development of orbital-free Density Functional Theory (ofDFT). However, scant benchmark information is available on temperature and pressure dependence of simple but realistic models in WDM regime. The present work aims to fill this critical gap using the restricted path-integral molecular dynamics (rPIMD) method. Within the discrete path integral representation, electrons are described as

  6. Path-integral molecular dynamics simulations for water anion clusters (HO)5- and (DO)5-

    Science.gov (United States)

    Takayanagi, Toshiyuki; Yoshikawa, Takehiro; Motegi, Haruki; Shiga, Motoyuki

    2009-11-01

    Quantum path-integral molecular dynamics simulations have been performed for the (HO)5- and (DO)5- anion clusters on the basis of a semiempirical one-electron pseudopotential-polarization model. Due to larger zero-point vibrational amplitudes for H atoms than that of D atoms, hydrogen-bond lengths in the (HO)5- cluster are slightly larger than those in (DO)5-. The distribution of the vertical detachment energies for (HO)5- also show a broader feature than that for (DO)5-. The present PIMD simulations thus demonstrate the importance of nuclear quantum effects in water anion clusters.

  7. Molecular verification of the integration of Tripsacum dactyloides DNA into wheat genome through wide hybridization

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    RAPD and RFLP analyses of double haploid lines which derived from hybridization between hexaploid wheat (Triticum aestivum L.2n=42) and eastern gamagrass (Tripsacum dactyloides L.2n=4x=72) are reported.Two of the 340 Operon primers have been screened,which stably amplified Tripsacum dactyloides (male parent) specific bands in the double haploid lines.These results confirm the fact that Tripsacum dactyloides DNA has been integrated into wheat genome by sexual hybridization at molecular level.This idea has been further testified by RFLP analysis.Application and potentials of transferring Tripsacum dactyloides DNA into wheat genome by sexual hybridization in wheat breeding are discussed.

  8. Ab Initio Path Integral Molecular Dynamics Simulation of Hydrogen in Silicon

    Science.gov (United States)

    Probert, M. I. J.; Glover, M. J.

    2006-05-01

    We report results of a first-principles theoretical study of an isolated neutral hydrogen atom in crystalline silicon. Spin-polarised density functional theory is used to treat the electrons, and the path-integral molecular dynamics method is used to describe the quantum properties of the nucleus at finite temperature. This is necessary as the hydrogen atom has sufficiently low mass that it exhibits significant nuclear quantum delocalisation and zero-point motion even at room temperature. Unlike post-hoc treatments, such as calculating a static potential energy surface, the path-integral treatment enables such effects to be included "on-the-fly". This is found to be significant, as a coupling is found between the structure of the host silicon lattice and the quantum delocalisation of the hydrogen defect.

  9. Proton momentum distributions in water: A path integral molecular dynamics study

    Science.gov (United States)

    Srinivasan, Varadharajan; Morrone, Joseph A.; Sebastiani, Daniel; Car, Roberto

    2007-03-01

    Recent neutron Compton scattering experiments have detected the proton momentum distributions of water. This density in momentum space is a quantum mechanical property of the proton, due to the confining anharmonic potential from covalent and hydrogen bonds. The theoretical calculation of this property can be carried out via ``open'' path integral expressions. In this work, we present an extension of the staging path integral molecular dynamics method, which is then employed to calculate the proton momentum distributions of water in the solid, liquid, and supercritical phases. We utilize the SPC/F2 empirical force field to model the system's interactions. The calculated momentum distributions depict both agreement and discrepancies with experiment. The differences may be explained by the deviation of the force field from the true interactions. These distributions provide an abundance of information about the environment and interactions surrounding the proton.

  10. Proton momentum distribution in water: an open path integral molecular dynamics study

    Science.gov (United States)

    Morrone, Joseph A.; Srinivasan, Varadharajan; Sebastiani, Daniel; Car, Roberto

    2007-06-01

    Recent neutron Compton scattering experiments have detected the proton momentum distribution in water. The theoretical calculation of this property can be carried out via "open" path integral expressions. In this work, present an extension of the staging path integral molecular dynamics method, which is then employed to calculate the proton momentum distributions of water in the solid, liquid, and supercritical phases. We utilize a flexible, single point charge empirical force field to model the system's interactions. The calculated momentum distributions depict both agreement and discrepancies with experiment. The differences may be explained by the deviation of the force field from the true interactions. These distributions provide an abundance of information about the environment and interactions surrounding the proton.

  11. Integrating open-source software applications to build molecular dynamics systems.

    Science.gov (United States)

    Allen, Bruce M; Predecki, Paul K; Kumosa, Maciej

    2014-04-05

    Three open-source applications, NanoEngineer-1, packmol, and mis2lmp are integrated using an open-source file format to quickly create molecular dynamics (MD) cells for simulation. The three software applications collectively make up the open-source software (OSS) suite known as MD Studio (MDS). The software is validated through software engineering practices and is verified through simulation of the diglycidyl ether of bisphenol-a and isophorone diamine (DGEBA/IPD) system. Multiple simulations are run using the MDS software to create MD cells, and the data generated are used to calculate density, bulk modulus, and glass transition temperature of the DGEBA/IPD system. Simulation results compare well with published experimental and numerical results. The MDS software prototype confirms that OSS applications can be analyzed against real-world research requirements and integrated to create a new capability. Copyright © 2014 Wiley Periodicals, Inc.

  12. Integrated genomics and molecular breeding approaches for dissecting the complex quantitative traits in crop plants

    Indian Academy of Sciences (India)

    Alice Kujur; Maneesha S Saxena; Deepak Bajaj; Laxmi; Swarup K Parida

    2013-12-01

    The enormous population growth, climate change and global warming are now considered major threats to agriculture and world’s food security. To improve the productivity and sustainability of agriculture, the development of high-yielding and durable abiotic and biotic stress-tolerant cultivars and/climate resilient crops is essential. Henceforth, understanding the molecular mechanism and dissection of complex quantitative yield and stress tolerance traits is the prime objective in current agricultural biotechnology research. In recent years, tremendous progress has been made in plant genomics and molecular breeding research pertaining to conventional and next-generation whole genome, transcriptome and epigenome sequencing efforts, generation of huge genomic, transcriptomic and epigenomic resources and development of modern genomics-assisted breeding approaches in diverse crop genotypes with contrasting yield and abiotic stress tolerance traits. Unfortunately, the detailed molecular mechanism and gene regulatory networks controlling such complex quantitative traits is not yet well understood in crop plants. Therefore, we propose an integrated strategies involving available enormous and diverse traditional and modern –omics (structural, functional, comparative and epigenomics) approaches/resources and genomics-assisted breeding methods which agricultural biotechnologist can adopt/utilize to dissect and decode the molecular and gene regulatory networks involved in the complex quantitative yield and stress tolerance traits in crop plants. This would provide clues and much needed inputs for rapid selection of novel functionally relevant molecular tags regulating such complex traits to expedite traditional and modern marker-assisted genetic enhancement studies in target crop species for developing high-yielding stress-tolerant varieties.

  13. Inferring Diversity and Evolution in Fish by Means of Integrative Molecular Cytogenetics.

    Science.gov (United States)

    Artoni, Roberto Ferreira; Castro, Jonathan Pena; Jacobina, Uedson Pereira; Lima-Filho, Paulo Augusto; da Costa, Gideão Wagner Werneck Félix; Molina, Wagner Franco

    2015-01-01

    Fish constitute a paraphyletic and profusely diversified group that has historically puzzled ichthyologists. Hard efforts are necessary to better understand this group, due to its extensive diversity. New species are often identified and it leads to questions about their phylogenetic aspects. Cytogenetics is becoming an important biodiversity-detection tool also used to measure biodiversity evolutionary aspects. Molecular cytogenetics by fluorescence in situ hybridization (FISH) allowed integrating quantitative and qualitative data from DNA sequences and their physical location in chromosomes and genomes. Although there is no intention on presenting a broader review, the current study presents some evidences on the need of integrating molecular cytogenetic data to other evolutionary biology tools to more precisely infer cryptic species detection, population structuring in marine environments, intra- and interspecific karyoevolutionary aspects of freshwater groups, evolutionary dynamics of marine fish chromosomes, and the origin and differentiation of sexual and B chromosomes. The new cytogenetic field, called cytogenomics, is spreading due to its capacity to give resolute answers to countless questions that cannot be answered by traditional methodologies. Indeed, the association between chromosomal markers and DNA sequencing as well as between biological diversity analysis methodologies and phylogenetics triggers the will to search for answers about fish evolutionary, taxonomic, and structural features.

  14. Transport properties of liquid para-hydrogen: The path integral centroid molecular dynamics approach

    Science.gov (United States)

    Yonetani, Yoshiteru; Kinugawa, Kenichi

    2003-11-01

    Several fundamental transport properties of a quantum liquid para-hydrogen (p-H2) at 17 K have been numerically evaluated by means of the quantum dynamics simulation called the path integral centroid molecular dynamics (CMD). For comparison, classical molecular dynamics (MD) simulations have also been performed under the same condition. In accordance with the previous path integral simulations, the calculated static properties of the liquid agree well with the experimental results. For the diffusion coefficient, thermal conductivity, and shear viscosity, the CMD predicts the values closer to the experimental ones though the classical MD results are far from the reality. The agreement of the CMD result with the experimental one is especially good for the shear viscosity with the difference less than 5%. The calculated diffusion coefficient and the thermal conductivity agree with the experimental values at least in the same order. We predict that the ratio of bulk viscosity to shear viscosity for liquid p-H2 is much larger than classical van der Waals simple liquids such as rare gas liquids.

  15. Spatiotemporal integration of molecular and anatomical data in virtual reality using semantic mapping

    Directory of Open Access Journals (Sweden)

    Jung Soh

    2009-03-01

    Full Text Available Jung Soh1, Andrei L Turinsky1, Quang M Trinh1, Jasmine Chang1, Ajay Sabhaney1, et al1Sun Center of Excellence for Visual Genomics, University of Calgary, Calgary, AB, Canada; 2Department of Biological Sciences, University of Alberta, Edmonton, AB, CanadaAbstract: We have developed a computational framework for spatiotemporal integration of molecular and anatomical datasets in a virtual reality environment. Using two case studies involving gene expression data and pharmacokinetic data, respectively, we demonstrate how existing knowledge bases for molecular data can be semantically mapped onto a standardized anatomical context of human body. Our data mapping methodology uses ontological representations of heterogeneous biomedical datasets and an ontology reasoner to create complex semantic descriptions of biomedical processes. This framework provides a means to systematically combine an increasing amount of biomedical imaging and numerical data into spatiotemporally coherent graphical representations. Our work enables medical researchers with different expertise to simulate complex phenomena visually and to develop insights through the use of shared data, thus paving the way for pathological inference, developmental pattern discovery and biomedical hypothesis testing.Keywords: anatomical atlas, gene expression, pharmacokinetics, biomedical data integration, CAVEman, virtual reality in medicine

  16. Which strategy for molecular probe design? An answer from the integration of spectroscopy and QM modeling.

    Science.gov (United States)

    Marini, Alberto; Muñoz-Losa, Aurora; Pucci, Andrea; Ruggeri, Giacomo; Mennucci, Benedetta

    2010-08-21

    With this study we show that the maturity reached by quantum-mechanical (QM) modeling has allowed a new analytical approach to the design of molecular probes. In this approach, the strategy is to integrate suited computational tools with multi-spectroscopic measurements to identify specific signals for the characterization of the molecular probe with respect to the perturbation used and the environmental conditions applied. The application of the strategy to a typical optical probe (2-acetylanthracene) has allowed the identification of specific IR and NMR signals for the characterization of the conformational states in both solid and solution states. This analysis has been successively extended to the investigation of specific optical signals. In particular we have shown that the introduction of a substituent in specific positions of the aromatic structure induces a different perturbation in the different excited states of the precursor anthracene with consequent differentiations of the states with respect to their solvent sensitivity (both in terms of bulk and specific effects). Finally, the integration of simulated and experimental emission spectra has revealed a possible isomerization in the excited state with resulting change of the conformational state in the absorbing and the emitting species.

  17. Inferring Diversity and Evolution in Fish by Means of Integrative Molecular Cytogenetics

    Directory of Open Access Journals (Sweden)

    Roberto Ferreira Artoni

    2015-01-01

    Full Text Available Fish constitute a paraphyletic and profusely diversified group that has historically puzzled ichthyologists. Hard efforts are necessary to better understand this group, due to its extensive diversity. New species are often identified and it leads to questions about their phylogenetic aspects. Cytogenetics is becoming an important biodiversity-detection tool also used to measure biodiversity evolutionary aspects. Molecular cytogenetics by fluorescence in situ hybridization (FISH allowed integrating quantitative and qualitative data from DNA sequences and their physical location in chromosomes and genomes. Although there is no intention on presenting a broader review, the current study presents some evidences on the need of integrating molecular cytogenetic data to other evolutionary biology tools to more precisely infer cryptic species detection, population structuring in marine environments, intra- and interspecific karyoevolutionary aspects of freshwater groups, evolutionary dynamics of marine fish chromosomes, and the origin and differentiation of sexual and B chromosomes. The new cytogenetic field, called cytogenomics, is spreading due to its capacity to give resolute answers to countless questions that cannot be answered by traditional methodologies. Indeed, the association between chromosomal markers and DNA sequencing as well as between biological diversity analysis methodologies and phylogenetics triggers the will to search for answers about fish evolutionary, taxonomic, and structural features.

  18. Efficient Threshold Signature Scheme

    Directory of Open Access Journals (Sweden)

    Sattar J Aboud

    2012-01-01

    Full Text Available In this paper, we introduce a new threshold signature RSA-typed scheme. The proposed scheme has the characteristics of un-forgeable and robustness in random oracle model. Also, signature generation and verification is entirely non-interactive. In addition, the length of the entity signature participate is restricted by a steady times of the length of the RSA signature modulus. Also, the signing process of the proposed scheme is more efficient in terms of time complexity and interaction.

  19. Evaluation and molecular characterization of human adenovirus in drinking water supplies: viral integrity and viability assays.

    Science.gov (United States)

    Fongaro, Gislaine; Nascimento, Mariana A do; Rigotto, Caroline; Ritterbusch, Giseli; da Silva, Alessandra D' A; Esteves, Paulo A; Barardi, Célia R M

    2013-05-28

    Human adenoviruses (HAdVs) are the second-leading cause of childhood gastroenteritis worldwide. This virus is commonly found in environmental waters and is very resistant to water disinfection and environmental stressors, especially UV light inactivation. Molecular techniques, such as PCR-based methods (Polymerase Chain Reaction), are commonly used to detect and identify viral contamination in water, although PCR alone does not allow the discrimination between infectious and non-infectious viral particles. A combination of cell culture and PCR has allowed detection of infectious viruses that grow slowly or fail to produce cytopathic effects (CPE) in cell culture. This study aimed to assess the integrity and viability of human adenovirus (HAdV) in environmental water and evaluate circulating strains by molecular characterization in three sites of the water supply in Florianópolis, Santa Catarina Island, Brazil: Peri Lagoon water, spring source water, and water from the public water supply system. Water samples were collected, concentrated and HAdV quantified by real-time PCR. Viral integrity was evaluated by enzymatic assay (DNase I) and infectivity by plaque assay (PA) and integrated cell culture using transcribed mRNA (ICC-RT-qPCR). Samples containing particles of infectious HAdV were selected for sequencing and molecular characterization. The analyzed sites contained 83, 66 and 58% undamaged HAdV particles (defined as those in which the genetic material is protected by the viral capsid) at Peri Lagoon, spring source water and public supply system water, respectively. Of these, 66% of the particles (by PA) and 75% (by ICC-RT-qPCR) HAdV were shown to be infectious, due to being undamaged in Peri Lagoon, 33% (by PA) and 58% (by ICC-RT-qPCR) in spring source water and 8% (by PA) and 25% (by ICC-RT-qPCR) in the public water supply system. ICC-RT-qPCR, a very sensitive and rapid technique, was able to detect as low as 1 × 102 HAdV genome copies per milliliter of

  20. All-optical integrated logic operations based on chemical communication between molecular switches.

    Science.gov (United States)

    Silvi, Serena; Constable, Edwin C; Housecroft, Catherine E; Beves, Jonathon E; Dunphy, Emma L; Tomasulo, Massimiliano; Raymo, Françisco M; Credi, Alberto

    2009-01-01

    Molecular logic gates process physical or chemical "inputs" to generate "outputs" based on a set of logical operators. We report the design and operation of a chemical ensemble in solution that behaves as integrated AND, OR, and XNOR gates with optical input and output signals. The ensemble is composed of a reversible merocyanine-type photoacid and a ruthenium polypyridine complex that functions as a pH-controlled three-state luminescent switch. The light-triggered release of protons from the photoacid is used to control the state of the transition-metal complex. Therefore, the two molecular switching devices communicate with one another through the exchange of ionic signals. By means of such a double (optical-chemical-optical) signal-transduction mechanism, inputs of violet light modulate a luminescence output in the red/far-red region of the visible spectrum. Nondestructive reading is guaranteed because the green light used for excitation in the photoluminescence experiments does not affect the state of the gate. The reset is thermally driven and, thus, does not involve the addition of chemicals and accumulation of byproducts. Owing to its reversibility and stability, this molecular device can afford many cycles of digital operation.

  1. Integrating Nanostructured Artificial Receptors with Whispering Gallery Mode Optical Microresonators via Inorganic Molecular Imprinting Techniques.

    Science.gov (United States)

    Hammond, G Denise; Vojta, Adam L; Grant, Sheila A; Hunt, Heather K

    2016-06-15

    The creation of label-free biosensors capable of accurately detecting trace contaminants, particularly small organic molecules, is of significant interest for applications in environmental monitoring. This is achieved by pairing a high-sensitivity signal transducer with a biorecognition element that imparts selectivity towards the compound of interest. However, many environmental pollutants do not have corresponding biorecognition elements. Fortunately, biomimetic chemistries, such as molecular imprinting, allow for the design of artificial receptors with very high selectivity for the target. Here, we perform a proof-of-concept study to show how artificial receptors may be created from inorganic silanes using the molecular imprinting technique and paired with high-sensitivity transducers without loss of device performance. Silica microsphere Whispering Gallery Mode optical microresonators are coated with a silica thin film templated by a small fluorescent dye, fluorescein isothiocyanate, which serves as our model target. Oxygen plasma degradation and solvent extraction of the template are compared. Extracted optical devices are interacted with the template molecule to confirm successful sorption of the template. Surface characterization is accomplished via fluorescence and optical microscopy, ellipsometry, optical profilometry, and contact angle measurements. The quality factors of the devices are measured to evaluate the impact of the coating on device sensitivity. The resulting devices show uniform surface coating with no microstructural damage with Q factors above 10⁶. This is the first report demonstrating the integration of these devices with molecular imprinting techniques, and could lead to new routes to biosensor creation for environmental monitoring.

  2. Integrating Nanostructured Artificial Receptors with Whispering Gallery Mode Optical Microresonators via Inorganic Molecular Imprinting Techniques

    Directory of Open Access Journals (Sweden)

    G. Denise Hammond

    2016-06-01

    Full Text Available The creation of label-free biosensors capable of accurately detecting trace contaminants, particularly small organic molecules, is of significant interest for applications in environmental monitoring. This is achieved by pairing a high-sensitivity signal transducer with a biorecognition element that imparts selectivity towards the compound of interest. However, many environmental pollutants do not have corresponding biorecognition elements. Fortunately, biomimetic chemistries, such as molecular imprinting, allow for the design of artificial receptors with very high selectivity for the target. Here, we perform a proof-of-concept study to show how artificial receptors may be created from inorganic silanes using the molecular imprinting technique and paired with high-sensitivity transducers without loss of device performance. Silica microsphere Whispering Gallery Mode optical microresonators are coated with a silica thin film templated by a small fluorescent dye, fluorescein isothiocyanate, which serves as our model target. Oxygen plasma degradation and solvent extraction of the template are compared. Extracted optical devices are interacted with the template molecule to confirm successful sorption of the template. Surface characterization is accomplished via fluorescence and optical microscopy, ellipsometry, optical profilometry, and contact angle measurements. The quality factors of the devices are measured to evaluate the impact of the coating on device sensitivity. The resulting devices show uniform surface coating with no microstructural damage with Q factors above 106. This is the first report demonstrating the integration of these devices with molecular imprinting techniques, and could lead to new routes to biosensor creation for environmental monitoring.

  3. An integrated analysis of molecular acclimation to high light in the marine diatom Phaeodactylum tricornutum.

    Directory of Open Access Journals (Sweden)

    Marianne Nymark

    Full Text Available Photosynthetic diatoms are exposed to rapid and unpredictable changes in irradiance and spectral quality, and must be able to acclimate their light harvesting systems to varying light conditions. Molecular mechanisms behind light acclimation in diatoms are largely unknown. We set out to investigate the mechanisms of high light acclimation in Phaeodactylum tricornutum using an integrated approach involving global transcriptional profiling, metabolite profiling and variable fluorescence technique. Algae cultures were acclimated to low light (LL, after which the cultures were transferred to high light (HL. Molecular, metabolic and physiological responses were studied at time points 0.5 h, 3 h, 6 h, 12 h, 24 h and 48 h after transfer to HL conditions. The integrated results indicate that the acclimation mechanisms in diatoms can be divided into an initial response phase (0-0.5 h, an intermediate acclimation phase (3-12 h and a late acclimation phase (12-48 h. The initial phase is recognized by strong and rapid regulation of genes encoding proteins involved in photosynthesis, pigment metabolism and reactive oxygen species (ROS scavenging systems. A significant increase in light protecting metabolites occur together with the induction of transcriptional processes involved in protection of cellular structures at this early phase. During the following phases, the metabolite profiling display a pronounced decrease in light harvesting pigments, whereas the variable fluorescence measurements show that the photosynthetic capacity increases strongly during the late acclimation phase. We show that P. tricornutum is capable of swift and efficient execution of photoprotective mechanisms, followed by changes in the composition of the photosynthetic machinery that enable the diatoms to utilize the excess energy available in HL. Central molecular players in light protection and acclimation to high irradiance have been identified.

  4. Integrative taxonomy and molecular phylogeny of genus Aplysina (Demospongiae: Verongida from Mexican Pacific.

    Directory of Open Access Journals (Sweden)

    José Antonio Cruz-Barraza

    Full Text Available Integrative taxonomy provides a major approximation to species delimitation based on integration of different perspectives (e.g. morphology, biochemistry and DNA sequences. The aim of this study was to assess the relationships and boundaries among Eastern Pacific Aplysina species using morphological, biochemical and molecular data. For this, a collection of sponges of the genus Aplysina from the Mexican Pacific was studied on the basis of their morphological, chemical (chitin composition, and molecular markers (mitochondrial COI and nuclear ribosomal rDNA: ITS1-5.8-ITS2. Three morphological species were identified, two of which are new to science. A. clathrata sp. nov. is a yellow to yellow-reddish or -brownish sponge, characterized by external clathrate-like morphology; A. revillagigedi sp. nov. is a lemon yellow to green, cushion-shaped sometimes lobate sponge, characterized by conspicuous oscules, which are slightly elevated and usually linearly distributed on rims; and A. gerardogreeni a known species distributed along the Mexican Pacific coast. Chitin was identified as the main structural component within skeletons of the three species using FTIR, confirming that it is shared among Verongida sponges. Morphological differences were confirmed by DNA sequences from nuclear ITS1-5.8-ITS2. Mitochondrial COI sequences showed extremely low but diagnostic variability for Aplysina revillagigedi sp. nov., thus our results corroborate that COI has limited power for DNA-barcoding of sponges and should be complemented with other markers (e.g. rDNA. Phylogenetic analyses of Aplysina sequences from the Eastern Pacific and Caribbean, resolved two allopatric and reciprocally monophyletic groups for each region. Eastern Pacific species were grouped in general accordance with the taxonomic hypothesis based on morphological characters. An identification key of Eastern Pacific Aplysina species is presented. Our results constitute one of the first approximations

  5. Accelerating ab initio path integral molecular dynamics with multilevel sampling of potential surface

    Energy Technology Data Exchange (ETDEWEB)

    Geng, Hua Y., E-mail: huay.geng@gmail.com [National Key Laboratory of Shock Wave and Detonation Physics, Institute of Fluid Physics, CAEP, P.O. Box 919-102, Mianyang, Sichuan, 621900 (China); Department of Chemistry and Chemical Biology, Cornell University, Baker Laboratory, Ithaca, NY 14853 (United States)

    2015-02-15

    A multilevel approach to sample the potential energy surface in a path integral formalism is proposed. The purpose is to reduce the required number of ab initio evaluations of energy and forces in ab initio path integral molecular dynamics (AI-PIMD) simulation, without compromising the overall accuracy. To validate the method, the internal energy and free energy of an Einstein crystal are calculated and compared with the analytical solutions. As a preliminary application, we assess the performance of the method in a realistic model—the FCC phase of dense atomic hydrogen, in which the calculated result shows that the acceleration rate is about 3 to 4-fold for a two-level implementation, and can be increased up to 10 times if extrapolation is used. With only 16 beads used for the ab initio potential sampling, this method gives a well converged internal energy. The residual error in pressure is just about 3 GPa, whereas it is about 20 GPa for a plain AI-PIMD calculation with the same number of beads. The vibrational free energy of the FCC phase of dense hydrogen at 300 K is also calculated with an AI-PIMD thermodynamic integration method, which gives a result of about 0.51 eV/proton at a density of r{sub s}=0.912.

  6. Accelerating ab initio path integral molecular dynamics with multilevel sampling of potential surface

    Science.gov (United States)

    Geng, Hua Y.

    2015-02-01

    A multilevel approach to sample the potential energy surface in a path integral formalism is proposed. The purpose is to reduce the required number of ab initio evaluations of energy and forces in ab initio path integral molecular dynamics (AI-PIMD) simulation, without compromising the overall accuracy. To validate the method, the internal energy and free energy of an Einstein crystal are calculated and compared with the analytical solutions. As a preliminary application, we assess the performance of the method in a realistic model-the FCC phase of dense atomic hydrogen, in which the calculated result shows that the acceleration rate is about 3 to 4-fold for a two-level implementation, and can be increased up to 10 times if extrapolation is used. With only 16 beads used for the ab initio potential sampling, this method gives a well converged internal energy. The residual error in pressure is just about 3 GPa, whereas it is about 20 GPa for a plain AI-PIMD calculation with the same number of beads. The vibrational free energy of the FCC phase of dense hydrogen at 300 K is also calculated with an AI-PIMD thermodynamic integration method, which gives a result of about 0.51 eV/proton at a density of rs = 0.912.

  7. Differential amplicons (ΔAmp—a new molecular method to assess RNA integrity

    Directory of Open Access Journals (Sweden)

    J. Björkman

    2016-01-01

    Full Text Available Integrity of the mRNA in clinical samples has major impact on the quality of measured expression levels. This is independent of the measurement technique being next generation sequencing (NGS, Quantitative real-time PCR (qPCR or microarray profiling. If mRNA is highly degraded or damaged, measured data will be very unreliable and the whole study is likely a waste of time and money. It is therefore common strategy to test the quality of RNA in samples before conducting large and costly studies. Most methods today to assess the quality of RNA are ignorant to the nature of the RNA and, therefore, reflect the integrity of ribosomal RNA, which is the dominant species, rather than of mRNAs, microRNAs and long non-coding RNAs, which usually are the species of interest. Here, we present a novel molecular approach to assess the quality of the targeted RNA species by measuring the differential amplification (ΔAmp of an Endogenous RNase Resistant (ERR marker relative to a reference gene, optionally combined with the measurement of two amplicons of different lengths. The combination reveals any mRNA degradation caused by ribonucleases as well as physical, chemical or UV damage. ΔAmp has superior sensitivity to common microfluidic electrophoretic methods, senses the integrity of the actual targeted RNA species, and allows for a smoother and more cost efficient workflow.

  8. Quantum threshold group signature

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In most situations, the signer is generally a single person. However, when the message is written on behalf of an organization, a valid message may require the approval or consent of several persons. Threshold signature is a solution to this problem. Generally speaking, as an authority which can be trusted by all members does not exist, a threshold signature scheme without a trusted party appears more attractive. Following some ideas of the classical Shamir’s threshold signature scheme, a quantum threshold group signature one is proposed. In the proposed scheme, only t or more of n persons in the group can generate the group signature and any t-1 or fewer ones cannot do that. In the verification phase, any t or more of n signature receivers can verify the message and any t-1 or fewer receivers cannot verify the validity of the signature.

  9. About group digital signatures

    Directory of Open Access Journals (Sweden)

    Adriana Cristina Enache

    2012-09-01

    Full Text Available

    Group signatures try to combine security (no framing, no cheating and privacy(anonymity, unlinkability.A group digital signature is a digital signature with enhanced privacy features that allows members of a given group to anonymously sign messages on behalf of the group, producing a group signature. However, in the case of dispute the identity of the signature's originator can be revealed by a designated entity (group manager. The present paper describes the main concepts about group signatures, along with a brief state of the art and shows a personal cryptographic library implemented in Java that includes two group signatures.

  10. Forward secure digital signature for electronic medical records.

    Science.gov (United States)

    Yu, Yao-Chang; Huang, To-Yeh; Hou, Ting-Wei

    2012-04-01

    The Technology Safeguard in Health Insurance Portability and Accountability Act (HIPAA) Title II has addressed a way to maintain the integrity and non-repudiation of Electronic Medical Record (EMR). One of the important cryptographic technologies is mentioned in the ACT is digital signature; however, the ordinary digital signature (e.g. DSA, RSA, GQ...) has an inherent weakness: if the key (certificate) is updated, than all signatures, even the ones generated before the update, are no longer trustworthy. Unfortunately, the current most frequently used digital signature schemes are categorized into the ordinary digital signature scheme; therefore, the objective of this paper is to analyze the shortcoming of using ordinary digital signatures in EMR and to propose a method to use forward secure digital signature to sign EMR to ensure that the past EMR signatures remain trustworthy while the key (certificate) is updated.

  11. Arbitrated quantum signature schemes without using entangled states

    CERN Document Server

    Zou, Xiangfu

    2010-01-01

    A digital signature is a mathematical scheme for demonstrating the authenticity of a digital message or document. For signing quantum messages, some arbitrated quantum signature schemes have being proposed. However, in the existing literature, arbitrated quantum signature schemes depend on entanglement. In this paper, we present two arbitrated quantum signature schemes without utilizing entangled states in the signing phase and the verifying phase. The first proposed scheme can preserve the merits in the existing schemes. Then, we point out, in this scheme and the prior schemes, there exists a problem that Bob can repudiate the integrality of the signatures. To conquer this problem, we construct another arbitrated quantum signature scheme without using quantum entangled states but using a public board. The new scheme has three advantages: it does not utilize entangled states while it can preserve all merits in the existing schemes; the integrality of the signature can avoid being disavowed by the receiver; an...

  12. Harnessing Integrative Omics to Facilitate Molecular Imaging of the Human Epidermal Growth Factor Receptor Family for Precision Medicine.

    Science.gov (United States)

    Pool, Martin; de Boer, H Rudolf; Hooge, Marjolijn N Lub-de; van Vugt, Marcel A T M; de Vries, Elisabeth G E

    2017-01-01

    Cancer is a growing problem worldwide. The cause of death in cancer patients is often due to treatment-resistant metastatic disease. Many molecularly targeted anticancer drugs have been developed against 'oncogenic driver' pathways. However, these treatments are usually only effective in properly selected patients. Resistance to molecularly targeted drugs through selective pressure on acquired mutations or molecular rewiring can hinder their effectiveness. This review summarizes how molecular imaging techniques can potentially facilitate the optimal implementation of targeted agents. Using the human epidermal growth factor receptor (HER) family as a model in (pre)clinical studies, we illustrate how molecular imaging may be employed to characterize whole body target expression as well as monitor drug effectiveness and the emergence of tumor resistance. We further discuss how an integrative omics discovery platform could guide the selection of 'effect sensors' - new molecular imaging targets - which are dynamic markers that indicate treatment effectiveness or resistance.

  13. Bulk and integrated acousto-optic spectrometers for molecular astronomy with heterodyne spectrometers

    Science.gov (United States)

    Chin, G.; Buhl, D.; Florez, J. M.

    1981-01-01

    A survey of acousto-optic spectrometers for molecular astronomy is presented, noting a technique of combining the acoustic bending of a collimated coherent light beam with a Bragg cell followed by an array of sensitive photodetectors. This acousto-optic spectrometer has a large bandwidth, a large number of channels, high resolution, and is energy efficient. Receiver development has concentrated on high-frequency heterodyne systems for the study of the chemical composition of the interstellar medium. RF spectrometers employing acousto-optic diffraction cells are described. Acousto-optic techniques have been suggested for applications to electronic warfare, electronic countermeasures and electronic support systems. Plans to use integrated optics for the further miniaturization of acousto-optic spectrometers are described. Bulk acousto-optic spectrometers with 300 MHz and 1 GHz bandwidths are being developed for use in the back-end of high-frequency heterodyne receivers for astronomical research.

  14. Path integral centroid molecular dynamics simulation of para-hydrogen sandwiched by graphene sheets

    Science.gov (United States)

    Minamino, Yuki; Kinugawa, Kenichi

    2016-11-01

    The carbon-hydrogen composite systems of para-hydrogen (p-H2) sandwiched by a couple of graphene sheets have been investigated by means of path integral centroid molecular dynamics simulations at 17 K. It has been shown that sandwiched hydrogen is liquid-like but p-H2 molecules are preferably adsorbed onto the graphene sheets because of attractive graphene-hydrogen interaction. The diffusion coefficient of p-H2 molecules in the direction parallel to the graphene sheets is comparable to that in pure liquid p-H2. There exists a characteristic mode of 140 cm-1 of the p-H2 molecules, attributed to adsorption-binding motion perpendicular to the graphene sheets.

  15. Geometric isotope effects on small chloride ion water clusters with path integral molecular dynamics simulations

    Science.gov (United States)

    Wang, Qi; Suzuki, Kimichi; Nagashima, Umpei; Tachikawa, Masanori; Yan, Shiwei

    2013-11-01

    The geometric isotope effects on the structures of hydrated chloride ionic hydrogen bonded clusters are explored by carrying out path integral molecular dynamics simulations. First, an outer shell coordinate is selected to display the rearrangement of single and multi hydration shell cluster structures. Next, to show the competition of intramolecular and intermolecular nuclear quantum effects, the intramolecular OH∗ stretching and intermolecular ion-water wagging motions are studied for single and multi shell structures, respectively. The results indicate that the intermolecular nuclear quantum effects stabilize the ionic hydrogen bonds in single shell structures, while they are destabilized through the competition with intramolecular nuclear quantum effects in multi shell structures. In addition, the correlations between ion-water stretching motion and other cluster vibrational coordinates are discussed. The results indicate that the intermolecular nuclear quantum effects on the cluster structures are strongly related to the cooperation of the water-water hydrogen bond interactions.

  16. Low-temperature anharmonicity of barium titanate: A path-integral molecular-dynamics study

    Science.gov (United States)

    Geneste, Grégory; Dammak, Hichem; Hayoun, Marc; Thiercelin, Mickael

    2013-01-01

    We investigate the influence of quantum effects on the dielectric and piezoelectric properties of barium titanate in its (low-temperature) rhombohedral phase, and show the strongly anharmonic character of this system even at low temperature. For this purpose, we perform path-integral molecular-dynamics simulations under fixed pressure and fixed temperature, using an efficient Langevin thermostat-barostat, and an effective Hamiltonian derived from first-principles calculations. The quantum fluctuations are shown to significantly enhance the static dielectric susceptibility (≈ by a factor of 2) and the piezoelectric constants, reflecting the strong anharmonicity of this ferroelectric system even at very low temperature. The slow temperature-evolution of the dielectric properties observed below ≈100 K is attributed (i) to zero-point energy contributions and (ii) to harmonic behavior if the quantum effects are turned off.

  17. Path Integral Monte Carlo and Density Functional Molecular Dynamics Simulations of Warm Dense Matter

    Science.gov (United States)

    Militzer, Burkhard; Driver, Kevin

    2011-10-01

    We analyze the applicability of two first-principles simulation techniques, path integral Monte Carlo (PIMC) and density functional molecular dynamics (DFT-MD), to study the regime of warm dense matter. We discuss the advantages as well as the limitations of each method and propose directions for future development. Results for dense, liquid helium, where both methods have been applied, demonstrate the range of each method's applicability. Comparison of the equations of state from simulations with analytical theories and free energy models show that DFT is useful for temperatures below 100000 K and then PIMC provides accurate results for all higher temperatures. We characterize the structure of the liquid in terms of pair correlation functions and study the closure of the band gap with increasing density and temperature. Finally, we discuss simulations of heavier elements and demonstrate the reliability are both methods in such cases with preliminary results.

  18. Mapping variable ring polymer molecular dynamics: A path-integral based method for nonadiabatic processes

    Science.gov (United States)

    Ananth, Nandini

    2013-09-01

    We introduce mapping-variable ring polymer molecular dynamics (MV-RPMD), a model dynamics for the direct simulation of multi-electron processes. An extension of the RPMD idea, this method is based on an exact, imaginary time path-integral representation of the quantum Boltzmann operator using continuous Cartesian variables for both electronic states and nuclear degrees of freedom. We demonstrate the accuracy of the MV-RPMD approach in calculations of real-time, thermal correlation functions for a range of two-state single-mode model systems with different coupling strengths and asymmetries. Further, we show that the ensemble of classical trajectories employed in these simulations preserves the Boltzmann distribution and provides a direct probe into real-time coupling between electronic state transitions and nuclear dynamics.

  19. Hydrogen and muonium in diamond: A path-integral molecular dynamics simulation

    Science.gov (United States)

    Herrero, Carlos P.; Ramírez, Rafael; Hernández, Eduardo R.

    2006-06-01

    Isolated hydrogen, deuterium, and muonium in diamond have been studied by path-integral molecular dynamics simulations in the canonical ensemble. Finite-temperature properties of these point defects were analyzed in the range from 100 to 800K . Interatomic interactions were modeled by a tight-binding potential fitted to density-functional calculations. The most stable position for these hydrogenic impurities is found at the C-C bond center. Vibrational frequencies have been obtained from a linear-response approach, based on correlations of atom displacements at finite temperatures. The results show a large anharmonic effect in impurity vibrations at the bond center site, which hardens the vibrational modes with respect to a harmonic approximation. Zero-point motion causes an appreciable shift of the defect level in the electronic gap, as a consequence of electron-phonon interaction. This defect level goes down by 70meV when replacing hydrogen by muonium.

  20. Quantum tautomerization in porphycene and its isotopomers: Path-integral molecular dynamics simulations

    Science.gov (United States)

    Yoshikawa, Takehiro; Sugawara, Shuichi; Takayanagi, Toshiyuki; Shiga, Motoyuki; Tachikawa, Masanori

    2012-02-01

    Path-integral molecular dynamics simulations have been performed for porphycene and its isotopic variants in order to understand the effect of isotopic substitution of inner protons on the double proton transfer mechanism. We have used an on-the-fly direct dynamics technique at the semiempirical PM6 level combined with specific reaction parameterization. Our quantum simulations show that double proton transfer of the unsubstituted porphycene at T = 300 K mainly occurs via a so-called concerted mechanism through the D2h second-order saddle point. In addition, we found that both isotopic substitution and temperature significantly affect the double proton transfer mechanism. For example, the contribution of the stepwise mechanism increases with a temperature increase. We have also carried out hypothetical simulations with the porphycene configurations being completely planar. It has been found that out-of-plane vibrational motions significantly decrease the contribution of the concerted proton transfer mechanism.

  1. Equilibrium fractionation of H and O isotopes in water from path integral molecular dynamics

    Science.gov (United States)

    Pinilla, Carlos; Blanchard, Marc; Balan, Etienne; Ferlat, Guillaume; Vuilleumier, Rodolphe; Mauri, Francesco

    2014-06-01

    The equilibrium fractionation factor between two phases is of importance for the understanding of many planetary and environmental processes. Although thermodynamic equilibrium can be achieved between minerals at high temperature, many natural processes involve reactions between liquids or aqueous solutions and solids. For crystals, the fractionation factor α can be theoretically determined using a statistical thermodynamic approach based on the vibrational properties of the phases. These calculations are mostly performed in the harmonic approximation, using empirical or ab-initio force fields. In the case of aperiodic and dynamic systems such as liquids or solutions, similar calculations can be done using finite-size molecular clusters or snapshots obtained from molecular dynamics (MD) runs. It is however difficult to assess the effect of these approximate models on the isotopic fractionation properties. In this work we present a systematic study of the calculation of the D/H and 18O/16O equilibrium fractionation factors in water for the liquid/vapour and ice/vapour phases using several levels of theory within the simulations. Namely, we use a thermodynamic integration approach based on Path Integral MD calculations (PIMD) and an empirical potential model of water. Compared with standard MD, PIMD takes into account quantum effects in the thermodynamic modeling of systems and the exact fractionation factor for a given potential can be obtained. We compare these exact results with those of modeling strategies usually used, which involve the mapping of the quantum system on its harmonic counterpart. The results show the importance of including configurational disorder for the estimation of isotope fractionation in liquid phases. In addition, the convergence of the fractionation factor as a function of parameters such as the size of the simulated system and multiple isotope substitution is analyzed, showing that isotope fractionation is essentially a local effect in

  2. Path Integral Molecular Dynamics within the Grand Canonical-like Adaptive Resolution Technique: Quantum-Classical Simulation of Liquid Water

    CERN Document Server

    Agarwal, Animesh

    2015-01-01

    Quantum effects due to the spatial delocalization of light atoms are treated in molecular simulation via the path integral technique. Among several methods, Path Integral (PI) Molecular Dynamics (MD) is nowadays a powerful tool to investigate properties induced by spatial delocalization of atoms; however computationally this technique is very demanding. The abovementioned limitation implies the restriction of PIMD applications to relatively small systems and short time scales. One possible solution to overcome size and time limitation is to introduce PIMD algorithms into the Adaptive Resolution Simulation Scheme (AdResS). AdResS requires a relatively small region treated at path integral level and embeds it into a large molecular reservoir consisting of generic spherical coarse grained molecules. It was previously shown that the realization of the idea above, at a simple level, produced reasonable results for toy systems or simple/test systems like liquid parahydrogen. Encouraged by previous results, in this ...

  3. Chemical and Physical Signatures for Microbial Forensics

    Energy Technology Data Exchange (ETDEWEB)

    Cliff, John B.; Kreuzer, Helen W.; Ehrhardt, Christopher J.; Wunschel, David S.

    2012-01-03

    Chemical and physical signatures for microbial forensics John Cliff and Helen Kreuzer-Martin, eds. Humana Press Chapter 1. Introduction: Review of history and statement of need. Randy Murch, Virginia Tech Chapter 2. The Microbe: Structure, morphology, and physiology of the microbe as they relate to potential signatures of growth conditions. Joany Jackman, Johns Hopkins University Chapter 3. Science for Forensics: Special considerations for the forensic arena - quality control, sample integrity, etc. Mark Wilson (retired FBI): Western Carolina University Chapter 4. Physical signatures: Light and electron microscopy, atomic force microscopy, gravimetry etc. Joseph Michael, Sandia National Laboratory Chapter 5. Lipids: FAME, PLFA, steroids, LPS, etc. James Robertson, Federal Bureau of Investigation Chapter 6. Carbohydrates: Cell wall components, cytoplasm components, methods Alvin Fox, University of South Carolina School of Medicine David Wunschel, Pacific Northwest National Laboratory Chapter 7. Peptides: Peptides, proteins, lipoproteins David Wunschel, Pacific Northwest National Laboratory Chapter 8. Elemental content: CNOHPS (treated in passing), metals, prospective cell types John Cliff, International Atomic Energy Agency Chapter 9. Isotopic signatures: Stable isotopes C,N,H,O,S, 14C dating, potential for heavy elements. Helen Kreuzer-Martin, Pacific Northwest National Laboratory Michaele Kashgarian, Lawrence Livermore National Laboratory Chapter 10. Extracellular signatures: Cellular debris, heme, agar, headspace, spent media, etc Karen Wahl, Pacific Northwest National Laboratory Chapter 11. Data Reduction and Integrated Microbial Forensics: Statistical concepts, parametric and multivariate statistics, integrating signatures Kristin Jarman, Pacific Northwest National Laboratory

  4. QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

    Science.gov (United States)

    Ribeiro, João V.; Bernardi, Rafael C.; Rudack, Till; Stone, John E.; Phillips, James C.; Freddolino, Peter L.; Schulten, Klaus

    2016-05-01

    The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services.

  5. Molecular classification based on apomorphic amino acids (Arthropoda, Hexapoda): Integrative taxonomy in the era of phylogenomics.

    Science.gov (United States)

    Wu, Hao-Yang; Wang, Yan-Hui; Xie, Qiang; Ke, Yun-Ling; Bu, Wen-Jun

    2016-06-17

    With the great development of sequencing technologies and systematic methods, our understanding of evolutionary relationships at deeper levels within the tree of life has greatly improved over the last decade. However, the current taxonomic methodology is insufficient to describe the growing levels of diversity in both a standardised and general way due to the limitations of using only morphological traits to describe clades. Herein, we propose the idea of a molecular classification based on hierarchical and discrete amino acid characters. Clades are classified based on the results of phylogenetic analyses and described using amino acids with group specificity in phylograms. Practices based on the recently published phylogenomic datasets of insects together with 15 de novo sequenced transcriptomes in this study demonstrate that such a methodology can accommodate various higher ranks of taxonomy. Such an approach has the advantage of describing organisms in a standard and discrete way within a phylogenetic framework, thereby facilitating the recognition of clades from the view of the whole lineage, as indicated by PhyloCode. By combining identification keys and phylogenies, the molecular classification based on hierarchical and discrete characters may greatly boost the progress of integrative taxonomy.

  6. Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity.

    Science.gov (United States)

    Pamplona, Reinald

    2008-10-01

    Nonenzymatic molecular modifications induced by reactive carbonyl species (RCS) generated by peroxidation of membrane phospholipids acyl chains play a causal role in the aging process. Most of the biological effects of RCS, mainly alpha,beta-unsaturated aldehydes, di-aldehydes, and keto-aldehydes, are due to their capacity to react with cellular constituents, forming advanced lipoxidation end-products (ALEs). Compared to reactive oxygen and nitrogen species, lipid-derived RCS are stable and can diffuse within or even escape from the cell and attack targets far from the site of formation. Therefore, these soluble reactive intermediates, precursors of ALEs, are not only cytotoxic per se, but they also behave as mediators and propagators of oxidative stress and cellular and tissue damage. The consequent loss-of-function and structural integrity of modified biomolecules can have a wide range of downstream functional consequences and may be the cause of subsequent cellular dysfunctions and tissue damage. The causal role of ALEs in aging and longevity is inferred from the findings that follow: a) its accumulation with aging in several tissues and species; b) physiological interventions (dietary restriction) that increase longevity, decrease ALEs content; c) the longer the longevity of a species, the lower is the lipoxidation-derived molecular damage; and finally d) exacerbated levels of ALEs are associated with pathological states.

  7. QwikMD - Integrative Molecular Dynamics Toolkit for Novices and Experts.

    Science.gov (United States)

    Ribeiro, João V; Bernardi, Rafael C; Rudack, Till; Stone, John E; Phillips, James C; Freddolino, Peter L; Schulten, Klaus

    2016-05-24

    The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services.

  8. Integrating Survey and Molecular Approaches to Better Understand Wildlife Disease Ecology

    Science.gov (United States)

    Cowled, Brendan D.; Ward, Michael P.; Laffan, Shawn W.; Galea, Francesca; Garner, M. Graeme; MacDonald, Anna J.; Marsh, Ian; Muellner, Petra; Negus, Katherine; Quasim, Sumaiya; Woolnough, Andrew P.; Sarre, Stephen D.

    2012-01-01

    Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa) population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design) versus transmission (molecular case series study design) and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37–45%). The median Salmonella DICE coefficient (or Salmonella genetic similarity) was 52% (interquartile range [IQR]: 42–62%). Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density) determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is driven by

  9. Integrating survey and molecular approaches to better understand wildlife disease ecology.

    Directory of Open Access Journals (Sweden)

    Brendan D Cowled

    Full Text Available Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design versus transmission (molecular case series study design and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37-45%. The median Salmonella DICE coefficient (or Salmonella genetic similarity was 52% (interquartile range [IQR]: 42-62%. Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is

  10. Accelerating ab initio path integral molecular dynamics with multilevel sampling of potential surface

    CERN Document Server

    Geng, Hua Y

    2014-01-01

    A multilevel approach to sample the potential energy surface in a path integral formalism is proposed. The purpose is to reduce the required number of ab initio evaluations of energy and forces in ab initio path integral molecular dynamics (AI-PIMD) simulation, without compromising the overall accuracy. To validate the method, the internal energy and free energy of an Einstein crystal are calculated and compared with the analytical solutions. As a preliminary application, we assess the performance of the method in a realistic model, the FCC phase of dense atomic hydrogen, in which the calculated result shows that the acceleration rate is about 3 to 4 fold for a two-level implementation, and can be increased to 10 times if extrapolation is used. With only 16 beads used for the ab initio potential sampling, this method gives a well converged internal energy. The residual error in pressure is just about 3 GPa, whereas it is about 20 GPa for a plain AI-PIMD calculation with the same number of beads. The vibration...

  11. Ab initio path-integral molecular dynamics and the quantum nature of hydrogen bonds

    Science.gov (United States)

    Yexin, Feng; Ji, Chen; Xin-Zheng, Li; Enge, Wang

    2016-01-01

    The hydrogen bond (HB) is an important type of intermolecular interaction, which is generally weak, ubiquitous, and essential to life on earth. The small mass of hydrogen means that many properties of HBs are quantum mechanical in nature. In recent years, because of the development of computer simulation methods and computational power, the influence of nuclear quantum effects (NQEs) on the structural and energetic properties of some hydrogen bonded systems has been intensively studied. Here, we present a review of these studies by focussing on the explanation of the principles underlying the simulation methods, i.e., the ab initio path-integral molecular dynamics. Its extension in combination with the thermodynamic integration method for the calculation of free energies will also be introduced. We use two examples to show how this influence of NQEs in realistic systems is simulated in practice. Project supported by the National Natural Science Foundation of China (Grant Nos. 11275008, 91021007, and 10974012) and the China Postdoctoral Science Foundation (Grant No. 2014M550005).

  12. The molecular architecture of the yeast spindle pole body core determined by Bayesian integrative modeling.

    Science.gov (United States)

    Viswanath, Shruthi; Bonomi, Massimiliano; Kim, Seung Joong; Klenchin, Vadim A; Taylor, Keenan C; Yabut, King C; Umbreit, Neil T; Van Epps, Heather A; Meehl, Janet; Jones, Michele H; Russel, Daniel; Velazquez-Muriel, Javier A; Winey, Mark; Rayment, Ivan; Davis, Trisha N; Sali, Andrej; Muller, Eric G

    2017-08-16

    Microtubule organizing centers (MTOCs) form, anchor and stabilize the polarized network of microtubules in a cell. The central MTOC is the centrosome that duplicates during the cell cycle and during mitosis assembles a bipolar spindle to capture and segregate sister chromatids. Yet, despite their importance in cell biology, the physical structure of MTOCs is poorly understood. Here we determine the molecular architecture of the core of the yeast spindle pole body (SPB) by Bayesian integrative structure modeling based on in vivo FRET, small-angle X-ray scattering (SAXS), X-ray crystallography, electron microscopy and two-hybrid analysis. The model is validated by several methods that include a genetic analysis of the conserved PACT domain that recruits Spc110, a protein related to pericentrin, to the SPB. The model suggests that calmodulin can act as a protein cross-linker and Spc29 is an extended, flexible protein. The model led to the identification of a single, essential heptad in the coiled coil of Spc110 and a minimal PACT domain. It also led to a proposed pathway for the integration of Spc110 into the SPB. © 2017 by The American Society for Cell Biology.

  13. Integrative Molecular Profiling Reveals Asparagine Synthetase Is a Target in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Sircar, Kanishka; Huang, Heng; Hu, Limei; Cogdell, David; Dhillon, Jasreman; Tzelepi, Vassiliki; Efstathiou, Eleni; Koumakpayi, Ismaël H.; Saad, Fred; Luo, Dijun; Bismar, Tarek A.; Aparicio, Ana; Troncoso, Patricia; Navone, Nora; Zhang, Wei

    2013-01-01

    The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy-resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen-responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells. PMID:22245216

  14. The eukaryotic cell originated in the integration and redistribution of hyperstructures from communities of prokaryotic cells based on molecular complementarity.

    Science.gov (United States)

    Norris, Vic; Root-Bernstein, Robert

    2009-06-04

    In the "ecosystems-first" approach to the origins of life, networks of non-covalent assemblies of molecules (composomes), rather than individual protocells, evolved under the constraints of molecular complementarity. Composomes evolved into the hyperstructures of modern bacteria. We extend the ecosystems-first approach to explain the origin of eukaryotic cells through the integration of mixed populations of bacteria. We suggest that mutualism and symbiosis resulted in cellular mergers entailing the loss of redundant hyperstructures, the uncoupling of transcription and translation, and the emergence of introns and multiple chromosomes. Molecular complementarity also facilitated integration of bacterial hyperstructures to perform cytoskeletal and movement functions.

  15. What is the molecular signature of mind-body interventions? A systematic review of gene expression changes induced by meditation and related practices

    NARCIS (Netherlands)

    Buric, I.; Farias, M.; Mee, C.J.; Jong, J.; Brazil, I.A.

    2017-01-01

    There is considerable evidence for the effectiveness of mind-body interventions (MBIs) in improving mental and physical health, but the molecular mechanisms of these benefits remain poorly understood. One hypothesis is that MBIs reverse expression of genes involved in inflammatory reactions that are

  16. Generalized Group Signature Scheme

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The concept of generalized group signature scheme will bepresent. Based on the generalized secret sharing scheme proposed by Lin and Ha rn, a non-interactive approach is designed for realizing such generalized group signature scheme. Using the new scheme, the authorized subsets of the group in w hich the group member can cooperate to produce the valid signature for any messa ge can be randomly specified

  17. Integration of Molecular Dynamics Based Predictions into the Optimization of De Novo Protein Designs: Limitations and Benefits.

    Science.gov (United States)

    Carvalho, Henrique F; Barbosa, Arménio J M; Roque, Ana C A; Iranzo, Olga; Branco, Ricardo J F

    2017-01-01

    Recent advances in de novo protein design have gained considerable insight from the intrinsic dynamics of proteins, based on the integration of molecular dynamics simulations protocols on the state-of-the-art de novo protein design protocols used nowadays. With this protocol we illustrate how to set up and run a molecular dynamics simulation followed by a functional protein dynamics analysis. New users will be introduced to some useful open-source computational tools, including the GROMACS molecular dynamics simulation software package and ProDy for protein structural dynamics analysis.

  18. Unconditionally Secure Quantum Signatures

    Directory of Open Access Journals (Sweden)

    Ryan Amiri

    2015-08-01

    Full Text Available Signature schemes, proposed in 1976 by Diffie and Hellman, have become ubiquitous across modern communications. They allow for the exchange of messages from one sender to multiple recipients, with the guarantees that messages cannot be forged or tampered with and that messages also can be forwarded from one recipient to another without compromising their validity. Signatures are different from, but no less important than encryption, which ensures the privacy of a message. Commonly used signature protocols—signatures based on the Rivest–Adleman–Shamir (RSA algorithm, the digital signature algorithm (DSA, and the elliptic curve digital signature algorithm (ECDSA—are only computationally secure, similar to public key encryption methods. In fact, since these rely on the difficulty of finding discrete logarithms or factoring large primes, it is known that they will become completely insecure with the emergence of quantum computers. We may therefore see a shift towards signature protocols that will remain secure even in a post-quantum world. Ideally, such schemes would provide unconditional or information-theoretic security. In this paper, we aim to provide an accessible and comprehensive review of existing unconditionally securesecure signature schemes for signing classical messages, with a focus on unconditionally secure quantum signature schemes.

  19. Radar Signature Calculation Facility

    Data.gov (United States)

    Federal Laboratory Consortium — FUNCTION: The calculation, analysis, and visualization of the spatially extended radar signatures of complex objects such as ships in a sea multipath environment and...

  20. Blind Collective Signature Protocol

    Directory of Open Access Journals (Sweden)

    Nikolay A. Moldovyan

    2011-06-01

    Full Text Available Using the digital signature (DS scheme specified by Belarusian DS standard there are designed the collective and blind collective DS protocols. Signature formation is performed simultaneously by all of the assigned signers, therefore the proposed protocols can be used also as protocols for simultaneous signing a contract. The proposed blind collective DS protocol represents a particular implementation of the blind multisignature schemes that is a novel type of the signature schemes. The proposed protocols are the first implementations of the multisignature schemes based on Belarusian signature standard.

  1. What Is the Molecular Signature of Mind–Body Interventions? A Systematic Review of Gene Expression Changes Induced by Meditation and Related Practices

    Directory of Open Access Journals (Sweden)

    Ivana Buric

    2017-06-01

    Full Text Available There is considerable evidence for the effectiveness of mind–body interventions (MBIs in improving mental and physical health, but the molecular mechanisms of these benefits remain poorly understood. One hypothesis is that MBIs reverse expression of genes involved in inflammatory reactions that are induced by stress. This systematic review was conducted to examine changes in gene expression that occur after MBIs and to explore how these molecular changes are related to health. We searched PubMed throughout September 2016 to look for studies that have used gene expression analysis in MBIs (i.e., mindfulness, yoga, Tai Chi, Qigong, relaxation response, and breath regulation. Due to the limited quantity of studies, we included both clinical and non-clinical samples with any type of research design. Eighteen relevant studies were retrieved and analyzed. Overall, the studies indicate that these practices are associated with a downregulation of nuclear factor kappa B pathway; this is the opposite of the effects of chronic stress on gene expression and suggests that MBI practices may lead to a reduced risk of inflammation-related diseases. However, it is unclear how the effects of MBIs compare to other healthy interventions such as exercise or nutrition due to the small number of available studies. More research is required to be able to understand the effects of MBIs at the molecular level.

  2. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-02-22

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC.

  3. Signatures of AGN feedback

    Science.gov (United States)

    Wylezalek, Dominika; Zakamska, Nadia L.; MaNGA-GMOS Team

    2017-01-01

    Feedback from actively accreting SMBHs (Active Galactic Nuclei, AGN) is now widely considered to be the main driver in regulating the growth of massive galaxies. Observational proof for this scenario has, however, been hard to come by. Many attempts at finding a conclusive observational proof that AGN may be able to quench star formation and regulate the host galaxies' growth have shown that this problem is highly complex.I will present results from several projects that focus on understanding the power, reach and impact of feedback processes exerted by AGN. I will describe recent efforts in our group of relating feedback signatures to the specific star formation rate in their host galaxies, where our results are consistent with the AGN having a `negative' impact through feedback on the galaxies' star formation history (Wylezalek+2016a,b). Furthermore, I will show that powerful AGN-driven winds can be easily hidden and not be apparent in the integrated spectrum of the galaxy. This implies that large IFU surveys, such as the SDSS-IV MaNGA survey, might uncover many previously unknown AGN and outflows that are potentially very relevant for understanding the role of AGN in galaxy evolution (Wylezalek+2016c)!

  4. An integrated approach to fast and informative morphological vouchering of nematodes for applications in molecular barcoding.

    Science.gov (United States)

    De Ley, Paul; De Ley, Irma Tandingan; Morris, Krystalynne; Abebe, Eyualem; Mundo-Ocampo, Manuel; Yoder, Melissa; Heras, Joseph; Waumann, Dora; Rocha-Olivares, Axayácatl; Jay Burr, A H; Baldwin, James G; Thomas, W Kelley

    2005-10-29

    Molecular surveys of meiofaunal diversity face some interesting methodological challenges when it comes to interstitial nematodes from soils and sediments. Morphology-based surveys are greatly limited in processing speed, while barcoding approaches for nematodes are hampered by difficulties of matching sequence data with traditional taxonomy. Intermediate technology is needed to bridge the gap between both approaches. An example of such technology is video capture and editing microscopy, which consists of the recording of taxonomically informative multifocal series of microscopy images as digital video clips. The integration of multifocal imaging with sequence analysis of the D2D3 region of large subunit (LSU) rDNA is illustrated here in the context of a combined morphological and barcode sequencing survey of marine nematodes from Baja California and California. The resulting video clips and sequence data are made available online in the database NemATOL (http://nematol.unh.edu/). Analyses of 37 barcoded nematodes suggest that these represent at least 32 species, none of which matches available D2D3 sequences in public databases. The recorded multifocal vouchers allowed us to identify most specimens to genus, and will be used to match specimens with subsequent species identifications and descriptions of preserved specimens. Like molecular barcodes, multifocal voucher archives are part of a wider effort at structuring and changing the process of biodiversity discovery. We argue that data-rich surveys and phylogenetic tools for analysis of barcode sequences are an essential component of the exploration of phyla with a high fraction of undiscovered species. Our methods are also directly applicable to other meiofauna such as for example gastrotrichs and tardigrades.

  5. Proton transport in triflic acid hydrates studied via path integral car-parrinello molecular dynamics.

    Science.gov (United States)

    Hayes, Robin L; Paddison, Stephen J; Tuckerman, Mark E

    2009-12-31

    The mono-, di-, and tetrahydrates of trifluoromethanesulfonic acid, which contain characteristic H(3)O(+), H(5)O(2)(+), and H(9)O(4)(+) structures, provide model systems for understanding proton transport in materials with high perfluorosulfonic acid density such as perfluorosulfonic acid membranes commonly employed in hydrogen fuel cells. Ab initio molecular dynamics simulations indicate that protons in these solids are predisposed to transfer to the water most strongly bound to sulfonate groups via a Grotthuss-type mechanism, but quickly return to the most solvated defect structure either due to the lack of a nearby species to stabilize the new defect or a preference for the proton to be maximally hydrated. Path integral molecular dynamics of the mono- and dihydrate reveal significant quantum effects that facilitate proton transfer to the "presolvated" water or SO(3)(-) in the first solvation shell and increase the Zundel character of all the defects. These trends are quantified in free energy profiles for each bonding environment. Hydrogen bonding criteria for HOH-OH(2) and HOH-O(3)S are extracted from the two-dimensional potential of mean force. The quantum radial distribution function, radius of gyration, and root-mean-square displacement position correlation function show that the protonic charge is distributed over two or more water molecules. Metastable structural defects with one excess proton shared between two sulfonate groups and another Zundel or Eigen type cation defect are found for the mono- and dihydrate but not for the tetrahydrate crystal. Results for the tetrahydrate native crystal exhibit minor differences at 210 and 250 K. IR spectra are calculated for all native and stable defect structures. Graph theory techniques are used to characterize the chain lengths and ring sizes in the hydrogen bond network. Low conductivities when limited water is present may be attributable to trapping of protons between SO(3)(-) groups and the increased

  6. Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet

    NARCIS (Netherlands)

    Derous, D.; Kelder, T.; Schothorst, E.M. van; Erk, M. van; Voigt, A.; Klaus, S.; Keijer, J.; Radonjic, M.

    2015-01-01

    Health is influenced by interplay of molecular, physiological and environmental factors. To effectively maintain health and prevent disease, health-relevant relations need to be understood at multiple levels of biological complexity. Network-based methods provide a powerful platform for integration

  7. Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet

    NARCIS (Netherlands)

    Derous, D.; Kelder, T.; Schothorst, E.M. van; Erk, M. van; Voigt, A.; Klaus, S.; Keijer, J.; Radonjic, M.

    2015-01-01

    Health is influenced by interplay of molecular, physiological and environmental factors. To effectively maintain health and prevent disease, health-relevant relations need to be understood at multiple levels of biological complexity. Network-based methods provide a powerful platform for integration

  8. Integrated Proteomic and Transcriptomic-Based Approaches to Identifying Signature Biomarkers and Pathways for Elucidation of Daoy and UW228 Subtypes

    Directory of Open Access Journals (Sweden)

    Roger Higdon

    2017-02-01

    Full Text Available Medulloblastoma (MB is the most common malignant pediatric brain tumor. Patient survival has remained largely the same for the past 20 years, with therapies causing significant health, cognitive, behavioral and developmental complications for those who survive the tumor. In this study, we profiled the total transcriptome and proteome of two established MB cell lines, Daoy and UW228, using high-throughput RNA sequencing (RNA-Seq and label-free nano-LC-MS/MS-based quantitative proteomics, coupled with advanced pathway analysis. While Daoy has been suggested to belong to the sonic hedgehog (SHH subtype, the exact UW228 subtype is not yet clearly established. Thus, a goal of this study was to identify protein markers and pathways that would help elucidate their subtype classification. A number of differentially expressed genes and proteins, including a number of adhesion, cytoskeletal and signaling molecules, were observed between the two cell lines. While several cancer-associated genes/proteins exhibited similar expression across the two cell lines, upregulation of a number of signature proteins and enrichment of key components of SHH and WNT signaling pathways were uniquely observed in Daoy and UW228, respectively. The novel information on differentially expressed genes/proteins and enriched pathways provide insights into the biology of MB, which could help elucidate their subtype classification.

  9. Revocable Ring Signature

    Institute of Scientific and Technical Information of China (English)

    Dennis Y. W. Liu; Joseph K. Liu; Yi Mu; Willy Susilo; Duncan S. Wong

    2007-01-01

    Group signature allows the anonymity of a real signer in a group to be revoked by a trusted party called group manager. It also gives the group manager the absolute power of controlling the formation of the group. Ring signature, on the other hand, does not allow anyone to revoke the signer anonymity, while allowing the real signer to forma group (also known as a ring) arbitrarily without being controlled by any other party. In this paper, we propose a new variant for ring signature, called Revocable Ring Signature. The signature allows a real signer to form a ring arbitrarily while allowing a set of authorities to revoke the anonymity of the real signer. This new variant inherits the desirable properties from both group signature and ring signature in such a way that the real signer will be responsible for what it has signed as the anonymity is revocable by authorities while the real signer still has the freedom on ring formation. We provide a formal security model for revocable ring signature and propose an efficient construction which is proven secure under our security model.

  10. Digital Signature Management.

    Science.gov (United States)

    Hassler, Vesna; Biely, Helmut

    1999-01-01

    Describes the Digital Signature Project that was developed in Austria to establish an infrastructure for applying smart card-based digital signatures in banking and electronic-commerce applications. Discusses the need to conform to international standards, an international certification infrastructure, and security features for a public directory…

  11. An integral equation and simulation study of hydrogen inclusions in a molecular crystal of short-capped nanotubes

    Science.gov (United States)

    Lomba, Enrique; Bores, Cecilia; Notario, Rafael; Sánchez-Gil, V.

    2016-09-01

    In this work we have assessed the ability of a recently proposed three-dimensional integral equation approach to describe the explicit spatial distribution of molecular hydrogen confined in a crystal formed by short-capped nanotubes of C50 H10. To that aim we have resorted to extensive molecular simulation calculations whose results have been compared with our three-dimensional integral equation approximation. We have first tested the ability of a single C50 H10 nanocage for the encapsulation of H2 by means of molecular dynamics simulations, in particular using targeted molecular dynamics to estimate the binding Gibbs energy of a host hydrogen molecule inside the nanocage. Then, we have investigated the adsorption isotherm of the nanocage crystal using grand canonical Monte Carlo simulations in order to evaluate the maximum load of molecular hydrogen. For a packing close to the maximum load explicit hydrogen density maps and density profiles have been determined using molecular dynamics simulations and the three-dimensional Ornstein-Zernike equation with a hypernetted chain closure. In these conditions of extremely tight confinement the theoretical approach has shown to be able to reproduce the three-dimensional structure of the adsorbed fluid with accuracy down to the finest details.

  12. Exometabolom analysis of breast cancer cell lines: Metabolic signature.

    Science.gov (United States)

    Willmann, Lucas; Erbes, Thalia; Halbach, Sebastian; Brummer, Tilman; Jäger, Markus; Hirschfeld, Marc; Fehm, Tanja; Neubauer, Hans; Stickeler, Elmar; Kammerer, Bernd

    2015-08-21

    Cancer cells show characteristic effects on cellular turnover and DNA/RNA modifications leading to elevated levels of excreted modified nucleosides. We investigated the molecular signature of different subtypes of breast cancer cell lines and the breast epithelial cell line MCF-10A. Prepurification of cell culture supernatants was performed by cis-diol specific affinity chromatography using boronate-derivatized polyacrylamide gel. Samples were analyzed by application of reversed phase chromatography coupled to a triple quadrupole mass spectrometer. Collectively, we determined 23 compounds from RNA metabolism, two from purine metabolism, five from polyamine/methionine cycle, one from histidine metabolism and two from nicotinate and nicotinamide metabolism. We observed major differences of metabolite excretion pattern between the breast cancer cell lines and MCF-10A, just as well as between the different breast cancer cell lines themselves. Differences in metabolite excretion resulting from cancerous metabolism can be integrated into altered processes on the cellular level. Modified nucleosides have great potential as biomarkers in due consideration of the heterogeneity of breast cancer that is reflected by the different molecular subtypes of breast cancer. Our data suggests that the metabolic signature of breast cancer cell lines might be a more subtype-specific tool to predict breast cancer, rather than a universal approach.

  13. The Transition from Atomic to Molecular Hydrogen in Interstellar Clouds: 21cm Signature of the Evolution of Cold Atomic Hydrogen in Dense Clouds

    CERN Document Server

    Goldsmith, P F; Krco, M; Goldsmith, Paul F.; Li, Di; Krco, Marko

    2006-01-01

    We have investigated the time scale for formation of molecular clouds by examining the conversion of HI to H2 using a time-dependent model. H2 formation on dust grains and cosmic ray and photo destruction are included in one-dimensional model slab clouds which incorporate time-independent density and temperature distributions. We calculate 21cm spectral line profiles seen in absorption against a background provided by general Galactic HI emission, and compare the model spectra with HI Narrow Self-Absorption, or HINSA, profiles absorbed in a number of nearby molecular clouds. The time evolution of the HI and H2 densities is dramatic, with the atomic hydrogen disappearing in a wave propagating from the central, denser regions which have a shorter H2 formation time scale, to the edges, where the density is lower and the time scale for H2 formation longer. The model 21cm spectra are characterized by very strong absorption at early times, when the HI column density through the model clouds is extremely large. The ...

  14. Deep sequencing revealed molecular signature of horizontal gene transfer of plant like transcripts in the mosquito Anopheles culicifacies: an evolutionary puzzle [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Punita Sharma

    2015-12-01

    Full Text Available In prokaryotes, horizontal gene transfer (HGT has been regarded as an important evolutionary drive to acquire and retain beneficial genes for their survival in diverse ecologies. However, in eukaryotes, the functional role of HGTs remains questionable, although current genomic tools are providing increased evidence of acquisition of novel traits within non-mating metazoan species. Here, we provide another transcriptomic evidence for the acquisition of massive plant genes in the mosquito, Anopheles culicifacies. Our multiple experimental validations including genomic PCR, RT-PCR, real-time PCR, immuno-blotting and immuno-florescence microscopy, confirmed that plant like transcripts (PLTs are of mosquito origin and may encode functional proteins. A comprehensive molecular analysis of the PLTs and ongoing metagenomic analysis of salivary microbiome provide initial clues that mosquitoes may have survival benefits through the acquisition of nuclear as well as chloroplast encoded plant genes. Our findings of PLTs further support the similar questionable observation of HGTs in other higher organisms, which is still a controversial and debatable issue in the community of evolutionists. We believe future understanding of the underlying mechanism of the feeding associated molecular responses may shed new insights in the functional role of PLTs in the mosquito.

  15. Critical zone study in Korea: integration of hydrogeology, mineralogy, sedimentology and molecular biogeochemistry

    Science.gov (United States)

    Lee, J. Y.; Kwon, K.; Jo, K. N.; Lee, J. S.

    2015-12-01

    Critical Zone (CZ) is the topmost layer of the Earth ranging from the vegetation canopy down to the soil, groundwater, and bedrock that sustains our ecosystem including human life. This CZ is being greatly influenced by the climate change and anthropogenic forces. We introduce the Critical Zone Frontier Research Laboratory (CFRL), a critical zone research lab recently funded by the Korean government for 2015-2020. The objective of CFRL is to unravel the relationships between climate and CZ changes to propose a prediction model for future responses of CZ to climate change. For this ultimate goal, we establish multiple CZ observatories in Kangwon areas and investigate soil, groundwater, and cave environments by integration of hydrogeology, mineralogy, sedimentology and molecular biogeochemistry. This study will enhance our understanding about CZ and local resolution of a climate change model. This research is financially supported by the Basic Research Laboratory Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning.

  16. On the Intramolecular Hydrogen Bond in Solution: Car-Parrinello and Path Integral Molecular Dynamics Perspective.

    Science.gov (United States)

    Dopieralski, Przemyslaw; Perrin, Charles L; Latajka, Zdzislaw

    2011-11-08

    The issue of the symmetry of short, low-barrier hydrogen bonds in solution is addressed here with advanced ab initio simulations of a hydrogen maleate anion in different environments, starting with the isolated anion, going through two crystal structures (sodium and potassium salts), then to an aqueous solution, and finally in the presence of counterions. By Car-Parrinello and path integral molecular dynamics simulations, it is demonstrated that the position of the proton in the intramolecular hydrogen bond of an aqueous hydrogen maleate anion is entirely related to the solvation pattern around the oxygen atoms of the intramolecular hydrogen bond. In particular, this anion has an asymmetric hydrogen bond, with the proton always located on the oxygen atom that is less solvated, owing to the instantaneous solvation environment. Simulations of water solutions of hydrogen maleate ion with two different counterions, K(+) and Na(+), surprisingly show that the intramolecular hydrogen-bond potential in the case of the Na(+) salt is always asymmetric, regardless of the hydrogen bonds to water, whereas for the K(+) salt, the potential for H motion depends on the location of the K(+). It is proposed that repulsion by the larger and more hydrated K(+) is weaker than that by Na(+) and competitive with solvation by water.

  17. Determination of the protonation state of the Asp dyad: conventional molecular dynamics versus thermodynamic integration.

    Science.gov (United States)

    Huang, Jinfeng; Zhu, Yali; Sun, Bin; Yao, Yuan; Liu, Junjun

    2016-03-01

    The protonation state of the Asp dyad is important as it can reveal enzymatic mechanisms, and the information this provides can be used in the development of drugs for proteins such as memapsin 2 (BACE-1), HIV-1 protease, and rennin. Conventional molecular dynamics (MD) simulations have been successfully used to determine the preferred protonation state of the Asp dyad. In the present work, we demonstrate that the results obtained from conventional MD simulations can be greatly influenced by the particular force field applied or the values used for control parameters. In principle, free-energy changes between possible protonation states can be used to determine the protonation state. We show that protonation state prediction by the thermodynamic integration (TI) method is insensitive to force field version or to the cutoff for calculating nonbonded interactions (a control parameter). In the present study, the protonation state of the Asp dyad predicted by TI calculations was the same regardless of the force field and cutoff value applied. Contrary to the intuition that conventional MD is more efficient, our results clearly show that the TI method is actually more efficient and more reliable for determining the protonation state of the Asp dyad.

  18. The quantum nature of the hydrogen bond: insight from path-integral molecular dynamics

    Science.gov (United States)

    Walker, Brent; Li, Xin-Zheng; Michaelides, Angelos

    2011-03-01

    Hydrogen (H) bonds are weak, generally intermolecular bonds, that hold together much of soft matter, the condensed phases of water, network liquids, and many ferroelectric crystals. The small mass of H means H-bonds are inherently quantum mechanical; effects such as zero point motion and tunneling should be considered, although often are not. In particular, a consistent picture of quantum nuclear effects on the strength of H-bonds and consequently the structure of H-bonded systems is still absent. Here, we report ab initio path-integral molecular dynamics studies on the quantum nature of the H-bond. Systematic examination of a range of H-bonded systems shows that quantum nuclei weaken weak H-bonds but strengthen relatively strong ones. This correlation arises from a competition between anharmonic intermolecular bond bending and intramolecular bond stretching. A simple rule of thumb enables predictions to be made for H-bonded bonded materials in general with merely classical knowledge (e.g. H-bond strength or H-bond length). Our work rationalizes the contrasting influence of quantum nuclear dynamics on a wide variety of materials, including liquid water and HF, and highlights the need for flexible molecules in force-field based studies of quantum nuclear dynamics.

  19. Path-integral molecular dynamics simulation of 3C-SiC

    Science.gov (United States)

    Ramírez, Rafael; Herrero, Carlos P.; Hernández, Eduardo R.; Cardona, Manuel

    2008-01-01

    Molecular dynamics simulations of 3C-SiC have been performed as a function of pressure and temperature. These simulations treat both electrons and atomic nuclei by quantum mechanical methods. While the electronic structure of the solid is described by an efficient tight-binding Hamiltonian, the nuclei dynamics is treated by the path-integral formulation of statistical mechanics. To assess the relevance of nuclear quantum effects, the results of quantum simulations are compared to others where either the Si nuclei, the C nuclei, or both atomic nuclei are treated as classical particles. We find that the experimental thermal expansion of 3C-SiC is realistically reproduced by our simulations. The calculated bulk modulus of 3C-SiC and its pressure derivative at room temperature show also good agreement with the available experimental data. The effect of the electron-phonon interaction on the direct electronic gap of 3C-SiC has been calculated as a function of temperature and related to results obtained for bulk diamond and Si. Comparison to available experimental data shows satisfactory agreement, although we observe that the employed tight-binding model tends to overestimate the magnitude of the electron-phonon interaction. The effect of treating the atomic nuclei as classical particles on the direct gap of 3C-SiC has been assessed. We find that nonlinear quantum effects related to the atomic masses are particularly relevant at temperatures below 250K .

  20. Geometric isotope effects on small chloride ion water clusters with path integral molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qi [Department of Chemistry, Tsukuba University, 1-1-1 Tennodai, Tsukuba 305-8571 (Japan); Suzuki, Kimichi [Research Institute for Nanosystem, National Institute of Advanced Industrial Science and Technology, Chuo-2, 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568 (Japan); Nagashima, Umpei, E-mail: u.nagashima@aist.go.jp [Department of Chemistry, Tsukuba University, 1-1-1 Tennodai, Tsukuba 305-8571 (Japan); Research Institute for Nanosystem, National Institute of Advanced Industrial Science and Technology, Chuo-2, 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568 (Japan); Tachikawa, Masanori [Quantum Chemistry Division, Graduate School of Science, Yokohama-City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027 (Japan); Yan, Shiwei [College of Nuclear Science and Technology, Beijing Normal University, Beijing 100875 (China)

    2013-11-29

    Highlights: • PIMD simulations with PM6-DH+ potential are carried out for Cl{sup −}(H{sub 2}O){sub n} clusters. • The geometric isotope effects on the rearrangement of single and multi shell structures are presented. • The competition of intramolecular and intermolecular nuclear quantum effects on the cluster structures is shown. • The correlations between r(Cl…O) and other vibration motions are discussed. - Abstract: The geometric isotope effects on the structures of hydrated chloride ionic hydrogen bonded clusters are explored by carrying out path integral molecular dynamics simulations. First, an outer shell coordinate is selected to display the rearrangement of single and multi hydration shell cluster structures. Next, to show the competition of intramolecular and intermolecular nuclear quantum effects, the intramolecular OH{sup ∗} stretching and intermolecular ion–water wagging motions are studied for single and multi shell structures, respectively. The results indicate that the intermolecular nuclear quantum effects stabilize the ionic hydrogen bonds in single shell structures, while they are destabilized through the competition with intramolecular nuclear quantum effects in multi shell structures. In addition, the correlations between ion–water stretching motion and other cluster vibrational coordinates are discussed. The results indicate that the intermolecular nuclear quantum effects on the cluster structures are strongly related to the cooperation of the water–water hydrogen bond interactions.

  1. Path integral Monte Carlo and density functional molecular dynamics simulations of hot, dense helium

    Science.gov (United States)

    Militzer, B.

    2009-04-01

    Two first-principles simulation techniques, path integral Monte Carlo (PIMC) and density functional molecular dynamics (DFT-MD), are applied to study hot, dense helium in the density-temperature range of 0.387-5.35gcm-3 and 500K-1.28×108K . One coherent equation of state is derived by combining DFT-MD data at lower temperatures with PIMC results at higher temperatures. Good agreement between both techniques is found in an intermediate-temperature range. For the highest temperatures, the PIMC results converge to the Debye-Hückel limiting law. In order to derive the entropy, a thermodynamically consistent free-energy fit is used that reproduces the internal energies and pressure derived from the first-principles simulations. The equation of state is presented in the form of a table as well as a fit and is compared with different free-energy models. Pair-correlation functions and the electronic density of states are discussed. Shock Hugoniot curves are compared with recent laser shock-wave experiments.

  2. Quantum tautomerization in porphycene and its isotopomers: Path-integral molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Takehiro; Sugawara, Shuichi [Department of Chemistry, Saitama University, Shimo-Okubo 255, Sakura-ku, Saitama City, Saitama 338-8570 (Japan); Takayanagi, Toshiyuki, E-mail: tako@mail.saitama-u.ac.jp [Department of Chemistry, Saitama University, Shimo-Okubo 255, Sakura-ku, Saitama City, Saitama 338-8570 (Japan); Shiga, Motoyuki [Center for Computational Science and E-systems, Japan Atomic Energy Agency, University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa City, Chiba 277-8563 (Japan); Tachikawa, Masanori [Quantum Chemistry Division, Graduate School of Nanobioscience, Yokohama-City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027 (Japan)

    2012-02-06

    Highlights: Black-Right-Pointing-Pointer Double proton transfer mechanisms in porphycene were studied with quantum simulations. Black-Right-Pointing-Pointer Both isotopic substitution and temperature significantly affect the transfer mechanism. Black-Right-Pointing-Pointer Nuclear quantum effects are playing important roles in the transfer mechanism. - Abstract: Path-integral molecular dynamics simulations have been performed for porphycene and its isotopic variants in order to understand the effect of isotopic substitution of inner protons on the double proton transfer mechanism. We have used an on-the-fly direct dynamics technique at the semiempirical PM6 level combined with specific reaction parameterization. Our quantum simulations show that double proton transfer of the unsubstituted porphycene at T = 300 K mainly occurs via a so-called concerted mechanism through the D{sub 2h} second-order saddle point. In addition, we found that both isotopic substitution and temperature significantly affect the double proton transfer mechanism. For example, the contribution of the stepwise mechanism increases with a temperature increase. We have also carried out hypothetical simulations with the porphycene configurations being completely planar. It has been found that out-of-plane vibrational motions significantly decrease the contribution of the concerted proton transfer mechanism.

  3. Integration of Morphological Data into Molecular Phylogenetic Analysis: Toward the Identikit of the Stylasterid Ancestor

    Science.gov (United States)

    Puce, Stefania; Pica, Daniela; Schiaparelli, Stefano; Negrisolo, Enrico

    2016-01-01

    Stylasteridae is a hydroid family including 29 worldwide-distributed genera, all provided with a calcareous skeleton. They are abundant in shallow and deep waters and represent an important component of marine communities. In the present paper, we studied the evolution of ten morphological characters, currently used in stylasterid taxonomy, using a phylogenetic approach. Our results indicate that stylasterid morphology is highly plastic and that many events of independent evolution and reversion have occurred. Our analysis also allows sketching a possible identikit of the stylasterid ancestor. It had calcareous skeleton, reticulate-granular coenosteal texture, polyps randomly arranged, gastrostyle, and dactylopore spines, while lacking a gastropore lip and dactylostyles. If the ancestor had single or double/multiple chambered gastropore tube is uncertain. These data suggest that the ancestor was similar to the extant genera Cyclohelia and Stellapora. Our investigation is the first attempt to integrate molecular and morphological information to clarify the stylasterid evolutionary scenario and represents the first step to infer the stylasterid ancestor morphology. PMID:27537333

  4. Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

    Science.gov (United States)

    Li, Jingjing; Shi, Minyi; Ma, Zhihai; Zhao, Shuchun; Euskirchen, Ghia; Ziskin, Jennifer; Urban, Alexander; Hallmayer, Joachim; Snyder, Michael

    2014-12-30

    Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

  5. Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.

    Directory of Open Access Journals (Sweden)

    Alessandro Furlan

    Full Text Available The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in

  6. Universal transport signatures in two-electron molecular quantum dots: gate-tunable Hund's rule, underscreened Kondo effect and quantum phase transitions.

    Science.gov (United States)

    Florens, Serge; Freyn, Axel; Roch, Nicolas; Wernsdorfer, Wolfgang; Balestro, Franck; Roura-Bas, Pablo; Aligia, A A

    2011-06-22

    We review here some universal aspects of the physics of two-electron molecular transistors in the absence of strong spin-orbit effects. Several recent quantum dot experiments have shown that an electrostatic backgate could be used to control the energy dispersion of magnetic levels. We discuss how the generally asymmetric coupling of the metallic contacts to two different molecular orbitals can indeed lead to a gate-tunable Hund's rule in the presence of singlet and triplet states in the quantum dot. For gate voltages such that the singlet constitutes the (non-magnetic) ground state, one generally observes a suppression of low voltage transport, which can yet be restored in the form of enhanced cotunneling features at finite bias. More interestingly, when the gate voltage is controlled to obtain the triplet configuration, spin S = 1 Kondo anomalies appear at zero bias, with non-Fermi liquid features related to the underscreening of a spin larger than 1/2. Finally, the small bare singlet-triplet splitting in our device allows fine-tuning with the gate between these two magnetic configurations, leading to an unscreening quantum phase transition. This transition occurs between the non-magnetic singlet phase, where a two-stage Kondo effect occurs, and the triplet phase, where the partially compensated (underscreened) moment is akin to a magnetically 'ordered' state. These observations are put theoretically into a consistent global picture by using new numerical renormalization group simulations, tailored to capture sharp finite-voltage cotunneling features within the Coulomb diamonds, together with complementary out-of-equilibrium diagrammatic calculations on the two-orbital Anderson model. This work should shed further light on the complicated puzzle still raised by multi-orbital extensions of the classic Kondo problem.

  7. An archaeal genomic signature

    Science.gov (United States)

    Graham, D. E.; Overbeek, R.; Olsen, G. J.; Woese, C. R.

    2000-01-01

    Comparisons of complete genome sequences allow the most objective and comprehensive descriptions possible of a lineage's evolution. This communication uses the completed genomes from four major euryarchaeal taxa to define a genomic signature for the Euryarchaeota and, by extension, the Archaea as a whole. The signature is defined in terms of the set of protein-encoding genes found in at least two diverse members of the euryarchaeal taxa that function uniquely within the Archaea; most signature proteins have no recognizable bacterial or eukaryal homologs. By this definition, 351 clusters of signature proteins have been identified. Functions of most proteins in this signature set are currently unknown. At least 70% of the clusters that contain proteins from all the euryarchaeal genomes also have crenarchaeal homologs. This conservative set, which appears refractory to horizontal gene transfer to the Bacteria or the Eukarya, would seem to reflect the significant innovations that were unique and fundamental to the archaeal "design fabric." Genomic protein signature analysis methods may be extended to characterize the evolution of any phylogenetically defined lineage. The complete set of protein clusters for the archaeal genomic signature is presented as supplementary material (see the PNAS web site, www.pnas.org).

  8. Machine Fault Signature Analysis

    Directory of Open Access Journals (Sweden)

    Pratesh Jayaswal

    2008-01-01

    Full Text Available The objective of this paper is to present recent developments in the field of machine fault signature analysis with particular regard to vibration analysis. The different types of faults that can be identified from the vibration signature analysis are, for example, gear fault, rolling contact bearing fault, journal bearing fault, flexible coupling faults, and electrical machine fault. It is not the intention of the authors to attempt to provide a detailed coverage of all the faults while detailed consideration is given to the subject of the rolling element bearing fault signature analysis.

  9. Proton transport in triflic acid pentahydrate studied via ab initio path integral molecular dynamics.

    Science.gov (United States)

    Hayes, Robin L; Paddison, Stephen J; Tuckerman, Mark E

    2011-06-16

    Trifluoromethanesulfonic acid hydrates provide a well-defined system to study proton dissociation and transport in perfluorosulfonic acid membranes, typically used as the electrolyte in hydrogen fuel cells, in the limit of minimal water. The triflic acid pentahydrate crystal (CF(3)SO(3)H·5H(2)O) is sufficiently aqueous that it contains an extended three-dimensional water network. Despite it being extended, however, long-range proton transport along the network is structurally unfavorable and would require considerable rearrangement. Nevertheless, the triflic acid pentahydrate crystal system can provide a clear picture of the preferred locations of local protonic defects in the water network, which provides insights about related structures in the disordered, low-hydration environment of perfluorosulfonic acid membranes. Ab initio molecular dynamics simulations reveal that the proton defect is most likely to transfer to the closest water that has the expected presolvation and only contains water in its first solvation shell. Unlike the tetrahydrate of triflic acid (CF(3)SO(3)H·4H(2)O), there is no evidence of the proton preferentially transferring to a water molecule bridging two of the sulfonate groups. However, this could be an artifact of the crystal structure since the only such water molecule is separated from the proton by long O-O distances. Hydrogen bonding criteria, using the two-dimensional potential of mean force, are extracted. Radial distribution functions, free energy profiles, radii of gyration, and the root-mean-square displacement computed from ab initio path integral molecular dynamics simulations reveal that quantum effects do significantly extend the size of the protonic defect and increase the frequency of proton transfer events by nearly 15%. The calculated IR spectra confirm that the dominant protonic defect mostly exists as an Eigen cation but contains some Zundel ion characteristics. Chain lengths and ring sizes determined from the

  10. 弱盲签名方案的构造的一种新方法%A New Method of Constructing Weak Blind Digital Signature Schemes

    Institute of Scientific and Technical Information of China (English)

    杜伟章; 陈克非

    2003-01-01

    In this paper, by integrating blind parameter digital signature schemes and the existing weak blind digital signature schemes,on the basis of generalized ElGamal type digital signature schemes,we construct some new weak blind digital signature schemes based on discrete logarithms. We check and analyze these digital signature schemes also.

  11. TRACING EMBEDDED STELLAR POPULATIONS IN CLUSTERS AND GALAXIES USING MOLECULAR EMISSION: METHANOL AS A SIGNATURE OF THE LOW-MASS END OF THE IMF

    Energy Technology Data Exchange (ETDEWEB)

    Kristensen, Lars E. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Bergin, Edwin A., E-mail: lkristensen@cfa.harvard.edu [Department of Astronomy, University of Michigan, 500 Church Street, Ann Arbor, MI 48109 (United States)

    2015-07-10

    Most low-mass protostars form in clusters, in particular high-mass clusters; however, how low-mass stars form in high-mass clusters and what the mass distribution is are still open questions both in our own Galaxy and elsewhere. To access the population of forming embedded low-mass protostars observationally, we propose using molecular outflows as tracers. Because the outflow emission scales with mass, the effective contrast between low-mass protostars and their high-mass cousins is greatly lowered. In particular, maps of methanol emission at 338.4 GHz (J = 7{sub 0}–6{sub 0} A{sup +}) in low-mass clusters illustrate that this transition is an excellent probe of the low-mass population. We present here a model of a forming cluster where methanol emission is assigned to every embedded low-mass protostar. The resulting model image of methanol emission is compared to recent ALMA observations toward a high-mass cluster and the similarity is striking: the toy model reproduces observations to better than a factor of two and suggests that approximately 50% of the total flux originates in low-mass outflows. Future fine-tuning of the model will eventually make it a tool for interpreting the embedded low-mass population of distant regions within our own Galaxy and ultimately higher-redshift starburst galaxies, not just for methanol emission but also water and high-J CO.

  12. Proteomics Analysis to Identify and Characterize the Molecular Signatures of Hepatic Steatosis in Ovariectomized Rats as a Model of Postmenopausal Status

    Directory of Open Access Journals (Sweden)

    Chen-Chung Liao

    2015-10-01

    Full Text Available Postmenopausal women are particularly at increased risk of developing non-alcoholic fatty liver disease (NAFLD. Here we aimed to determine the impact of postmenopausal-induced NAFLD (PM-NAFLD in an ovariectomized rat model. Sixteen six-week-old Sprague-Dawley female rats were randomly divided into two groups (eight per group, for sham-operation (Sham or bilateral ovariectomy (Ovx. Four months after surgery, indices of liver damage and liver histomorphometry were measured. Both serum aspartate aminotransferase (AST and alanine aminotranferease (ALT levels were significantly higher in the Ovx than Sham group. We performed quantitative LC-MS/MS-based proteomic profiling of livers from rats with PM-NAFLD to provide baseline knowledge of the PM-NAFLD proteome and to investigate proteins involved in PM-NAFLD by ingenuity pathways analysis (IPA to provide corroborative evidence for differential regulation of molecular and cellular functions affecting metabolic processes. Of the 586 identified proteins, the levels of 59 (10.0% and 48 (8.2% were significantly higher and lower, respectively, in the Ovx group compared to the Sham group. In conclusion, the changes in regulation of proteins implicated in PM-NAFLD may affect other vital biological processes in the body apart from causing postmenopause-mediated liver dysfunction. Our quantitative proteomics analysis may also suggest potential biomarkers and further clinical applications for PM-NAFLD.

  13. Signature of Al{sub 11}Sm{sub 3} fragments in undercooled Al{sub 90}Sm{sub 10} liquid from ab initio molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Fang, X W; Ding, Z J [Hefei National Laboratory for Physical Sciences at Microscale and Department of Physics, University of Science and Technology of China, Hefei, Anhui 230026 (China); Wang, C Z; Yao, Y X; Ho, K M, E-mail: wangcz@ameslab.gov, E-mail: zjding@ustc.edu.cn [Ames Laboratory-US Department of Energy and Department of Physics, Iowa State University, Ames, IA 50011 (United States)

    2011-06-15

    An ab initio molecular dynamics (MD) simulation is performed to investigate the structural evolution in Al{sub 90}Sm{sub 10} liquid from 1500 to 900 K. Development of Al{sub 11}Sm{sub 3} local order upon rapid cooling is suggested by the Honeycutt-Anderson (HA) index analysis and the appearance of a predominant Sm-Sm-Sm bond angle around 90{sup 0} when the liquid approaches the melting point ({approx}920 K). Direct structural evidence of Al{sub 11}Sm{sub 3} fragments at 900 K is obtained using an atomic cluster alignment method developed recently. Meanwhile, development of strong icosahedral short range order (ISRO) and a non-negligible amount of fcc-type clusters around Al in the system are also observed. These results suggest that fcc Al and Al{sub 11}Sm{sub 3} crystalline phases would compete strongly with the formation of an amorphous phase that exhibits ISRO in the diffusionless solidification limit upon rapid quenching.

  14. Tracing Embedded Stellar Populations in Clusters and Galaxies using Molecular Emission: Methanol as a Signature of the Low-Mass End of the IMF

    CERN Document Server

    Kristensen, L E

    2015-01-01

    Most low-mass protostars form in clusters, in particular high-mass clusters; however, how low-mass stars form in high-mass clusters and what the mass distribution is, are still open questions both in our own Galaxy and elsewhere. To access the population of forming embedded low-mass protostars observationally, we propose to use molecular outflows as tracers. Because the outflow emission scales with mass, the effective contrast between low-mass protostars and their high-mass cousins is greatly lowered. In particular, maps of methanol emission at 338.4 GHz (J=7_0 - 6_0 A+) in low-mass clusters illustrate that this transition is an excellent probe of the low-mass population. We here present a model of a forming cluster where methanol emission is assigned to every embedded low-mass protostar. The resulting model image of methanol emission is compared to recent ALMA observations toward a high-mass cluster and the similarity is striking: the toy model reproduces observations to better than a factor of two and sugge...

  15. A novel aerosol mass spectrometric approach - Analysis of the organic molecular signature of PM by coupling of thermal EC/OC-carbon analysis to photo-ionization mass spectrometry

    Science.gov (United States)

    Zimmermann, R.; Grabowski, J.; Streibel, T.; Sklorz, M.; Chow, J.

    2012-12-01

    Carbonaceous material in airborne particulate matter (PM) is of increasing interest e.g. due to its adverse health effects and its potential influence on the climate. Its analytical assessment on a molecular level is still very challenging. Hence, analysis of carbonaceous fractions for many studies is often solely carried out by determining sum parameters such as the overall content of organic carbon (OC) and elemental carbon (EC) as well as the total carbon content, TC (sum of OC and EC). The used thermal procedure, however, allows getting additional interesting information: By defining different thermal OC fractions (i.e. temperature steps) also information on the refractory properties of the carbonaceous material is obtained. In this context it is particularly interesting to investigate the release and formation behaviors of the molecular species responsible for the different OC and EC fractions. Thus after initial promising results of pre-studies [1,2] in the current work an EC/OC carbon analyzer (Model DRI 2000) and a homebuilt photo-ionization time-of-flight mass spectrometer (PI-TOFMS) were hyphenated and applied to investigate individual organic compounds especially from the different OC fractions. The carbon analyzer enables the stepwise heating of PM loaded filter samples and provides the sum values of the "carbon" release ("Improve protocol" [2]: OC1 - 120 °C, OC2 - 250°C, OC3 - 450°C OC4 - 550°C). With the on-line coupled PI-TOFMS evolved organic compounds, as released during the thermal program, are detectable in real time. This is possible by MS with soft photo ionization methods (SPI - single photon ionization and REMPI - resonance-enhanced multi photon ionization). Soft ionization suppresses fragmentation upon the ionization step and generates molecular signatures in the MS. The EC/OC-analyzer-PI-TOFMS instrument was applied to several types of PM samples, such as ambient aerosol, emission samples (gasoline/diesel car, wood combustion) or

  16. Path integral molecular dynamics calculations of the H6+ and D6+ clusters on an ab initio potential energy surface

    Science.gov (United States)

    Kakizaki, Akira; Takayanagi, Toshiyuki; Shiga, Motoyuki

    2007-11-01

    Path integral molecular dynamics simulations for the H6+ and D6+ cluster cations have been carried out in order to understand the floppy nature of their molecular structure due to quantum-mechanical fluctuation. A full-dimensional analytical potential energy surface for the ground electronic state of H6+ has been developed on the basis of accurate ab initio electronic structure calculations at the CCSD(T)/cc-pVTZ level. It is found that the outer H 2(D 2) nuclei rotate almost freely and that the probability density distributions of the central H 2(D 2) nuclei show strong spatial delocalization.

  17. Nuclear quantum effect on intramolecular hydrogen bond of hydrogen maleate anion: An ab initio path integral molecular dynamics study

    Science.gov (United States)

    Kawashima, Yukio; Tachikawa, Masanori

    2013-05-01

    Ab initio path integral molecular dynamics simulation was performed to understand the nuclear quantum effect on the hydrogen bond of hydrogen malonate anion. Static calculation predicted the proton transfer barrier as 0.12 kcal/mol. Conventional ab initio molecular dynamics simulation at 300 K found proton distribution with a double peak on the proton transfer coordinate. Inclusion of thermal effect alone elongates the hydrogen bond length, which increases the barrier height. Inclusion of nuclear quantum effect washes out this barrier, and distributes a single broad peak in the center. H/D isotope effect on the proton transfer is also discussed.

  18. Prevalence and molecular characterization of Salmonella enterica isolates throughout an integrated broiler supply chain in China.

    Science.gov (United States)

    Ren, X; Li, M; Xu, C; Cui, K; Feng, Z; Fu, Y; Zhang, J; Liao, M

    2016-10-01

    A total of 1145 samples were collected from chicken breeder farms, hatcheries, broiler farms, a slaughterhouse and retail refrigerated chicken stores in an integrated broiler supply chain in Guangdong Province, China, in 2013. One-hundred and two Salmonella enterica strains were isolated and subjected to serotyping, antimicrobial susceptibility testing, virulence profile determination and molecular subtyping by pulsed field gel electrophoresis (PFGE). The contamination rates in samples from breeder farms, hatcheries, broiler farms, the slaughterhouse and retail stores were 1·46%, 4·31%, 7·00%, 62·86% and 54·67%, respectively. The isolated strains of S. enterica belonged to 10 serotypes; most of them were S. Weltevreden (46·08%, 47/102) and S. Agona (18·63%, 19/102). Isolates were frequently resistant to streptomycin (38·2%), tetracycline (36·3%), sulfisoxazole (35·3%) and gentamicin (34·3%); 31·4% of isolates were multidrug resistant. The isolates were screened for 10 virulence factors. The Salmonella pathogenicity island genes avrA, ssaQ, mgtC, siiD, and sopB and the fimbrial gene bcfC were present in 100% of the strains. PFGE genotyping of the 102 S. enterica isolates yielded 24 PFGE types at an 85% similarity threshold. The PFGE patterns show that the genotypes of S. enterica in the production chain are very diverse, but some strains have 100% similarity in different parts of the production chain, which indicates that some S. enterica persist throughout the broiler supply chain.

  19. Unraveling the molecular signatures of oxidative phosphorylation to cope with the nutritionally changing metabolic capabilities of liver and muscle tissues in farmed fish.

    Science.gov (United States)

    Bermejo-Nogales, Azucena; Calduch-Giner, Josep Alvar; Pérez-Sánchez, Jaume

    2015-01-01

    Mitochondrial oxidative phosphorylation provides over 90% of the energy produced by aerobic organisms, therefore the regulation of mitochondrial activity is a major issue for coping with the changing environment and energy needs. In fish, there is a large body of evidence of adaptive changes in enzymatic activities of the OXPHOS pathway, but less is known at the transcriptional level and the first aim of the present study was to define the molecular identity of the actively transcribed subunits of the mitochondrial respiratory chain of a livestock animal, using gilthead sea bream as a model of farmed fish with a high added value for European aquaculture. Extensive BLAST searches in our transcriptomic database (www.nutrigroup-iats.org/seabreamdb) yielded 97 new sequences with a high coverage of catalytic, regulatory and assembly factors of Complex I to V. This was the basis for the development of a PCR array for the simultaneous profiling of 88 selected genes. This new genomic resource allowed the differential gene expression of liver and muscle tissues in a model of 10 fasting days. A consistent down-regulated response involving 72 genes was made by the liver, whereas an up-regulated response with 29 and 10 differentially expressed genes was found in white skeletal muscle and heart, respectively. This differential regulation was mostly mediated by nuclear-encoded genes (skeletal muscle) or both mitochondrial- and nuclear-encoded genes (liver, heart), which is indicative of a complex and differential regulation of mitochondrial and nuclear genomes, according to the changes in the lipogenic activity of liver and the oxidative capacity of glycolytic and highly oxidative muscle tissues. These insights contribute to the identification of the most responsive elements of OXPHOS in each tissue, which is of relevance for the appropriate gene targeting of nutritional and/or environmental metabolic disturbances in livestock animals.

  20. Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition.

    Directory of Open Access Journals (Sweden)

    Stuart J Smith

    Full Text Available INTRODUCTION: Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS. METHODS: CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. RESULTS: Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. CONCLUSIONS: Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system.

  1. THE ELECTRONIC SIGNATURE

    Directory of Open Access Journals (Sweden)

    Voiculescu Madalina Irena

    2009-05-01

    Full Text Available Article refers to significance and the digital signature in electronic commerce. Internet and electronic commerce open up many new opportunities for the consumer, yet, the security (or perceived lack of security of exchanging personal and financial data

  2. Advanced Missile Signature Center

    Data.gov (United States)

    Federal Laboratory Consortium — The Advanced Missile Signature Center (AMSC) is a national facility supporting the Missile Defense Agency (MDA) and other DoD programs and customers with analysis,...

  3. Stateless Transitive Signature Schemes

    Institute of Scientific and Technical Information of China (English)

    MA Chun-guang; CAI Man-chun; YANG Yi-xian

    2004-01-01

    A new practical method is introduced to transform the stateful transitive signature scheme to stateless one without the loss of security. According to the approach, two concrete stateless transitive signature schemes based on Factoring and RSA are presented respectively. Under the assumption of the hardness of factoring and one-more- RSA-inversion problem, both two schemes are secure under the adaptive chosen-message attacks in random oracle model.

  4. A new approach to calculate charge carrier transport mobility in organic molecular crystals from imaginary time path integral simulations.

    Science.gov (United States)

    Song, Linze; Shi, Qiang

    2015-05-07

    We present a new non-perturbative method to calculate the charge carrier mobility using the imaginary time path integral approach, which is based on the Kubo formula for the conductivity, and a saddle point approximation to perform the analytic continuation. The new method is first tested using a benchmark calculation from the numerical exact hierarchical equations of motion method. Imaginary time path integral Monte Carlo simulations are then performed to explore the temperature dependence of charge carrier delocalization and mobility in organic molecular crystals (OMCs) within the Holstein and Holstein-Peierls models. The effects of nonlocal electron-phonon interaction on mobility in different charge transport regimes are also investigated.

  5. Building gene expression signatures indicative of transcription factor activation to predict AOP modulation

    Science.gov (United States)

    Building gene expression signatures indicative of transcription factor activation to predict AOP modulation Adverse outcome pathways (AOPs) are a framework for predicting quantitative relationships between molecular initiatin...

  6. Integrative Transcriptomic and Metabonomic Molecular Profiling of Colonic Mucosal Biopsies Indicates a Unique Molecular Phenotype for Ulcerative Colitis

    DEFF Research Database (Denmark)

    Rantalainen, Mattias; Bjerrum, Jacob Tveiten; Olsen, Jørgen

    2015-01-01

    Ulcerative colitis is the most prevailing entity of several disorders under the umbrella term inflammatory bowel disease, with potentially serious symptoms and devastating consequences for affected patients. The exact molecular etiology of ulcerative colitis is not yet revealed. In this study, we...... controls and other disease-related phenotypes such as steroid dependency and age at diagnosis, to determine if there is evidence of enrichment of differential expression in candidate genes from genome-wide association studies and if there are particular pathways influenced by disease-associated genes. Both...

  7. A Proxy Blind Signature Scheme Based on ECDLP

    Institute of Scientific and Technical Information of China (English)

    WANGHaiyan; WANGRuchuan

    2005-01-01

    While proxy signature scheme enables an original signer to fully authorize a proxy to sign a message on his or her behalf legally and undeniably, blind signature scheme keeps the message blind from the signer so that the signer cannot make a linkage between the signature and the identity of requester (receiver). Both schemes have been widely applied in the electronic business. A new ECDLP (Elliptic curve discrete problem)-based proxy blind signature scheme is to be proposed in this paper by integrating the security properties of both schemes.

  8. Car-Parrinello and path integral molecular dynamics study of the hydrogen bond in the chloroacetic acid dimer system.

    Science.gov (United States)

    Durlak, Piotr; Morrison, Carole A; Middlemiss, Derek S; Latajka, Zdzislaw

    2007-08-14

    We have studied the double proton transfer (DPT) reaction in the cyclic dimer of chloroacetic acid using both classical and path integral Car-Parrinello molecular dynamics. We also attempt to quantify the errors in the potential energy surface that arise from the use of a pure density functional. In the classical dynamics a clear reaction mechanism can be identified, where asynchronized DPT arises due to coupling between the O-H stretching oscillator and several low energy intermolecular vibrational modes. This mechanism is considerably altered when quantum tunneling is permitted in the simulation. The introduction of path integrals leads to considerable changes in the thermally averaged molecular geometry, leading to shorter and more centered hydrogen bond linkages.

  9. Car-Parrinello and path integral molecular dynamics study of the hydrogen bond in the chloroacetic acid dimer system

    Science.gov (United States)

    Durlak, Piotr; Morrison, Carole A.; Middlemiss, Derek S.; Latajka, Zdzislaw

    2007-08-01

    We have studied the double proton transfer (DPT) reaction in the cyclic dimer of chloroacetic acid using both classical and path integral Car-Parrinello molecular dynamics. We also attempt to quantify the errors in the potential energy surface that arise from the use of a pure density functional. In the classical dynamics a clear reaction mechanism can be identified, where asynchronized DPT arises due to coupling between the O-H stretching oscillator and several low energy intermolecular vibrational modes. This mechanism is considerably altered when quantum tunneling is permitted in the simulation. The introduction of path integrals leads to considerable changes in the thermally averaged molecular geometry, leading to shorter and more centered hydrogen bond linkages.

  10. Ab initio path integral molecular dynamics simulation study on the dihydrogen bond of NH4+⋯BeH2

    Science.gov (United States)

    Hayashi, Aiko; Shiga, Motoyuki; Tachikawa, Masanori

    2005-07-01

    An ab initio path integral molecular dynamics simulation has been performed to study the quantum and thermal effects of a dihydrogen bonded cation, NH4+⋯BeH2. In this system, an attractive interaction exists between two neighboring hydrogen atoms as N δ- H δ+ ⋯H δ- Be δ+ involving large-amplitude of vibration. Some properties playing a key role for this dihydrogen bonded system, such as the bond length, bond angle, and distribution of atomic charges, are investigated in detail by comparing the results of path integral and classical molecular dynamics with those of the equilibrium structure. It was found that the atomic charges of H δ+ and H δ- are decreased and the dihydrogen H δ+ ⋯H δ- bond length is expanded as the thermal and zero-point quantum effects.

  11. Uncovering the Molecular Machinery of the Human Spindle-An Integration of Wet and Dry Systems Biology

    DEFF Research Database (Denmark)

    Rojas, Ana M.; Santamaria, Anna; Malik, Rainer

    2012-01-01

    The mitotic spindle is an essential molecular machine involved in cell division, whose composition has been studied extensively by detailed cellular biology, high-throughput proteomics, and RNA interference experiments. However, because of its dynamic organization and complex regulation it is dif....... Combining integrated bio-computational approaches and single gene experimental follow-ups could be key to exploring the still hidden regions of the human spindle system....... it is difficult to obtain a complete description of its molecular composition. We have implemented an integrated computational approach to characterize novel human spindle components and have analysed in detail the individual candidates predicted to be spindle proteins, as well as the network of predicted...... of interactions is still poorly characterised by experimental means and which are thought to influence the functionality of the mitotic spindle on a large scale. Our analyses suggest that we are still far from knowing the complete repertoire of functionally important components of the human spindle network...

  12. The Eukaryotic Cell Originated in the Integration and Redistribution of Hyperstructures from Communities of Prokaryotic Cells Based on Molecular Complementarity

    OpenAIRE

    Vic Norris; Robert Root-Bernstein

    2009-01-01

    In the “ecosystems-first” approach to the origins of life, networks of non-covalent assemblies of molecules (composomes), rather than individual protocells, evolved under the constraints of molecular complementarity. Composomes evolved into the hyperstructures of modern bacteria. We extend the ecosystems-first approach to explain the origin of eukaryotic cells through the integration of mixed populations of bacteria. We suggest that mutualism and symbiosis resulted in cellular mergers entaili...

  13. Path integral molecular dynamics within the grand canonical-like adaptive resolution technique: Simulation of liquid water

    Energy Technology Data Exchange (ETDEWEB)

    Agarwal, Animesh, E-mail: animesh@zedat.fu-berlin.de; Delle Site, Luigi, E-mail: dellesite@fu-berlin.de [Institute for Mathematics, Freie Universität Berlin, Berlin (Germany)

    2015-09-07

    Quantum effects due to the spatial delocalization of light atoms are treated in molecular simulation via the path integral technique. Among several methods, Path Integral (PI) Molecular Dynamics (MD) is nowadays a powerful tool to investigate properties induced by spatial delocalization of atoms; however, computationally this technique is very demanding. The above mentioned limitation implies the restriction of PIMD applications to relatively small systems and short time scales. One of the possible solutions to overcome size and time limitation is to introduce PIMD algorithms into the Adaptive Resolution Simulation Scheme (AdResS). AdResS requires a relatively small region treated at path integral level and embeds it into a large molecular reservoir consisting of generic spherical coarse grained molecules. It was previously shown that the realization of the idea above, at a simple level, produced reasonable results for toy systems or simple/test systems like liquid parahydrogen. Encouraged by previous results, in this paper, we show the simulation of liquid water at room conditions where AdResS, in its latest and more accurate Grand-Canonical-like version (GC-AdResS), is merged with two of the most relevant PIMD techniques available in the literature. The comparison of our results with those reported in the literature and/or with those obtained from full PIMD simulations shows a highly satisfactory agreement.

  14. Path integral molecular dynamics within the grand canonical-like adaptive resolution technique: Simulation of liquid water

    Science.gov (United States)

    Agarwal, Animesh; Delle Site, Luigi

    2015-09-01

    Quantum effects due to the spatial delocalization of light atoms are treated in molecular simulation via the path integral technique. Among several methods, Path Integral (PI) Molecular Dynamics (MD) is nowadays a powerful tool to investigate properties induced by spatial delocalization of atoms; however, computationally this technique is very demanding. The above mentioned limitation implies the restriction of PIMD applications to relatively small systems and short time scales. One of the possible solutions to overcome size and time limitation is to introduce PIMD algorithms into the Adaptive Resolution Simulation Scheme (AdResS). AdResS requires a relatively small region treated at path integral level and embeds it into a large molecular reservoir consisting of generic spherical coarse grained molecules. It was previously shown that the realization of the idea above, at a simple level, produced reasonable results for toy systems or simple/test systems like liquid parahydrogen. Encouraged by previous results, in this paper, we show the simulation of liquid water at room conditions where AdResS, in its latest and more accurate Grand-Canonical-like version (GC-AdResS), is merged with two of the most relevant PIMD techniques available in the literature. The comparison of our results with those reported in the literature and/or with those obtained from full PIMD simulations shows a highly satisfactory agreement.

  15. Toward molecular trait-based ecology through integration of biogeochemical, geographical and metagenomic data

    DEFF Research Database (Denmark)

    Raes, Jeroen; Letunic, Ivica; Yamada, Takuji;

    2011-01-01

    Using metagenomic 'parts lists' to infer global patterns on microbial ecology remains a significant challenge. To deduce important ecological indicators such as environmental adaptation, molecular trait dispersal, diversity variation and primary production from the gene pool of an ecosystem, we...... provincialism). Molecular functional richness and diversity show a distinct latitudinal gradient peaking at 20° N and correlate with primary production. The latter can also be predicted from the molecular functional composition of an environmental sample. Together, our results show that the functional community...... composition derived from metagenomes is an important quantitative readout for molecular trait-based biogeography and ecology....

  16. Calculation of molecular integrals over Slater-type orbitals using recurrence relations for overlap integrals and basic one-center Coulomb integrals.

    Science.gov (United States)

    Guseinov, Israfil; Mamedov, Bahtiyar; Rzaeva, Afet

    2002-04-01

    The recurrence relations are established for the basic one-center Coulomb integrals over Slater-type orbitals (STOs). These formulae and the recurrence relations for basic overlap integrals are utilized for the calculation of multicenter electron-repulsion integrals. The calculations of multicenter electron-repulsion integrals are performed by the use of translation formulae for STOs obtained from the Lambda and Coulomb Sturmian exponential-type functions (ETFs). It is shown that these integrals show a faster convergence rate in the case of Coulomb Sturmian ETFs. The accuracy of the results is quite high for the quantum numbers of STOs and for the arbitrary values of internuclear distances and screening constants of atomic orbitals.

  17. Integrating molecular QTL data into genome-wide genetic association analysis: Probabilistic assessment of enrichment and colocalization

    Science.gov (United States)

    2017-01-01

    We propose a novel statistical framework for integrating the result from molecular quantitative trait loci (QTL) mapping into genome-wide genetic association analysis of complex traits, with the primary objectives of quantitatively assessing the enrichment of the molecular QTLs in complex trait-associated genetic variants and the colocalizations of the two types of association signals. We introduce a natural Bayesian hierarchical model that treats the latent association status of molecular QTLs as SNP-level annotations for candidate SNPs of complex traits. We detail a computational procedure to seamlessly perform enrichment, fine-mapping and colocalization analyses, which is a distinct feature compared to the existing colocalization analysis procedures in the literature. The proposed approach is computationally efficient and requires only summary-level statistics. We evaluate and demonstrate the proposed computational approach through extensive simulation studies and analyses of blood lipid data and the whole blood eQTL data from the GTEx project. In addition, a useful utility from our proposed method enables the computation of expected colocalization signals using simple characteristics of the association data. Using this utility, we further illustrate the importance of enrichment analysis on the ability to discover colocalized signals and the potential limitations of currently available molecular QTL data. The software pipeline that implements the proposed computation procedures, enloc, is freely available at https://github.com/xqwen/integrative. PMID:28278150

  18. Spectral flow, index and the signature operator

    CERN Document Server

    Azzali, Sara

    2009-01-01

    We relate the spectral flow to the index for paths of selfadjoint Breuer-Fredholm operators affiliated to a semifinite von Neumann algebra, generalizing results of Robbin-Salamon and Pushnitski. Then we prove the vanishing of the von Neumann spectral flow for the tangential signature operator of a foliated manifold when the metric is varied. We conclude that the tangential signature of a foliated manifold with boundary does not depend on the metric. In the Appendix we reconsider integral formulas for the spectral flow of paths of bounded operators.

  19. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

    DEFF Research Database (Denmark)

    Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie-Claude

    2017-01-01

    intrahepatic CCA cases and propose a molecular