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Sample records for subpopulation structure identified

  1. Epidemic spreading between two coupled subpopulations with inner structures

    Science.gov (United States)

    Ruan, Zhongyuan; Tang, Ming; Gu, Changgui; Xu, Jinshan

    2017-10-01

    The structure of underlying contact network and the mobility of agents are two decisive factors for epidemic spreading in reality. Here, we study a model consisting of two coupled subpopulations with intra-structures that emphasizes both the contact structure and the recurrent mobility pattern of individuals simultaneously. We show that the coupling of the two subpopulations (via interconnections between them and round trips of individuals) makes the epidemic threshold in each subnetwork to be the same. Moreover, we find that the interconnection probability between two subpopulations and the travel rate are important factors for spreading dynamics. In particular, as a function of interconnection probability, the epidemic threshold in each subpopulation decreases monotonously, which enhances the risks of an epidemic. While the epidemic threshold displays a non-monotonic variation as travel rate increases. Moreover, the asymptotic infected density as a function of travel rate in each subpopulation behaves differently depending on the interconnection probability.

  2. Examination of heterogeneous societies: Identifying subpopulations by contrasting cultures

    DEFF Research Database (Denmark)

    Glückstad, Fumiko Kano; Schmidt, Mikkel Nørgaard; Mørup, Morten

    2017-01-01

    , the infinite relational model (IRM) is a new and disruptive type of unsupervised clustering approach that has been developed recently by cognitive psychologists and computer scientists. In this article, an extended version of the IRM coined the multinominal IRM—or mIRM in short—is applied to a cross......-cultural analysis of survey data available from the World Value Survey organization. Specifically, the present work analyzes response patterns of the Portrait Value Questionnaire (PVQ) representing Schwartz’s 10 basic values of Japanese and Swedes. The applied model exposes heterogeneous structures of the two...

  3. Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP.

    Science.gov (United States)

    Lazar, Ann A; Bonetti, Marco; Cole, Bernard F; Yip, Wai-Ki; Gelber, Richard D

    2016-04-01

    Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of

  4. Micropapillary Structures in Colorectal Cancer: An Anoikis-resistant Subpopulation.

    Science.gov (United States)

    Patankar, Madhura; Väyrynen, Sara; Tuomisto, Anne; Mäkinen, Markus; Eskelinen, Sinikka; Karttunen, Tuomo J

    2018-05-01

    Micropapillary structures (MIPs) are focal piles of columnar cells without extracellular matrix contact, and common in serrated colorectal carcinoma (CRC). In order to characterize biology of MIPs in colorectal cancer (CRC), the proliferation and apoptosis rates, and survivin expression were compared between MIPs and other cancer epithelial cells of CRC (non-MIPs). We assessed 46 samples of normal colorectal mucosa, 62 carcinomas and 54 polyps for proliferation (Ki67), apoptosis (M30), and survivin expression by immunohistochemistry. MIPs in carcinoma showed lower rates of proliferation and apoptosis than non-MIPs. A low rate of apotosis in MIPs was associated with poor prognosis in local carcinoma. In normal crypts, nuclear-to-cytoplasmic transition of survivin indicated epithelial cell maturation. Cancer cases showed increased cytoplasmic expression of survivin than normal mucosa and polyps. However, MIPs showed lower nuclear and cytoplasmic survivin expression than non-MIPs. Our findings suggest that MIPs represent a biologically distinct subpopulation of carcinoma cells with features of anoikis resistance and possibly quiescence. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  5. Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations.

    Science.gov (United States)

    Philippeos, Christina; Telerman, Stephanie B; Oulès, Bénédicte; Pisco, Angela O; Shaw, Tanya J; Elgueta, Raul; Lombardi, Giovanna; Driskell, Ryan R; Soldin, Mark; Lynch, Magnus D; Watt, Fiona M

    2018-04-01

    Previous studies have shown that mouse dermis is composed of functionally distinct fibroblast lineages. To explore the extent of fibroblast heterogeneity in human skin, we used a combination of comparative spatial transcriptional profiling of human and mouse dermis and single-cell transcriptional profiling of human dermal fibroblasts. We show that there are at least four distinct fibroblast populations in adult human skin, not all of which are spatially segregated. We define markers permitting their isolation and show that although marker expression is lost in culture, different fibroblast subpopulations retain distinct functionality in terms of Wnt signaling, responsiveness to IFN-γ, and ability to support human epidermal reconstitution when introduced into decellularized dermis. These findings suggest that ex vivo expansion or in vivo ablation of specific fibroblast subpopulations may have therapeutic applications in wound healing and diseases characterized by excessive fibrosis. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Use of stable isotopes to identify dietary differences across subpopulations and sex for a free-ranging generalist herbivore.

    Science.gov (United States)

    Walter, W David

    2014-01-01

    Carbon and nitrogen isotopes in tissues can be used to understand plants consumed by various taxa, but can they provide additional information about consumers? Values of δ(13)C and δ(15)N were assessed from tissue of free-ranging elk (Cervus elaphus) occupying disparate habitats of mixed prairie-oak savannah that contained C3 agricultural crops in a C4-dominated landscape and in key plants consumed by elk. Muscle and hoof samples were collected from female and male elk in two subpopulations (forested land and grassland) from private land and one subpopulation from the Wichita Mountains Wildlife Refuge (refuge) in 2001-2006. Previous research identified differences between mean muscle δ(13)C and δ(15)N and mean hoof δ(13)C and δ(15)N indicating that isotopes differed between tissues of varying metabolic activity. Mean δ(13)C in hoof of elk on forested land and grassland were lower than hoof δ(13)C from elk in the refuge indicating greater long-term consumption of C3 plants by elk on forested land and grassland subpopulations. The δ(15)N in hoof was greater for elk outside the refuge than that for elk in the refuge. Interaction of sex and subpopulation only occurred for hoof δ(15)N suggesting that factors such as tissue type, sex, and habitat need to be considered to understand free-ranging ecology of generalist herbivores using stable isotopes. Availability of C3 agricultural crops high in percent nitrogen on a nearly annual basis in a C4-dominated landscape was likely driving differences in tissue δ(13)C and δ(15)N among subpopulations of free-ranging elk. An increase in tissue δ(15)N resulted from an increase in the consumption of higher δ(15)N in forage for sexes and subpopulations of a free-ranging ungulate in North America but δ(15)N should be further evaluated as an index of nutrition for subpopulations of generalist herbivores.

  7. ODE constrained mixture modelling: a method for unraveling subpopulation structures and dynamics.

    Directory of Open Access Journals (Sweden)

    Jan Hasenauer

    2014-07-01

    Full Text Available Functional cell-to-cell variability is ubiquitous in multicellular organisms as well as bacterial populations. Even genetically identical cells of the same cell type can respond differently to identical stimuli. Methods have been developed to analyse heterogeneous populations, e.g., mixture models and stochastic population models. The available methods are, however, either incapable of simultaneously analysing different experimental conditions or are computationally demanding and difficult to apply. Furthermore, they do not account for biological information available in the literature. To overcome disadvantages of existing methods, we combine mixture models and ordinary differential equation (ODE models. The ODE models provide a mechanistic description of the underlying processes while mixture models provide an easy way to capture variability. In a simulation study, we show that the class of ODE constrained mixture models can unravel the subpopulation structure and determine the sources of cell-to-cell variability. In addition, the method provides reliable estimates for kinetic rates and subpopulation characteristics. We use ODE constrained mixture modelling to study NGF-induced Erk1/2 phosphorylation in primary sensory neurones, a process relevant in inflammatory and neuropathic pain. We propose a mechanistic pathway model for this process and reconstructed static and dynamical subpopulation characteristics across experimental conditions. We validate the model predictions experimentally, which verifies the capabilities of ODE constrained mixture models. These results illustrate that ODE constrained mixture models can reveal novel mechanistic insights and possess a high sensitivity.

  8. ODE constrained mixture modelling: a method for unraveling subpopulation structures and dynamics.

    Science.gov (United States)

    Hasenauer, Jan; Hasenauer, Christine; Hucho, Tim; Theis, Fabian J

    2014-07-01

    Functional cell-to-cell variability is ubiquitous in multicellular organisms as well as bacterial populations. Even genetically identical cells of the same cell type can respond differently to identical stimuli. Methods have been developed to analyse heterogeneous populations, e.g., mixture models and stochastic population models. The available methods are, however, either incapable of simultaneously analysing different experimental conditions or are computationally demanding and difficult to apply. Furthermore, they do not account for biological information available in the literature. To overcome disadvantages of existing methods, we combine mixture models and ordinary differential equation (ODE) models. The ODE models provide a mechanistic description of the underlying processes while mixture models provide an easy way to capture variability. In a simulation study, we show that the class of ODE constrained mixture models can unravel the subpopulation structure and determine the sources of cell-to-cell variability. In addition, the method provides reliable estimates for kinetic rates and subpopulation characteristics. We use ODE constrained mixture modelling to study NGF-induced Erk1/2 phosphorylation in primary sensory neurones, a process relevant in inflammatory and neuropathic pain. We propose a mechanistic pathway model for this process and reconstructed static and dynamical subpopulation characteristics across experimental conditions. We validate the model predictions experimentally, which verifies the capabilities of ODE constrained mixture models. These results illustrate that ODE constrained mixture models can reveal novel mechanistic insights and possess a high sensitivity.

  9. Testing job typologies and identifying at-risk subpopulations using factor mixture models.

    Science.gov (United States)

    Keller, Anita C; Igic, Ivana; Meier, Laurenz L; Semmer, Norbert K; Schaubroeck, John M; Brunner, Beatrice; Elfering, Achim

    2017-10-01

    Research in occupational health psychology has tended to focus on the effects of single job characteristics or various job characteristics combined into 1 factor. However, such a variable-centered approach does not account for the clustering of job attributes among groups of employees. We addressed this issue by using a person-centered approach to (a) investigate the occurrence of different empirical constellations of perceived job stressors and resources and (b) validate the meaningfulness of profiles by analyzing their association with employee well-being and performance. We applied factor mixture modeling to identify profiles in 4 large samples consisting of employees in Switzerland (Studies 1 and 2) and the United States (Studies 3 and 4). We identified 2 profiles that spanned the 4 samples, with 1 reflecting a combination of relatively low stressors and high resources (P1) and the other relatively high stressors and low resources (P3). The profiles differed mainly in terms of their organizational and social aspects. Employees in P1 reported significantly higher mean levels of job satisfaction, performance, and general health, and lower means in exhaustion compared with P3. Additional analyses showed differential relationships between job attributes and outcomes depending on profile membership. These findings may benefit organizational interventions as they show that perceived work stressors and resources more strongly influence satisfaction and well-being in particular profiles. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  10. Global chromosomal structural instability in a subpopulation of starving Escherichia coli cells.

    Directory of Open Access Journals (Sweden)

    Dongxu Lin

    2011-08-01

    Full Text Available Copy-number variations (CNVs constitute very common differences between individual humans and possibly all genomes and may therefore be important fuel for evolution, yet how they form remains elusive. In starving Escherichia coli, gene amplification is induced by stress, controlled by the general stress response. Amplification has been detected only encompassing genes that confer a growth advantage when amplified. We studied the structure of stress-induced gene amplification in starving cells in the Lac assay in Escherichia coli by array comparative genomic hybridization (aCGH, with polymerase chain reaction (pcr and DNA sequencing to establish the structures generated. About 10% of 300 amplified isolates carried other chromosomal structural change in addition to amplification. Most of these were inversions and duplications associated with the amplification event. This complexity supports a mechanism similar to that seen in human non-recurrent copy number variants. We interpret these complex events in terms of repeated template switching during DNA replication. Importantly, we found a significant occurrence (6 out of 300 of chromosomal structural changes that were apparently not involved in the amplification event. These secondary changes were absent from 240 samples derived from starved cells not carrying amplification, suggesting that amplification happens in a differentiated subpopulation of stressed cells licensed for global chromosomal structural change and genomic instability. These data imply that chromosomal structural changes occur in bursts or showers of instability that may have the potential to drive rapid evolution.

  11. Comparison of sperm motility subpopulation structure among wild anadromous and farmed male Atlantic salmon (Salmo salar) parr using a CASA system.

    Science.gov (United States)

    Caldeira, Carina; García-Molina, Almudena; Valverde, Anthony; Bompart, Daznia; Hassane, Megan; Martin, Patrick; Soler, Carles

    2018-04-13

    Atlantic salmon (Salmo salar) is an endangered freshwater species that needs help to recover its wild stocks. However, the priority in aquaculture is to obtain successful fertilisation and genetic variability to secure the revival of the species. The aims of the present work were to study sperm subpopulation structure and motility patterns in wild anadromous males and farmed male Atlantic salmon parr. Salmon sperm samples were collected from wild anadromous salmon (WS) and two generations of farmed parr males. Sperm samples were collected from sexually mature males and sperm motility was analysed at different times after activation (5 and 35s). Differences among the three groups were analysed using statistical techniques based on Cluster analysis the Bayesian method. Atlantic salmon were found to have three sperm subpopulations, and the spermatozoa in ejaculates of mature farmed parr males had a higher velocity and larger size than those of WS males. This could be an adaptation to high sperm competition because salmonid species are naturally adapted to this process. Motility analysis enables us to identify sperm subpopulations, and it may be useful to correlate these sperm subpopulations with fertilisation ability to test whether faster-swimming spermatozoa have a higher probability of success.

  12. Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex.

    Science.gov (United States)

    Fame, Ryann M; Dehay, Colette; Kennedy, Henry; Macklis, Jeffrey D

    2017-03-01

    Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum and are implicated in associative integration of multimodal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons-and more extensive and varied connections in neocortical gray and white matter-in primates compared with rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and postmigratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g., Ptn, Nnmt, Cited2, Dkk3), in contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g., EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. TaqMan real-time PCR assays for single-nucleotide polymorphisms which identify Francisella tularensis and its subspecies and subpopulations.

    Directory of Open Access Journals (Sweden)

    Dawn N Birdsell

    Full Text Available Francisella tularensis, the etiologic agent of tularemia and a Class A Select Agent, is divided into three subspecies and multiple subpopulations that differ in virulence and geographic distribution. Given these differences, there is a need to rapidly and accurately determine if a strain is F. tularensis and, if it is, assign it to subspecies and subpopulation. We designed TaqMan real-time PCR genotyping assays using eleven single nucleotide polymorphisms (SNPs that were potentially specific to closely related groups within the genus Francisella, including numerous subpopulations within F. tularensis species. We performed extensive validation studies to test the specificity of these SNPs to particular populations by screening the assays across a set of 565 genetically and geographically diverse F. tularensis isolates and an additional 21 genetic near-neighbor (outgroup isolates. All eleven assays correctly determined the genetic groups of all 565 F. tularensis isolates. One assay differentiates F. tularensis, F. novicida, and F. hispaniensis from the more genetically distant F. philomiragia and Francisella-like endosymbionts. Another assay differentiates F. tularensis isolates from near neighbors. The remaining nine assays classify F. tularensis-confirmed isolates into F. tularensis subspecies and subpopulations. The genotyping accuracy of these nine assays diminished when tested on outgroup isolates (i.e. non F. tularensis, therefore a hierarchical approach of assay usage is recommended wherein the F. tularensis-specific assay is used before the nine downstream assays. Among F. tularensis isolates, all eleven assays were highly sensitive, consistently amplifying very low concentrations of DNA. Altogether, these eleven TaqMan real-time PCR assays represent a highly accurate, rapid, and sensitive means of identifying the species, subspecies, and subpopulation of any F. tularensis isolate if used in a step-wise hierarchical scheme. These assays

  14. Identifying structural damage with ground penetrating radar

    CSIR Research Space (South Africa)

    Van Schoor, Abraham M

    2008-07-01

    Full Text Available Ground penetrating radar (GPR) and electrical resistance tomography (ERT) surveys were conducted in an urban environment in an attempt to identify the cause of severe structural damage to a historically significant residential property...

  15. Structural Identifiability of Dynamic Systems Biology Models.

    Science.gov (United States)

    Villaverde, Alejandro F; Barreiro, Antonio; Papachristodoulou, Antonis

    2016-10-01

    A powerful way of gaining insight into biological systems is by creating a nonlinear differential equation model, which usually contains many unknown parameters. Such a model is called structurally identifiable if it is possible to determine the values of its parameters from measurements of the model outputs. Structural identifiability is a prerequisite for parameter estimation, and should be assessed before exploiting a model. However, this analysis is seldom performed due to the high computational cost involved in the necessary symbolic calculations, which quickly becomes prohibitive as the problem size increases. In this paper we show how to analyse the structural identifiability of a very general class of nonlinear models by extending methods originally developed for studying observability. We present results about models whose identifiability had not been previously determined, report unidentifiabilities that had not been found before, and show how to modify those unidentifiable models to make them identifiable. This method helps prevent problems caused by lack of identifiability analysis, which can compromise the success of tasks such as experiment design, parameter estimation, and model-based optimization. The procedure is called STRIKE-GOLDD (STRuctural Identifiability taKen as Extended-Generalized Observability with Lie Derivatives and Decomposition), and it is implemented in a MATLAB toolbox which is available as open source software. The broad applicability of this approach facilitates the analysis of the increasingly complex models used in systems biology and other areas.

  16. Human corneal epithelial subpopulations

    DEFF Research Database (Denmark)

    Søndergaard, Chris Bath

    2013-01-01

    Corneal epithelium is being regenerated throughout life by limbal epithelial stem cells (LESCs) believed to be located in histologically defined stem cell niches in corneal limbus. Defective or dysfunctional LESCs result in limbal stem cell deficiency (LSCD) causing pain and decreased visual acuity...... subpopulations in human corneal epithelium using a combination of laser capture microdissection and RNA sequencing for global transcriptomic profiling. We compared dissociation cultures, using either expansion on γ-irradiated NIH/3T3 feeder cells in serum-rich medium or expansion directly on plastic in serum...

  17. Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations

    KAUST Repository

    Diez Benavente, Ernest

    2017-09-18

    The macaque parasite Plasmodium knowlesi is a significant concern in Malaysia where cases of human infection are increasing. Parasites infecting humans originate from genetically distinct subpopulations associated with the long-tailed (Macaca fascicularis (Mf)) or pig-tailed macaques (Macaca nemestrina (Mn)). We used a new high-quality reference genome to re-evaluate previously described subpopulations among human and macaque isolates from Malaysian-Borneo and Peninsular-Malaysia. Nuclear genomes were dimorphic, as expected, but new evidence of chromosomal-segment exchanges between subpopulations was found. A large segment on chromosome 8 originating from the Mn subpopulation and containing genes encoding proteins expressed in mosquito-borne parasite stages, was found in Mf genotypes. By contrast, non-recombining organelle genomes partitioned into 3 deeply branched lineages, unlinked with nuclear genomic dimorphism. Subpopulations which diverged in isolation have re-connected, possibly due to deforestation and disruption of wild macaque habitats. The resulting genomic mosaics reveal traits selected by host-vector-parasite interactions in a setting of ecological transition.

  18. Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations

    KAUST Repository

    Diez Benavente, Ernest; Florez de Sessions, Paola; Moon, Robert W.; Holder, Anthony A.; Blackman, Michael J.; Roper, Cally; Drakeley, Christopher J.; Pain, Arnab; Sutherland, Colin J.; Hibberd, Martin L.; Campino, Susana; Clark, Taane G.

    2017-01-01

    The macaque parasite Plasmodium knowlesi is a significant concern in Malaysia where cases of human infection are increasing. Parasites infecting humans originate from genetically distinct subpopulations associated with the long-tailed (Macaca fascicularis (Mf)) or pig-tailed macaques (Macaca nemestrina (Mn)). We used a new high-quality reference genome to re-evaluate previously described subpopulations among human and macaque isolates from Malaysian-Borneo and Peninsular-Malaysia. Nuclear genomes were dimorphic, as expected, but new evidence of chromosomal-segment exchanges between subpopulations was found. A large segment on chromosome 8 originating from the Mn subpopulation and containing genes encoding proteins expressed in mosquito-borne parasite stages, was found in Mf genotypes. By contrast, non-recombining organelle genomes partitioned into 3 deeply branched lineages, unlinked with nuclear genomic dimorphism. Subpopulations which diverged in isolation have re-connected, possibly due to deforestation and disruption of wild macaque habitats. The resulting genomic mosaics reveal traits selected by host-vector-parasite interactions in a setting of ecological transition.

  19. Genetic Structuration, Demography and Evolutionary History of Mycobacterium tuberculosis LAM9 Sublineage in the Americas as Two Distinct Subpopulations Revealed by Bayesian Analyses

    Science.gov (United States)

    Reynaud, Yann; Millet, Julie; Rastogi, Nalin

    2015-01-01

    Tuberculosis (TB) remains broadly present in the Americas despite intense global efforts for its control and elimination. Starting from a large dataset comprising spoligotyping (n = 21183 isolates) and 12-loci MIRU-VNTRs data (n = 4022 isolates) from a total of 31 countries of the Americas (data extracted from the SITVIT2 database), this study aimed to get an overview of lineages circulating in the Americas. A total of 17119 (80.8%) strains belonged to the Euro-American lineage 4, among which the most predominant genotypic family belonged to the Latin American and Mediterranean (LAM) lineage (n = 6386, 30.1% of strains). By combining classical phylogenetic analyses and Bayesian approaches, this study revealed for the first time a clear genetic structuration of LAM9 sublineage into two subpopulations named LAM9C1 and LAM9C2, with distinct genetic characteristics. LAM9C1 was predominant in Chile, Colombia and USA, while LAM9C2 was predominant in Brazil, Dominican Republic, Guadeloupe and French Guiana. Globally, LAM9C2 was characterized by higher allelic richness as compared to LAM9C1 isolates. Moreover, LAM9C2 sublineage appeared to expand close to twenty times more than LAM9C1 and showed older traces of expansion. Interestingly, a significant proportion of LAM9C2 isolates presented typical signature of ancestral LAM-RDRio MIRU-VNTR type (224226153321). Further studies based on Whole Genome Sequencing of LAM strains will provide the needed resolution to decipher the biogeographical structure and evolutionary history of this successful family. PMID:26517715

  20. POSTER : Identifying dynamic data structures in Malware

    NARCIS (Netherlands)

    Rupprecht, Thomas; Chen, Xi; White, David H.; Mühlberg, Jan Tobias; Bos, Herbert; Lüttgen, Gerald

    2016-01-01

    As the complexity of malware grows, so does the necessity of employing program structuring mechanisms during development. While control ow structuring is often obfuscated, the dynamic data structures employed by the program are typically untouched. We report on work in progress that exploits this

  1. Structural identifiability of polynomial and rational systems

    NARCIS (Netherlands)

    J. Nemcová (Jana)

    2010-01-01

    htmlabstractSince analysis and simulation of biological phenomena require the availability of their fully specified models, one needs to be able to estimate unknown parameter values of the models. In this paper we deal with identifiability of parametrizations which is the property of one-to-one

  2. Identifying Quantum Structures in the Ellsberg Paradox

    Science.gov (United States)

    Aerts, Diederik; Sozzo, Sandro; Tapia, Jocelyn

    2014-10-01

    Empirical evidence has confirmed that quantum effects occur frequently also outside the microscopic domain, while quantum structures satisfactorily model various situations in several areas of science, including biological, cognitive and social processes. In this paper, we elaborate a quantum mechanical model which faithfully describes the Ellsberg paradox in economics, showing that the mathematical formalism of quantum mechanics is capable to represent the ambiguity present in this kind of situations, because of the presence of contextuality. Then, we analyze the data collected in a concrete experiment we performed on the Ellsberg paradox and work out a complete representation of them in complex Hilbert space. We prove that the presence of quantum structure is genuine, that is, interference and superposition in a complex Hilbert space are really necessary to describe the conceptual situation presented by Ellsberg. Moreover, our approach sheds light on `ambiguity laden' decision processes in economics and decision theory, and allows to deal with different Ellsberg-type generalizations, e.g., the Machina paradox.

  3. Structure formation cosmic rays: Identifying observational constraints

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    Prodanović T.

    2005-01-01

    Full Text Available Shocks that arise from baryonic in-fall and merger events during the structure formation are believed to be a source of cosmic rays. These "structure formation cosmic rays" (SFCRs would essentially be primordial in composition, namely, mostly made of protons and alpha particles. However, very little is known about this population of cosmic rays. One way to test the level of its presence is to look at the products of hadronic reactions between SFCRs and the ISM. A perfect probe of these reactions would be Li. The rare isotope Li is produced only by cosmic rays, dominantly in αα → 6Li fusion reactions with the ISM helium. Consequently, this nuclide provides a unique diagnostic of the history of cosmic rays. Exactly because of this unique property is Li affected most by the presence of an additional cosmic ray population. In turn, this could have profound consequences for the Big-Bang nucleosynthesis: cosmic rays created during cosmic structure formation would lead to pre-Galactic Li production, which would act as a "contaminant" to the primordial 7Li content of metalpoor halo stars. Given the already existing problem of establishing the concordance between Li observed in halo stars and primordial 7Li as predicted by the WMAP, it is crucial to set limits to the level of this "contamination". However, the history of SFCRs is not very well known. Thus we propose a few model-independent ways of testing the SFCR species and their history, as well as the existing lithium problem: 1 we establish the connection between gamma-ray and Li production, which enables us to place constraints on the SFCR-made lithium by using the observed Extragalactic Gamma-Ray Background (EGRB; 2 we propose a new site for testing the primordial and SFCR-made lithium, namely, low-metalicity High-Velocity Clouds (HVCs, which retain the pre-Galactic composition without any significant depletion. Although using one method alone may not give us strong constraints, using them in

  4. Can a structured questionnaire identify patients with reduced renal function?

    DEFF Research Database (Denmark)

    Azzouz, Manal; Rømsing, Janne; Thomsen, Henrik

    2014-01-01

    To evaluate a structured questionnaire in identifying outpatients with renal dysfunction before MRI or CT in various age groups.......To evaluate a structured questionnaire in identifying outpatients with renal dysfunction before MRI or CT in various age groups....

  5. Sperm subpopulational dinamycs during the cryopreservation procedure in caprine (Capra aegagrus hircus ejaculates

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    Barbas JP

    2017-08-01

    Full Text Available The objective of the present research was to determine specific sperm subpopulational dynamics in different processing steps during cryopreservation process by using objective functional sperm kinematic descriptors in goat ejaculates. Fresh ejaculates (n=40 collected from eight bucks were analised for volume, concentration, sperm viability, acrosome integrity, and sperm motility using computer-assisted sperm analysis (CASA system. Eight sperm kinematic descriptors (VCL, VSL, VAP, LIN, STR, BCF, ALH, and WOB were assessed using CASA system after five different handling step (1st: fresh semen collection (F; 2nd: 1st washing/centrifugation step (1WC; 3rd: 2nd washing / centrifugation step (2WC; 4th: cooling step at 4ºC (CL; and 5th: post-thawing step at 37ºC (PT during a standard cryopreservation protocol for goat semen. The results obtained from the kinematic parameters were analysed by using Principal Component Analysis (PCA and multivariate clustering procedures to identify specific kinematic subpopulations and establish the relationship between the distribution of the subpopulations found and the functional sperm motility in each step. Except for the 1st (SbpF1-SbpF3 and 4th (SbpCL1-SbpCL3 intervals, four sperm kinematic subpopulations (Sbp1LC1-Sbp1LC4, Sbp2LC1-Sbp2LC4 and SbpPD1-SbpPD4 were observed. Based on kinematic velocity parameters and the subpopulation disclosed, rapid, slow, vigorous, passive, non-progressive and progressive sperm were discerned. Moreover, based on kinematic linearity parameters and depending on the subpopulation uncovered, curvilinear, regular-linear, parabolic and erratic-non-linear trajectories were detected. Subpopulations remained varible throughout handling steps and multiple significant differences among the sperm kinematic parameters were observed (p<0.001 as well as in the frequency of distribution of kinematic subpopulations among steps (p<0.05. In conclusion, this study confirms the variability and

  6. Comparison of sperm subpopulation structures in first and second ejaculated semen from Japanese black bulls by a cluster analysis of sperm motility evaluated by a CASA system.

    Science.gov (United States)

    Kanno, Chihiro; Sakamoto, Kentaro Q; Yanagawa, Yojiro; Takahashi, Yoshiyuki; Katagiri, Seiji; Nagano, Masashi

    2017-08-04

    In the present study, bull sperm in the first and second ejaculates were divided into subpopulations based on their motility characteristics using a cluster analysis of data from computer-assisted sperm motility analysis (CASA). Semen samples were collected from 4 Japanese black bulls. Data from 9,228 motile sperm were classified into 4 clusters; 1) very rapid and progressively motile sperm, 2) rapid and circularly motile sperm with widely moving heads, 3) moderately motile sperm with heads moving frequently in a short length, and 4) poorly motile sperm. The percentage of cluster 1 varied between bulls. The first ejaculates had a higher proportion of cluster 2 and lower proportion of cluster 3 than the second ejaculates.

  7. Structural parameter identifiability analysis for dynamic reaction networks

    DEFF Research Database (Denmark)

    Davidescu, Florin Paul; Jørgensen, Sten Bay

    2008-01-01

    method based on Lie derivatives. The proposed systematic two phase methodology is illustrated on a mass action based model for an enzymatically catalyzed reaction pathway network where only a limited set of variables is measured. The methodology clearly pinpoints the structurally identifiable parameters...... where for a given set of measured variables it is desirable to investigate which parameters may be estimated prior to spending computational effort on the actual estimation. This contribution addresses the structural parameter identifiability problem for the typical case of reaction network models....... The proposed analysis is performed in two phases. The first phase determines the structurally identifiable reaction rates based on reaction network stoichiometry. The second phase assesses the structural parameter identifiability of the specific kinetic rate expressions using a generating series expansion...

  8. Identifying structural variants using linked-read sequencing data.

    Science.gov (United States)

    Elyanow, Rebecca; Wu, Hsin-Ta; Raphael, Benjamin J

    2017-11-03

    Structural variation, including large deletions, duplications, inversions, translocations, and other rearrangements, is common in human and cancer genomes. A number of methods have been developed to identify structural variants from Illumina short-read sequencing data. However, reliable identification of structural variants remains challenging because many variants have breakpoints in repetitive regions of the genome and thus are difficult to identify with short reads. The recently developed linked-read sequencing technology from 10X Genomics combines a novel barcoding strategy with Illumina sequencing. This technology labels all reads that originate from a small number (~5-10) DNA molecules ~50Kbp in length with the same molecular barcode. These barcoded reads contain long-range sequence information that is advantageous for identification of structural variants. We present Novel Adjacency Identification with Barcoded Reads (NAIBR), an algorithm to identify structural variants in linked-read sequencing data. NAIBR predicts novel adjacencies in a individual genome resulting from structural variants using a probabilistic model that combines multiple signals in barcoded reads. We show that NAIBR outperforms several existing methods for structural variant identification - including two recent methods that also analyze linked-reads - on simulated sequencing data and 10X whole-genome sequencing data from the NA12878 human genome and the HCC1954 breast cancer cell line. Several of the novel somatic structural variants identified in HCC1954 overlap known cancer genes. Software is available at compbio.cs.brown.edu/software. braphael@princeton.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  9. Selection of viable cell subpopulations from murine tumours using FACS

    International Nuclear Information System (INIS)

    Chaplin, D.J.; Durand, R.E.; Olive, P.L.

    1985-01-01

    The authors developed a technique which enables isolation of viable tumour cells subpopulation as a function of their distance from the blood supply. The basis for this separation procedure is that the fluorochrome, Hoechst 33342, as a result of its high avidity for cellular DNA, exhibits a marked diffusion/consumption gradient when it has to pass through several cell layers. As a result intravenous injection of Hoechst 33342 into tumour bearing animals, results in a heterogeneous straining pattern within the tumour with cells close to blood vessels being brightly fluorescent while those more distant are less intensely stained. Since these differences in staining intensity persist after tumour disaggregation, cells can be sorted into subpopulations on the basis of their fluorescence intensity using a fluorescence activated cell sorter. This technique offers the unique possibility of identifying the location of those cell subpopulations resistant to treatment with either radiation or chemotherapeutic drugs

  10. Wilms Tumor 1b defines a wound-specific sheath cell subpopulation associated with notochord repair

    Science.gov (United States)

    Lopez-Baez, Juan Carlos; Zeng, Zhiqiang; Brunsdon, Hannah; Salzano, Angela; Brombin, Alessandro; Wyatt, Cameron; Rybski, Witold; Huitema, Leonie F A; Dale, Rodney M; Kawakami, Koichi; Englert, Christoph; Chandra, Tamir; Schulte-Merker, Stefan

    2018-01-01

    Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that wt1b+cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. Wt1b+sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, wt1b+and entpd5+ cells constitute separate, tightly-associated subpopulations. Surprisingly, wt1b expression at the site of injury is maintained even into adult stages in developing vertebrae, which form in an untypical manner via a cartilage intermediate. Given that notochord cells are retained in adult intervertebral discs, the identification of novel subpopulations may have important implications for regenerative spine disorder treatments. PMID:29405914

  11. Structural identifiability analysis of a cardiovascular system model.

    Science.gov (United States)

    Pironet, Antoine; Dauby, Pierre C; Chase, J Geoffrey; Docherty, Paul D; Revie, James A; Desaive, Thomas

    2016-05-01

    The six-chamber cardiovascular system model of Burkhoff and Tyberg has been used in several theoretical and experimental studies. However, this cardiovascular system model (and others derived from it) are not identifiable from any output set. In this work, two such cases of structural non-identifiability are first presented. These cases occur when the model output set only contains a single type of information (pressure or volume). A specific output set is thus chosen, mixing pressure and volume information and containing only a limited number of clinically available measurements. Then, by manipulating the model equations involving these outputs, it is demonstrated that the six-chamber cardiovascular system model is structurally globally identifiable. A further simplification is made, assuming known cardiac valve resistances. Because of the poor practical identifiability of these four parameters, this assumption is usual. Under this hypothesis, the six-chamber cardiovascular system model is structurally identifiable from an even smaller dataset. As a consequence, parameter values computed from limited but well-chosen datasets are theoretically unique. This means that the parameter identification procedure can safely be performed on the model from such a well-chosen dataset. Thus, the model may be considered suitable for use in diagnosis. Copyright © 2016 IPEM. Published by Elsevier Ltd. All rights reserved.

  12. Psychometric Consequences of Subpopulation Item Parameter Drift

    Science.gov (United States)

    Huggins-Manley, Anne Corinne

    2017-01-01

    This study defines subpopulation item parameter drift (SIPD) as a change in item parameters over time that is dependent on subpopulations of examinees, and hypothesizes that the presence of SIPD in anchor items is associated with bias and/or lack of invariance in three psychometric outcomes. Results show that SIPD in anchor items is associated…

  13. Subpopulations in purified platelets adhering on glass.

    Science.gov (United States)

    Donati, Alessia; Gupta, Swati; Reviakine, Ilya

    2016-06-22

    Understanding how platelet activation is regulated is important in the context of cardiovascular disorders and their management with antiplatelet therapy. Recent evidence points to different platelet subpopulations performing different functions. In particular, procoagulant and aggregating subpopulations have been reported in the literature in platelets treated with the GPVI agonists. How the formation of platelet subpopulations upon activation is regulated remains unclear. Here, it is shown that procoagulant and aggregating platelet subpopulations arise spontaneously upon adhesion of purified platelets on clean glass surfaces. Calcium ionophore treatment of the adhering platelets resulted in one platelet population expressing both the procoagulant and the adherent population markers phosphatidylserine and the activated form of GPIIb/IIIa, while all of the platelets expressed CD62P independently of the ionophore treatment. Therefore, all platelets have the capacity to express all three activation markers. It is concluded that platelet subpopulations observed in various studies reflect the dynamics of the platelet activation process.

  14. Identification of geographically distributed sub-populations of Leishmania (Leishmania major by microsatellite analysis

    Directory of Open Access Journals (Sweden)

    Schwenkenbecher Jan

    2008-06-01

    Full Text Available Abstract Background Leishmania (Leishmania major, one of the agents causing cutaneous leishmaniasis (CL in humans, is widely distributed in the Old World where different species of wild rodent and phlebotomine sand fly serve as animal reservoir hosts and vectors, respectively. Despite this, strains of L. (L. major isolated from many different sources over many years have proved to be relatively uniform. To investigate the population structure of the species highly polymorphic microsatellite markers were employed for greater discrimination among it's otherwise closely related strains, an approach applied successfully to other species of Leishmania. Results Multilocus Microsatellite Typing (MLMT based on 10 different microsatellite markers was applied to 106 strains of L. (L. major from different regions where it is endemic. On applying a Bayesian model-based approach, three main populations were identified, corresponding to three separate geographical regions: Central Asia (CA; the Middle East (ME; and Africa (AF. This was congruent with phylogenetic reconstructions based on genetic distances. Re-analysis separated each of the populations into two sub-populations. The two African sub-populations did not correlate well with strains' geographical origin. Strains falling into the sub-populations CA and ME did mostly group according to their place of isolation although some anomalies were seen, probably, owing to human migration. Conclusion The model- and distance-based analyses of the microsatellite data exposed three main populations of L. (L. major, Central Asia, the Middle East and Africa, each of which separated into two sub-populations. This probably correlates with the different species of rodent host.

  15. Vacuolar structures can be identified by AFM elasticity mapping

    International Nuclear Information System (INIS)

    Riethmueller, Christoph; Schaeffer, Tilman E.; Kienberger, Ferry; Stracke, Werner; Oberleithner, Hans

    2007-01-01

    Fluid-filled organelles like vesicles, endosomes and pinosomes are inevitable parts of cellular signalling and transport. Endothelial cells, building a barrier between blood and tissue, can form vacuolar organelles. These structures are implicated in upregulated fluid transport across the endothelium under inflammatory conditions. Vacuolar organelles have been described by transmission electron microscopy so far. Here, we present a method that images and mechanically characterizes intracellular structures in whole cells by atomic force microscopy (AFM). After crosslinking the cellular proteins with the fixative glutaraldehyde, plasma membrane depressions become observable, which are scattered around the cell nucleus. Nanomechanical analysis identifies them as spots of reduced stiffness. Scanning electron microscopy confirms their pit-like appearance. In addition, fluorescence microscopy detects an analogous pattern of protein-poor spots, thereby confirming mechanical rigidity to arise from crosslinked proteins. This AFM application opens up a mechanical dimension for the investigation of intracellular organelles

  16. Structural and practical identifiability analysis of S-system.

    Science.gov (United States)

    Zhan, Choujun; Li, Benjamin Yee Shing; Yeung, Lam Fat

    2015-12-01

    In the field of systems biology, biological reaction networks are usually modelled by ordinary differential equations. A sub-class, the S-systems representation, is a widely used form of modelling. Existing S-systems identification techniques assume that the system itself is always structurally identifiable. However, due to practical limitations, biological reaction networks are often only partially measured. In addition, the captured data only covers a limited trajectory, therefore data can only be considered as a local snapshot of the system responses with respect to the complete set of state trajectories over the entire state space. Hence the estimated model can only reflect partial system dynamics and may not be unique. To improve the identification quality, the structural and practical identifiablility of S-system are studied. The S-system is shown to be identifiable under a set of assumptions. Then, an application on yeast fermentation pathway was conducted. Two case studies were chosen; where the first case is based on a larger state trajectories and the second case is based on a smaller one. By expanding the dataset which span a relatively larger state space, the uncertainty of the estimated system can be reduced. The results indicated that initial concentration is related to the practical identifiablity.

  17. Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells.

    Science.gov (United States)

    Reyes, M; Verfaillie, C M

    2001-06-01

    Mesenchymal stem cells were isolated and a subpopulation of cells--multipotent adult progenitor cells--were identified that have the potential for multilineage differentiation. Their ability to engraft and differentiate in vivo is under investigation.

  18. Connectivity among subpopulations of Louisiana black bears as estimated by a step selection function

    Science.gov (United States)

    Clark, Joseph D.; Jared S. Laufenberg,; Maria Davidson,; Jennifer L. Murrow,

    2015-01-01

    Habitat fragmentation is a fundamental cause of population decline and increased risk of extinction for many wildlife species; animals with large home ranges and small population sizes are particularly sensitive. The Louisiana black bear (Ursus americanus luteolus) exists only in small, isolated subpopulations as a result of land clearing for agriculture, but the relative potential for inter-subpopulation movement by Louisiana black bears has not been quantified, nor have characteristics of effective travel routes between habitat fragments been identified. We placed and monitored global positioning system (GPS) radio collars on 8 female and 23 male bears located in 4 subpopulations in Louisiana, which included a reintroduced subpopulation located between 2 of the remnant subpopulations. We compared characteristics of sequential radiolocations of bears (i.e., steps) with steps that were possible but not chosen by the bears to develop step selection function models based on conditional logistic regression. The probability of a step being selected by a bear increased as the distance to natural land cover and agriculture at the end of the step decreased and as distance from roads at the end of a step increased. To characterize connectivity among subpopulations, we used the step selection models to create 4,000 hypothetical correlated random walks for each subpopulation representing potential dispersal events to estimate the proportion that intersected adjacent subpopulations (hereafter referred to as successful dispersals). Based on the models, movement paths for males intersected all adjacent subpopulations but paths for females intersected only the most proximate subpopulations. Cross-validation and genetic and independent observation data supported our findings. Our models also revealed that successful dispersals were facilitated by a reintroduced population located between 2 distant subpopulations. Successful dispersals for males were dependent on natural land

  19. DSIbin : Identifying dynamic data structures in C/C++ binaries

    NARCIS (Netherlands)

    Rupprecht, Thomas; Chen, Xi; White, David H.; Boockmann, Jan H.; Luttgen, Gerald; Bos, Herbert

    2017-01-01

    Reverse engineering binary code is notoriously difficult and, especially, understanding a binary's dynamic data structures. Existing data structure analyzers are limited wrt. program comprehension: they do not detect complex structures such as skip lists, or lists running through nodes of different

  20. Distinct neutrophil subpopulations phenotype by flow cytometry in myelodysplastic syndromes.

    Science.gov (United States)

    Vikentiou, Myrofora; Psarra, Katerina; Kapsimali, Violetta; Liapis, Konstantinos; Michael, Michalis; Tsionos, Konstantinos; Lianidou, Evi; Papasteriades, Chryssa

    2009-03-01

    The cardinal feature of myelodysplastic syndromes (MDS) is dysplasia involving one or more myeloid cell lineages. In the present study, we used 4-color flow cytometric analysis to investigate dysgranulopoiesis in bone marrow specimens from 65 patients with MDS. The antigen expression patterns of total neutrophil granulocytes (TNG) and of the two distinct neutrophil granulocytic subpopulations (NGSs), NGS-1 (dimmer CD45 expression) and NGS-2 (stronger CD45 expression) identified on the side scatter (SS) vs. CD45-intensity plot, were studied. The neutrophil granulocytes from patients with MDS showed characteristic antigen expression aberrancies which were more pronounced in NGS-2 subpopulation. Studying separately the NGS-2 subpopulation with the CD16/MPO/LF combination, the low CD16(+)/MPO(+) and low CD16(+)/LF(+) percentages seemed to discriminate between lower-risk and higher-risk patients with MDS in most occasions. Furthermore, a detailed assessment of the NGS-1 and NGS-2 immunophenotypic patterns revealed early dysplastic changes, not otherwise observed by standard TNG analysis, especially in cases of lower-risk MDS.

  1. Identification of subpopulations of prairie voles differentially susceptible to peer influence to decrease high alcohol intake.

    Science.gov (United States)

    Anacker, Allison M J; Ryabinin, Andrey E

    2013-01-01

    Peer influences are critical in the decrease of alcohol (ethanol) abuse and maintenance of abstinence. We previously developed an animal model of inhibitory peer influences on ethanol drinking using prairie voles and here sought to understand whether this influential behavior was due to specific changes in drinking patterns and to variation in a microsatellite sequence in the regulatory region of the vasopressin receptor 1a gene (avpr1a). Adult prairie voles' drinking patterns were monitored in a lickometer apparatus that recorded each lick a subject exhibited during continuous access to water and 10% ethanol during periods of isolation, pair housing of high and low drinkers, and subsequent isolation. Analysis of fluid consumption confirmed previous results that high drinkers typically decrease ethanol intake when paired with low drinkers, but that a subset of voles do not decrease. Analysis of bout structure revealed differences in the number of ethanol drinking bouts in the subpopulations of high drinkers when paired with low drinkers. Lickometer drinking patterns analyzed by visual and by cross-correlation analyses demonstrated that pair housing did not increase the rate of subjects drinking in bouts occurring at the same time. The length of the avpr1a microsatellite did not predict susceptibility to peer influence or any other drinking behaviors. In summary, subpopulations of high drinkers were identified, by fluid intake and number of drinking bouts, which did or did not lower their ethanol intake when paired with a low drinking peer, and these subpopulations should be explored for testing the efficacy of treatments to decrease ethanol use in groups that are likely to be responsive to different types of therapy.

  2. Identification of subpopulations of prairie voles differentially susceptible to peer influence to decrease high alcohol intake

    Directory of Open Access Journals (Sweden)

    Allison M.J. Anacker

    2013-07-01

    Full Text Available Peer influences are critical in the decrease of alcohol (ethanol abuse and maintenance of abstinence. We previously developed an animal model of inhibitory peer influences on ethanol drinking using prairie voles and here sought to understand whether this influential behavior was due to specific changes in drinking patterns and to variation in a microsatellite sequence in the regulatory region of the vasopressin receptor 1a gene (avpr1a. Adult prairie voles’ drinking patterns were monitored in a lickometer apparatus that recorded each lick a subject exhibited during continuous access to water and 10% ethanol during periods of isolation, pair housing of high and low drinkers, and subsequent isolation. Analysis of fluid consumption confirmed previous results that high drinkers typically decrease ethanol intake when paired with low drinkers, but that a subset of voles do not decrease. Analysis of bout structure revealed differences in the number of ethanol drinking bouts in the subpopulations of high drinkers when paired with low drinkers. Lickometer drinking patterns analyzed by visual and by cross-correlation analyses demonstrated that pair housing did not increase the rate of subjects drinking in bouts occurring at the same time. The length of the avpr1a microsatellite did not predict susceptibility to peer influence or any other drinking behaviors. In summary, subpopulations of high drinkers were identified by fluid intake and number of drinking bouts, which did or did not lower their ethanol intake when paired with a low drinking peer, and these subpopulations should be explored for testing the efficacy of treatments to decrease ethanol use in groups that are likely to be responsive to different types of therapy.

  3. Structural health monitoring (vibration) as a tool for identifying structural alterations of the lumbar spine

    DEFF Research Database (Denmark)

    Kawchuk, Gregory N; Hartvigsen, Jan; Edgecombe, Tiffany

    2016-01-01

    Structural health monitoring (SHM) is an engineering technique used to identify mechanical abnormalities not readily apparent through other means. Recently, SHM has been adapted for use in biological systems, but its invasive nature limits its clinical application. As such, the purpose of this pr......Structural health monitoring (SHM) is an engineering technique used to identify mechanical abnormalities not readily apparent through other means. Recently, SHM has been adapted for use in biological systems, but its invasive nature limits its clinical application. As such, the purpose...... of this project was to determine if a non-invasive form of SHM could identify structural alterations in the spines of living human subjects. Lumbar spines of 10 twin pairs were visualized by magnetic resonance imaging then assessed by a blinded radiologist to determine whether twin pairs were structurally...... concordant or discordant. Vibration was then applied to each subject's spine and the resulting response recorded from sensors overlying lumbar spinous processes. The peak frequency, area under the curve and the root mean square were computed from the frequency response function of each sensor. Statistical...

  4. Financial crisis and market risk premium: Identifying multiple structural changes

    Directory of Open Access Journals (Sweden)

    Juan J. García-Machado

    2011-03-01

    Full Text Available The relationship between macroeconomic variables and stock market returns is, by now, well-documented in the literature. However, in this article we examine the long-run relationship between stock and bond markets returns over the period from 1991:11 to 2009:11, using Bai and Perron’s multiple structural change approach. Findings indicate that while the market risk premium is usually positive, periods with negative values appear only in three periods (1991:1-1993:2, 1998:3-2002:2 and from 2007:1-2009:11 leading to changes in the GDP evolution. Thereby, the study shows the presence of structural breaks in the Spanish market risk premium and its relationship with business cycle. These findings contribute to a better understanding of close linkages between the financial markets and the macroeconomic variables such as GDP. Implications of the study and suggestions for future research are provided.

  5. Raman spectroscopy of single extracellular vesicles reveals subpopulations with varying membrane content (Conference Presentation)

    Science.gov (United States)

    Smith, Zachary J.; Lee, Changwon; Rojalin, Tatu; Carney, Randy P.; Hazari, Sidhartha; Knudson, Alisha; Lam, Kit S.; Saari, Heikki; Lazaro Ibañez, Elisa; Viitala, Tapani; Laaksonen, Timo; Yliperttula, Marjo; Wachsmann-Hogiu, Sebastian

    2016-03-01

    Exosomes are small (~100nm) membrane bound vesicles excreted by cells as part of their normal biological processes. These extracellular vesicles are currently an area of intense research, since they were recently found to carry functional mRNA that allows transfer of proteins and other cellular instructions between cells. Exosomes have been implicated in a wide range of diseases, including cancer. Cancer cells are known to have increased exosome production, and may use those exosomes to prepare remote environments for metastasis. Therefore, there is a strong need to develop characterization methods to help understand the structure and function of these vesicles. However, current techniques, such as proteomics and genomics technologies, rely on aggregating a large amount of exosome material and reporting on chemical content that is averaged over many millions of exosomes. Here we report on the use of laser-tweezers Raman spectroscopy (LTRS) to probe individual vesicles, discovering distinct heterogeneity among exosomes both within a cell line, as well as between different cell lines. Through principal components analysis followed by hierarchical clustering, we have identified four "subpopulations" of exosomes shared across seven cell lines. The key chemical differences between these subpopulations, as determined by spectral analysis of the principal component loadings, are primarily related to membrane composition. Specifically, the differences can be ascribed to cholesterol content, cholesterol to phospholipid ratio, and surface protein expression. Thus, we have shown LTRS to be a powerful method to probe the chemical content of single extracellular vesicles.

  6. Smart skin structures for identifying and locating laser irradiation

    Energy Technology Data Exchange (ETDEWEB)

    LaDelfe, P.C.; Goeller, R.M.; Murray, H.S.

    1992-12-31

    A pyramidal arrangement of wavelength-selective optical detectors can be used to determine the identity (wavelength), intensity, and direction-of-arrival of faser irradiation. The advantages of this technique are that only unobtrusive, skin-like structures are required and that large collection areas provide high sensitivity. The disadvantage is that the angular resolution (approximately 5 degrees in a 60 degree field-of--view) is less than that which can be achieved using methods requiring thicker structures. The detector elements are large-area, polyvinylidine fluoride, pyroelectric devices with wavelength selective coatinits. Four identical arrays of these elements are situated on the top and sides of a frustrated, three--sided prism. Since only the relative orientations are significant, these faces can be selected regions on the surface of an existing structure. We first describe the construction of the detectors and the system, then develop the mathematical description of the system. Using coated detectors whose performance has been experimentally verified, we will model the response to in-channel, monochromatic irradiation and then describe the data analysis algorithm. Although we will limit our model to a simple, two-channel system, the concept and algorithm can easily be extended to a system of any reasonable number of nonoverlapping channels.

  7. Smart skin structures for identifying and locating laser irradiation

    Energy Technology Data Exchange (ETDEWEB)

    LaDelfe, P.C.; Goeller, R.M.; Murray, H.S.

    1992-01-01

    A pyramidal arrangement of wavelength-selective optical detectors can be used to determine the identity (wavelength), intensity, and direction-of-arrival of faser irradiation. The advantages of this technique are that only unobtrusive, skin-like structures are required and that large collection areas provide high sensitivity. The disadvantage is that the angular resolution (approximately 5 degrees in a 60 degree field-of--view) is less than that which can be achieved using methods requiring thicker structures. The detector elements are large-area, polyvinylidine fluoride, pyroelectric devices with wavelength selective coatinits. Four identical arrays of these elements are situated on the top and sides of a frustrated, three--sided prism. Since only the relative orientations are significant, these faces can be selected regions on the surface of an existing structure. We first describe the construction of the detectors and the system, then develop the mathematical description of the system. Using coated detectors whose performance has been experimentally verified, we will model the response to in-channel, monochromatic irradiation and then describe the data analysis algorithm. Although we will limit our model to a simple, two-channel system, the concept and algorithm can easily be extended to a system of any reasonable number of nonoverlapping channels.

  8. Extracting and identifying concrete structural defects in GPR images

    Science.gov (United States)

    Ye, Qiling; Jiao, Liangbao; Liu, Chuanxin; Cao, Xuehong; Huston, Dryver; Xia, Tian

    2018-03-01

    Traditionally most GPR data interpretations are performed manually. With the advancement of computing technologies, how to automate GPR data interpretation to achieve high efficiency and accuracy has become an active research subject. In this paper, analytical characterizations of major defects in concrete structures, including delamination, air void and moisture in GPR images, are performed. In the study, the image features of different defects are compared. Algorithms are developed for defect feature extraction and identification. For validations, both simulation results and field test data are utilized.

  9. HREELS to identify electronic structures of organic thin films.

    Science.gov (United States)

    Oeter, D; Ziegler, C; Göpel, W

    1995-10-01

    The electronic structure of alpha-oligothiophene (alphanT) thin films has been investigated for increasing chain lengths of n= 4-8 thiophene units with high resolution electron energy loss spectroscopy (HREELS) in the specular reflection geometry at a primary energy of 15 eV. The great advantage of this technique in contrast to UV/VIS absorption spectroscopy results from the fact, that the impact scattering mechanism of HREELS makes it possible to also detect optically forbidden electronic transitions. On the other hand, the electrons used as probes in HREELS have a wavelength which is two orders of magnitudes smaller if compared to those of photons used in UV/VIS absorption spectroscopy. Therefore individual molecules are excited by HREELS independent from each other and hence the excitation of collective excitons is not possible. As a result, information about the orientation of the molecules cannot be achieved with HREELS, which, however, is possible in polarization-dependent UV/VIS spectroscopy.

  10. Characteristics and Travel Patterns of New York Residents: Subpopulations of Persons with a Disability in 2009

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Ho-Ling [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Reuscher, Tim [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wilson, Daniel W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-08-01

    In this study, Oak Ridge National Laboratory (ORNL) was tasked by the NYS Department of Transportation (DOT) to conduct a detailed examination of travel behaviors, and identify patterns and trends, on several NYS subpopulations, including disabled persons. Unlike other studies that concentrated on national level statistics, this research is focused on examining issues associated with travelers among NYS residents only. For each special subpopulation group, ORNL will identify differences, if any, in travel patterns that are attributable to demographic characteristics, household characteristics, modal characteristics, geographic location, and other concepts. Focus will be given to trip frequency, trip chaining, as well as travel by time of day, trip purpose, and mode choice.

  11. Identification of subpopulations in mesenchymal stem cell-like cultures from human umbilical cord

    Directory of Open Access Journals (Sweden)

    Majore Ingrida

    2009-03-01

    Full Text Available Abstract Background A variety of cell types can be identified in the adherent fraction of bone marrow mononuclear cells including more primitive and embryonic-like stem cells, mesenchymal stem cells (MSC, lineage-committed progenitors as well as mature cells such as osteoblasts and fibroblasts. Different methods are described for the isolation of single bone marrow stem cell subpopulations – beginning from ordinary size sieving, long term cultivation under specific conditions to FACS-based approaches. Besides bone marrow-derived subpopulations, also other tissues including human umbilical cord (UC have been recently suggested to provide a potential source for MSC. Although of clinical importance, these UC-derived MSC populations remain to be characterized. It was thus the aim of the present study to identify possible subpopulations in cultures of MSC-like cells obtained from UC. We used counterflow centrifugal elutriation (CCE as a novel strategy to successfully address this question. Results UC-derived primary cells were separated by CCE and revealed differentially-sized populations in the fractions. Thus, a subpopulation with an average diameter of about 11 μm and a small flat cell body was compared to a large sized subpopulation of about 19 μm average diameter. Flow cytometric analysis revealed the expression of certain MSC stem cell markers including CD44, CD73, CD90 and CD105, respectively, although these markers were expressed at higher levels in the small-sized population. Moreover, this small-sized subpopulation exhibited a higher proliferative capacity as compared to the total UC-derived primary cultures and the large-sized cells and demonstrated a reduced amount of aging cells. Conclusion Using the CCE technique, we were the first to demonstrate a subpopulation of small-sized UC-derived primary cells carrying MSC-like characteristics according to the presence of various mesenchymal stem cell markers. This is also supported by the

  12. Population genomic analysis reveals differential evolutionary histories and patterns of diversity across subgenomes and subpopulations of Brassica napus L.

    Directory of Open Access Journals (Sweden)

    Elodie eGazave

    2016-04-01

    Full Text Available The allotetraploid species Brassica napus L. is a global crop of major economic importance, providing canola oil (seed and vegetables for human consumption and fodder and meal for livestock feed. Characterizing the genetic diversity present in the extant germplasm pool of B. napus is fundamental to better conserve, manage and utilize the genetic resources of this species. We used sequence-based genotyping to identify and genotype 30,881 SNPs in a diversity panel of 782 B. napus accessions, representing samples of winter and spring growth habits originating from 33 countries across Europe, Asia and America. We detected strong population structure broadly concordant with growth habit and geography, and identified three major genetic groups: spring (SP, winter Europe (WE, and winter Asia (WA. Subpopulation-specific polymorphism patterns suggest enriched genetic diversity within the WA group and a smaller effective breeding population for the SP group compared to WE. Interestingly, the two subgenomes of B. napus appear to have different geographic origins, with phylogenetic analysis placing WE and WA as basal clades for the other subpopulations in the C and A subgenomes, respectively. Finally, we identified 16 genomic regions where the patterns of diversity differed markedly from the genome-wide average, several of which are suggestive of genomic inversions. The results obtained in this study constitute a valuable resource for worldwide breeding efforts and the genetic dissection and prediction of complex B. napus traits.

  13. Characteristics of T lymphocyte subpopulations 

    Directory of Open Access Journals (Sweden)

    Paulina Niedźwiedzka-Rystwej

    2013-05-01

    Full Text Available The paper describes the characteristics, receptor profile and functions of T lymphocyte subpopulations (helper, cytotoxic, regulatory, memory and others. Among T helper cells one can enumerate Th0, Th1, Th2, Th9, Th17, Th22, TFH and nTh2, while T cytotoxic cells include Tc, NKT, Tγδ, and T CD8αα (IEL. Among regulatory cells there are nTreg, iTreg, TR1, and iTR35, as well as T lymphocytes with CD8, such as CD8 CD122 , CD8 CD28-, and CD11c CD8 . And among memory T cells there are Tcm and Tem. Moreover, there are some so-called other T cells, such as Tn (T αβ CD4 and T αβ CD8 , T exhausted and T anergic. 

  14. Genetic and epigenetic divergence between disturbed and undisturbed subpopulations of a Mediterranean shrub: a 20-year field experiment.

    Science.gov (United States)

    Herrera, Carlos M; Bazaga, Pilar

    2016-06-01

    Little is known on the potential of ecological disturbance to cause genetic and epigenetic changes in plant populations. We take advantage of a long-term field experiment initiated in 1986 to study the demography of the shrub Lavandula latifolia , and compare genetic and epigenetic characteristics of plants in two adjacent subplots, one experimentally disturbed and one left undisturbed, 20 years after disturbance. Experimental setup was comparable to an unreplicated 'Before-After-Control-Impact' (BACI) design where a single pair of perturbed and control areas were compared. When sampled in 2005, plants in the two subplots had roughly similar ages, but they had established in contrasting environments: dense conspecific population ('Undisturbed' subpopulation) versus open area with all conspecifics removed ('Disturbed' subpopulation). Plants were characterized genetically and epigenetically using amplified fragment length polymorphism (AFLP) and two classes of methylation-sensitive AFLP (MSAP) markers. Subpopulations were similar in genetic diversity but differed in epigenetic diversity and multilocus genetic and epigenetic characteristics. Epigenetic divergence between subpopulations was statistically unrelated to genetic divergence. Bayesian clustering revealed an abrupt linear boundary between subpopulations closely coincident with the arbitrary demarcation line between subplots drawn 20 years back, which supports that genetic and epigenetic divergence between subpopulations was caused by artificial disturbance. There was significant fine-scale spatial structuring of MSAP markers in both subpopulations, which in the Undisturbed one was indistinguishable from that of AFLP markers. Genetic differences between subpopulations could be explained by divergent selection alone, while the concerted action of divergent selection and disturbance-driven appearance of new methylation variants in the Disturbed subpopulation is proposed to explain epigenetic differences. This

  15. Structural identifiability of cyclic graphical models of biological networks with latent variables.

    Science.gov (United States)

    Wang, Yulin; Lu, Na; Miao, Hongyu

    2016-06-13

    Graphical models have long been used to describe biological networks for a variety of important tasks such as the determination of key biological parameters, and the structure of graphical model ultimately determines whether such unknown parameters can be unambiguously obtained from experimental observations (i.e., the identifiability problem). Limited by resources or technical capacities, complex biological networks are usually partially observed in experiment, which thus introduces latent variables into the corresponding graphical models. A number of previous studies have tackled the parameter identifiability problem for graphical models such as linear structural equation models (SEMs) with or without latent variables. However, the limited resolution and efficiency of existing approaches necessarily calls for further development of novel structural identifiability analysis algorithms. An efficient structural identifiability analysis algorithm is developed in this study for a broad range of network structures. The proposed method adopts the Wright's path coefficient method to generate identifiability equations in forms of symbolic polynomials, and then converts these symbolic equations to binary matrices (called identifiability matrix). Several matrix operations are introduced for identifiability matrix reduction with system equivalency maintained. Based on the reduced identifiability matrices, the structural identifiability of each parameter is determined. A number of benchmark models are used to verify the validity of the proposed approach. Finally, the network module for influenza A virus replication is employed as a real example to illustrate the application of the proposed approach in practice. The proposed approach can deal with cyclic networks with latent variables. The key advantage is that it intentionally avoids symbolic computation and is thus highly efficient. Also, this method is capable of determining the identifiability of each single parameter and

  16. Toward the Relevance of Platelet Subpopulations for Transfusion Medicine

    Directory of Open Access Journals (Sweden)

    Stefan Handtke

    2018-02-01

    Full Text Available Circulating platelets consist of subpopulations with different age, maturation state and size. In this review, we address the association between platelet size and platelet function and summarize the current knowledge on platelet subpopulations including reticulated platelets, procoagulant platelets and platelets exposing signals to mediate their clearance. Thereby, we emphasize the impact of platelet turnover as an important condition for platelet production in vivo. Understanding of the features that characterize platelet subpopulations is very relevant for the methods of platelet concentrate production, which may enrich or deplete particular platelet subpopulations. Moreover, the concept of platelet size being associated with platelet function may be attractive for transfusion medicine as it holds the perspective to separate platelet subpopulations with specific functional capabilities.

  17. Evidence for discrete subpopulations of sea perch (Helicolenus ercoides) across four fjords in Fiordland, New Zealand

    International Nuclear Information System (INIS)

    Lawton, R.J.; Wing, S.R.; Lewis, A.M.

    2010-01-01

    In coastal populations of invertebrates and fishes, the distribution of discrete subpopulations is influenced by adult and larval dispersal, as well as by the effects of habitat heterogeneity on site fidelity or connectivity. Here, we examine evidence for spatial structure of sea perch, Helicolenus percoides, populations among four fjords in the Fiordland region of southwestern New Zealand. We examine patterns in adult morphology, length-at-age, δ 13 C and δ 15 N of muscle tissue, and trace elemental composition of whole otoliths as proxies for population isolation among the four inner fjord regions. A multivariate analysis of morphometrics reveals significant differences among populations from each of the four sites, suggesting existence of four distinct subpopulations. These patterns are consistent with observed differences in δ 13 C and δ 15 N, and length-at-age estimates among the four subpopulations. Differences in whole otolith concentrations of Sr, Ba, Mg and Li, and high classification scores based on the whole otolith elemental fingerprint are also consistent with significant subdivision among areas. Patterns across all four markers are consistent with discrete subpopulation structure of adult sea perch among the four study sites. These data indicate that the newly implemented network of marine protected areas in Fiordland is likely to contain discrete populations of sea perch. (author).

  18. Differential radiosensitivity among B cell subpopulations

    International Nuclear Information System (INIS)

    Riggs, J.E.

    1988-01-01

    The selective radiosensitivity of sIgM >> sIgD marginal zone B cells is associated with the selective loss of B cell function. The simultaneous restoration of impaired function and recovery of these cells with time supports this premise. B cell recovery, delayed one week after irradiation, is in progress at two weeks, and virtually complete by three weeks. XID mice reveal similar recovery kinetics although there are fewer recovering cells and these bear reduced levels of Ia. This observation represents additional evidence that xid B cells are distinct from those of normal mice. The simultaneous loss, and concurrent recovery, of sIgM >> sIgD B cells and TI-2 responsiveness in irradiated mice suggests the existence of a unique B cell subpopulation possessing both phenotypes. Additional support for this hypothesis is provided by demonstrating that splenocytes, depleted of IgD + cells adoptively reconstitute this response in XID mice. The peritoneal B cell pool, which, compared to the spleen, consist of increased numbers of sIgM >> sIgD B cells, is shown to be a source of radiosensitive B cells that are TI-2 responsive. These observations represent additional evidence for an association between sIgM >> sIgD B cells and TI-2 responsiveness

  19. Three novel approaches to structural identifiability analysis in mixed-effects models.

    Science.gov (United States)

    Janzén, David L I; Jirstrand, Mats; Chappell, Michael J; Evans, Neil D

    2016-05-06

    Structural identifiability is a concept that considers whether the structure of a model together with a set of input-output relations uniquely determines the model parameters. In the mathematical modelling of biological systems, structural identifiability is an important concept since biological interpretations are typically made from the parameter estimates. For a system defined by ordinary differential equations, several methods have been developed to analyse whether the model is structurally identifiable or otherwise. Another well-used modelling framework, which is particularly useful when the experimental data are sparsely sampled and the population variance is of interest, is mixed-effects modelling. However, established identifiability analysis techniques for ordinary differential equations are not directly applicable to such models. In this paper, we present and apply three different methods that can be used to study structural identifiability in mixed-effects models. The first method, called the repeated measurement approach, is based on applying a set of previously established statistical theorems. The second method, called the augmented system approach, is based on augmenting the mixed-effects model to an extended state-space form. The third method, called the Laplace transform mixed-effects extension, is based on considering the moment invariants of the systems transfer function as functions of random variables. To illustrate, compare and contrast the application of the three methods, they are applied to a set of mixed-effects models. Three structural identifiability analysis methods applicable to mixed-effects models have been presented in this paper. As method development of structural identifiability techniques for mixed-effects models has been given very little attention, despite mixed-effects models being widely used, the methods presented in this paper provides a way of handling structural identifiability in mixed-effects models previously not

  20. New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes

    DEFF Research Database (Denmark)

    Parker, Brian John; Moltke, Ida; Roth, Adam

    2011-01-01

    a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein...

  1. On-line structural response analysis: using the extended Kalman estimator/identifier

    International Nuclear Information System (INIS)

    Candy, J.V.

    1979-01-01

    This report disucsses the development of on-line state and parameter estimators used to analyze the structural response of buildings. The estimator/identifier is an extended Kalman filter (EKF), which has been applied with great success in other technological areas. It is shown that the EKF can perform quite well on simulated noisy structural response data

  2. Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations.

    Science.gov (United States)

    Gormley, Matthew; Ona, Katherine; Kapidzic, Mirhan; Garrido-Gomez, Tamara; Zdravkovic, Tamara; Fisher, Susan J

    2017-08-01

    syncytiotrophoblast data highlighted the dysregulation of immune functions, morphogenesis, transport, and responses to vascular endothelial growth factor and progesterone. The invasive cytotrophoblast data provided evidence of alterations in cellular movement, which is consistent with the shallow invasion often associated with severe preeclampsia. Other dysregulated pathways included immune, lipid, oxygen, and transforming growth factor-beta responses. The data for endovascular cytotrophoblasts showed disordered metabolism, signaling, and vascular development. Additionally, the transcriptional data revealed the differential expression in severe preeclampsia of 2 classes of non-coding RNAs: long non-coding RNAs and small nucleolar RNAs. The long non-coding RNA, urothelial cancer associated 1, was the most highly up-regulated in this class. In situ hybridization confirmed severe preeclampsia-associated expression in syncytiotrophoblasts. The small nucleolar RNAs, which chemically modify RNA structure, also correlated with severe preeclampsia. Thus, we enumerated Cajal body foci, sites of small nucleolar RNA activity, in primary cytotrophoblasts that were isolated from control and severe preeclampsia placentas. In severe preeclampsia, cytotrophoblasts had approximately double the number of these foci as the control samples. A laser microdissection approach enabled the identification of novel messenger RNAs and non-coding RNAs that were misexpressed by various trophoblast subpopulations in severe preeclampsia. The results suggested new avenues of investigation, in particular, the roles of PRG2, Kell blood group determinants, and urothelial cancer associated 1 in syncytiotrophoblast diseases. Additionally, many of the newly identified dysregulated molecules might have clinical utility as biomarkers of severe preeclampsia. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  3. Dynamical compensation and structural identifiability of biological models: Analysis, implications, and reconciliation.

    Science.gov (United States)

    Villaverde, Alejandro F; Banga, Julio R

    2017-11-01

    The concept of dynamical compensation has been recently introduced to describe the ability of a biological system to keep its output dynamics unchanged in the face of varying parameters. However, the original definition of dynamical compensation amounts to lack of structural identifiability. This is relevant if model parameters need to be estimated, as is often the case in biological modelling. Care should we taken when using an unidentifiable model to extract biological insight: the estimated values of structurally unidentifiable parameters are meaningless, and model predictions about unmeasured state variables can be wrong. Taking this into account, we explore alternative definitions of dynamical compensation that do not necessarily imply structural unidentifiability. Accordingly, we show different ways in which a model can be made identifiable while exhibiting dynamical compensation. Our analyses enable the use of the new concept of dynamical compensation in the context of parameter identification, and reconcile it with the desirable property of structural identifiability.

  4. New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes.

    Science.gov (United States)

    Parker, Brian J; Moltke, Ida; Roth, Adam; Washietl, Stefan; Wen, Jiayu; Kellis, Manolis; Breaker, Ronald; Pedersen, Jakob Skou

    2011-11-01

    Regulatory RNA structures are often members of families with multiple paralogous instances across the genome. Family members share functional and structural properties, which allow them to be studied as a whole, facilitating both bioinformatic and experimental characterization. We have developed a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein-coding regions comprising 725 individual structures, including 48 families with known structural RNA elements. Known families identified include both noncoding RNAs, e.g., miRNAs and the recently identified MALAT1/MEN β lincRNA family; and cis-regulatory structures, e.g., iron-responsive elements. We also identify tens of new families supported by strong evolutionary evidence and other statistical evidence, such as GO term enrichments. For some of these, detailed analysis has led to the formulation of specific functional hypotheses. Examples include two hypothesized auto-regulatory feedback mechanisms: one involving six long hairpins in the 3'-UTR of MAT2A, a key metabolic gene that produces the primary human methyl donor S-adenosylmethionine; the other involving a tRNA-like structure in the intron of the tRNA maturation gene POP1. We experimentally validate the predicted MAT2A structures. Finally, we identify potential new regulatory networks, including large families of short hairpins enriched in immunity-related genes, e.g., TNF, FOS, and CTLA4, which include known transcript destabilizing elements. Our findings exemplify the diversity of post-transcriptional regulation and provide a resource for further characterization of new regulatory mechanisms and families of noncoding RNAs.

  5. Beyond BLASTing: Tertiary and Quaternary Structure Analysis Helps Identify Major Vault Proteins

    Science.gov (United States)

    Daly, Toni K.; Sutherland-Smith, Andrew J.; Penny, David

    2013-01-01

    We examine the advantages of going beyond sequence similarity and use both protein three-dimensional (3D) structure prediction and then quaternary structure (docking) of inferred 3D structures to help evaluate whether comparable sequences can fold into homologous structures with sufficient lateral associations for quaternary structure formation. Our test case is the major vault protein (MVP) that oligomerizes in multiple copies to form barrel-like vault particles and is relatively widespread among eukaryotes. We used the iterative threading assembly refinement server (I-TASSER) to predict whether putative MVP sequences identified by BLASTp and PSI Basic Local Alignment Search Tool are structurally similar to the experimentally determined rodent MVP tertiary structures. Then two identical predicted quaternary structures from I-TASSER are analyzed by RosettaDock to test whether a pair-wise association occurs, and hence whether the oligomeric vault complex is likely to form for a given MVP sequence. Positive controls for the method are the experimentally determined rat (Rattus norvegicus) vault X-ray crystal structure and the purple sea urchin (Strongylocentrotus purpuratus) MVP sequence that forms experimentally observed vaults. These and two kinetoplast MVP structural homologs were predicted with high confidence value, and RosettaDock predicted that these MVP sequences would dock laterally and therefore could form oligomeric vaults. As the negative control, I-TASSER did not predict an MVP-like structure from a randomized rat MVP sequence, even when constrained to the rat MVP crystal structure (PDB:2ZUO), thus further validating the method. The protocol identified six putative homologous MVP sequences in the heterobolosean Naegleria gruberi within the excavate kingdom. Two of these sequences are predicted to be structurally similar to rat MVP, despite being in excess of 300 residues shorter. The method can be used generally to help test predictions of homology via

  6. Identifying Time Periods of Minimal Thermal Gradient for Temperature-Driven Structural Health Monitoring

    Directory of Open Access Journals (Sweden)

    John Reilly

    2018-03-01

    Full Text Available Temperature changes play a large role in the day to day structural behavior of structures, but a smaller direct role in most contemporary Structural Health Monitoring (SHM analyses. Temperature-Driven SHM will consider temperature as the principal driving force in SHM, relating a measurable input temperature to measurable output generalized strain (strain, curvature, etc. and generalized displacement (deflection, rotation, etc. to create three-dimensional signatures descriptive of the structural behavior. Identifying time periods of minimal thermal gradient provides the foundation for the formulation of the temperature–deformation–displacement model. Thermal gradients in a structure can cause curvature in multiple directions, as well as non-linear strain and stress distributions within the cross-sections, which significantly complicates data analysis and interpretation, distorts the signatures, and may lead to unreliable conclusions regarding structural behavior and condition. These adverse effects can be minimized if the signatures are evaluated at times when thermal gradients in the structure are minimal. This paper proposes two classes of methods based on the following two metrics: (i the range of raw temperatures on the structure, and (ii the distribution of the local thermal gradients, for identifying time periods of minimal thermal gradient on a structure with the ability to vary the tolerance of acceptable thermal gradients. The methods are tested and validated with data collected from the Streicker Bridge on campus at Princeton University.

  7. Identifying Time Periods of Minimal Thermal Gradient for Temperature-Driven Structural Health Monitoring.

    Science.gov (United States)

    Reilly, John; Glisic, Branko

    2018-03-01

    Temperature changes play a large role in the day to day structural behavior of structures, but a smaller direct role in most contemporary Structural Health Monitoring (SHM) analyses. Temperature-Driven SHM will consider temperature as the principal driving force in SHM, relating a measurable input temperature to measurable output generalized strain (strain, curvature, etc.) and generalized displacement (deflection, rotation, etc.) to create three-dimensional signatures descriptive of the structural behavior. Identifying time periods of minimal thermal gradient provides the foundation for the formulation of the temperature-deformation-displacement model. Thermal gradients in a structure can cause curvature in multiple directions, as well as non-linear strain and stress distributions within the cross-sections, which significantly complicates data analysis and interpretation, distorts the signatures, and may lead to unreliable conclusions regarding structural behavior and condition. These adverse effects can be minimized if the signatures are evaluated at times when thermal gradients in the structure are minimal. This paper proposes two classes of methods based on the following two metrics: (i) the range of raw temperatures on the structure, and (ii) the distribution of the local thermal gradients, for identifying time periods of minimal thermal gradient on a structure with the ability to vary the tolerance of acceptable thermal gradients. The methods are tested and validated with data collected from the Streicker Bridge on campus at Princeton University.

  8. Extending existing structural identifiability analysis methods to mixed-effects models.

    Science.gov (United States)

    Janzén, David L I; Jirstrand, Mats; Chappell, Michael J; Evans, Neil D

    2018-01-01

    The concept of structural identifiability for state-space models is expanded to cover mixed-effects state-space models. Two methods applicable for the analytical study of the structural identifiability of mixed-effects models are presented. The two methods are based on previously established techniques for non-mixed-effects models; namely the Taylor series expansion and the input-output form approach. By generating an exhaustive summary, and by assuming an infinite number of subjects, functions of random variables can be derived which in turn determine the distribution of the system's observation function(s). By considering the uniqueness of the analytical statistical moments of the derived functions of the random variables, the structural identifiability of the corresponding mixed-effects model can be determined. The two methods are applied to a set of examples of mixed-effects models to illustrate how they work in practice. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Identifying Structural Flow Defects in Disordered Solids Using Machine-Learning Methods

    Science.gov (United States)

    Cubuk, E. D.; Schoenholz, S. S.; Rieser, J. M.; Malone, B. D.; Rottler, J.; Durian, D. J.; Kaxiras, E.; Liu, A. J.

    2015-03-01

    We use machine-learning methods on local structure to identify flow defects—or particles susceptible to rearrangement—in jammed and glassy systems. We apply this method successfully to two very different systems: a two-dimensional experimental realization of a granular pillar under compression and a Lennard-Jones glass in both two and three dimensions above and below its glass transition temperature. We also identify characteristics of flow defects that differentiate them from the rest of the sample. Our results show it is possible to discern subtle structural features responsible for heterogeneous dynamics observed across a broad range of disordered materials.

  10. Structural and functional characterization of Rpn12 identifies residues required for Rpn10 proteasome incorporation.

    Science.gov (United States)

    Boehringer, Jonas; Riedinger, Christiane; Paraskevopoulos, Konstantinos; Johnson, Eachan O D; Lowe, Edward D; Khoudian, Christina; Smith, Dominique; Noble, Martin E M; Gordon, Colin; Endicott, Jane A

    2012-11-15

    The ubiquitin-proteasome system targets selected proteins for degradation by the 26S proteasome. Rpn12 is an essential component of the 19S regulatory particle and plays a role in recruiting the extrinsic ubiquitin receptor Rpn10. In the present paper we report the crystal structure of Rpn12, a proteasomal PCI-domain-containing protein. The structure helps to define a core structural motif for the PCI domain and identifies potential sites through which Rpn12 might form protein-protein interactions. We demonstrate that mutating residues at one of these sites impairs Rpn12 binding to Rpn10 in vitro and reduces Rpn10 incorporation into proteasomes in vivo.

  11. Structural health monitoring (vibration) as a tool for identifying structural alterations of the lumbar spine: a twin control study.

    Science.gov (United States)

    Kawchuk, Gregory N; Hartvigsen, Jan; Edgecombe, Tiffany; Prasad, Narasimha; van Dieen, Jaap H

    2016-03-11

    Structural health monitoring (SHM) is an engineering technique used to identify mechanical abnormalities not readily apparent through other means. Recently, SHM has been adapted for use in biological systems, but its invasive nature limits its clinical application. As such, the purpose of this project was to determine if a non-invasive form of SHM could identify structural alterations in the spines of living human subjects. Lumbar spines of 10 twin pairs were visualized by magnetic resonance imaging then assessed by a blinded radiologist to determine whether twin pairs were structurally concordant or discordant. Vibration was then applied to each subject's spine and the resulting response recorded from sensors overlying lumbar spinous processes. The peak frequency, area under the curve and the root mean square were computed from the frequency response function of each sensor. Statistical analysis demonstrated that in twins whose structural appearance was discordant, peak frequency was significantly different between twin pairs while in concordant twins, no outcomes were significantly different. From these results, we conclude that structural changes within the spine can alter its vibration response. As such, further investigation of SHM to identify spinal abnormalities in larger human populations is warranted.

  12. Identifying secondary structures in proteins using NMR chemical shift 3D correlation maps

    Science.gov (United States)

    Kumari, Amrita; Dorai, Kavita

    2013-06-01

    NMR chemical shifts are accurate indicators of molecular environment and have been extensively used as aids in protein structure determination. This work focuses on creating empirical 3D correlation maps of backbone chemical shift nuclei for use as identifiers of secondary structure elements in proteins. A correlated database of backbone nuclei chemical shifts was constructed from experimental structural data gathered from entries in the Protein Data Bank (PDB) as well as isotropic chemical shift values from the RefDB database. Rigorous statistical analysis of the maps led to the conclusion that specific correlations between triplets of backbone chemical shifts are best able to differentiate between different secondary structures such as α-helices, β-strands and turns. The method is compared with similar techniques that use NMR chemical shift information as aids in biomolecular structure determination and performs well in tests done on experimental data determined for different types of proteins, including large multi-domain proteins and membrane proteins.

  13. Polycentric Structures in Latin American Metropolitan Areas : Identifying Employment Sub-centres

    NARCIS (Netherlands)

    Fernández-Maldonado, Ana María; Romein, Arie; Verkoren, Otto|info:eu-repo/dai/nl/073181773; Parente Paula Pessoa, Renata

    2014-01-01

    Fernández-Maldonado A. M., Romein A., Verkoren O. and Parente Paula Pessoa R. Polycentric structures in Latin American metropolitan areas: identifying employment sub-centres, Regional Studies. The significant spatial transformations that have occurred within Latin American metropolitan areas since

  14. Use of tiling array data and RNA secondary structure predictions to identify noncoding RNA genes

    DEFF Research Database (Denmark)

    Weile, Christian; Gardner, Paul P; Hedegaard, Mads M

    2007-01-01

    neuroblastoma cell line SK-N-AS. Using this strategy, we identify thousands of human candidate RNA genes. To further verify the expression of these genes, we focused on candidate genes that had a stable hairpin structures or a high level of covariance. Using northern blotting, we verify the expression of 2 out...

  15. Flow cytometric techniques for detection of candidate cancer stem cell subpopulations in canine tumour models.

    Science.gov (United States)

    Blacking, T M; Waterfall, M; Samuel, K; Argyle, D J

    2012-12-01

    The cancer stem cell (CSC) hypothesis proposes that tumour growth is maintained by a distinct subpopulation of 'CSC'. This study applied flow cytometric methods, reported to detect CSC in both primary and cultured cancer cells of other species, to identify candidate canine subpopulations. Cell lines representing diverse canine malignancies, and cells derived from spontaneous canine tumours, were evaluated for expression of stem cell-associated surface markers (CD34, CD44, CD117 and CD133) and functional properties [Hoecsht 33342 efflux, aldehyde dehydrogenase (ALDH) activity]. No discrete marker-defined subsets were identified within established cell lines; cells derived directly from spontaneous tumours demonstrated more heterogeneity, although this diminished upon in vitro culture. Functional assays produced variable results, suggesting context-dependency. Flow cytometric methods may be adopted to identify putative canine CSC. Whilst cell lines are valuable in assay development, primary cells may provide a more rewarding model for studying tumour heterogeneity in the context of CSC. However, it will be essential to fully characterize any candidate subpopulations to ensure that they meet CSC criteria. © 2011 Blackwell Publishing Ltd.

  16. Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake.

    Science.gov (United States)

    Grandjean, Thomas R B; Chappell, Michael J; Yates, James W T; Evans, Neil D

    2014-05-01

    In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available. Copyright © 2013. Published by Elsevier Ireland Ltd.

  17. Catalytic site identification—a web server to identify catalytic site structural matches throughout PDB

    Science.gov (United States)

    Kirshner, Daniel A.; Nilmeier, Jerome P.; Lightstone, Felice C.

    2013-01-01

    The catalytic site identification web server provides the innovative capability to find structural matches to a user-specified catalytic site among all Protein Data Bank proteins rapidly (in less than a minute). The server also can examine a user-specified protein structure or model to identify structural matches to a library of catalytic sites. Finally, the server provides a database of pre-calculated matches between all Protein Data Bank proteins and the library of catalytic sites. The database has been used to derive a set of hypothesized novel enzymatic function annotations. In all cases, matches and putative binding sites (protein structure and surfaces) can be visualized interactively online. The website can be accessed at http://catsid.llnl.gov. PMID:23680785

  18. Shakespearean tragedies dynamics: identifying a generic structure in Shakespeare's four major tragedies

    Science.gov (United States)

    Domínguez-Rué, Emma; Mrotzek, Maximilian

    2012-10-01

    Many interpretations of Shakespearean tragedy have been conducted, mostly following the principles of interpretation in literary study. In our paper, four tragedies by William Shakespeare - Hamlet, King Lear, Othello, and Macbeth - were analysed systemically to find out whether they inhabit a common structure. Using the plot structure as the basis for our analysis, we identified the most important system elements, their connections, and interactive behaviour using causal loop diagrams (CLDs). Our results revealed that all four tragedies basically conform to Senge's archetypal structure 'shifting the burden', adding the action of the heroine or villain and the characters' boundaries of perception. The results suggest that, even though characters and settings vary highly, these tragedies have similar structures and archetypal solutions exist to overcome the problem. Furthermore, we propose that CLDs and systems archetypes are a reasonable hermeneutic tool to analyse not only Shakespearean tragedies but also other literary works.

  19. Structural identifiability of systems biology models: a critical comparison of methods.

    Directory of Open Access Journals (Sweden)

    Oana-Teodora Chis

    Full Text Available Analysing the properties of a biological system through in silico experimentation requires a satisfactory mathematical representation of the system including accurate values of the model parameters. Fortunately, modern experimental techniques allow obtaining time-series data of appropriate quality which may then be used to estimate unknown parameters. However, in many cases, a subset of those parameters may not be uniquely estimated, independently of the experimental data available or the numerical techniques used for estimation. This lack of identifiability is related to the structure of the model, i.e. the system dynamics plus the observation function. Despite the interest in knowing a priori whether there is any chance of uniquely estimating all model unknown parameters, the structural identifiability analysis for general non-linear dynamic models is still an open question. There is no method amenable to every model, thus at some point we have to face the selection of one of the possibilities. This work presents a critical comparison of the currently available techniques. To this end, we perform the structural identifiability analysis of a collection of biological models. The results reveal that the generating series approach, in combination with identifiability tableaus, offers the most advantageous compromise among range of applicability, computational complexity and information provided.

  20. Expressions of machismo in colorectal cancer screening among New Mexico Hispanic subpopulations.

    Science.gov (United States)

    Getrich, Christina M; Sussman, Andrew L; Helitzer, Deborah L; Hoffman, Richard M; Warner, Teddy D; Sánchez, Victoria; Solares, Angélica; Rhyne, Robert L

    2012-04-01

    Although national colorectal cancer (CRC) incidence rates have steadily decreased, the rate for New Mexico Hispanics has been increasing, and screening rates are low. We conducted an exploratory qualitative study to determine barriers to CRC screening for New Mexico Hispanics. We found that machismo served as a dynamic influence on men's health-seeking behaviors; however, it was conceptualized differently by two distinct Hispanic subpopulations, and therefore appeared to play a different role in shaping their screening attitudes and behaviors. Machismo emerged as more of an influence for Mexican men, who expressed concern over colonoscopies being potentially transformative and/or stigmatizing, but was not as salient for Hispanos, who viewed the colonoscopy as "strictly medical," and were more concerned with discomfort and pain. Findings from the study highlight the importance of identifying varying characteristics among subpopulations to better understand screening barriers and provide optimal CRC screening counseling in primary care settings.

  1. Identifying the Critical Links in Road Transportation Networks: Centrality-based approach utilizing structural properties

    Energy Technology Data Exchange (ETDEWEB)

    Chinthavali, Supriya [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-04-01

    Surface transportation road networks share structural properties similar to other complex networks (e.g., social networks, information networks, biological networks, and so on). This research investigates the structural properties of road networks for any possible correlation with the traffic characteristics such as link flows those determined independently. Additionally, we define a criticality index for the links of the road network that identifies the relative importance in the network. We tested our hypotheses with two sample road networks. Results show that, correlation exists between the link flows and centrality measures of a link of the road (dual graph approach is followed) and the criticality index is found to be effective for one test network to identify the vulnerable nodes.

  2. The proliferative human monocyte subpopulation contains osteoclast precursors

    Science.gov (United States)

    Lari, Roya; Kitchener, Peter D; Hamilton, John A

    2009-01-01

    Introduction Immediate precursors of bone-resorbing osteoclasts are cells of the monocyte/macrophage lineage. Particularly during clinical conditions showing bone loss, it would appear that osteoclast precursors are mobilized from bone marrow into the circulation prior to entering tissues undergoing such loss. The observed heterogeneity of peripheral blood monocytes has led to the notion that different monocyte subpopulations may have special or restricted functions, including as osteoclast precursors. Methods Human peripheral blood monocytes were sorted based upon their degree of proliferation and cultured in macrophage colony-stimulating factor (M-CSF or CSF-1) and receptor activator of nuclear factor-kappa-B ligand (RANKL). Results The monocyte subpopulation that is capable of proliferation gave rise to significantly more multinucleated, bone-resorbing osteoclasts than the bulk of the monocytes. Conclusions Human peripheral blood osteoclast precursors reside in the proliferative monocyte subpopulation. PMID:19222861

  3. Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases

    Science.gov (United States)

    Xu, Qifang; Malecka, Kimberly L.; Fink, Lauren; Jordan, E. Joseph; Duffy, Erin; Kolander, Samuel; Peterson, Jeffrey; Dunbrack, Roland L.

    2016-01-01

    Protein kinase autophosphorylation is a common regulatory mechanism in cell signaling pathways. Crystal structures of several homomeric protein kinase complexes have a serine, threonine, or tyrosine autophosphorylation site of one kinase monomer located in the active site of another monomer, a structural complex that we call an “autophosphorylation complex.” We developed and applied a structural bioinformatics method to identify all such autophosphorylation kinase complexes in X-ray crystallographic structures in the Protein Data Bank (PDB). We identified 15 autophosphorylation complexes in the PDB, of which 5 complexes had not previously been described in the publications describing the crystal structures. These 5 consist of tyrosine residues in the N-terminal juxtamembrane regions of colony stimulating factor 1 receptor (CSF1R, Tyr561) and EPH receptor A2 (EPHA2, Tyr594), tyrosine residues in the activation loops of the SRC kinase family member LCK (Tyr394) and insulin-like growth factor 1 receptor (IGF1R, Tyr1166), and a serine in a nuclear localization signal region of CDC-like kinase 2 (CLK2, Ser142). Mutations in the complex interface may alter autophosphorylation activity and contribute to disease; therefore we mutated residues in the autophosphorylation complex interface of LCK and found that two mutations impaired autophosphorylation (T445V and N446A) and mutation of Pro447 to Ala, Gly, or Leu increased autophosphorylation. The identified autophosphorylation sites are conserved in many kinases, suggesting that, by homology, these complexes may provide insight into autophosphorylation complex interfaces of kinases that are relevant drug targets. PMID:26628682

  4. Resolving anatomical and functional structure in human brain organization: identifying mesoscale organization in weighted network representations.

    Science.gov (United States)

    Lohse, Christian; Bassett, Danielle S; Lim, Kelvin O; Carlson, Jean M

    2014-10-01

    Human brain anatomy and function display a combination of modular and hierarchical organization, suggesting the importance of both cohesive structures and variable resolutions in the facilitation of healthy cognitive processes. However, tools to simultaneously probe these features of brain architecture require further development. We propose and apply a set of methods to extract cohesive structures in network representations of brain connectivity using multi-resolution techniques. We employ a combination of soft thresholding, windowed thresholding, and resolution in community detection, that enable us to identify and isolate structures associated with different weights. One such mesoscale structure is bipartivity, which quantifies the extent to which the brain is divided into two partitions with high connectivity between partitions and low connectivity within partitions. A second, complementary mesoscale structure is modularity, which quantifies the extent to which the brain is divided into multiple communities with strong connectivity within each community and weak connectivity between communities. Our methods lead to multi-resolution curves of these network diagnostics over a range of spatial, geometric, and structural scales. For statistical comparison, we contrast our results with those obtained for several benchmark null models. Our work demonstrates that multi-resolution diagnostic curves capture complex organizational profiles in weighted graphs. We apply these methods to the identification of resolution-specific characteristics of healthy weighted graph architecture and altered connectivity profiles in psychiatric disease.

  5. Identify High-Quality Protein Structural Models by Enhanced K-Means.

    Science.gov (United States)

    Wu, Hongjie; Li, Haiou; Jiang, Min; Chen, Cheng; Lv, Qiang; Wu, Chuang

    2017-01-01

    Background. One critical issue in protein three-dimensional structure prediction using either ab initio or comparative modeling involves identification of high-quality protein structural models from generated decoys. Currently, clustering algorithms are widely used to identify near-native models; however, their performance is dependent upon different conformational decoys, and, for some algorithms, the accuracy declines when the decoy population increases. Results. Here, we proposed two enhanced K -means clustering algorithms capable of robustly identifying high-quality protein structural models. The first one employs the clustering algorithm SPICKER to determine the initial centroids for basic K -means clustering ( SK -means), whereas the other employs squared distance to optimize the initial centroids ( K -means++). Our results showed that SK -means and K -means++ were more robust as compared with SPICKER alone, detecting 33 (59%) and 42 (75%) of 56 targets, respectively, with template modeling scores better than or equal to those of SPICKER. Conclusions. We observed that the classic K -means algorithm showed a similar performance to that of SPICKER, which is a widely used algorithm for protein-structure identification. Both SK -means and K -means++ demonstrated substantial improvements relative to results from SPICKER and classical K -means.

  6. Phenotypic variations in chondrocyte subpopulations and their response to in vitro culture and external stimuli.

    Science.gov (United States)

    Coates, Emily E; Fisher, John P

    2010-11-01

    Articular cartilage defects have limited capacity to self-repair, and cost society up to 60 billion dollars annually in both medical treatments and loss of working days. Recent developments in cartilage tissue engineering have resulted in many new products coming to market or entering clinical trials. However, there is a distinct lack of treatments which aim to recreate the complex zonal organization of articular cartilage. Cartilage tissue withstands repetitive strains throughout an individual's lifetime and provides frictionless movement between joints. The structure and composition of its intricately organized extracellular matrix varies with tissue depth to provide optimal resistance to loading, ensure ease of movement, and integrate with the subchondral bone. Each tissue zone is specially designed to resist the load it experiences, and maximize the tissue properties needed for its location. It is unlikely that a homogenous solution to tissue repair will be able to optimally restore the function of such a heterogeneous tissue. For zonal engineering of articular cartilage to become practical, maintenance of phenotypically stable zonal cell populations must be achieved. The chondrocyte phenotype varies considerably by zone, and it is the activity of these cells that help achieve the structural organization of the tissue. This review provides an examination of literature which has studied variations in cellular phenotype between cartilage zones. By doing so, we have identified critical differences between cell populations and highlighted areas of research which show potential in the field. Current research has made the morphological and metabolic variations between these cell populations clear, but an ideal way of maintaining these differences in vitro culture is yet to be established. Combinations of delivered growth factors, mechanical loading, and layered three-dimensional culture systems all show potential for achieving this goal. Furthermore, differentiation

  7. Summary of SMIRT20 Preconference Topical Workshop - Identifying Structural Issues in Advanced Reactors

    International Nuclear Information System (INIS)

    Richins, William; Novascone, Stephen; O'Brien, Cheryl

    2009-01-01

    The Idaho National Laboratory (INL, USA) and IASMiRT sponsored an international forum Nov 5-6, 2008 in Porvoo, Finland for nuclear industry, academic, and regulatory representatives to identify structural issues in current and future advanced reactor design, especially for extreme conditions and external threats. The purpose of this Topical Workshop was to articulate research, engineering, and regulatory Code development needs. The topics addressed by the Workshop were selected to address critical industry needs specific to advanced reactor structures that have long lead times and can be the subject of future SMiRT technical sessions. The topics were; (1) structural/materials needs for extreme conditions and external threats in contemporary (Gen. III) and future (Gen. IV and NGNP) advanced reactors and (2) calibrating simulation software and methods that address topic 1. The workshop discussions and research needs identified are presented. The Workshop successfully produced interactive discussion on the two topics resulting in a list of research and technology needs. It is recommended that IASMiRT communicate the results of the discussion to industry and researchers to encourage new ideas and projects. In addition, opportunities exist to retrieve research reports and information that currently exists, and encourage more international cooperation and collaboration. It is recommended that IASMiRT continue with an off-year workshop series on select topics.

  8. Structural magnetic resonance imaging can identify trigeminal system abnormalities in classical trigeminal neuralgia

    Directory of Open Access Journals (Sweden)

    Danielle DeSouza

    2016-10-01

    Full Text Available Classical trigeminal neuralgia (TN is a chronic pain disorder that has been described as one ofthe most severe pains one can suffer. The most prevalent theory of TN etiology is that the trigeminal nerve is compressed at the root entry zone (REZ by blood vessels. However, there is significant evidence showing a lack of neurovascular compression (NVC for many cases of classical TN. Furthermore, a considerable number of patients who are asymptomatic have MR evidence of NVC. Since there is no validated animal model that reproduces the clinical features of TN, our understanding of TN pathology mainly comes from biopsy studies that have limitations. Sophisticated structural MRI techniques including diffusion tensor imaging provide new opportunities to assess the trigeminal nerves and CNS to provide insight into TN etiology and pathogenesis. Specifically, studies have used high-resolution structural MRI methods to visualize patterns of trigeminal nerve-vessel relationships and to detect subtle pathological features at the trigeminal REZ. Structural MRI has also identified CNS abnormalities in cortical and subcortical gray matter and white matter and demonstrated that effective neurosurgical treatment for TN is associated with a reversal of specific nerve and brain abnormalities. In conclusion, this review highlights the advanced structural neuroimaging methods that are valuable tools to assess the trigeminal system in TN and may inform our current understanding of TN pathology. These methods may in the future have clinical utility for the development of neuroimaging-based biomarkers of TN.

  9. Identifying Associations Between Brain Imaging Phenotypes and Genetic Factors via A Novel Structured SCCA Approach.

    Science.gov (United States)

    Du, Lei; Zhang, Tuo; Liu, Kefei; Yan, Jingwen; Yao, Xiaohui; Risacher, Shannon L; Saykin, Andrew J; Han, Junwei; Guo, Lei; Shen, Li

    2017-06-01

    Brain imaging genetics attracts more and more attention since it can reveal associations between genetic factors and the structures or functions of human brain. Sparse canonical correlation analysis (SCCA) is a powerful bi-multivariate association identification technique in imaging genetics. There have been many SCCA methods which could capture different types of structured imaging genetic relationships. These methods either use the group lasso to recover the group structure, or employ the graph/network guided fused lasso to find out the network structure. However, the group lasso methods have limitation in generalization because of the incomplete or unavailable prior knowledge in real world. The graph/network guided methods are sensitive to the sign of the sample correlation which may be incorrectly estimated. We introduce a new SCCA model using a novel graph guided pairwise group lasso penalty, and propose an efficient optimization algorithm. The proposed method has a strong upper bound for the grouping effect for both positively and negatively correlated variables. We show that our method performs better than or equally to two state-of-the-art SCCA methods on both synthetic and real neuroimaging genetics data. In particular, our method identifies stronger canonical correlations and captures better canonical loading profiles, showing its promise for revealing biologically meaningful imaging genetic associations.

  10. Atomic structure of a peptide coated gold nanocluster identified using theoretical and experimental studies

    Science.gov (United States)

    Wang, Hui; Li, Xu; Gao, Liang; Zhai, Jiao; Liu, Ru; Gao, Xueyun; Wang, Dongqi; Zhao, Lina

    2016-06-01

    Peptide coated gold nanoclusters (AuNCs) have a precise molecular formula and atomic structure, which are critical for their unique applications in targeting specific proteins either for protein analysis or drug design. To date, a study of the crystal structure of peptide coated AuNCs is absent primarily due to the difficulty of obtaining their crystalline phases in an experiment. Here we study a typical peptide coated AuNC (Au24Peptide8, Peptide = H2N-CCYKKKKQAGDV-COOH, Anal. Chem., 2015, 87, 2546) to figure out its atomic structure and electronic structure using a theoretical method for the first time. In this work, we identify the explicit configuration of the essential structure of Au24Peptide8, Au24(Cys-Cys)8, using density functional theory (DFT) computations and optical spectroscopic experiments, where Cys denotes cysteine without H bonded to S. As the first multidentate ligand binding AuNC, Au24(Cys-Cys)8 is characterized as a distorted Au13 core with Oh symmetry covered by two Au(Cys-Cys) and three Au3(Cys-Cys)2 staple motifs in its atomic structure. The most stable configuration of Au24(Cys-Cys)8 is confirmed by comparing its UV-vis absorption spectrum from time-dependent density-functional theory (TDDFT) calculations with optical absorption measurements, and these results are consistent with each other. Furthermore, we carry out frontier molecular orbital (FMO) calculations to elucidate that the electronic structure of Au24(Cys-Cys)8 is different from that of Au24(SR)20 as they have a different Au/S ratio, where SR represents alkylthiolate. Importantly, the different ligand coatings, Cys-Cys and SR, in Au24(Cys-Cys)8 and Au24(SR)20 cause the different Au/S ratios in the coated Au24. The reason is that the Au/S ratio is crucial in determining the size of the Au core of the ligand protected AuNC, and the size of the Au core corresponds to a specific electronic structure. By the adjustment of ligand coatings from alkylthiolate to peptide, the Au/S ratio

  11. SoftSearch: integration of multiple sequence features to identify breakpoints of structural variations.

    Directory of Open Access Journals (Sweden)

    Steven N Hart

    Full Text Available BACKGROUND: Structural variation (SV represents a significant, yet poorly understood contribution to an individual's genetic makeup. Advanced next-generation sequencing technologies are widely used to discover such variations, but there is no single detection tool that is considered a community standard. In an attempt to fulfil this need, we developed an algorithm, SoftSearch, for discovering structural variant breakpoints in Illumina paired-end next-generation sequencing data. SoftSearch combines multiple strategies for detecting SV including split-read, discordant read-pair, and unmated pairs. Co-localized split-reads and discordant read pairs are used to refine the breakpoints. RESULTS: We developed and validated SoftSearch using real and synthetic datasets. SoftSearch's key features are 1 not requiring secondary (or exhaustive primary alignment, 2 portability into established sequencing workflows, and 3 is applicable to any DNA-sequencing experiment (e.g. whole genome, exome, custom capture, etc.. SoftSearch identifies breakpoints from a small number of soft-clipped bases from split reads and a few discordant read-pairs which on their own would not be sufficient to make an SV call. CONCLUSIONS: We show that SoftSearch can identify more true SVs by combining multiple sequence features. SoftSearch was able to call clinically relevant SVs in the BRCA2 gene not reported by other tools while offering significantly improved overall performance.

  12. The use of deconvolution techniques to identify the fundamental mixing characteristics of urban drainage structures.

    Science.gov (United States)

    Stovin, V R; Guymer, I; Chappell, M J; Hattersley, J G

    2010-01-01

    Mixing and dispersion processes affect the timing and concentration of contaminants transported within urban drainage systems. Hence, methods of characterising the mixing effects of specific hydraulic structures are of interest to drainage network modellers. Previous research, focusing on surcharged manholes, utilised the first-order Advection-Dispersion Equation (ADE) and Aggregated Dead Zone (ADZ) models to characterise dispersion. However, although systematic variations in travel time as a function of discharge and surcharge depth have been identified, the first order ADE and ADZ models do not provide particularly good fits to observed manhole data, which means that the derived parameter values are not independent of the upstream temporal concentration profile. An alternative, more robust, approach utilises the system's Cumulative Residence Time Distribution (CRTD), and the solute transport characteristics of a surcharged manhole have been shown to be characterised by just two dimensionless CRTDs, one for pre- and the other for post-threshold surcharge depths. Although CRTDs corresponding to instantaneous upstream injections can easily be generated using Computational Fluid Dynamics (CFD) models, the identification of CRTD characteristics from non-instantaneous and noisy laboratory data sets has been hampered by practical difficulties. This paper shows how a deconvolution approach derived from systems theory may be applied to identify the CRTDs associated with urban drainage structures.

  13. Using machine learning to identify structural breaks in single-group interrupted time series designs.

    Science.gov (United States)

    Linden, Ariel; Yarnold, Paul R

    2016-12-01

    Single-group interrupted time series analysis (ITSA) is a popular evaluation methodology in which a single unit of observation is being studied, the outcome variable is serially ordered as a time series and the intervention is expected to 'interrupt' the level and/or trend of the time series, subsequent to its introduction. Given that the internal validity of the design rests on the premise that the interruption in the time series is associated with the introduction of the treatment, treatment effects may seem less plausible if a parallel trend already exists in the time series prior to the actual intervention. Thus, sensitivity analyses should focus on detecting structural breaks in the time series before the intervention. In this paper, we introduce a machine-learning algorithm called optimal discriminant analysis (ODA) as an approach to determine if structural breaks can be identified in years prior to the initiation of the intervention, using data from California's 1988 voter-initiated Proposition 99 to reduce smoking rates. The ODA analysis indicates that numerous structural breaks occurred prior to the actual initiation of Proposition 99 in 1989, including perfect structural breaks in 1983 and 1985, thereby casting doubt on the validity of treatment effects estimated for the actual intervention when using a single-group ITSA design. Given the widespread use of ITSA for evaluating observational data and the increasing use of machine-learning techniques in traditional research, we recommend that structural break sensitivity analysis is routinely incorporated in all research using the single-group ITSA design. © 2016 John Wiley & Sons, Ltd.

  14. Fingerprints of zones in boreholes. An approach to identify the characteristics of structures

    Energy Technology Data Exchange (ETDEWEB)

    Straeng, Thomas; Waenstedt, Stefan; Tiren, Sven (GEOSIGMA AB (Sweden))

    2010-11-15

    The classification of geophysical borehole data in order to identify and characterize structures, which intercepts the borehole, is an important part of 3D modelling of the structural pattern of the bedrock. The objective of this study is to test a statistical approach, cluster analysis, on site data in order to see if it is possible to classify complex data set, geological and geophysical borehole data, in order to identify borehole intersects with increased brittle deformation, i.e. brittle deformation zones. The base data used in the study have been provided and delivered by SKB and consist of borehole logging data from the cored borehole KFM03A. The statistical method chosen for this study, cluster analysis using K-means method, groups data into a pre-defined number of clusters with the goal to minimize the variance of data within the group and to maximize the variance between the clusters. The idea is that data can and should be grouped into two categories, two clusters -corresponding to homogeneous bedrock (matrix) in one cluster and open fractures in the other cluster. The analysis also includes a repetition of the cluster analysis, with a stepwise refined data set to see whether strongly accentuated features could be identified. The results show that the use of K-mean Cluster analysis will present clusters that could represent the spatial distribution of bedrock matrix and the location of fractures respectively down the borehole. The results were compared with fracture frequency data (from core mapping) and also with the geological Single Hole Interpretation of KFM03A performed by SKB. The fracture zones identified in the Single Hole Interpretation process are all indicated in the cluster analysis results. The cluster analysis revealed eight additional possible zones. A majority of these are smaller than 5 metres (section width in the borehole) but they are still pronounced in the analysis. Based on the geophysical data, these sections should be taken into

  15. Identifying the Structure and Effect of Drinking-Related Self-Schemas.

    Science.gov (United States)

    Domenico, Lisa H; Strobbe, Stephen; Stein, Karen Farchaus; Giordani, Bruno J; Hagerty, Bonnie M; Pressler, Susan J

    2017-07-01

    Self-schemas have received increased attention as favorable targets for therapeutic intervention because of their central role in self-perception and behavior. The purpose of this integrative review was to identify, evaluate, and synthesize existing research pertaining to drinking-related self-schemas. Russell's integrative review strategy guided the search. Sixteen published works were identified, meeting criteria for evaluation ( n = 12 data-based publications and n = 4 models). The retrieved data-based publications rated fair-good using Polit and Beck's criteria; the overall body of literature rated "B" using Grimes and Schulz criteria. Retrieved models rated 4 to 7 using Fitzpatrick and Whall's criteria. The existing literature strongly supports the availability of a drinking-related self-schema among moderate-to-heavy drinking samples, and suggests a positive relationship between elaboration and drinking behavior. The relationship between valenced content of the schema and drinking behavior remains unexplored. Identifying variation in the structural properties of drinking-related self-schemas could lay the foundation for future interventions.

  16. Discrete particle swarm optimization for identifying community structures in signed social networks.

    Science.gov (United States)

    Cai, Qing; Gong, Maoguo; Shen, Bo; Ma, Lijia; Jiao, Licheng

    2014-10-01

    Modern science of networks has facilitated us with enormous convenience to the understanding of complex systems. Community structure is believed to be one of the notable features of complex networks representing real complicated systems. Very often, uncovering community structures in networks can be regarded as an optimization problem, thus, many evolutionary algorithms based approaches have been put forward. Particle swarm optimization (PSO) is an artificial intelligent algorithm originated from social behavior such as birds flocking and fish schooling. PSO has been proved to be an effective optimization technique. However, PSO was originally designed for continuous optimization which confounds its applications to discrete contexts. In this paper, a novel discrete PSO algorithm is suggested for identifying community structures in signed networks. In the suggested method, particles' status has been redesigned in discrete form so as to make PSO proper for discrete scenarios, and particles' updating rules have been reformulated by making use of the topology of the signed network. Extensive experiments compared with three state-of-the-art approaches on both synthetic and real-world signed networks demonstrate that the proposed method is effective and promising. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Structural and functional insights of β-glucosidases identified from the genome of Aspergillus fumigatus

    Science.gov (United States)

    Dodda, Subba Reddy; Aich, Aparajita; Sarkar, Nibedita; Jain, Piyush; Jain, Sneha; Mondal, Sudipa; Aikat, Kaustav; Mukhopadhyay, Sudit S.

    2018-03-01

    Thermostable glucose tolerant β-glucosidase from Aspergillus species has attracted worldwide interest for their potentiality in industrial applications and bioethanol production. A strain of Aspergillus fumigatus (AfNITDGPKA3) identified by our laboratory from straw retting ground showed higher cellulase activity, specifically the β-glucosidase activity, compared to other contemporary strains. Though A. fumigatus has been known for high cellulase activity, detailed identification and characterization of the cellulase genes from their genome is yet to be done. In this work we have been analyzed the cellulase genes from the genome sequence database of Aspergillus fumigatus (Af293). Genome analysis suggests two cellobiohydrolase, eleven endoglucanase and seventeen β-glucosidase genes present. β-Glucosidase genes belong to either Glycohydro1 (GH1 or Bgl1) or Glycohydro3 (GH3 or Bgl3) family. The sequence similarity suggests that Bgl1 and Bgl3 of A. fumagatus are phylogenetically close to those of A. fisheri and A. oryzae. The modelled structure of the Bgl1 predicts the (β/α)8 barrel type structure with deep and narrow active site, whereas, Bgl3 shows the (α/β)8 barrel and (α/β)6 sandwich structure with shallow and open active site. Docking results suggest that amino acids Glu544, Glu466, Trp408,Trp567,Tyr44,Tyr222,Tyr770,Asp844,Asp537,Asn212,Asn217 of Bgl3 and Asp224,Asn242,Glu440, Glu445, Tyr367, Tyr365,Thr994,Trp435,Trp446 of Bgl1 are involved in the hydrolysis. Binding affinity analyses suggest that Bgl3 and Bgl1 enzymes are more active on the substrates like 4-methylumbelliferyl glycoside (MUG) and p-nitrophenyl-β-D-1, 4-glucopyranoside (pNPG) than on cellobiose. Further docking with glucose suggests that Bgl1 is more glucose tolerant than Bgl3. Analysis of the Aspergillus fumigatus genome may help to identify a β-glucosidase enzyme with better property and the structural information may help to develop an engineered recombinant enzyme.

  18. Identifying the Social Structure and the Inequality in Monetary Income of Russian Population

    Directory of Open Access Journals (Sweden)

    Vyacheslav Nikolaevich Bobkov

    2017-12-01

    Full Text Available The article aims at identifying the social structure and the inequality in monetary income of the population in Russia. identification of the social groups with different levels of material well-being in a society with a high inequality in the distribution of living standard is a relevant topic. The integration of normative and statistical methods allows to consider the limitations of the existing model of the distribution of cash income and adjust the boundaries of social groups with different levels of material well-being. At the same time, we stay within the criteria for the social standards of the differentiation of living standards. The authors have corrected the specific weight of the Russian social groups with different levels of material well-being. To define these social groups, we have applied the system of normative consumer budgets for different level of material well-being. This paper discovers the intervals for the levels of income and consumption, which are not in contradiction with the normative approach and existing conditions of the Russian economic development. These intervals are advisable for the identification of the social groups with different levels of life. The proposed tools allow to integrate the measurements into the international system and define the place of Russia in terms of economic inequalities among other countries. The authors have assessed the weights of the different social groups, their share in the total volume of monetary income and their polarization in terms of living standards. The main conclusions of the article can be used as a theoretical, methodological and practical basis for identifying social structures in terms of living standards, determining their numbers and economic inequality. The research results can be introduced into the statistical monitoring of the living standards of the population.

  19. The application of structure from motion (SfM) to identify the geological structure and outcrop studies

    Science.gov (United States)

    Saputra, Aditya; Rahardianto, Trias; Gomez, Christopher

    2017-07-01

    Adequate knowledge of geological structure is an essential for most studies in geoscience, mineral exploration, geo-hazard and disaster management. The geological map is still one the datasets the most commonly used to obtain information about the geological structure such as fault, joint, fold, and unconformities, however in rural areas such as Central Java data is still sparse. Recent progress in data acquisition technologies and computing have increased the interest in how to capture the high-resolution geological data effectively and for a relatively low cost. Some methods such as Airborne Laser Scanning (ALS), Terrestrial Laser Scanning (TLS), and Unmanned Aerial Vehicles (UAVs) have been widely used to obtain this information, however, these methods need a significant investment in hardware, software, and time. Resolving some of those issues, the photogrammetric method structure from motion (SfM) is an image-based method, which can provide solutions equivalent to laser technologies for a relatively low-cost with minimal time, specialization and financial investment. Using SfM photogrammetry, it is possible to generate high resolution 3D images rock surfaces and outcrops, in order to improve the geological understanding of Indonesia. In the present contribution, it is shown that the information about fault and joint can be obtained at high-resolution and in a shorter time than with the conventional grid mapping and remotely sensed topographic surveying. The SfM method produces a point-cloud through image matching and computing. This task can be run with open- source or commercial image processing and 3D reconstruction software. As the point cloud has 3D information as well as RGB values, it allows for further analysis such as DEM extraction and image orthorectification processes. The present paper describes some examples of SfM to identify the fault in the outcrops and also highlight the future possibilities in terms of earthquake hazard assessment, based on

  20. Identifying mechanisms that structure ecological communities by snapping model parameters to empirically observed tradeoffs.

    Science.gov (United States)

    Thomas Clark, Adam; Lehman, Clarence; Tilman, David

    2018-04-01

    Theory predicts that interspecific tradeoffs are primary determinants of coexistence and community composition. Using information from empirically observed tradeoffs to augment the parametrisation of mechanism-based models should therefore improve model predictions, provided that tradeoffs and mechanisms are chosen correctly. We developed and tested such a model for 35 grassland plant species using monoculture measurements of three species characteristics related to nitrogen uptake and retention, which previous experiments indicate as important at our site. Matching classical theoretical expectations, these characteristics defined a distinct tradeoff surface, and models parameterised with these characteristics closely matched observations from experimental multi-species mixtures. Importantly, predictions improved significantly when we incorporated information from tradeoffs by 'snapping' characteristics to the nearest location on the tradeoff surface, suggesting that the tradeoffs and mechanisms we identify are important determinants of local community structure. This 'snapping' method could therefore constitute a broadly applicable test for identifying influential tradeoffs and mechanisms. © 2018 The Authors. Ecology Letters published by CNRS and John Wiley & Sons Ltd.

  1. Identifying the community structure of the food-trade international multi-network

    Science.gov (United States)

    Torreggiani, S.; Mangioni, G.; Puma, M. J.; Fagiolo, G.

    2018-05-01

    Achieving international food security requires improved understanding of how international trade networks connect countries around the world through the import-export flows of food commodities. The properties of international food trade networks are still poorly documented, especially from a multi-network perspective. In particular, nothing is known about the multi-network’s community structure. Here we find that the individual crop-specific layers of the multi-network have densely connected trading groups, a consistent characteristic over the period 2001–2011. Further, the multi-network is characterized by low variability over this period but with substantial heterogeneity across layers in each year. In particular, the layers are mostly assortative: more-intensively connected countries tend to import from and export to countries that are themselves more connected. We also fit econometric models to identify social, economic and geographic factors explaining the probability that any two countries are co-present in the same community. Our estimates indicate that the probability of country pairs belonging to the same food trade community depends more on geopolitical and economic factors—such as geographical proximity and trade-agreement co-membership—than on country economic size and/or income. These community-structure findings of the multi-network are especially valuable for efforts to understand past and emerging dynamics in the global food system, especially those that examine potential ‘shocks’ to global food trade.

  2. A longitudinal genetic survey identifies temporal shifts in the population structure of Dutch house sparrows

    Science.gov (United States)

    Cousseau, L; Husemann, M; Foppen, R; Vangestel, C; Lens, L

    2016-01-01

    Dutch house sparrow (Passer domesticus) densities dropped by nearly 50% since the early 1980s, and similar collapses in population sizes have been reported across Europe. Whether, and to what extent, such relatively recent demographic changes are accompanied by concomitant shifts in the genetic population structure of this species needs further investigation. Therefore, we here explore temporal shifts in genetic diversity, genetic structure and effective sizes of seven Dutch house sparrow populations. To allow the most powerful statistical inference, historical populations were resampled at identical locations and each individual bird was genotyped using nine polymorphic microsatellites. Although the demographic history was not reflected by a reduction in genetic diversity, levels of genetic differentiation increased over time, and the original, panmictic population (inferred from the museum samples) diverged into two distinct genetic clusters. Reductions in census size were supported by a substantial reduction in effective population size, although to a smaller extent. As most studies of contemporary house sparrow populations have been unable to identify genetic signatures of recent population declines, results of this study underpin the importance of longitudinal genetic surveys to unravel cryptic genetic patterns. PMID:27273323

  3. Statistical Evaluation of the Identified Structural Parameters of an idling Offshore Wind Turbine

    International Nuclear Information System (INIS)

    Kramers, Hendrik C.; Van der Valk, Paul L.C.; Van Wingerden, Jan-Willem

    2016-01-01

    With the increased need for renewable energy, new offshore wind farms are being developed at an unprecedented scale. However, as the costs of offshore wind energy are still too high, design optimization and new innovations are required for lowering its cost. The design of modern day offshore wind turbines relies on numerical models for estimating ultimate and fatigue loads of the turbines. The dynamic behavior and the resulting structural loading of the turbines is determined for a large part by its structural properties, such as the natural frequencies and damping ratios. Hence, it is important to obtain accurate estimates of these modal properties. For this purpose stochastic subspace identification (SSI), in combination with clustering and statistical evaluation methods, is used to obtain the variance of the identified modal properties of an installed 3.6MW offshore wind turbine in idling conditions. It is found that one is able to obtain confidence intervals for the means of eigenfrequencies and damping ratios of the fore-aft and side-side modes of the wind turbine. (paper)

  4. Subpopulations Within Juvenile Psoriatic Arthritis: A Review of the Literature

    Directory of Open Access Journals (Sweden)

    Matthew L. Stoll

    2006-01-01

    Full Text Available The presentation of juvenile psoriatic arthritis (JPsA has long been recognized to be clinically heterogeneous. As the definition of JPsA expanded to accommodate atypical manifestations of psoriasis in young children, studies began to reflect an increasingly clear biphasic distribution of age of onset, with peaks in the first few years of life and again in early adolescence. These two subpopulations differ in gender ratio, pattern of joint involvement, laboratory findings and potentially response to therapy. Intriguingly, a similar distribution of age of onset has been observed in juvenile rheumatoid arthritis (JRA, and correlates with patterns of HLA association. While a secure classification of subpopulations within JPsA awaits improved pathophysiologic understanding, future research must consider the possibility that different disease mechanisms may be operative in distinct subsets of patients with this disorder.

  5. Structural Elements in a Persistent Identifier Infrastructure and Resulting Benefits for the Earth Science Community

    Science.gov (United States)

    Weigel, T.; Toussaiant, F.; Stockhause, M.; Höck, H.; Kindermann, S.; Lautenschlager, M.; Ludwig, T.

    2012-12-01

    We propose a wide adoption of structural elements (typed links, collections, trees) in the Handle System to improve identification and access of scientific data, metadata and software as well as traceability of data provenance. Typed links target the issue of data provenance as a means to assess the quality of scientific data. Data provenance is seen here as a directed acyclic graph with nodes representing data and vertices representing derivative operations (Moreau 2010). Landing pages can allow a human user to explore the provenance graph back to the primary unprocessed data, thereby also giving credit to the original data producer. As in Earth System Modeling no single infrastructure with complete data lifecycle coverage exists, we propose to split the problem domain in two parts. Project-specific infrastructures such as the German project C3-Grid or the Earth System Grid Federation (ESGF) for CMIP5 data are aware of data and data operations (Toussaint et al. 2012) and can thus detect and accumulate single nodes and vertices in the provenance graph, assigning Handles to data, metadata and software. With a common schema for typed links, the provenance graph is established as downstream infrastructures refer incoming Handles. Data in this context is for example hierarchically structured Earth System model output data, which receives DataCite DOIs only for the most coarse-granular elements. Using Handle tree structures, the lower levels of the hierarchy can also receive Handles, allowing authors to more precisely identify the data they used (Lawrence et al. 2011). We can e.g. define a DOI for just the 2m-temperature variable of CMIP5 data across many CMIP5 experiments or a DOI for model and observational data coming from different sources. The structural elements should be implemented through Handle values at the Handle infrastructure level for two reasons. Handle values are more durable than downstream websites or databases, and thus the provenance chain does not

  6. A method of identifying social structures in siting regions for deep geological repositories in Switzerland

    International Nuclear Information System (INIS)

    Brander, Simone

    2010-09-01

    Acceptance is a key element in the site selection process for deep geological repositories for high-level and low and intermediate-level radioactive waste in Switzerland. Participation requirements such as comprehensive negotiation issues and adequate resources have thus been defined by the Swiss Federal Office of Energy (SFOE). In 2008, on the basis of technical criteria Nagra (National Cooperative for the Disposal of Radioactive Waste) proposed several potential areas for deep geological repositories. The number of potential areas will be narrowed down within the next few years. All municipalities within the planning perimeter (the area in which surface facilities can be realised) are affected and form the siting region. In order to ensure that the local population have their say in the forthcoming discussions, regional participation bodies including all municipalities within a siting region are being set up by the SFOE. Regional participation ensures that local interests, needs and values are taken into account in the site selection process. Assembling the regional participation bodies is therefore of great importance. Before such bodies can be formed, however, the various interests, needs and values have to be identified, and special attention has to be paid to long-term interests of future generations, as well as to non-organised and under-represented interests. According to the concept of proportional representation, the interests, needs and values that are identified and weighted by the local population are to be represented in the regional participation procedure. The aim of this study is to share a method of mapping existing social structures in a defined geographical area. This involves a combination of an analysis of socio-economic statistical data and qualitative and quantitative social research methods

  7. A structured elicitation method to identify key direct risk factors for the management of natural resources

    Directory of Open Access Journals (Sweden)

    Michael Smith

    2015-11-01

    Full Text Available The high level of uncertainty inherent in natural resource management requires planners to apply comprehensive risk analyses, often in situations where there are few resources. In this paper, we demonstrate a broadly applicable, novel and structured elicitation approach to identify important direct risk factors. This new approach combines expert calibration and fuzzy based mathematics to capture and aggregate subjective expert estimates of the likelihood that a set of direct risk factors will cause management failure. A specific case study is used to demonstrate the approach; however, the described methods are widely applicable in risk analysis. For the case study, the management target was to retain all species that characterise a set of natural biological elements. The analysis was bounded by the spatial distribution of the biological elements under consideration and a 20-year time frame. Fourteen biological elements were expected to be at risk. Eleven important direct risk factors were identified that related to surrounding land use practices, climate change, problem species (e.g., feral predators, fire and hydrological change. In terms of their overall influence, the two most important risk factors were salinisation and a lack of water which together pose a considerable threat to the survival of nine biological elements. The described approach successfully overcame two concerns arising from previous risk analysis work: (1 the lack of an intuitive, yet comprehensive scoring method enabling the detection and clarification of expert agreement and associated levels of uncertainty; and (2 the ease with which results can be interpreted and communicated while preserving a rich level of detail essential for informed decision making.

  8. Methods and Measures: Growth Mixture Modeling--A Method for Identifying Differences in Longitudinal Change among Unobserved Groups

    Science.gov (United States)

    Ram, Nilam; Grimm, Kevin J.

    2009-01-01

    Growth mixture modeling (GMM) is a method for identifying multiple unobserved sub-populations, describing longitudinal change within each unobserved sub-population, and examining differences in change among unobserved sub-populations. We provide a practical primer that may be useful for researchers beginning to incorporate GMM analysis into their…

  9. High-resolution Anorectal Manometry for Identifying Defecatory Disorders and Rectal Structural Abnormalities in Women.

    Science.gov (United States)

    Prichard, David O; Lee, Taehee; Parthasarathy, Gopanandan; Fletcher, Joel G; Zinsmeister, Alan R; Bharucha, Adil E

    2017-03-01

    Contrary to conventional wisdom, the rectoanal gradient during evacuation is negative in many healthy people, undermining the utility of anorectal high-resolution manometry (HRM) for diagnosing defecatory disorders. We aimed to compare HRM and magnetic resonance imaging (MRI) for assessing rectal evacuation and structural abnormalities. We performed a retrospective analysis of 118 patients (all female; 51 with constipation, 48 with fecal incontinence, and 19 with rectal prolapse; age, 53 ± 1 years) assessed by HRM, the rectal balloon expulsion test (BET), and MRI at Mayo Clinic, Rochester, Minnesota, from February 2011 through March 2013. Thirty healthy asymptomatic women (age, 37 ± 2 years) served as controls. We used principal components analysis of HRM variables to identify rectoanal pressure patterns associated with rectal prolapse and phenotypes of patients with prolapse. Compared with patients with normal findings from the rectal BET, patients with an abnormal BET had lower median rectal pressure (36 vs 22 mm Hg, P = .002), a more negative median rectoanal gradient (-6 vs -29 mm Hg, P = .006) during evacuation, and a lower proportion of evacuation on the basis of MRI analysis (median of 40% vs 80%, P < .0001). A score derived from rectal pressure and anorectal descent during evacuation and a patulous anal canal was associated (P = .005) with large rectoceles (3 cm or larger). A principal component (PC) logistic model discriminated between patients with and without prolapse with 96% accuracy. Among patients with prolapse, there were 2 phenotypes, which were characterized by high (PC1) or low (PC2) anal pressures at rest and squeeze along with higher rectal and anal pressures (PC1) or a higher rectoanal gradient during evacuation (PC2). In a retrospective analysis of patients assessed by HRM, measurements of rectal evacuation by anorectal HRM, BET, and MRI were correlated. HRM alone and together with anorectal descent during evacuation may identify

  10. Sperm subpopulations in avian species: a comparative study between the rooster (Gallus domesticus and Guinea fowl (Numida meleagris

    Directory of Open Access Journals (Sweden)

    Manuel García-Herreros

    2016-01-01

    Full Text Available The main aims of this research were to study possible differences in objective morphometric sperm characteristics, establish normative sperm morphometry standards, and evaluate the presumed different subpopulation distribution of avian spermatozoa from the rooster (Gallus domesticus and Guinea fowl (Numida meleagris as model avian species. Seventy-two ejaculates (36 per species studied were obtained manually, following a training period involving gently combined dorso-abdominal and lumbo-sacral massage of the birds. Ejaculates were processed for volume, sperm concentration, viability, motility, and morphology. Moreover, samples were submitted for sperm morphometric assessment using objective Computer-Assisted Semen Analysis for Morphometry (CASA-Morph methods, with sperm morphometric descriptors evaluated by Principal Component Analysis (PCA and multivariate clustering analyses. There were several differences observed between the avian species in values obtained for ejaculate volume and sperm concentration (P < 0.001. Irrespective of species, PCA revealed two Principal Components (PCs explaining more than 80% of the variance. In addition, the number of subpopulations differed with species (three and five subpopulations for rooster and Guinea fowl, respectively. Moreover, the distribution of the sperm subpopulations was found to be structurally different between species. In conclusion, our findings from using CASA-Morph methods indicate pronounced sperm morphometric variation between these two avian species. Because of the strong differences observed in morphometric parameter values and their subpopulation distribution, these results suggest that application of objective analytical methods such as CASA-Morph could substantially improve the reliability of comparative studies and help establish valid normative sperm morphological values for avian species.

  11. Assessment of the validity of the CUDIT-R in a subpopulation of cannabis users.

    Science.gov (United States)

    Loflin, Mallory; Babson, Kimberly; Browne, Kendall; Bonn-Miller, Marcel

    2018-01-01

    The Cannabis Use Disorders Identification Test-Revised (CUDIT-R) is an 8-item measure used to screen for cannabis use disorders (CUD). Despite widespread use of the tool, assessments of the CUDIT-R's validity in subpopulations are limited. The current study tested the structural validity and internal consistency of one of the most widely used screening measures for CUD (i.e., CUDIT-R) among a sample of military veterans who use cannabis for medicinal purposes. The present study used confirmatory factor analysis (CFA) to test the internal consistency and validity of the single-factor structure of the original screener among a sample of veterans who use cannabis for medicinal purposes (n = 90 [90% male]; M age  = 55.31, SD = 15.37). Measures included demographics and the CUDIT-R, obtained from the baseline assessment of an ongoing longitudinal study. The CFA revealed that the single-factor model previously validated in recreational using samples only accounted for 38.34% of total variance in responses on the CUDIT-R (χ 2  = 66.09, df = 28, p medicinal cannabis and other subpopulations of cannabis users.

  12. Diagnostic SNPs for inferring population structure in American mink (Neovison vison) identified through RAD sequencing

    DEFF Research Database (Denmark)

    2015-01-01

    Data from: "Diagnostic SNPs for inferring population structure in American mink (Neovison vison) identified through RAD sequencing" in Genomic Resources Notes accepted 1 October 2014 to 30 November 2014....

  13. Can structural and functional characteristics be used to identify riparian zone width in southern Appalachian headwater catchments?

    Science.gov (United States)

    Barton Clinton; James Vose; Jennifer Knoepp; Katherine Elliott; Barbara Reynolds; Stanley Zarnock

    2010-01-01

    We characterized structural and functional attributes along hillslope gradients in headwater catchments. We endeavored to identify parameters that described significant transitions along the hillslope. On each of four catchments, we installed eight 50 m transects perpendicular to the stream. Structural attributes included woody and herbaceous vegetation; woody debris...

  14. Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

    International Nuclear Information System (INIS)

    Corcelle, V.; Stieger, B.; Gjinovci, A.; Wollheim, C.B.; Gauthier, B.R.

    2006-01-01

    Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl 4 . Livers were removed 9 to 13 days post-CCl 4 treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b + cells fail to propagate while c-kit + -HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit + -HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion

  15. Selection of wheat subpopulations obtained by recurrent radiation

    International Nuclear Information System (INIS)

    Morales Gomez Jose Antonio; Cervantes Santana Tarcicio

    1990-01-01

    The purpose of this study was the analysis of the effect of one cycle of divergent selection for number of tillers per plant, in subpopulations M1 to M4 after each of six cycles of radiation of seed of wheat (Triticum aestivum L.) var. Salamanca S-75 with gamma rays. Irradiated materials and the original variety were field evaluated under two seeding densities. Results varied significantly for the two seeding densities. The 5 kr recurrent dose of radiation caused first a decrease in the number of tillers per plant and then an increase; doses of 20 and 40 kr were lethal in the fifth time of radiation, and 60 kr were lethal at the second radiation time. One cycle of divergent selection was more effective for more tillers per plant in the radiated subpopulations than in the original variety showing at the same time, an increase in the number of tillers as the number of generations of segregation (M) increased for the first four radiations [es

  16. Bionomics of Aedes aegypti subpopulations (Diptera: Culicidae) from Misiones Province, northeastern Argentina.

    Science.gov (United States)

    Tejerina, Edmundo Fabricio; Almeida, Francisco Felipe Ludueña; Almirón, Walter Ricardo

    2009-01-01

    Life statistics of four Aedes aegypti subpopulations from the subtropical province of Misiones were studied during autumn and winter, under semi-natural conditions, coming from the localities of Posadas (SW), San Javier (SE), Bernardo de Irigoyen (NE) and Puerto Libertad (NW). The eastern subpopulations are geographically separated by the central mountain system of the province from the western subpopulations. High percentages of larval and pupal survival (97-100%) were recorded, and no significant differences were detected among the four subpopulations. Larvae and pupae lasted approximately 8 days to complete their development, no significant differences being detected among the four subpopulations studied. Sex ratio recorded did not differ significantly from 1:1. Male longevity did not show difference among the different subpopulations, but female longevity was remarkably different among the four subpopulations (F=16.27; d.f.=(3;8); P=0.0009), ranging among 11.45 days for San Javier and 57.87 days for Posadas. Fecundity also varied considerably among subpopulations, the greatest number (307.44 eggs/female) being recorded for Posadas (F=4.13; d.f.=(3;8); P=0.04). Ae. aegypti females of the western subpopulations lived longer than the eastern subpopulations studied, therefore, the risk of dengue outbreak would be greater on the Misiones Province border with Paraguay.

  17. A Systematic Approach for Identifying Level-1 Error Covariance Structures in Latent Growth Modeling

    Science.gov (United States)

    Ding, Cherng G.; Jane, Ten-Der; Wu, Chiu-Hui; Lin, Hang-Rung; Shen, Chih-Kang

    2017-01-01

    It has been pointed out in the literature that misspecification of the level-1 error covariance structure in latent growth modeling (LGM) has detrimental impacts on the inferences about growth parameters. Since correct covariance structure is difficult to specify by theory, the identification needs to rely on a specification search, which,…

  18. Precision of Discrete and Rhythmic Forelimb Movements Requires a Distinct Neuronal Subpopulation in the Interposed Anterior Nucleus

    Directory of Open Access Journals (Sweden)

    Aloysius Y.T. Low

    2018-02-01

    Full Text Available The deep cerebellar nuclei (DCN represent output channels of the cerebellum, and they transmit integrated sensorimotor signals to modulate limb movements. But the functional relevance of identifiable neuronal subpopulations within the DCN remains unclear. Here, we examine a genetically tractable population of neurons in the mouse interposed anterior nucleus (IntA. We show that these neurons represent a subset of glutamatergic neurons in the IntA and constitute a specific element of an internal feedback circuit within the cerebellar cortex and cerebello-thalamo-cortical pathway associated with limb control. Ablation and optogenetic stimulation of these neurons disrupt efficacy of skilled reach and locomotor movement and reveal that they control positioning and timing of the forelimb and hindlimb. Together, our findings uncover the function of a distinct neuronal subpopulation in the deep cerebellum and delineate the anatomical substrates and kinematic parameters through which it modulates precision of discrete and rhythmic limb movements.

  19. Testing job typologies and identifying at-risk subpopulations using factor mixture models

    NARCIS (Netherlands)

    Keller, A. C.; Igic, Ivana; Meier, Laurenz L.; Semmer, N. K.; Schaubroeck, J.; Brunner, Beatrice; Elfering, Achim

    2017-01-01

    Research in occupational health psychology has tended to focus on the effects of single job characteristics or various job characteristics combined into 1 factor. However, such a variable-centered approach does not account for the clustering of job attributes among groups of employees. We addressed

  20. Exact calculation of loop formation probability identifies folding motifs in RNA secondary structures

    Science.gov (United States)

    Sloma, Michael F.; Mathews, David H.

    2016-01-01

    RNA secondary structure prediction is widely used to analyze RNA sequences. In an RNA partition function calculation, free energy nearest neighbor parameters are used in a dynamic programming algorithm to estimate statistical properties of the secondary structure ensemble. Previously, partition functions have largely been used to estimate the probability that a given pair of nucleotides form a base pair, the conditional stacking probability, the accessibility to binding of a continuous stretch of nucleotides, or a representative sample of RNA structures. Here it is demonstrated that an RNA partition function can also be used to calculate the exact probability of formation of hairpin loops, internal loops, bulge loops, or multibranch loops at a given position. This calculation can also be used to estimate the probability of formation of specific helices. Benchmarking on a set of RNA sequences with known secondary structures indicated that loops that were calculated to be more probable were more likely to be present in the known structure than less probable loops. Furthermore, highly probable loops are more likely to be in the known structure than the set of loops predicted in the lowest free energy structures. PMID:27852924

  1. Booth Revisited: Identifying the Determinants of Capital Structure in the Sugar Sector

    Directory of Open Access Journals (Sweden)

    A.A. Kanwar

    2007-07-01

    Full Text Available The study assesses whether selected exogenous variables: tax rate, size, asset tangibility, volatility and profitability, affect capital structure in a significant manner in the sugar industry. It suggests that decision on capital structuring is found to be weakly affected by the variables chosen in our study. This is also consistent with the results of Booth et al (2001 where modern financial theory is found to be weakly portable across a group of developed and developing countries. It is recommended that more empirical work is done in order to understand the impact of capital structure choices.

  2. High-Density Lipoprotein Reduction Differentially Modulates to Classical and Nonclassical Monocyte Subpopulations in Metabolic Syndrome Patients and in LPS-Stimulated Primary Human Monocytes In Vitro

    Science.gov (United States)

    Grün, Johanna L.; Manjarrez-Reyna, Aaron N.; Gómez-Arauz, Angélica Y.; Leon-Cabrera, Sonia; Bueno-Hernández, Nallely; Islas-Andrade, Sergio

    2018-01-01

    The effect of metabolic syndrome on human monocyte subpopulations has not yet been studied. Our main goal was to examine monocyte subpopulations in metabolic syndrome patients, while also identifying the risk factors that could directly influence these cells. Eighty-six subjects were divided into metabolic syndrome patients and controls. Monocyte subpopulations were quantified by flow cytometry, and interleukin- (IL-) 1β secretion levels were measured by ELISA. Primary human monocytes were cultured in low or elevated concentrations of high-density lipoprotein (HDL) and stimulated with lipopolysaccharide (LPS). The nonclassical monocyte (NCM) percentage was significantly increased in metabolic syndrome patients as compared to controls, whereas classical monocytes (CM) were reduced. Among all metabolic syndrome risk factors, HDL reduction exhibited the most important correlation with monocyte subpopulations and then was studied in vitro. Low HDL concentration reduced the CM percentage, whereas it increased the NCM percentage and IL-1β secretion in LPS-treated monocytes. The LPS effect was abolished when monocytes were cultured in elevated HDL concentrations. Concurring with in vitro results, IL-1β serum values significantly increased in metabolic syndrome patients with low HDL levels as compared to metabolic syndrome patients without HDL reduction. Our data demonstrate that HDL directly modulates monocyte subpopulations in metabolic syndrome. PMID:29850624

  3. High-Density Lipoprotein Reduction Differentially Modulates to Classical and Nonclassical Monocyte Subpopulations in Metabolic Syndrome Patients and in LPS-Stimulated Primary Human Monocytes In Vitro

    Directory of Open Access Journals (Sweden)

    Johanna L. Grün

    2018-01-01

    Full Text Available The effect of metabolic syndrome on human monocyte subpopulations has not yet been studied. Our main goal was to examine monocyte subpopulations in metabolic syndrome patients, while also identifying the risk factors that could directly influence these cells. Eighty-six subjects were divided into metabolic syndrome patients and controls. Monocyte subpopulations were quantified by flow cytometry, and interleukin- (IL- 1β secretion levels were measured by ELISA. Primary human monocytes were cultured in low or elevated concentrations of high-density lipoprotein (HDL and stimulated with lipopolysaccharide (LPS. The nonclassical monocyte (NCM percentage was significantly increased in metabolic syndrome patients as compared to controls, whereas classical monocytes (CM were reduced. Among all metabolic syndrome risk factors, HDL reduction exhibited the most important correlation with monocyte subpopulations and then was studied in vitro. Low HDL concentration reduced the CM percentage, whereas it increased the NCM percentage and IL-1β secretion in LPS-treated monocytes. The LPS effect was abolished when monocytes were cultured in elevated HDL concentrations. Concurring with in vitro results, IL-1β serum values significantly increased in metabolic syndrome patients with low HDL levels as compared to metabolic syndrome patients without HDL reduction. Our data demonstrate that HDL directly modulates monocyte subpopulations in metabolic syndrome.

  4. Identifying the Core Content and Structure of a Schema for Cultural Understanding

    Science.gov (United States)

    2009-06-01

    Guatemala, Haiti, Holland, Honduras, Iraq, Italy, Japan, Korea, Kuwait, Malaysia , Mexico, Nassau, Nicaragua, Pakistan, Panama, Peru, Philippines... Leisure Orientation toward U.S. Military/Civilian Religion Technology Time Work Taboos Social structure Similarities and differences Key

  5. Structure modeling of all identified G protein-coupled receptors in the human genome.

    Science.gov (United States)

    Zhang, Yang; Devries, Mark E; Skolnick, Jeffrey

    2006-02-01

    G protein-coupled receptors (GPCRs), encoded by about 5% of human genes, comprise the largest family of integral membrane proteins and act as cell surface receptors responsible for the transduction of endogenous signal into a cellular response. Although tertiary structural information is crucial for function annotation and drug design, there are few experimentally determined GPCR structures. To address this issue, we employ the recently developed threading assembly refinement (TASSER) method to generate structure predictions for all 907 putative GPCRs in the human genome. Unlike traditional homology modeling approaches, TASSER modeling does not require solved homologous template structures; moreover, it often refines the structures closer to native. These features are essential for the comprehensive modeling of all human GPCRs when close homologous templates are absent. Based on a benchmarked confidence score, approximately 820 predicted models should have the correct folds. The majority of GPCR models share the characteristic seven-transmembrane helix topology, but 45 ORFs are predicted to have different structures. This is due to GPCR fragments that are predominantly from extracellular or intracellular domains as well as database annotation errors. Our preliminary validation includes the automated modeling of bovine rhodopsin, the only solved GPCR in the Protein Data Bank. With homologous templates excluded, the final model built by TASSER has a global C(alpha) root-mean-squared deviation from native of 4.6 angstroms, with a root-mean-squared deviation in the transmembrane helix region of 2.1 angstroms. Models of several representative GPCRs are compared with mutagenesis and affinity labeling data, and consistent agreement is demonstrated. Structure clustering of the predicted models shows that GPCRs with similar structures tend to belong to a similar functional class even when their sequences are diverse. These results demonstrate the usefulness and robustness

  6. Structure modeling of all identified G protein-coupled receptors in the human genome.

    Directory of Open Access Journals (Sweden)

    Yang Zhang

    2006-02-01

    Full Text Available G protein-coupled receptors (GPCRs, encoded by about 5% of human genes, comprise the largest family of integral membrane proteins and act as cell surface receptors responsible for the transduction of endogenous signal into a cellular response. Although tertiary structural information is crucial for function annotation and drug design, there are few experimentally determined GPCR structures. To address this issue, we employ the recently developed threading assembly refinement (TASSER method to generate structure predictions for all 907 putative GPCRs in the human genome. Unlike traditional homology modeling approaches, TASSER modeling does not require solved homologous template structures; moreover, it often refines the structures closer to native. These features are essential for the comprehensive modeling of all human GPCRs when close homologous templates are absent. Based on a benchmarked confidence score, approximately 820 predicted models should have the correct folds. The majority of GPCR models share the characteristic seven-transmembrane helix topology, but 45 ORFs are predicted to have different structures. This is due to GPCR fragments that are predominantly from extracellular or intracellular domains as well as database annotation errors. Our preliminary validation includes the automated modeling of bovine rhodopsin, the only solved GPCR in the Protein Data Bank. With homologous templates excluded, the final model built by TASSER has a global C(alpha root-mean-squared deviation from native of 4.6 angstroms, with a root-mean-squared deviation in the transmembrane helix region of 2.1 angstroms. Models of several representative GPCRs are compared with mutagenesis and affinity labeling data, and consistent agreement is demonstrated. Structure clustering of the predicted models shows that GPCRs with similar structures tend to belong to a similar functional class even when their sequences are diverse. These results demonstrate the usefulness

  7. Experimental Stroke Differentially Affects Discrete Subpopulations of Splenic Macrophages

    Directory of Open Access Journals (Sweden)

    Laura McCulloch

    2018-05-01

    Full Text Available Changes to the immune system after stroke are complex and can result in both pro-inflammatory and immunosuppressive consequences. Following ischemic stroke, brain resident microglia are activated and circulating monocytes are recruited to the injury site. In contrast, there is a systemic deactivation of monocytes/macrophages that may contribute to immunosuppression and the high incidence of bacterial infection experienced by stroke patients. The manipulation of macrophage subsets may be a useful therapeutic strategy to reduce infection and improve outcome in patients after stroke. Recent research has enhanced our understanding of the heterogeneity of macrophages even within the same tissue. The spleen is the largest natural reservoir of immune cells, many of which are mobilized to the site of injury after ischemic stroke and is notable for the diversity of its functionally distinct macrophage subpopulations associated with specific micro-anatomical locations. Here, we describe the effects of experimental stroke in mice on these distinct splenic macrophage subpopulations. Red pulp (RP and marginal zone macrophages (MZM specifically showed increases in density and alterations in micro-anatomical location. These changes were not due to increased recruitment from the bone marrow but may be associated with increases in local proliferation. Genes associated with phagocytosis and proteolytic processing were upregulated in the spleen after stroke with increased expression of the lysosome-associated protein lysosomal-associated membrane proteins specifically increased in RP and MZM subsets. In contrast, MHC class II expression was reduced specifically in these populations. Furthermore, genes associated with macrophage ability to communicate with other immune cells, such as co-stimulatory molecules and inflammatory cytokine production, were also downregulated in the spleen after stroke. These findings suggest that selective splenic macrophage functions

  8. Identifying Copy Number Variants under Selection in Geographically Structured Populations Based on -statistics

    Directory of Open Access Journals (Sweden)

    Hae-Hiang Song

    2012-06-01

    Full Text Available Large-scale copy number variants (CNVs in the human provide the raw material for delineating population differences, as natural selection may have affected at least some of the CNVs thus far discovered. Although the examination of relatively large numbers of specific ethnic groups has recently started in regard to inter-ethnic group differences in CNVs, identifying and understanding particular instances of natural selection have not been performed. The traditional FST measure, obtained from differences in allele frequencies between populations, has been used to identify CNVs loci subject to geographically varying selection. Here, we review advances and the application of multinomial-Dirichlet likelihood methods of inference for identifying genome regions that have been subject to natural selection with the FST estimates. The contents of presentation are not new; however, this review clarifies how the application of the methods to CNV data, which remains largely unexplored, is possible. A hierarchical Bayesian method, which is implemented via Markov Chain Monte Carlo, estimates locus-specific FST and can identify outlying CNVs loci with large values of FST. By applying this Bayesian method to the publicly available CNV data, we identified the CNV loci that show signals of natural selection, which may elucidate the genetic basis of human disease and diversity.

  9. Identifying the structure of group correlation in the Korean financial market

    Science.gov (United States)

    Ahn, Sanghyun; Choi, Jaewon; Lim, Gyuchang; Cha, Kil Young; Kim, Sooyong; Kim, Kyungsik

    2011-06-01

    We investigate the structure of the cross-correlation in the Korean stock market. We analyze daily cross-correlations between price fluctuations of 586 different Korean stock entities for the 6-year time period from 2003 to 2008. The main purpose is to investigate the structure of group correlation and its stability by undressing the market-wide effect using the Markowitz multi-factor model and the network-based approach. We find the explicit list of significant firms in the few largest eigenvectors from the undressed correlation matrix. We also observe that each contributor is involved in the same business sectors. The structure of group correlation can not remain constant during each 1-year time period with different starting points, whereas only two largest eigenvectors are stable for 6 years 8-9 eigenvectors remain stable for half-year. The structure of group correlation in the Korean financial market is disturbed during a sufficiently short time period even though the group correlation exists as an ensemble for the 6-year time period in the evolution of the system. We verify the structure of group correlation by applying a network-based approach. In addition, we examine relations between market capitalization and businesses. The Korean stock market shows a different behavior compared to mature markets, implying that the KOSPI is a target for short-positioned investors.

  10. Structural and mechanistic analysis of a β-glycoside phosphorylase identified by screening a metagenomic library.

    Science.gov (United States)

    Macdonald, Spencer S; Patel, Ankoor; Larmour, Veronica L C; Morgan-Lang, Connor; Hallam, Steven J; Mark, Brian L; Withers, Stephen G

    2018-03-02

    Glycoside phosphorylases have considerable potential as catalysts for the assembly of useful glycans for products ranging from functional foods and prebiotics to novel materials. However, the substrate diversity of currently identified phosphorylases is relatively small, limiting their practical applications. To address this limitation, we developed a high-throughput screening approach using the activated substrate 2,4-dinitrophenyl β-d-glucoside (DNPGlc) and inorganic phosphate for identifying glycoside phosphorylase activity and used it to screen a large insert metagenomic library. The initial screen, based on release of 2,4-dinitrophenyl from DNPGlc in the presence of phosphate, identified the gene bglP, encoding a retaining β-glycoside phosphorylase from the CAZy GH3 family. Kinetic and mechanistic analysis of the gene product, BglP, confirmed a double displacement ping-pong mechanism involving a covalent glycosyl-enzyme intermediate. X-ray crystallographic analysis provided insights into the phosphate-binding mode and identified a key glutamine residue in the active site important for substrate recognition. Substituting this glutamine for a serine swapped the substrate specificity from glucoside to N -acetylglucosaminide. In summary, we present a high-throughput screening approach for identifying β-glycoside phosphorylases, which was robust, simple to implement, and useful in identifying active clones within a metagenomics library. Implementation of this screen enabled discovery of a new glycoside phosphorylase class and has paved the way to devising simple ways in which enzyme specificity can be encoded and swapped, which has implications for biotechnological applications. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Population structure of Aphis spiraecola (Hemiptera: Aphididae) on pear trees in China identified using microsatellites.

    Science.gov (United States)

    Cao, Jinjun; Li, Jie; Niu, Jianqun; Liu, Xiaoxia; Zhang, Qingwen

    2012-04-01

    The spiraea aphid (Aphis spiraecola Patch) is a primary pest of fruit trees, particularly pear trees in China. Despite the economic importance of this pest, little is known about its genetic structure or its patterns of dispersal at local and regional scales; however, knowledge of these characteristics is important for establishing effective control strategies for this pest. The genetic variability of 431 individuals from 21 populations on pear trees in China was investigated using eight polymorphic microsatellite loci. The high polymorphism of these markers was evident from the expected heterozygosity value (He = 0.824) and the Polymorphism Information Content (PIC = 0.805), indicating that the spiraea aphid maintains a high level of genetic diversity. The analysis of molecular variance revealed a middle level of population differentiation (F(ST) = 0.1478) among A. spiraecola populations. This result is consistent with the results of the STRUCTURE analysis (K = 3), the unweighted pair-group method with arithmetic average tree and the Mantel test (r = 0.6392; P < 0.05). Our results indicate high levels of genetic exchange in the spiraea aphid, possibly facilitated by geography and climate. Our findings emphasize the importance of considering regional differences in studies of population structure, even when strong isolation-by-distance influences the genetic population structure of species.

  12. Identifying the Component Structure of Satisfaction Scales by Nonlinear Principal Components Analysis

    NARCIS (Netherlands)

    Manisera, M.; Kooij, A.J. van der; Dusseldorp, E.

    2010-01-01

    The component structure of 14 Likert-type items measuring different aspects of job satisfaction was investigated using nonlinear Principal Components Analysis (NLPCA). NLPCA allows for analyzing these items at an ordinal or interval level. The participants were 2066 workers from five types of social

  13. Experimental approaches to identify cellular G-quadruplex structures and functions.

    Science.gov (United States)

    Di Antonio, Marco; Rodriguez, Raphaël; Balasubramanian, Shankar

    2012-05-01

    Guanine-rich nucleic acids can fold into non-canonical DNA secondary structures called G-quadruplexes. The formation of these structures can interfere with the biology that is crucial to sustain cellular homeostases and metabolism via mechanisms that include transcription, translation, splicing, telomere maintenance and DNA recombination. Thus, due to their implication in several biological processes and possible role promoting genomic instability, G-quadruplex forming sequences have emerged as potential therapeutic targets. There has been a growing interest in the development of synthetic molecules and biomolecules for sensing G-quadruplex structures in cellular DNA. In this review, we summarise and discuss recent methods developed for cellular imaging of G-quadruplexes, and the application of experimental genomic approaches to detect G-quadruplexes throughout genomic DNA. In particular, we will discuss the use of engineered small molecules and natural proteins to enable pull-down, ChIP-Seq, ChIP-chip and fluorescence imaging of G-quadruplex structures in cellular DNA. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Family Structure and Functions Identified by Persons Living with HIV/AIDS.

    Science.gov (United States)

    Wong-Wylie, Gina; Doherty-Poirier, Maryanne; Kieren, Dianne

    1999-01-01

    A study looked at the structural and functional aspects of family from the perspective of six people living with acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV). Results showing how HIV/AIDS affects all members of the sufferer's family have implications for family practitioners. (Author/JOW)

  15. Half-trek criterion for generic identifiability of linear structural equation models

    NARCIS (Netherlands)

    Foygel, R.; Draisma, J.; Drton, M.

    2012-01-01

    A linear structural equation model relates random variables of interest and corresponding Gaussian noise terms via a linear equation system. Each such model can be represented by a mixed graph in which directed edges encode the linear equations, and bidirected edges indicate possible correlations

  16. Half-trek criterion for generic identifiability of linear structural equation models

    NARCIS (Netherlands)

    Foygel, R.; Draisma, J.; Drton, M.

    2011-01-01

    A linear structural equation model relates random variables of interest and corresponding Gaussian noise terms via a linear equation system. Each such model can be represented by a mixed graph in which directed edges encode the linear equations, and bidirected edges indicate possible correlations

  17. Two subpopulations of stem cells for T cell lineage

    International Nuclear Information System (INIS)

    Katsura, Y.; Amagai, T.; Kina, T.; Sado, T.; Nishikawa, S.

    1985-01-01

    An assay system for the stem cell that colonizes the thymus and differentiates into T cells was developed, and by using this assay system the existence of two subpopulations of stem cells for T cell lineage was clarified. Part-body-shielded and 900-R-irradiated C57BL/6 (H-2b, Thy-1.2) recipient mice, which do not require the transfer of pluripotent stem cells for their survival, were transferred with cells from B10 X Thy-1.1 (H-2b, Thy-1.1) donor mice. The reconstitution of the recipient's thymus lymphocytes was accomplished by stem cells in the donor cells and those spared in the shielded portion of the recipient that competitively colonize the thymus. Thus, the stem cell activity of donor cells can be evaluated by determining the proportion of donor-type (Thy-1.1+) cells in the recipient's thymus. Bone marrow cells were the most potent source of stem cells. By contrast, when the stem cell activity was compared between spleen and bone marrow cells of whole-body-irradiated (800 R) C57BL/6 mice reconstituted with B10 X Thy-1.1 bone marrow cells by assaying in part-body-shielded and irradiated C57BL/6 mice, the activity of these two organs showed quite a different time course of development. The results strongly suggest that the stem cells for T cell lineage in the bone marrow comprise at least two subpopulations, spleen-seeking and bone marrow-seeking cells

  18. Human papillomavirus vaccine initiation in Asian Indians and Asian subpopulations: a case for examining disaggregated data in public health research.

    Science.gov (United States)

    Budhwani, H; De, P

    2017-12-01

    Vaccine disparities research often focuses on differences between the five main racial and ethnic classifications, ignoring heterogeneity of subpopulations. Considering this knowledge gap, we examined human papillomavirus (HPV) vaccine initiation in Asian Indians and Asian subpopulations. National Health Interview Survey data (2008-2013), collected by the National Center for Health Statistics, were analyzed. Multiple logistic regression analysis was conducted on adults aged 18-26 years (n = 20,040). Asian Indians had high income, education, and health insurance coverage, all positive predictors of preventative health engagement and vaccine uptake. However, we find that Asian Indians had comparatively lower rates of HPV vaccine initiation (odds ratio = 0.41; 95% confidence interval = 0.207-0.832), and foreign-born Asian Indians had the lowest rate HPV vaccination of all subpopulations (2.3%). Findings substantiate the need for research on disaggregated data rather than evaluating vaccination behaviors solely across standard racial and ethnic categories. We identified two populations that were initiating HPV vaccine at abysmal levels: foreign-born persons and Asian Indians. Development of culturally appropriate messaging has the potential to improve these initiation rates and improve population health. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  19. Differential distribution of sperm subpopulations and incidence of pleiomorphisms in ejaculates of captive howling monkeys ( Alouatta caraya)

    Science.gov (United States)

    Valle, R. R.; Carvalho, F. M.; Muniz, J. A. P. C.; Leal, C. L. V.; García-Herreros, M.

    2013-10-01

    The aim of this study was to develop an objective method to determine the incidence of pleiomorphisms and its influence on the distribution of sperm morphometric subpopulations in ejaculates of howling monkeys ( Alouatta caraya) by using a combination of computerized analysis system (ASMA) and principal component analysis (PCA) methods. Ejaculates were collected by electroejaculation methods on a regular basis from five individuals maintained under identical captive environmental, nutritional, and management conditions. Each sperm head was measured for dimensional parameters (Area [ A, (square micrometers)], Perimeter [ P, (micrometers)], Length [ L, (micrometers)], and Width [ W, (micrometers)]) and shape-derived parameters (Ellipticity [( L/ W)], Elongation [( L - W)/( L + W)], and Rugosity [(4л A/ P 2)]). PCA revealed two principal components explaining more than the 96 % of the variance. Clustering methods and discriminant analyzes were performed and seven separate subpopulations were identified. There were differences ( P ASMA and PCA is a useful clinical diagnostic resource for detecting deficiencies in sperm morphology and sperm subpopulations in A. caraya ejaculates that could be used in ex situ conservation programs of threatened species in Alouatta genus or even other endangered neotropical primate species.

  20. Sperm subpopulations in avian species: a comparative study between the rooster (Gallus domesticus) and Guinea fowl (Numida meleagris).

    Science.gov (United States)

    García-Herreros, Manuel

    2016-01-01

    The main aims of this research were to study possible differences in objective morphometric sperm characteristics, establish normative sperm morphometry standards, and evaluate the presumed different subpopulation distribution of avian spermatozoa from the rooster (Gallus domesticus ) and Guinea fowl (Numida meleagris ) as model avian species. Seventy-two ejaculates (36 per species studied) were obtained manually, following a training period involving gently combined dorso-abdominal and lumbo-sacral massage of the birds. Ejaculates were processed for volume, sperm concentration, viability, motility, and morphology. Moreover, samples were submitted for sperm morphometric assessment using objective Computer-Assisted Semen Analysis for Morphometry (CASA-Morph) methods, with sperm morphometric descriptors evaluated by Principal Component Analysis (PCA) and multivariate clustering analyses. There were several differences observed between the avian species in values obtained for ejaculate volume and sperm concentration (P rooster and Guinea fowl, respectively). Moreover, the distribution of the sperm subpopulations was found to be structurally different between species. In conclusion, our findings from using CASA-Morph methods indicate pronounced sperm morphometric variation between these two avian species. Because of the strong differences observed in morphometric parameter values and their subpopulation distribution, these results suggest that application of objective analytical methods such as CASA-Morph could substantially improve the reliability of comparative studies and help establish valid normative sperm morphological values for avian species.

  1. Structured methodology review identified seven (RETREAT) criteria for selecting qualitative evidence synthesis approaches.

    Science.gov (United States)

    Booth, Andrew; Noyes, Jane; Flemming, Kate; Gerhardus, Ansgar; Wahlster, Philip; van der Wilt, Gert Jan; Mozygemba, Kati; Refolo, Pietro; Sacchini, Dario; Tummers, Marcia; Rehfuess, Eva

    2018-07-01

    To compare and contrast different methods of qualitative evidence synthesis (QES) against criteria identified from the literature and to map their attributes to inform selection of the most appropriate QES method to answer research questions addressed by qualitative research. Electronic databases, citation searching, and a study register were used to identify studies reporting QES methods. Attributes compiled from 26 methodological papers (2001-2014) were used as a framework for data extraction. Data were extracted into summary tables by one reviewer and then considered within the author team. We identified seven considerations determining choice of methods from the methodological literature, encapsulated within the mnemonic Review question-Epistemology-Time/Timescale-Resources-Expertise-Audience and purpose-Type of data. We mapped 15 different published QES methods against these seven criteria. The final framework focuses on stand-alone QES methods but may also hold potential when integrating quantitative and qualitative data. These findings offer a contemporary perspective as a conceptual basis for future empirical investigation of the advantages and disadvantages of different methods of QES. It is hoped that this will inform appropriate selection of QES approaches. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia[S

    Science.gov (United States)

    Mendoza-Barberá, Elena; Julve, Josep; Nilsson, Stefan K.; Lookene, Aivar; Martín-Campos, Jesús M.; Roig, Rosa; Lechuga-Sancho, Alfonso M.; Sloan, John H.; Fuentes-Prior, Pablo; Blanco-Vaca, Francisco

    2013-01-01

    During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del, p.Leu253Pro, and p.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in severe hypertriglyceridemia remain poorly understood, and the functional impairment/s induced by these specific mutations was not obvious. Therefore, we performed a thorough structural and functional analysis that included follow-up of patients and their closest relatives, measurement of apoA-V serum concentrations, and sequencing of the APOA5 gene in 200 nonhyperlipidemic controls. Further, we cloned, overexpressed, and purified both wild-type and mutant apoA-V variants and characterized their capacity to activate LPL. The interactions of recombinant wild-type and mutated apoA-V variants with liposomes of different composition, heparin, LRP1, sortilin, and SorLA/LR11 were also analyzed. Finally, to explore the possible structural consequences of these mutations, we developed a three-dimensional model of full-length, lipid-free human apoA-V. A complex, wide array of impairments was found in each of the three mutants, suggesting that the specific residues affected are critical structural determinants for apoA-V function in lipoprotein metabolism and, therefore, that these APOA5 mutations are a direct cause of hypertriglyceridemia. PMID:23307945

  3. Structural equation modeling identifies markers of damage and function in the aging male Fischer 344 rat.

    Science.gov (United States)

    Grunz-Borgmann, Elizabeth A; Nichols, LaNita A; Wiedmeyer, Charles E; Spagnoli, Sean; Trzeciakowski, Jerome P; Parrish, Alan R

    2016-06-01

    The male Fischer 344 rat is an established model to study progressive renal dysfunction that is similar, but not identical, to chronic kidney disease (CKD) in humans. These studies were designed to assess age-dependent alterations in renal structure and function at late-life timepoints, 16-24 months. Elevations in BUN and plasma creatinine were not significant until 24 months, however, elevations in the more sensitive markers of function, plasma cystatin C and proteinuria, were detectable at 16 and 18 months, respectively. Interestingly, cystatin C levels were not corrected by caloric restriction. Urinary Kim-1, a marker of CKD, was elevated as early as 16 months. Klotho gene expression was significantly decreased at 24 months, but not at earlier timepoints. Alterations in renal structure, glomerulosclerosis and tubulointerstitial fibrosis, were noted at 16 months, with little change from 18 to 24 months. Tubulointerstitial inflammation was increased at 16 months, and remained similar from 18 to 24 months. A SEM (structural equation modeling) model of age-related renal dysfunction suggests that proteinuria is a marker of renal damage, while urinary Kim-1 is a marker of both damage and function. Taken together, these results demonstrate that age-dependent nephropathy begins as early as 16 months and progresses rapidly over the next 8 months. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. An interactive algorithm for identifying multiattribute measurable value functions based on finite-order independence of structural difference

    International Nuclear Information System (INIS)

    Tamura, Hiroyuki; Hikita, Shiro

    1985-01-01

    In this paper, we develop an interactive algorithm for identifying multiattribute measurable value functions based on the concept of finite-order independence of structural difference. This concept includes Dyer and Sarin's weak difference independence as special cases. The algorithm developed is composed of four major parts: 1) formulation of the problem 2) assessment of normalized conditional value functions and structural difference functions 3) assessment of corner values 4) assessment of the order of independence of structural difference and selection of the model. A hypothetical numerical example of a trade-off analysis for siting a nuclear power plant is included. (author)

  5. Expected Shannon Entropy and Shannon Differentiation between Subpopulations for Neutral Genes under the Finite Island Model.

    Science.gov (United States)

    Chao, Anne; Jost, Lou; Hsieh, T C; Ma, K H; Sherwin, William B; Rollins, Lee Ann

    2015-01-01

    Shannon entropy H and related measures are increasingly used in molecular ecology and population genetics because (1) unlike measures based on heterozygosity or allele number, these measures weigh alleles in proportion to their population fraction, thus capturing a previously-ignored aspect of allele frequency distributions that may be important in many applications; (2) these measures connect directly to the rich predictive mathematics of information theory; (3) Shannon entropy is completely additive and has an explicitly hierarchical nature; and (4) Shannon entropy-based differentiation measures obey strong monotonicity properties that heterozygosity-based measures lack. We derive simple new expressions for the expected values of the Shannon entropy of the equilibrium allele distribution at a neutral locus in a single isolated population under two models of mutation: the infinite allele model and the stepwise mutation model. Surprisingly, this complex stochastic system for each model has an entropy expressable as a simple combination of well-known mathematical functions. Moreover, entropy- and heterozygosity-based measures for each model are linked by simple relationships that are shown by simulations to be approximately valid even far from equilibrium. We also identify a bridge between the two models of mutation. We apply our approach to subdivided populations which follow the finite island model, obtaining the Shannon entropy of the equilibrium allele distributions of the subpopulations and of the total population. We also derive the expected mutual information and normalized mutual information ("Shannon differentiation") between subpopulations at equilibrium, and identify the model parameters that determine them. We apply our measures to data from the common starling (Sturnus vulgaris) in Australia. Our measures provide a test for neutrality that is robust to violations of equilibrium assumptions, as verified on real world data from starlings.

  6. Expected Shannon Entropy and Shannon Differentiation between Subpopulations for Neutral Genes under the Finite Island Model.

    Directory of Open Access Journals (Sweden)

    Anne Chao

    Full Text Available Shannon entropy H and related measures are increasingly used in molecular ecology and population genetics because (1 unlike measures based on heterozygosity or allele number, these measures weigh alleles in proportion to their population fraction, thus capturing a previously-ignored aspect of allele frequency distributions that may be important in many applications; (2 these measures connect directly to the rich predictive mathematics of information theory; (3 Shannon entropy is completely additive and has an explicitly hierarchical nature; and (4 Shannon entropy-based differentiation measures obey strong monotonicity properties that heterozygosity-based measures lack. We derive simple new expressions for the expected values of the Shannon entropy of the equilibrium allele distribution at a neutral locus in a single isolated population under two models of mutation: the infinite allele model and the stepwise mutation model. Surprisingly, this complex stochastic system for each model has an entropy expressable as a simple combination of well-known mathematical functions. Moreover, entropy- and heterozygosity-based measures for each model are linked by simple relationships that are shown by simulations to be approximately valid even far from equilibrium. We also identify a bridge between the two models of mutation. We apply our approach to subdivided populations which follow the finite island model, obtaining the Shannon entropy of the equilibrium allele distributions of the subpopulations and of the total population. We also derive the expected mutual information and normalized mutual information ("Shannon differentiation" between subpopulations at equilibrium, and identify the model parameters that determine them. We apply our measures to data from the common starling (Sturnus vulgaris in Australia. Our measures provide a test for neutrality that is robust to violations of equilibrium assumptions, as verified on real world data from starlings.

  7. Relationship of Sibling Structure and Interaction to Categorization Ability. Final Report.

    Science.gov (United States)

    Cicirelli, Victor G.; And Others

    This study identified behaviors of sibling pairs interacting on a cognitive task and related these behaviors to sibling structure variables (age and sex of each sibling and age spacing between them) and to measure of cognitive abilities of the younger sibling. Subjects were 160 sibling pairs randomly selected from appropriate subpopulations of…

  8. On structural identifiability analysis of the cascaded linear dynamic systems in isotopically non-stationary 13C labelling experiments.

    Science.gov (United States)

    Lin, Weilu; Wang, Zejian; Huang, Mingzhi; Zhuang, Yingping; Zhang, Siliang

    2018-06-01

    The isotopically non-stationary 13C labelling experiments, as an emerging experimental technique, can estimate the intracellular fluxes of the cell culture under an isotopic transient period. However, to the best of our knowledge, the issue of the structural identifiability analysis of non-stationary isotope experiments is not well addressed in the literature. In this work, the local structural identifiability analysis for non-stationary cumomer balance equations is conducted based on the Taylor series approach. The numerical rank of the Jacobian matrices of the finite extended time derivatives of the measured fractions with respect to the free parameters is taken as the criterion. It turns out that only one single time point is necessary to achieve the structural identifiability analysis of the cascaded linear dynamic system of non-stationary isotope experiments. The equivalence between the local structural identifiability of the cascaded linear dynamic systems and the local optimum condition of the nonlinear least squares problem is elucidated in the work. Optimal measurements sets can then be determined for the metabolic network. Two simulated metabolic networks are adopted to demonstrate the utility of the proposed method. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Atmospheric reaction systems as null-models to identify structural traces of evolution in metabolism.

    Directory of Open Access Journals (Sweden)

    Petter Holme

    Full Text Available The metabolism is the motor behind the biological complexity of an organism. One problem of characterizing its large-scale structure is that it is hard to know what to compare it to. All chemical reaction systems are shaped by the same physics that gives molecules their stability and affinity to react. These fundamental factors cannot be captured by standard null-models based on randomization. The unique property of organismal metabolism is that it is controlled, to some extent, by an enzymatic machinery that is subject to evolution. In this paper, we explore the possibility that reaction systems of planetary atmospheres can serve as a null-model against which we can define metabolic structure and trace the influence of evolution. We find that the two types of data can be distinguished by their respective degree distributions. This is especially clear when looking at the degree distribution of the reaction network (of reaction connected to each other if they involve the same molecular species. For the Earth's atmospheric network and the human metabolic network, we look into more detail for an underlying explanation of this deviation. However, we cannot pinpoint a single cause of the difference, rather there are several concurrent factors. By examining quantities relating to the modular-functional organization of the metabolism, we confirm that metabolic networks have a more complex modular organization than the atmospheric networks, but not much more. We interpret the more variegated modular arrangement of metabolism as a trace of evolved functionality. On the other hand, it is quite remarkable how similar the structures of these two types of networks are, which emphasizes that the constraints from the chemical properties of the molecules has a larger influence in shaping the reaction system than does natural selection.

  10. Identifying with fictive characters: structural brain correlates of the personality trait 'fantasy'.

    Science.gov (United States)

    Cheetham, Marcus; Hänggi, Jürgen; Jancke, Lutz

    2014-11-01

    The perception of oneself as absorbed in the thoughts, feelings and happenings of a fictive character (e.g. in a novel or film) as if the character's experiences were one's own is referred to as identification. We investigated whether individual variation in the personality trait of identification is associated with individual variation in the structure of specific brain regions, using surface and volume-based morphometry. The hypothesized regions of interest were selected on the basis of their functional role in subserving the cognitive processing domains considered important for identification (i.e. mental imagery, empathy, theory of mind and merging) and for the immersive experience called 'presence'. Controlling for age, sex, whole-brain volume and other traits, identification covaried significantly with the left hippocampal volume, cortical thickness in the right anterior insula and the left dorsal medial prefrontal cortex, and with gray matter volume in the dorsolateral prefrontal cortex. These findings show that trait identification is associated with structural variation in specific brain regions. The findings are discussed in relation to the potential functional contribution of these regions to identification. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  11. Structured decision making as a conceptual framework to identify thresholds for conservation and management

    Science.gov (United States)

    Martin, J.; Runge, M.C.; Nichols, J.D.; Lubow, B.C.; Kendall, W.L.

    2009-01-01

    Thresholds and their relevance to conservation have become a major topic of discussion in the ecological literature. Unfortunately, in many cases the lack of a clear conceptual framework for thinking about thresholds may have led to confusion in attempts to apply the concept of thresholds to conservation decisions. Here, we advocate a framework for thinking about thresholds in terms of a structured decision making process. The purpose of this framework is to promote a logical and transparent process for making informed decisions for conservation. Specification of such a framework leads naturally to consideration of definitions and roles of different kinds of thresholds in the process. We distinguish among three categories of thresholds. Ecological thresholds are values of system state variables at which small changes bring about substantial changes in system dynamics. Utility thresholds are components of management objectives (determined by human values) and are values of state or performance variables at which small changes yield substantial changes in the value of the management outcome. Decision thresholds are values of system state variables at which small changes prompt changes in management actions in order to reach specified management objectives. The approach that we present focuses directly on the objectives of management, with an aim to providing decisions that are optimal with respect to those objectives. This approach clearly distinguishes the components of the decision process that are inherently subjective (management objectives, potential management actions) from those that are more objective (system models, estimates of system state). Optimization based on these components then leads to decision matrices specifying optimal actions to be taken at various values of system state variables. Values of state variables separating different actions in such matrices are viewed as decision thresholds. Utility thresholds are included in the objectives

  12. IDENTIFYING BANK LENDING CHANNEL IN INDONESIA: A VECTOR ERROR CORRECTION APPROACH WITH STRUCTURAL BREAK

    Directory of Open Access Journals (Sweden)

    Akhsyim Afandi

    2017-03-01

    Full Text Available There was a question whether monetary policy works through bank lending channelrequired a monetary-induced change in bank loans originates from the supply side. Mostempirical studies that employed vector autoregressive (VAR models failed to fulfill thisrequirement. Aiming to offer a solution to this identification problem, this paper developed afive-variable vector error correction (VEC model of two separate bank credit markets inIndonesia. Departing from previous studies, the model of each market took account of onestructural break endogenously determined by implementing a unit root test. A cointegrationtest that took account of one structural break suggested two cointegrating vectors identifiedas bank lending supply and demand relations. The estimated VEC system for both marketssuggested that bank loans adjusted more strongly in the direction of the supply equation.

  13. Identifying the Best-Fitting Factor Structure of the Experience of Close Relations

    DEFF Research Database (Denmark)

    Esbjørn, Barbara Hoff; Breinholst, Sonja; Niclasen, Janni

    2015-01-01

    . The present study used a Danish sample with the purpose of addressing limitations in previous studies, such as the lack of diversity in cultural back- ground, restricted sample characteristics, and poorly fitting structure models. Participants consisted of 253 parents of children between the ages of 7 and 12...... years, 53% being moth- ers. The parents completed the paper version of the questionnaire. Confirmatory Factor Analyses were carried out to determine whether theoretically and empirically established models including one and two factors would also provide adequate fits in a Danish sample. A previous...... study using the original ECR suggested that Scandinavian samples may best be described using a five-factor solution. Our results indicated that the one- and two-factor models of the ECR-R did not fit the data well. Exploratory Factor Analysis revealed a five- factor model. Our study provides evidence...

  14. Monitoring early hydration of reinforced concrete structures using structural parameters identified by piezo sensors via electromechanical impedance technique

    Science.gov (United States)

    Talakokula, Visalakshi; Bhalla, Suresh; Gupta, Ashok

    2018-01-01

    Concrete is the most widely used material in civil engineering construction. Its life begins when the hydration process is activated after mixing the cement granulates with water. In this paper, a non-dimensional hydration parameter, obtained from piezoelectric ceramic (PZT) patches bonded to rebars embedded inside concrete, is employed to monitor the early age hydration of concrete. The non-dimensional hydration parameter is derived from the equivalent stiffness determined from the piezo-impedance transducers using the electro-mechanical impedance (EMI) technique. The focus of the study is to monitor the hydration process of cementitious materials commencing from the early hours and continue till 28 days using single non-dimensional parameter. The experimental results show that the proposed piezo-based non-dimensional hydration parameter is very effective in monitoring the early age hydration, as it has been derived from the refined structural impedance parameters, obtained by eliminating the PZT contribution, and using both the real and imaginary components of the admittance signature.

  15. Identifying mechanistic indicators of childhood asthma from blood gene expression

    Science.gov (United States)

    Asthmatic individuals have been identified as a susceptible subpopulation for air pollutants. However, asthma represents a syndrome with multiple probable etiologies, and the identification of these asthma endotypes is critical to accurately define the most susceptible subpopula...

  16. Using Functional or Structural Magnetic Resonance Images and Personal Characteristic Data to Identify ADHD and Autism.

    Directory of Open Access Journals (Sweden)

    Sina Ghiassian

    Full Text Available A clinical tool that can diagnose psychiatric illness using functional or structural magnetic resonance (MR brain images has the potential to greatly assist physicians and improve treatment efficacy. Working toward the goal of automated diagnosis, we propose an approach for automated classification of ADHD and autism based on histogram of oriented gradients (HOG features extracted from MR brain images, as well as personal characteristic data features. We describe a learning algorithm that can produce effective classifiers for ADHD and autism when run on two large public datasets. The algorithm is able to distinguish ADHD from control with hold-out accuracy of 69.6% (over baseline 55.0% using personal characteristics and structural brain scan features when trained on the ADHD-200 dataset (769 participants in training set, 171 in test set. It is able to distinguish autism from control with hold-out accuracy of 65.0% (over baseline 51.6% using functional images with personal characteristic data when trained on the Autism Brain Imaging Data Exchange (ABIDE dataset (889 participants in training set, 222 in test set. These results outperform all previously presented methods on both datasets. To our knowledge, this is the first demonstration of a single automated learning process that can produce classifiers for distinguishing patients vs. controls from brain imaging data with above-chance accuracy on large datasets for two different psychiatric illnesses (ADHD and autism. Working toward clinical applications requires robustness against real-world conditions, including the substantial variability that often exists among data collected at different institutions. It is therefore important that our algorithm was successful with the large ADHD-200 and ABIDE datasets, which include data from hundreds of participants collected at multiple institutions. While the resulting classifiers are not yet clinically relevant, this work shows that there is a signal in

  17. A suite of molecular markers for identifying species, detecting introgression and describing population structure in spadefoot toads (Spea spp.).

    Science.gov (United States)

    Pfennig, Karin S; Allenby, Ashley; Martin, Ryan A; Monroy, Anaïs; Jones, Corbin D

    2012-09-01

    Two congeneric species of spadefoot toad, Spea multiplicata and Spea bombifrons, have been the focus of hybridization studies since the 1970s. Because complex hybrids are not readily distinguished phenotypically, genetic markers are needed to identify introgressed individuals. We therefore developed a set of molecular markers (amplified fragment length polymorphism, polymerase chain reaction-restriction fragment length polymorphism and single nucleotide polymorphism) for identifying pure-species, F1 hybrids and more complex introgressed types. To do so, we tested a series of markers across both species and known hybrids using populations in both allopatry and sympatry. We retained those markers that differentiated the two pure-species and also consistently identified known species hybrids. These markers are well suited for identifying hybrids between these species. Moreover, those markers that show variation within each species can be used in conjunction with existing molecular markers in studies of population structure and gene flow. © 2012 Blackwell Publishing Ltd.

  18. Effects of microwave radiation on peripheral lymphocyte subpopulations in rats

    Directory of Open Access Journals (Sweden)

    Jin-ling YIN

    2011-10-01

    Full Text Available Objective To investigate the effects and mechanisms of microwave radiation on peripheral lymphocyte subpopulations in Wistar rats.Methods A total of 100 Wistar rats(180-220g were exposed to microwave with different average power densities of 5,10,30 and 60 mW/cm2,and sham exposure of 0mW/cm2 was performed in a control group at the same time.At day 1,7,14 and 28 after microwave irradiation,the changes in peripheral CD3+,CD4+,CD8+ T cells,ratio of CD4+/CD8+ and CD45RA+ B lymphocyte in rats were analyzed by flow cytometry(FCM.Results The CD3+ T cells decreased significantly in 10-30mW/cm2 groups at day 7 and in 5-30 mW/cm2 groups at day 14 after radiation as compared with control group(P < 0.05,and CD4+ T cells decreased significantly in 10mW/cm2 group at day 14 after radiation as compared with control group(P < 0.01.From day 1 to day 14 after radiation,CD8+ T cells showed a reduction in number in all irradiated groups when compared with the control,but statistical significance was only found in the 30mW/cm2 group(P < 0.05.The CD4+/CD8+ ratio increased in 5mW/cm2 group on day 1,while decreased significantly in 5-30mW/cm2 groups on day 14 after radiation as compared with control group(P < 0.05.After microwave exposure,however,CD45RA+ B cells in 30mW/cm2 group at day 1 and in 30-60mW/cm2 groups at day 14 after radiation increased significantly in a dose-dependent manner.Conclusion A definite dosage of microwave radiation,ranging from 5-60mW/cm2,may induce changes in subpopulations of peripheral lymphocytes and cause acute immune function impairment in rats.

  19. A combined structural dynamics approach identifies a putative switch in factor VIIa employed by tissue factor to initiate blood coagulation

    DEFF Research Database (Denmark)

    Olsen, Ole H; Rand, Kasper D; Østergaard, Henrik

    2007-01-01

    Coagulation factor VIIa (FVIIa) requires tissue factor (TF) to attain full catalytic competency and to initiate blood coagulation. In this study, the mechanism by which TF allosterically activates FVIIa is investigated by a structural dynamics approach that combines molecular dynamics (MD......) simulations and hydrogen/deuterium exchange (HX) mass spectrometry on free and TF-bound FVIIa. The differences in conformational dynamics from MD simulations are shown to be confined to regions of FVIIa observed to undergo structural stabilization as judged by HX experiments, especially implicating activation...... in the presence of TF or an active-site inhibitor. Based on MD simulations, a key switch of the TF-induced structural changes is identified as the interacting pair Leu305{163} and Phe374{225} in FVIIa, whose mutual conformations are guided by the presence of TF and observed to be closely linked to the structural...

  20. Identifying and Structuring Values to Guide the Choice of Sustainability Indicators for Tourism Development

    Directory of Open Access Journals (Sweden)

    José Alberto Alcántara Maya

    2010-09-01

    Full Text Available In Mexico, the National Trust for Tourism Promotion (FONATUR needs to lead development of Integrally Planned Tourist Centers (IPC towards sustainability. As the development of these IPCs leads to changes in local communities and their environment, it is necessary to define how to establish a path towards sustainability and how to measure progress towards that goal. The objective of this study is to contribute toward identifying the main stakeholder’s values, defining sustainability indicators at a local level, and to discuss their adequacy in the context of tourism development. The study was performed in a Mexican community facing its probable inclusion in tourism development and special attention was given to the values of stakeholders in defining which objectives to monitor. Using Value-Focused Thinking as a framework, a series of interviews were analyzed and the opinions were organized in a tree of values, encompassing environmental, economic, social and political/institutional aspects. A set of indicators associated with these objectives was subsequently proposed. This information may serve as a guide to design and monitor plans that are more appealing from a sustainability perspective and as an aid in the identification of future information needs.

  1. Application of Nonlinear Analysis Methods for Identifying Relationships Between Microbial Community Structure and Groundwater Geochemistry

    International Nuclear Information System (INIS)

    Schryver, Jack C.; Brandt, Craig C.; Pfiffner, Susan M.; Palumbo, A V.; Peacock, Aaron D.; White, David C.; McKinley, James P.; Long, Philip E.

    2006-01-01

    The relationship between groundwater geochemistry and microbial community structure can be complex and difficult to assess. We applied nonlinear and generalized linear data analysis methods to relate microbial biomarkers (phospholipids fatty acids, PLFA) to groundwater geochemical characteristics at the Shiprock uranium mill tailings disposal site that is primarily contaminated by uranium, sulfate, and nitrate. First, predictive models were constructed using feedforward artificial neural networks (NN) to predict PLFA classes from geochemistry. To reduce the danger of overfitting, parsimonious NN architectures were selected based on pruning of hidden nodes and elimination of redundant predictor (geochemical) variables. The resulting NN models greatly outperformed the generalized linear models. Sensitivity analysis indicated that tritium, which was indicative of riverine influences, and uranium were important in predicting the distributions of the PLFA classes. In contrast, nitrate concentration and inorganic carbon were least important, and total ionic strength was of intermediate importance. Second, nonlinear principal components (NPC) were extracted from the PLFA data using a variant of the feedforward NN. The NPC grouped the samples according to similar geochemistry. PLFA indicators of Gram-negative bacteria and eukaryotes were associated with the groups of wells with lower levels of contamination. The more contaminated samples contained microbial communities that were predominated by terminally branched saturates and branched monounsaturates that are indicative of metal reducers, actinomycetes, and Gram-positive bacteria. These results indicate that the microbial community at the site is coupled to the geochemistry and knowledge of the geochemistry allows prediction of the community composition

  2. Problems identified in quantifying leak before break in pressure containing structures

    International Nuclear Information System (INIS)

    Darlaston, B.J.L.; Connors, D.C.; Hellen, R.A.J.

    1979-01-01

    The leak before break approach is often applied to pressure containing plant as part of the safety assessment. The assumptions used in this approach are sometimes very pessimistic. It is therefore desirable to be able to quantify the concept more precisely. The two aspects which are of considerable importance are the way the crack profile develops and what happens when the remaining ligament below the crack fails. These two aspects are receiving attention and together with the development of the basic concept of 'leak before break' form the basis of this paper. Some thirty burst tests have been carried out on straight pipes of various dimensions. The results have been analysed using the CEGB Failure Assessment Route for structures containing defects. It was shown that in most cases the leaks and the breaks could be separated by this procedure. However all these tests involved machined rather than fatigue grown defects. A complementary program on pipes has the objective of examining defect growth under cyclic loads. The tests on the 152 mm diameter pipes showed that these defects did not grow in a uniform manner but after a while began to tunnel through the wall locally leading to failure of part of the ligament. This implies that some defects considered to be in the break category would only lead to leaks. As a consequence of these results the experimental programme was redesigned to concentrate on the growth of defects which it was thought would span the boundary of leak and break. For the pipe dimensions and materials used, this represented long defects which would penetrate well into the wall before ligament failure occurred. The analysis and interpretation of this aspect of the programme is part analytical part empirical. (orig.)

  3. Automation method to identify the geological structure of seabed using spatial statistic analysis of echo sounding data

    Science.gov (United States)

    Kwon, O.; Kim, W.; Kim, J.

    2017-12-01

    Recently construction of subsea tunnel has been increased globally. For safe construction of subsea tunnel, identifying the geological structure including fault at design and construction stage is more than important. Then unlike the tunnel in land, it's very difficult to obtain the data on geological structure because of the limit in geological survey. This study is intended to challenge such difficulties in a way of developing the technology to identify the geological structure of seabed automatically by using echo sounding data. When investigation a potential site for a deep subsea tunnel, there is the technical and economical limit with borehole of geophysical investigation. On the contrary, echo sounding data is easily obtainable while information reliability is higher comparing to above approaches. This study is aimed at developing the algorithm that identifies the large scale of geological structure of seabed using geostatic approach. This study is based on theory of structural geology that topographic features indicate geological structure. Basic concept of algorithm is outlined as follows; (1) convert the seabed topography to the grid data using echo sounding data, (2) apply the moving window in optimal size to the grid data, (3) estimate the spatial statistics of the grid data in the window area, (4) set the percentile standard of spatial statistics, (5) display the values satisfying the standard on the map, (6) visualize the geological structure on the map. The important elements in this study include optimal size of moving window, kinds of optimal spatial statistics and determination of optimal percentile standard. To determine such optimal elements, a numerous simulations were implemented. Eventually, user program based on R was developed using optimal analysis algorithm. The user program was designed to identify the variations of various spatial statistics. It leads to easy analysis of geological structure depending on variation of spatial statistics

  4. Influence of radiation therapy on T-lymphocyte subpopulations

    International Nuclear Information System (INIS)

    Job, G.

    1984-01-01

    The author claims this to be the first time where monoclonal antibodies are used in a long-term study in order to determine the influence of radiation therapy on T-lymphozyte-subpopulations in patients suffering from malignant growths. The influence of radiation therapy on B-cells, T-cells and macrophages was also checked. Two groups of patients were given two different radiation doses, and examined separately in order to discover possible effects of the dosage. Radiation therapy reduced B- and T-lymphocytes to the same degree as the total lymphozyte population so that their shares in percent remained unchanged. The same was also found for macrophages. Determination of clones and suppressor T-lymphozytes before, during and after radiation showed T-lymphozytes to have a higher resistance against the influence of radiation than clones. Suppressor cells also regenerated more quickly than clones after the end of the therapy. While radiation therapy was applied the clone/suppressor cell ratio dropped to values lower than those of the healthy reference group. After the end of the therapy this quotient dropped even further in some cases while in others it began to rise slowly, but even 6 months after the end of the therapy it was still lower than normal. As a number of diseases show an increased 'immunoregulatory quotient' it would be conceivable to influence this quotient with radiation therapy in order to achieve a therapeutic effect. (orig./MG) [de

  5. TH-E-BRF-08: Subpopulations of Similarly-Responding Lesions in Metastatic Prostate Cancer

    International Nuclear Information System (INIS)

    Lin, C; Harmon, S; Perk, T; Jeraj, R

    2014-01-01

    Purpose: In patients with multiple lesions, resistance to cancer treatments and subsequent disease recurrence may be due to heterogeneity of response across lesions. This study aims to identify subpopulations of similarly-responding metastatic prostate cancer lesions in bone using quantitative PET metrics. Methods: Seven metastatic prostate cancer patients treated with AR-directed therapy received pre-treatment and mid-treatment [F-18]NaF PET/CT scans. Images were registered using an articulated CT registration algorithm and transformations were applied to PET segmentations. Midtreatment response was calculated on PET-based texture features. Hierarchical agglomerative clustering was used to form groups of similarly-responding lesions, with the number of natural clusters (K) determined by the inconsistency coefficient. Lesion clustering was performed within each patient, and for the pooled population. The cophenetic coefficient (C) quantified how well the data was clustered. The Jaccard Index (JI) assessed similarity of cluster assignments from patient clustering and from population clustering. Results: 188 lesions in seven patients were identified for analysis (between 6 to 53 lesions per patient). Lesion response was defined as percent change relative to pre-treatment for 23 uncorrelated PET-based feature identifiers. . High response heterogeneity was found across all lesions (i.e. range ΔSUVmax =−95.98% to 775.00%). For intra-patient clustering, K ranged from 1–20. Population-based clustering resulted in 75 clusters, of 1-6 lesions each. Intra-patient clustering resulted in higher quality clusters than population clustering (mean C=0.95, range=0.89 to 1.00). For all patients, cluster assignments from population clustering showed good agreement to intra-patient clustering (mean JI=0.87, range=0.68 to 1.00). Conclusion: Subpopulations of similarly-responding lesions were identified in patients with multiple metastatic lesions. Good agreement was found between

  6. Identifying individuals at high risk of psychosis: predictive utility of Support Vector Machine using structural and functional MRI data

    Directory of Open Access Journals (Sweden)

    Isabel eValli

    2016-04-01

    Full Text Available The identification of individuals at high risk of developing psychosis is entirely based on clinical assessment, associated with limited predictive potential. There is therefore increasing interest in the development of biological markers that could be used in clinical practice for this purpose. We studied 25 individuals with an At Risk Mental State for psychosis and 25 healthy controls using structural MRI, and functional MRI in conjunction with a verbal memory task. Data were analysed using a standard univariate analysis, and with Support Vector Machine (SVM, a multivariate pattern recognition technique that enables statistical inferences to be made at the level of the individual, yielding results with high translational potential. The application of SVM to structural MRI data permitted the identification of individuals at high risk of psychosis with a sensitivity of 68% and a specificity of 76%, resulting in an accuracy of 72% (p<0.001. Univariate volumetric between-group differences did not reach statistical significance. In contrast, the univariate fMRI analysis identified between-group differences (p<0.05 corrected while the application of SVM to the same data did not. Since SVM is well suited at identifying the pattern of abnormality that distinguishes two groups, whereas univariate methods are more likely to identify regions that individually are most different between two groups, our results suggest the presence of focal functional abnormalities in the context of a diffuse pattern of structural abnormalities in individuals at high clinical risk of psychosis.

  7. The Distinctive Sensitivity to Microgravity of Immune Cell Subpopulations

    Science.gov (United States)

    Chen, Hui; Luo, Haiying; Liu, Jing; Wang, Peng; Dong, Dandan; Shang, Peng; Zhao, Yong

    2015-11-01

    Immune dysfunction in astronauts is well documented after spaceflights. Microgravity is one of the key factors directly suppressing the function of immune system. However, it is unclear which subpopulations of immune cells including innate and adaptive immune cells are more sensitive to microgravity We herein investigated the direct effects of modeled microgravity (MMg) on different immune cells in vitro. Mouse splenocytes, thymocytes and bone marrow cells were exposed to MMg for 16 hrs. The survival and the phenotypes of different subsets of immune cells including CD4+T cells, CD8+T cells, CD4+Foxp3+ regulatory T cells (Treg), B cells, monocytes/macrophages, dendritic cells (DCs), natural killer cells (NK) were determined by flow cytometry. After splenocytes were cultured under MMg for 16h, the cell frequency and total numbers of monocytes, macrophages and CD4+Foxp3+T cells were significantly decreased more than 70 %. MMg significantly decreased the cell numbers of CD8+ T cells, B cells and neutrophils in splenocytes. The cell numbers of CD4+T cells and NK cells were unchanged significantly when splenocytes were cultured under MMg compared with controls. However, MMg significantly increased the ratio of mature neutrophils to immature neutrophils in bone marrow and the cell number of DCs in splenocytes. Based on the cell survival ability, monocytes, macrophages and CD4+Foxp3+Treg cells are most sensitive to microgravity; CD4+T cells and NK cells are resistant to microgravity; CD8+T cells and neutrophils are impacted by short term microgravity exposure. Microgravity promoted the maturation of neutrophils and development of DCs in vitro. The present studies offered new insights on the direct effects of MMg on the survival and homeostasis of immune cell subsets.

  8. Variations of B cell subpopulations in peripheral blood of healthy Mexican population according to age: Relevance for diagnosis of primary immunodeficiencies.

    Science.gov (United States)

    Berrón-Ruíz, L; López-Herrera, G; Ávalos-Martínez, C E; Valenzuela-Ponce, C; Ramírez-SanJuan, E; Santoyo-Sánchez, G; Mújica Guzmán, F; Espinosa-Rosales, F J; Santos-Argumedo, L

    Peripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population. Peripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naïve, memory with and without isotype switch, double-negative, transitional, and plasmablast cells. We observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age. In order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected. Copyright © 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

  9. Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells

    Directory of Open Access Journals (Sweden)

    Walter Blum

    2017-04-01

    Full Text Available Summary: Malignant mesothelioma (MM is an aggressive neoplasm characterized by a poor patient survival rate, because of rapid tumor recurrence following first-line therapy. Cancer stem cells (CSCs are assumed to be responsible for initiating tumorigenesis and driving relapse after therapeutic interventions. CSC-enriched MM cell subpopulations were identified by an OCT4/SOX2 reporter approach and were characterized by (1 increased resistance to cisplatin, (2 increased sensitivity toward the FAK inhibitor VS-6063 in vitro, and (3 a higher tumor-initiating capacity in vivo in orthotopic xenograft and allograft mouse models. Overexpression of NF2 (neurofibromatosis 2, merlin, a tumor suppressor often mutated or lost in MM, did not affect proliferation and viability of CSC-enriched MM populations but robustly decreased the viability of reporter-negative cells. In contrast, downregulation of calretinin strongly decreased proliferation and viability of both populations. In summary, we have enriched and characterized a small MM cell subpopulation that bears the expected CSC characteristics. : A cancer stem cell (CSC-enriched malignant mesothelioma (MM cell subpopulation was identified by an OCT4/SOX2 reporter approach. These EGFP-expressing cells showed an altered sensitivity toward chemotherapeutic drugs and a higher tumor-initiating capacity in vivo in orthotopic xenograft and allograft mouse models. While NF2 overexpression had no effect on proliferation/viability of CSC-enriched MM populations, they were susceptible to downregulation of calretinin. Keywords: mesothelioma, cancer stem cells, SOX2, OCT4, NF2, merlin, calretinin, defactinib

  10. Optimal allocation of conservation effort among subpopulations of a threatened species: how important is patch quality?

    Science.gov (United States)

    Chauvenet, Aliénor L M; Baxter, Peter W J; McDonald-Madden, Eve; Possingham, Hugh P

    2010-04-01

    Money is often a limiting factor in conservation, and attempting to conserve endangered species can be costly. Consequently, a framework for optimizing fiscally constrained conservation decisions for a single species is needed. In this paper we find the optimal budget allocation among isolated subpopulations of a threatened species to minimize local extinction probability. We solve the problem using stochastic dynamic programming, derive a useful and simple alternative guideline for allocating funds, and test its performance using forward simulation. The model considers subpopulations that persist in habitat patches of differing quality, which in our model is reflected in different relationships between money invested and extinction risk. We discover that, in most cases, subpopulations that are less efficient to manage should receive more money than those that are more efficient to manage, due to higher investment needed to reduce extinction risk. Our simple investment guideline performs almost as well as the exact optimal strategy. We illustrate our approach with a case study of the management of the Sumatran tiger, Panthera tigris sumatrae, in Kerinci Seblat National Park (KSNP), Indonesia. We find that different budgets should be allocated to the separate tiger subpopulations in KSNP. The subpopulation that is not at risk of extinction does not require any management investment. Based on the combination of risks of extinction and habitat quality, the optimal allocation for these particular tiger subpopulations is an unusual case: subpopulations that occur in higher-quality habitat (more efficient to manage) should receive more funds than the remaining subpopulation that is in lower-quality habitat. Because the yearly budget allocated to the KSNP for tiger conservation is small, to guarantee the persistence of all the subpopulations that are currently under threat we need to prioritize those that are easier to save. When allocating resources among subpopulations

  11. The value of structured data elements from electronic health records for identifying subjects for primary care clinical trials.

    Science.gov (United States)

    Ateya, Mohammad B; Delaney, Brendan C; Speedie, Stuart M

    2016-01-11

    An increasing number of clinical trials are conducted in primary care settings. Making better use of existing data in the electronic health records to identify eligible subjects can improve efficiency of such studies. Our study aims to quantify the proportion of eligibility criteria that can be addressed with data in electronic health records and to compare the content of eligibility criteria in primary care with previous work. Eligibility criteria were extracted from primary care studies downloaded from the UK Clinical Research Network Study Portfolio. Criteria were broken into elemental statements. Two expert independent raters classified each statement based on whether or not structured data items in the electronic health record can be used to determine if the statement was true for a specific patient. Disagreements in classification were discussed until 100 % agreement was reached. Statements were also classified based on content and the percentages of each category were compared to two similar studies reported in the literature. Eligibility criteria were retrieved from 228 studies and decomposed into 2619 criteria elemental statements. 74 % of the criteria elemental statements were considered likely associated with structured data in an electronic health record. 79 % of the studies had at least 60 % of their criteria statements addressable with structured data likely to be present in an electronic health record. Based on clinical content, most frequent categories were: "disease, symptom, and sign", "therapy or surgery", and "medication" (36 %, 13 %, and 10 % of total criteria statements respectively). We also identified new criteria categories related to provider and caregiver attributes (2.6 % and 1 % of total criteria statements respectively). Electronic health records readily contain much of the data needed to assess patients' eligibility for clinical trials enrollment. Eligibility criteria content categories identified by our study can be

  12. Modeling Aerobic Carbon Source Degradation Processes using Titrimetric Data and Combined Respirometric-Titrimetric Data: Structural and Practical Identifiability

    DEFF Research Database (Denmark)

    Gernaey, Krist; Petersen, B.; Dochain, D.

    2002-01-01

    The structural and practical identifiability of a model for description of respirometric-titrimetric data derived from aerobic batch substrate degradation experiments of a CxHyOz carbon source with activated sludge was evaluated. The model processes needed to describe titrimetric data included su...... the initial substrate concentration S-S(O) is known. The values found correspond to values reported in literature, but, interestingly, also seem able to reflect the occurrence of storage processes when pulses of acetate and dextrose are added. (C) 2002 Wiley Periodicals, Inc....

  13. Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations.

    Science.gov (United States)

    Andersson, Anna; Olofsson, Tor; Lindgren, David; Nilsson, Björn; Ritz, Cecilia; Edén, Patrik; Lassen, Carin; Råde, Johan; Fontes, Magnus; Mörse, Helena; Heldrup, Jesper; Behrendtz, Mikael; Mitelman, Felix; Höglund, Mattias; Johansson, Bertil; Fioretos, Thoas

    2005-12-27

    Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1, IGH@/MYC, ETV6(TEL)/RUNX1(AML1), 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.

  14. Versatile Cas9-Driven Subpopulation Selection Toolbox for Lactococcus lactis.

    Science.gov (United States)

    van der Els, Simon; James, Jennelle K; Kleerebezem, Michiel; Bron, Peter A

    2018-04-15

    CRISPR-Cas9 technology has been exploited for the removal or replacement of genetic elements in a wide range of prokaryotes and eukaryotes. Here, we describe the extension of the Cas9 application toolbox to the industrially important dairy species Lactococcus lactis The Cas9 expression vector pLABTarget, encoding the Streptocccus pyogenes Cas9 under the control of a constitutive promoter, was constructed, allowing plug and play introduction of short guide RNA (sgRNA) sequences to target specific genetic loci. Introduction of a pepN -targeting derivative of pLABTarget into L. lactis strain MG1363 led to a strong reduction in the number of transformants obtained, which did not occur in a pepN deletion derivative of the same strain, demonstrating the specificity and lethality of the Cas9-mediated double-strand breaks in the lactococcal chromosome. Moreover, the same pLABTarget derivative allowed the selection of a pepN deletion subpopulation from its corresponding single-crossover plasmid integrant precursor, accelerating the construction and selection of gene-specific deletion derivatives in L. lactis Finally, pLABTarget, which contained sgRNAs designed to target mobile genetic elements, allowed the effective curing of plasmids, prophages, and integrative conjugative elements (ICEs). These results establish that pLABTarget enables the effective exploitation of Cas9 targeting in L. lactis , while the broad-host-range vector used suggests that this toolbox could readily be expanded to other Gram-positive bacteria. IMPORTANCE Mobile genetic elements in Lactococcus lactis and other lactic acid bacteria (LAB) play an important role in dairy fermentation, having both positive and detrimental effects during the production of fermented dairy products. The pLABTarget vector offers an efficient cloning platform for Cas9 application in lactic acid bacteria. Targeting Cas9 toward mobile genetic elements enabled their effective curing, which is of particular interest in the

  15. Effect of I125 on oxidation behavior of lipoprotein subpopulations

    International Nuclear Information System (INIS)

    Majtenyi, S.

    2002-07-01

    Lipoproteins play a central role in lipid metabolism. They serve as a transport vehicle for cholesterol and triglycerides keeping them in plasma in solution. Lipoproteins are characterized by the content of specific apoproteins and differences in the hydrated density ranges. Moreover, they are distinguished by electrophoretic mobility and other characteristics as high and low-density lipoproteins, respectively lipoprotein (a). More specifically, HDL is classified into HDL 2 and HDL 3 . In atherogenesis, lipoproteins are considered to play a key-role. Oxidatively modified LDL is selectively taken up via scavenger receptors of the macrophage-monocyte system. These cells are transformed into foam cells promoting atherogenesis in vessels in the subendothelial space. Oxidized HDL essentially appears to loose its protective effects on LDL and its beneficial function in reverse cholesterol transport. Thus, it turns proatherogenic. The effects various species of free radicals exert on lipoproteins are the reason for this oxidative modification. Thyroid function also influences lipoproteins in a complex manner. Based on their hydrated density ranges, lipoprotein subpopulations were fractionated and isolated via isopycnic density gradient ultracentrifugation. After investigation of the general oxidation behavior, initiated by addition of CuSO 4 to the isolated samples of HDL 3 , HDL 2 , LDL and Lp(a), the influence of different activities of radioiodine-125 on the kinetics of the formation of conjugated dienes was assessed. This was achieved by coincubation of plasma with I 125 . The spectrophotometrical measurement of the concentration of conjugated dienes in the course of CuSO 4 -induced lipid peroxidation leads to measurable changes in absorption at 234 nm. These changes in absorption over time result in a characteristically shaped curve graphically plotted. The shape of these curves mirrors different indicators of lipid peroxidation. Therefrom lag time, maximal

  16. Synergism between two helper cell subpopulations characterized by different radiosensitivity and nylon adherence

    International Nuclear Information System (INIS)

    Agarossi, G.; Mancini, C.; Doria, G.

    1981-01-01

    The present work extends our previous results on the radiosensitivity of the helper cell function. Two helper cell subpopulations, 1 radiosensitive and the other radioresistant, have been demonstrated in the spleen of mice at different times after priming with HRBC. The radiosensitive subpopulation increases with the increasing time interval between carrier-priming and irradiation. The 2 cell subpopulations have been further characterized by different nylon adherence properties: radioresistant helper cells adhere to nylon wool, whereas radiosensitive cells pass through. The 2 cell subpopulations were separated by x-irradiation and nylon wool filtration, and their helper activity was assessed separately or after recombination. The results favor the notion that 2 functionally independent helper T cells, as characterized by different radiosensitivity and nylon adherence, participate synergistically in the helper activity of primed spleen cells

  17. MicroRNA-181a* Targets Nanog in a Subpopulation of CD34+ Cells Isolated From Peripheral Blood

    Directory of Open Access Journals (Sweden)

    Paul J Mintz

    2012-01-01

    Full Text Available Exploiting the properties of stem cells by microRNA (miRNA profiling offers an attractive approach to identify new regulators of stem cell fate. Although numerous miRNA have been screened from hematopoietic stem cells (HSC, the targets corresponding to many of these miRNA have not yet been fully elucidated. By miRNA profiling in a subpopulation of CD34+ cells isolated from peripheral blood, we have identified eight clusters of miRNA that were differentially expressed. Further analysis of one of the clusters by bioinformatics revealed that a miRNA, miR-181a*, which is highly expressed in the adherent CD34+ cells, affects the expression levels of Nanog, a stem cell surrogate marker. We show specifically by reporter assay and mutational analysis that miR-181a* targets a seedless 3′ compensatory site in the 3′UTR of Nanog and affects gene expression. We demonstrate that inhibiting miR-181a* upregulates the Nanog expression level, in addition to an increase in alkaline phosphatase activity. Our studies suggest that miR-181a* may be important in controlling the expression level of Nanog in a subpopulation of CD34+ cells.

  18. CHARACTERIZATION OF TWO MONOCLONAL ANTIBODIES WHICH RECOGNIZE DIFFERENT SUBPOPULATIONS OF CHICKEN T LYMPHOCYTES

    OpenAIRE

    KONDO, Takashi; HATTORI, Masakazu; KODAMA, Hiroshi; ONUMA, Misao; MIKAMI, Takeshi

    1990-01-01

    Distribution among peripheral T lymphocyte subpopulations and biochemical properties of the chicken lymphocyte surface antigens defined by monoclonal antibodies (mAbs) Lc-4 and Lc-6 were examined. Two-color immunofluorescence analysis revealed that Lc-4 and Lc-6 antigens were expressed on mutually exclusive subpopulations of peripheral T lymphocytes but not on B lymphocytes. Lc-4 mAb precipitated a polypeptide with apparent molecular mass of 35 and 65 kilodalton under reducing and non-reducin...

  19. Albumin Homodimers in Patients with Cirrhosis: Clinical and Prognostic Relevance of a Novel Identified Structural Alteration of the Molecule.

    Science.gov (United States)

    Baldassarre, Maurizio; Domenicali, Marco; Naldi, Marina; Laggetta, Maristella; Giannone, Ferdinando A; Biselli, Maurizio; Patrono, Daniela; Bertucci, Carlo; Bernardi, Mauro; Caraceni, Paolo

    2016-10-26

    Decompensated cirrhosis is associated to extensive post-transcriptional changes of human albumin (HA). This study aims to characterize the occurrence of HA homodimerization in a large cohort of patients with decompensated cirrhosis and to evaluate its association with clinical features and prognosis. HA monomeric and dimeric isoforms were identified in peripheral blood by using a HPLC-ESI-MS technique in 123 cirrhotic patients hospitalized for acute decompensation and 50 age- and sex-comparable healthy controls. Clinical and biochemical parameters were recorded and patients followed up to one year. Among the monomeric isoforms identified, the N- and C-terminal truncated and the native HA underwent homodimerization. All three homodimers were significantly more abundant in patients with cirrhosis, acute-on-chronic liver failure and correlate with the prognostic scores. The homodimeric N-terminal truncated isoform was independently associated to disease complications and was able to stratify 1-year survival. As a result of all these changes, the monomeric native HA was significantly decreased in patients with cirrhosis, being also associated with a poorer prognosis. In conclusion homodimerization is a novel described structural alteration of the HA molecule in decompensated cirrhosis and contributes to the progressive reduction of the monomeric native HA, the only isoform provided of structural and functional integrity.

  20. Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.

    Science.gov (United States)

    Guo, Xingyi; Shi, Jiajun; Cai, Qiuyin; Shu, Xiao-Ou; He, Jing; Wen, Wanqing; Allen, Jamie; Pharoah, Paul; Dunning, Alison; Hunter, David J; Kraft, Peter; Easton, Douglas F; Zheng, Wei; Long, Jirong

    2018-03-01

    Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

  1. An integrated structure- and system-based framework to identify new targets of metabolites and known drugs

    KAUST Repository

    Naveed, Hammad

    2015-08-18

    Motivation: The inherent promiscuity of small molecules towards protein targets impedes our understanding of healthy versus diseased metabolism. This promiscuity also poses a challenge for the pharmaceutical industry as identifying all protein targets is important to assess (side) effects and repositioning opportunities for a drug. Results: Here, we present a novel integrated structure- and system-based approach of drug-target prediction (iDTP) to enable the large-scale discovery of new targets for small molecules, such as pharmaceutical drugs, co-factors and metabolites (collectively called ‘drugs’). For a given drug, our method uses sequence order–independent structure alignment, hierarchical clustering, and probabilistic sequence similarity to construct a probabilistic pocket ensemble (PPE) that captures promiscuous structural features of different binding sites on known targets. A drug’s PPE is combined with an approximation of its delivery profile to reduce false positives. In our cross-validation study, we use iDTP to predict the known targets of eleven drugs, with 63% sensitivity and 81% specificity. We then predicted novel targets for these drugs—two that are of high pharmacological interest, the nuclear receptor PPARγ and the oncogene Bcl-2, were successfully validated through in vitro binding experiments. Our method is broadly applicable for the prediction of protein-small molecule interactions with several novel applications to biological research and drug development.

  2. Survival and PHA-stimulation of #betta#-irradiated human peripheral blood T lymphocyte subpopulations

    International Nuclear Information System (INIS)

    Schwartz, J.L.; Darr, D.C.; Daulden, M.E.

    1983-01-01

    Human peripheral blood T lymphocyte subpopulations were identified and isolated on the basis of their ability to bind IgG (T-G), IgM (T-M), or neither immunoglobulin class (T-null). Lymphocytes were exposed to 0, 0.5, 1.0, 2.5 or 5.0 Gy of 60 Co #betta#-rays either as a T-cell suspension or as separated T cell subsets. Survival curves, determined 5 days after irradiation, revealed that each subset has radiosensitive and radioresistant portions, and that the T-G cell is the most sensitive subset. Mitotic indices of 48-h cultures showed that the response of unirradiated T lymphocytes to PHA varied greatly among the subsets, the highest indices being obtained for the T-M and the lowest for the T-G cells. With the possible exception of the T-G cells, the subsets are realtively resistant to mitotic effects of #betta#-rays. T-G cells suppress the PHA-induced mitotic response of the other T lymphocyte subsets, and this suppressor effect is radiosensitive, being abolished by 1.0 Gy. It is concluded that lymphocytes exposed to >= 1 Gy of #betta#-rays will have very few dividing B lymphocytes or T-G cells. This together with radiation-induced loss of T-G suppressor action means that the predominant lymphocyte types in mitosis after >=1 Gy are the radioresistant T-M and T-null cells. (orig.)

  3. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

    Science.gov (United States)

    Priego, Neibla; Zhu, Lucía; Monteiro, Cátia; Mulders, Manon; Wasilewski, David; Bindeman, Wendy; Doglio, Laura; Martínez, Liliana; Martínez-Saez, Elena; Cajal, Santiago Ramón Y; Megías, Diego; Hernández-Encinas, Elena; Blanco-Aparicio, Carmen; Martínez, Lola; Zarzuela, Eduardo; Muñoz, Javier; Fustero-Torres, Coral; Pineiro, Elena; Hernández-Laín, Aurelio; Bertero, Luca; Poli, Valeria; Sánchez-Martínez, Melchor; Menendez, Javier A; Soffietti, Riccardo; Bosch-Barrera, Joaquim; Valiente, Manuel

    2018-06-11

    The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

  4. Clinical applications and implications of common and founder mutations in Indian subpopulations.

    Science.gov (United States)

    Ankala, Arunkanth; Tamhankar, Parag M; Valencia, C Alexander; Rayam, Krishna K; Kumar, Manisha M; Hegde, Madhuri R

    2015-01-01

    South Asian Indians represent a sixth of the world's population and are a racially, geographically, and genetically diverse people. Their unique anthropological structure, prevailing caste system, and ancient religious practices have all impacted the genetic composition of most of the current-day Indian population. With the evolving socio-religious and economic activities of the subsects and castes, endogamous and consanguineous marriages became a commonplace. Consequently, the frequency of founder mutations and the burden of heritable genetic disorders rose significantly. Specifically, the incidence of certain autosomal-recessive disorders is relatively high in select Indian subpopulations and communities that share common recent ancestry. Although today clinical genetics and molecular diagnostic services are making inroads in India, the high costs associated with the technology and the tests often keep patients from an exact molecular diagnosis, making more customized and tailored tests, such as those interrogating the most common and founder mutations or those that cater to select sects within the population, highly attractive. These tests offer a quick first-hand affordable diagnostic and carrier screening tool. Here, we provide a comprehensive catalog of known common mutations and founder mutations in the Indian population and discuss them from a molecular, clinical, and historical perspective. © 2014 WILEY PERIODICALS, INC.

  5. The Use of Chemical-Chemical Interaction and Chemical Structure to Identify New Candidate Chemicals Related to Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Lei Chen

    Full Text Available Lung cancer causes over one million deaths every year worldwide. However, prevention and treatment methods for this serious disease are limited. The identification of new chemicals related to lung cancer may aid in disease prevention and the design of more effective treatments. This study employed a weighted network, constructed using chemical-chemical interaction information, to identify new chemicals related to two types of lung cancer: non-small lung cancer and small-cell lung cancer. Then, a randomization test as well as chemical-chemical interaction and chemical structure information were utilized to make further selections. A final analysis of these new chemicals in the context of the current literature indicates that several chemicals are strongly linked to lung cancer.

  6. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

    Directory of Open Access Journals (Sweden)

    Thomas S Peat

    Full Text Available A fragment-based screen against human immunodeficiency virus type 1 (HIV integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

  7. Precision of Discrete and Rhythmic Forelimb Movements Requires a Distinct Neuronal Subpopulation in the Interposed Anterior Nucleus.

    Science.gov (United States)

    Low, Aloysius Y T; Thanawalla, Ayesha R; Yip, Alaric K K; Kim, Jinsook; Wong, Kelly L L; Tantra, Martesa; Augustine, George J; Chen, Albert I

    2018-02-27

    The deep cerebellar nuclei (DCN) represent output channels of the cerebellum, and they transmit integrated sensorimotor signals to modulate limb movements. But the functional relevance of identifiable neuronal subpopulations within the DCN remains unclear. Here, we examine a genetically tractable population of neurons in the mouse interposed anterior nucleus (IntA). We show that these neurons represent a subset of glutamatergic neurons in the IntA and constitute a specific element of an internal feedback circuit within the cerebellar cortex and cerebello-thalamo-cortical pathway associated with limb control. Ablation and optogenetic stimulation of these neurons disrupt efficacy of skilled reach and locomotor movement and reveal that they control positioning and timing of the forelimb and hindlimb. Together, our findings uncover the function of a distinct neuronal subpopulation in the deep cerebellum and delineate the anatomical substrates and kinematic parameters through which it modulates precision of discrete and rhythmic limb movements. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. Identifying shared genetic structure patterns among Pacific Northwest forest taxa: insights from use of visualization tools and computer simulations.

    Directory of Open Access Journals (Sweden)

    Mark P Miller

    2010-10-01

    Full Text Available Identifying causal relationships in phylogeographic and landscape genetic investigations is notoriously difficult, but can be facilitated by use of multispecies comparisons.We used data visualizations to identify common spatial patterns within single lineages of four taxa inhabiting Pacific Northwest forests (northern spotted owl: Strix occidentalis caurina; red tree vole: Arborimus longicaudus; southern torrent salamander: Rhyacotriton variegatus; and western white pine: Pinus monticola. Visualizations suggested that, despite occupying the same geographical region and habitats, species responded differently to prevailing historical processes. S. o. caurina and P. monticola demonstrated directional patterns of spatial genetic structure where genetic distances and diversity were greater in southern versus northern locales. A. longicaudus and R. variegatus displayed opposite patterns where genetic distances were greater in northern versus southern regions. Statistical analyses of directional patterns subsequently confirmed observations from visualizations. Based upon regional climatological history, we hypothesized that observed latitudinal patterns may have been produced by range expansions. Subsequent computer simulations confirmed that directional patterns can be produced by expansion events.We discuss phylogeographic hypotheses regarding historical processes that may have produced observed patterns. Inferential methods used here may become increasingly powerful as detailed simulations of organisms and historical scenarios become plausible. We further suggest that inter-specific comparisons of historical patterns take place prior to drawing conclusions regarding effects of current anthropogenic change within landscapes.

  9. Genome-wide analysis of Epstein-Barr virus identifies variants and genes associated with gastric carcinoma and population structure.

    Science.gov (United States)

    Yao, Youyuan; Xu, Miao; Liang, Liming; Zhang, Haojiong; Xu, Ruihua; Feng, Qisheng; Feng, Lin; Luo, Bing; Zeng, Yi-Xin

    2017-10-01

    Epstein-Barr virus is a ubiquitous virus and is associated with several human malignances, including the significant subset of gastric carcinoma, Epstein-Barr virus-associated gastric carcinoma. Some Epstein-Barr virus-associated diseases are uniquely prevalent in populations with different geographic origins. However, the features of the disease and geographically associated Epstein-Barr virus genetic variation as well as the roles that the variation plays in carcinogenesis and evolution remain unclear. Therefore, in this study, we sequenced 95 geographically distinct Epstein-Barr virus isolates from Epstein-Barr virus-associated gastric carcinoma biopsies and saliva of healthy donors to detect variants and genes associated with gastric carcinoma and population structure from a genome-wide spectrum. We demonstrated that Epstein-Barr virus revealed the population structure between North China and South China. In addition, we observed population stratification between Epstein-Barr virus strains from gastric carcinoma and healthy controls, indicating that certain Epstein-Barr virus subtypes are associated with different gastric carcinoma risks. We identified that the BRLF1, BBRF3, and BBLF2/BBLF3 genes had significant associations with gastric carcinoma. LMP1 and BNLF2a genes were strongly geographically associated genes in Epstein-Barr virus. Our study provides insights into the genetic basis of oncogenic Epstein-Barr virus for gastric carcinoma, and the genetic variants associated with gastric carcinoma can serve as biomarkers for oncogenic Epstein-Barr virus.

  10. Identifying the default mode network structure using dynamic causal modeling on resting-state functional magnetic resonance imaging.

    Science.gov (United States)

    Di, Xin; Biswal, Bharat B

    2014-02-01

    The default mode network is part of the brain structure that shows higher neural activity and energy consumption when one is at rest. The key regions in the default mode network are highly interconnected as conveyed by both the white matter fiber tracing and the synchrony of resting-state functional magnetic resonance imaging signals. However, the causal information flow within the default mode network is still poorly understood. The current study used the dynamic causal modeling on a resting-state fMRI data set to identify the network structure underlying the default mode network. The endogenous brain fluctuations were explicitly modeled by Fourier series at the low frequency band of 0.01-0.08Hz, and those Fourier series were set as driving inputs of the DCM models. Model comparison procedures favored a model wherein the MPFC sends information to the PCC and the bilateral inferior parietal lobule sends information to both the PCC and MPFC. Further analyses provide evidence that the endogenous connectivity might be higher in the right hemisphere than in the left hemisphere. These data provided insight into the functions of each node in the DMN, and also validate the usage of DCM on resting-state fMRI data. © 2013.

  11. A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay.

    Directory of Open Access Journals (Sweden)

    Jing Lu

    Full Text Available Polo-like kinase 1 (PLK1, one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.

  12. A quadratically regularized functional canonical correlation analysis for identifying the global structure of pleiotropy with NGS data.

    Science.gov (United States)

    Lin, Nan; Zhu, Yun; Fan, Ruzong; Xiong, Momiao

    2017-10-01

    Investigating the pleiotropic effects of genetic variants can increase statistical power, provide important information to achieve deep understanding of the complex genetic structures of disease, and offer powerful tools for designing effective treatments with fewer side effects. However, the current multiple phenotype association analysis paradigm lacks breadth (number of phenotypes and genetic variants jointly analyzed at the same time) and depth (hierarchical structure of phenotype and genotypes). A key issue for high dimensional pleiotropic analysis is to effectively extract informative internal representation and features from high dimensional genotype and phenotype data. To explore correlation information of genetic variants, effectively reduce data dimensions, and overcome critical barriers in advancing the development of novel statistical methods and computational algorithms for genetic pleiotropic analysis, we proposed a new statistic method referred to as a quadratically regularized functional CCA (QRFCCA) for association analysis which combines three approaches: (1) quadratically regularized matrix factorization, (2) functional data analysis and (3) canonical correlation analysis (CCA). Large-scale simulations show that the QRFCCA has a much higher power than that of the ten competing statistics while retaining the appropriate type 1 errors. To further evaluate performance, the QRFCCA and ten other statistics are applied to the whole genome sequencing dataset from the TwinsUK study. We identify a total of 79 genes with rare variants and 67 genes with common variants significantly associated with the 46 traits using QRFCCA. The results show that the QRFCCA substantially outperforms the ten other statistics.

  13. Monoclonal antibody identification of subpopulations of cerebral cortical neurons affected in Alzheimer's disease

    International Nuclear Information System (INIS)

    Miller, C.A.; Rudnicka, M.; Hinton, D.R.; Blanks, J.C.; Kozlowski, M.

    1987-01-01

    Neuronal degeneration is one of the hallmarks of Alzheimer's disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, the authors have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mAbs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAb 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1 do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands of immunoblots of homogenates of normal and AD cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired-helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible

  14. Sperm kinematic, head morphometric and kinetic-morphometric subpopulations in the blue fox (Alopex lagopus

    Directory of Open Access Journals (Sweden)

    Carles Soler

    2017-01-01

    Full Text Available This work provides information on the blue fox ejaculated sperm quality needed for seminal dose calculations. Twenty semen samples, obtained by masturbation, were analyzed for kinematic and morphometric parameters by using CASA-Mot and CASA-Morph system and principal component (PC analysis. For motility, eight kinematic parameters were evaluated, which were reduced to PC1, related to linear variables, and PC2, related to oscillatory movement. The whole population was divided into three independent subpopulations: SP1, fast cells with linear movement; SP2, slow cells and nonoscillatory motility; and SP3, medium speed cells and oscillatory movement. In almost all cases, the subpopulation distribution by animal was significantly different. Head morphology analysis generated four size and four shape parameters, which were reduced to PC1, related to size, and PC2, related to shape of the cells. Three morphometric subpopulations existed: SP1: large oval cells; SP2: medium size elongated cells; and SP3: small and short cells. The subpopulation distribution differed between animals. Combining the kinematic and morphometric datasets produced PC1, related to morphometric parameters, and PC2, related to kinematics, which generated four sperm subpopulations - SP1: high oscillatory motility, large and short heads; SP2: medium velocity with small and short heads; SP3: slow motion small and elongated cells; and SP4: high linear speed and large elongated cells. Subpopulation distribution was different in all animals. The establishment of sperm subpopulations from kinematic, morphometric, and combined variables not only improves the well-defined fox semen characteristics and offers a good conceptual basis for fertility and sperm preservation techniques in this species, but also opens the door to use this approach in other species, included humans.

  15. The seesaw space, a vector space to identify and characterize large-scale structures at 1 AU

    Science.gov (United States)

    Lara, A.; Niembro, T.

    2017-12-01

    We introduce the seesaw space, an orthonormal space formed by the local and the global fluctuations of any of the four basic solar parameters: velocity, density, magnetic field and temperature at any heliospheric distance. The fluctuations compare the standard deviation of a moving average of three hours against the running average of the parameter in a month (consider as the local fluctuations) and in a year (global fluctuations) We created this new vectorial spaces to identify the arrival of transients to any spacecraft without the need of an observer. We applied our method to the one-minute resolution data of WIND spacecraft from 1996 to 2016. To study the behavior of the seesaw norms in terms of the solar cycle, we computed annual histograms and fixed piecewise functions formed by two log-normal distributions and observed that one of the distributions is due to large-scale structures while the other to the ambient solar wind. The norm values in which the piecewise functions change vary in terms of the solar cycle. We compared the seesaw norms of each of the basic parameters due to the arrival of coronal mass ejections, co-rotating interaction regions and sector boundaries reported in literature. High seesaw norms are due to large-scale structures. We found three critical values of the norms that can be used to determined the arrival of coronal mass ejections. We present as well general comparisons of the norms during the two maxima and the minimum solar cycle periods and the differences of the norms due to large-scale structures depending on each period.

  16. RECOVERY IN VIVO OF NONCULTURABLE SUBPOPULATION OF SALMONELLA ENTERICA

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    Yudin I.P.

    2015-12-01

    Full Text Available Introduction. As one of mesophilic, easily cultivated species of pathogenic bacteria, Salmonella enterica transformed into viable but nonculturable (VNC state in response to environmental stresses, including action of biocides. The cells in this state, preserve the integrity of membranes and metabolism of some, but not detected by conventional methods of cultivation. Some researchers suggest that the evolutionary significance of this phenomenon is part of an adaptive response aimed at long-term survival of bacteria in adverse conditions; others argue that it is the result of stochastic cellular damage, in which nonculturable cells are in a state of gradual death. In any case, the phenomenon of existence VNC pathogens if they retain the ability to restore its growth in vivo is a significant problem in medicine, pharmaceutical, veterinary, food industry. VNC subpopulation of S. enterica was obtained under action of ethanol. In this paper was investigated in vivo resuscitation VNC S. enterica using intraperitoneal injection of mice. Materials and methods. Obtaining of stressful S. enterica populations. Bacteria were grown to exponential phase in broth Luria–Bertani (LB. To 1.0 ml sample suspension diluted to 1.5 × 106 cells/ml was added 1.0 ml of ethanol at a concentration of 40 % (v/v. After exposure of 10 to 600 minutes in the suspension were added 8.0 ml of phosphate buffered saline (FBS, washed by centrifugation (4500 g for 5 minutes and serially diluted at a ratio of 1:10 (v/v samples were stained with LIVE/DEAD BacLight (produced by "Invitrogen", USA, filtrated on membrane filters for fluorescence microscopy and parallel plated on LB agar cup to determine colony-forming units (CFU per ml. In vivo resuscitation VNC S. enterica was made following way. Three groups of animals were inoculated by intraperitoneal injection: 1 103 culturable cells (0.1 ml suspension containing 104 CFU / ml; 2 103 VNC cells (0.1 ml suspension containing 104 cells

  17. Isolated in an ocean of grass: low levels of gene flow between termite subpopulations.

    Science.gov (United States)

    Schmidt, Anna M; Jacklyn, Peter; Korb, Judith

    2013-04-01

    Habitat fragmentation is one of the most important causes of biodiversity loss, but many species are distributed in naturally patchy habitats. Such species are often organized in highly dynamic metapopulations or in patchy populations with high gene flow between subpopulations. Yet, there are also species that exist in stable patchy habitats with small subpopulations and presumably low dispersal rates. Here, we present population genetic data for the 'magnetic' termite Amitermes meridionalis, which show that short distances between subpopulations do not hinder exceptionally strong genetic differentiation (FST : 0.339; RST : 0.636). Despite the strong genetic differentiation between subpopulations, we did not find evidence for genetic impoverishment. We propose that loss of genetic diversity might be counteracted by a long colony life with low colony turnover. Indeed, we found evidence for the inheritance of colonies by so-called 'replacement reproductives'. Inhabiting a mound for several generations might result in loss of gene diversity within a colony but maintenance of gene diversity at the subpopulation level. © 2013 Blackwell Publishing Ltd.

  18. Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation

    Science.gov (United States)

    Stubbendieck, Reed M.; Straight, Paul D.

    2015-01-01

    Bacteria have diverse mechanisms for competition that include biosynthesis of extracellular enzymes and antibiotic metabolites, as well as changes in community physiology, such as biofilm formation or motility. Considered collectively, networks of competitive functions for any organism determine success or failure in competition. How bacteria integrate different mechanisms to optimize competitive fitness is not well studied. Here we study a model competitive interaction between two soil bacteria: Bacillus subtilis and Streptomyces sp. Mg1 (S. Mg1). On an agar surface, colonies of B. subtilis suffer cellular lysis and progressive degradation caused by S. Mg1 cultured at a distance. We identify the lytic and degradative activity (LDA) as linearmycins, which are produced by S. Mg1 and are sufficient to cause lysis of B. subtilis. We obtained B. subtilis mutants spontaneously resistant to LDA (LDAR) that have visibly distinctive morphology and spread across the agar surface. Every LDAR mutant identified had a missense mutation in yfiJK, which encodes a previously uncharacterized two-component signaling system. We confirmed that gain-of-function alleles in yfiJK cause a combination of LDAR, changes in colony morphology, and motility. Downstream of yfiJK are the yfiLMN genes, which encode an ATP-binding cassette transporter. We show that yfiLMN genes are necessary for LDA resistance. The developmental phenotypes of LDAR mutants are genetically separable from LDA resistance, suggesting that the two competitive functions are distinct, but regulated by a single two-component system. Our findings suggest that a subpopulation of B. subtilis activate an array of defensive responses to counter lytic stress imposed by competition. Coordinated regulation of development and antibiotic resistance is a streamlined mechanism to promote competitive fitness of bacteria. PMID:26647299

  19. Molecular and functional analyses of a maize autoactive NB-LRR protein identify precise structural requirements for activity.

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    Guan-Feng Wang

    2015-02-01

    Full Text Available Plant disease resistance is often mediated by nucleotide binding-leucine rich repeat (NLR proteins which remain auto-inhibited until recognition of specific pathogen-derived molecules causes their activation, triggering a rapid, localized cell death called a hypersensitive response (HR. Three domains are recognized in one of the major classes of NLR proteins: a coiled-coil (CC, a nucleotide binding (NB-ARC and a leucine rich repeat (LRR domains. The maize NLR gene Rp1-D21 derives from an intergenic recombination event between two NLR genes, Rp1-D and Rp1-dp2 and confers an autoactive HR. We report systematic structural and functional analyses of Rp1 proteins in maize and N. benthamiana to characterize the molecular mechanism of NLR activation/auto-inhibition. We derive a model comprising the following three main features: Rp1 proteins appear to self-associate to become competent for activity. The CC domain is signaling-competent and is sufficient to induce HR. This can be suppressed by the NB-ARC domain through direct interaction. In autoactive proteins, the interaction of the LRR domain with the NB-ARC domain causes de-repression and thus disrupts the inhibition of HR. Further, we identify specific amino acids and combinations thereof that are important for the auto-inhibition/activity of Rp1 proteins. We also provide evidence for the function of MHD2, a previously uncharacterized, though widely conserved NLR motif. This work reports several novel insights into the precise structural requirement for NLR function and informs efforts towards utilizing these proteins for engineering disease resistance.

  20. Characterization of macular structure and function in two Swedish families with genetically identified autosomal dominant retinitis pigmentosa

    Science.gov (United States)

    Abdulridha-Aboud, Wissam; Kjellström, Ulrika; Andréasson, Sten

    2016-01-01

    Purpose To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions These two families demonstrate the extreme inter- and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype. PMID:27212874

  1. T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire.

    Science.gov (United States)

    Beausang, John F; Wheeler, Amanda J; Chan, Natalie H; Hanft, Violet R; Dirbas, Frederick M; Jeffrey, Stefanie S; Quake, Stephen R

    2017-11-28

    Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment. Copyright © 2017 the Author(s). Published by PNAS.

  2. Molecular and functional analyses of a maize autoactive NB-LRR protein identify precise structural requirements for activity.

    Science.gov (United States)

    Wang, Guan-Feng; Ji, Jiabing; El-Kasmi, Farid; Dangl, Jeffery L; Johal, Guri; Balint-Kurti, Peter J

    2015-02-01

    Plant disease resistance is often mediated by nucleotide binding-leucine rich repeat (NLR) proteins which remain auto-inhibited until recognition of specific pathogen-derived molecules causes their activation, triggering a rapid, localized cell death called a hypersensitive response (HR). Three domains are recognized in one of the major classes of NLR proteins: a coiled-coil (CC), a nucleotide binding (NB-ARC) and a leucine rich repeat (LRR) domains. The maize NLR gene Rp1-D21 derives from an intergenic recombination event between two NLR genes, Rp1-D and Rp1-dp2 and confers an autoactive HR. We report systematic structural and functional analyses of Rp1 proteins in maize and N. benthamiana to characterize the molecular mechanism of NLR activation/auto-inhibition. We derive a model comprising the following three main features: Rp1 proteins appear to self-associate to become competent for activity. The CC domain is signaling-competent and is sufficient to induce HR. This can be suppressed by the NB-ARC domain through direct interaction. In autoactive proteins, the interaction of the LRR domain with the NB-ARC domain causes de-repression and thus disrupts the inhibition of HR. Further, we identify specific amino acids and combinations thereof that are important for the auto-inhibition/activity of Rp1 proteins. We also provide evidence for the function of MHD2, a previously uncharacterized, though widely conserved NLR motif. This work reports several novel insights into the precise structural requirement for NLR function and informs efforts towards utilizing these proteins for engineering disease resistance.

  3. Use of the Operon Structure of the C. elegans Genome as a Tool to Identify Functionally Related Proteins

    Directory of Open Access Journals (Sweden)

    Silvia Dossena

    2013-12-01

    Full Text Available One of the most pressing challenges in the post genomic era is the identification and characterization of protein-protein interactions (PPIs, as these are essential in understanding the cellular physiology of health and disease. Experimental techniques suitable for characterizing PPIs (X-ray crystallography or nuclear magnetic resonance spectroscopy, among others are usually laborious, time-consuming and often difficult to apply to membrane proteins, and therefore require accurate prediction of the candidate interacting partners. High-throughput experimental methods (yeast two-hybrid and affinity purification succumb to the same shortcomings, and can also lead to high rates of false positive and negative results. Therefore, reliable tools for predicting PPIs are needed. The use of the operon structure in the eukaryote Caenorhabditis elegans genome is a valuable, though underserved, tool for identifying physically or functionally interacting proteins. Based on the concept that genes organized in the same operon may encode physically or functionally related proteins, this algorithm is easy to be applied and, importantly, gives a limited number of candidate partners of a given protein, allowing for focused experimental verification. Moreover, this approach can be successfully used to predict PPIs in the human system, including those of membrane proteins.

  4. Osteoarthritis subpopulations and implications for clinical trial design

    NARCIS (Netherlands)

    S.M. Bierma-Zeinstra (Sita); A.P. Verhagen (Arianne)

    2011-01-01

    textabstractTreatment guidelines for osteoarthritis have stressed the need for research on clinical predictors of response to different treatments. However, identifying such clinical predictors of response is less easy than it seems, and there is not a given classification of osteoarthritis

  5. Phenotypic Diversity and Plasticity in Circulating Neutrophil Subpopulations in Cancer

    Directory of Open Access Journals (Sweden)

    Jitka Y. Sagiv

    2015-02-01

    Full Text Available Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs. LDNs consist of both immature myeloid-derived suppressor cells (MDSCs and mature cells that are derived from HDNs in a TGF-β-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.

  6. Case-crossover analysis of heat-coded deaths and vulnerable subpopulations: Oklahoma, 1990-2011

    Science.gov (United States)

    Moore, Brianna F.; Brooke Anderson, G.; Johnson, Matthew G.; Brown, Sheryll; Bradley, Kristy K.; Magzamen, Sheryl

    2017-11-01

    The extent of the association between temperature and heat-coded deaths, for which heat is the primary cause of death, remains largely unknown. We explored the association between temperature and heat-coded deaths and potential interactions with various demographic and environmental factors. A total of 335 heat-coded deaths that occurred in Oklahoma from 1990 through 2011 were identified using heat-related International Classification of Diseases codes, cause-of-death nomenclature, and narrative descriptions. Conditional logistic regression models examined the association between temperature and heat index on heat-coded deaths. Interaction by demographic factors (age, sex, marital status, living alone, outdoor/heavy labor occupations) and environmental factors (ozone, PM10, PM2.5) was also explored. Temperatures ≥99 °F (the median value) were associated with approximately five times higher odds of a heat-coded death as compared to temperatures effect estimates were attenuated when exposure to heat was characterized by heat index. The interaction results suggest that effect of temperature on heat-coded deaths may depend on sex and occupation. For example, the odds of a heat-coded death among outdoor/heavy labor workers exposed to temperatures ≥99 °F was greater than expected based on the sum of the individual effects (observed OR = 14.0, 95% CI 2.7, 72.0; expected OR = 4.1 [2.8 + 2.3-1.0]). Our results highlight the extent of the association between temperature and heat-coded deaths and emphasize the need for a comprehensive, multisource definition of heat-coded deaths. Furthermore, based on the interaction results, we recommend that states implement or expand heat safety programs to protect vulnerable subpopulations, such as outdoor workers.

  7. Identification of seipin-linked factors that act as determinants of a lipid droplet subpopulation

    NARCIS (Netherlands)

    Eisenberg-Bord, Michal; Mari, Muriel; Weill, Uri; Rosenfeld-Gur, Eden; Moldavski, Ofer; Castro, Ines G.; Soni, Krishnakant G.; Harpaz, Nofar; Levine, Tim P.; Futerman, Anthony H.; Reggiori, Fulvio; Bankaitis, Vytas A.; Schuldiner, Maya; Bohnert, Maria

    Functional heterogeneity within the lipid droplet (LD) pool of a single cell has been observed, yet the underlying mechanisms remain enigmatic. Here, we report on identification of a specialized LD subpopulation characterized by a unique proteome and a defined geographical location at the

  8. Meta-STEPP: subpopulation treatment effect pattern plot for individual patient data meta-analysis.

    Science.gov (United States)

    Wang, Xin Victoria; Cole, Bernard; Bonetti, Marco; Gelber, Richard D

    2016-09-20

    We have developed a method, called Meta-STEPP (subpopulation treatment effect pattern plot for meta-analysis), to explore treatment effect heterogeneity across covariate values in the meta-analysis setting for time-to-event data when the covariate of interest is continuous. Meta-STEPP forms overlapping subpopulations from individual patient data containing similar numbers of events with increasing covariate values, estimates subpopulation treatment effects using standard fixed-effects meta-analysis methodology, displays the estimated subpopulation treatment effect as a function of the covariate values, and provides a statistical test to detect possibly complex treatment-covariate interactions. Simulation studies show that this test has adequate type-I error rate recovery as well as power when reasonable window sizes are chosen. When applied to eight breast cancer trials, Meta-STEPP suggests that chemotherapy is less effective for tumors with high estrogen receptor expression compared with those with low expression. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Connecting endangered brown bear subpopulations in the Cantabrian Range (north-western Spain)

    Science.gov (United States)

    M. C. Mateo-Sanchez; Samuel Cushman; S. Saura

    2014-01-01

    The viability of many species depends on functional connectivity of their populations through dispersal across broad landscapes. This is particularly the case for the endangered brown bear in north-western Spain, with a total population of about 200 individuals in two subpopulations that are separated by a wide gap with low permeability. Our goal in this paper...

  10. Endothelial cell subpopulations in vitro: cell volume, cell cycle, and radiosensitivity

    International Nuclear Information System (INIS)

    Rubin, D.B.; Drab, E.A.; Bauer, K.D.

    1989-01-01

    Vascular endothelial cells (EC) are important clinical targets of radiation and other forms of free radical/oxidant stresses. In this study, we found that the extent of endothelial damage may be determined by the different cytotoxic responses of EC subpopulations. The following characteristics of EC subpopulations were examined: (1) cell volume; (2) cell cycle position; and (3) cytotoxic indexes for both acute cell survival and proliferative capacity after irradiation (137Cs, gamma, 0-10 Gy). EC cultured from bovine aortas were separated by centrifugal elutriation into subpopulations of different cell volumes. Through flow cytometry, we found that cell volume was related to the cell cycle phase distribution. The smallest EC were distributed in G1 phase and the larger cells were distributed in either early S, middle S, or late S + G2M phases. Cell cycle phase at the time of irradiation was not associated with acute cell loss. However, distribution in the cell cycle did relate to cell survival based on proliferative capacity (P less than 0.01). The order of increasing radioresistance was cells in G1 (D0 = 110 cGy), early S (135 cGy), middle S (145 cGy), and late S + G2M phases (180 cGy). These findings (1) suggest an age-related response to radiation in a nonmalignant differentiated cell type and (2) demonstrate EC subpopulations in culture

  11. The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin

    NARCIS (Netherlands)

    Bos, J. D.; Zonneveld, I.; Das, P. K.; Krieg, S. R.; van der Loos, C. M.; Kapsenberg, M. L.

    1987-01-01

    The complexity of immune response-associated cells present in normal human skin was recently redefined as the skin immune system (SIS). In the present study, the exact immunophenotypes of lymphocyte subpopulations with their localizations in normal human skin were determined quantitatively. B cells

  12. Pyoverdine and PQS Mediated Subpopulation Interactions Involved in Pseudomonas aeruginosa Biofilm Formation

    DEFF Research Database (Denmark)

    Yang, Liang; Nilsson, Martin; Gjermansen, Morten

    2009-01-01

    Using flow chamber-grown Pseudomonas aeruginosa biofilms as model system, we show in the present study that formation of heterogeneous biofilms may occur through mechanisms that involve complex subpopulation interactions. One example of this phenomenon is expression of the iron...

  13. Carotenoids located in human lymphocyte subpopulations and Natural Killer cells by Raman microspectroscopy

    NARCIS (Netherlands)

    Puppels, G.J.; Puppels, G.J.; Garritsen, H.S.P.; Garritsen, H.S.P.; Kummer, J.A.; Greve, Jan

    1993-01-01

    The presence and subcellular location of carotenoids in human lymphocyte sub-populations (CD4+, CD8+, T-cell receptor-γδ+, and CD19+ ) and natural killer cells (CD16+ ) were studied by means of Raman microspectroscopy. In CD4+ lymphocytes a high concentration (10-3M) of carotenoids was found in the

  14. The value of some Corsican sub-populations for genetic association studies

    Directory of Open Access Journals (Sweden)

    Vona Giuseppe

    2008-07-01

    Full Text Available Abstract Background Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. In these populations the disease allele reveals Linkage Disequilibrium (LD with markers over significant genetic intervals, therefore facilitating disease locus identification. In a previous study we examined the LD extension on the Xq13 region in three Corsican sub-populations from the inner mountainous region of the island. On the basis of those previous results we have proposed a multistep procedure to carry out studies aimed at the identification of genes involved in complex diseases in Corsica. A prerequisite to carry out the proposed multi-step procedure was the presence of different degrees of LD on the island and a common genetic derivation of the different Corsican sub-populations. In order to evaluate the existence of these conditions in the present paper we extended the analysis to the Corsican coastal populations. Methods Samples were analyzed using seven dinucleotide microsatellite markers on chromosome Xq13-21: DXS983, DXS986, DXS8092, DXS8082, DXS1225, DXS8037 and DXS995 spanning approximately 4.0 cM (13.3 Mb. We have also investigated the distribution of the DXS1225-DXS8082 haplotype which has been recently proposed as a good marker of population genetic history due to its low recombination rate. Results the results obtained indicate a decrease of LD on the island from the central mountainous toward the coastal sub-populations. In addition the analysis of the DXS1225-DXS8082 haplotype revealed: 1 the presence of a particular haplotype with high frequency; 2 the derivation from a common genetic pool of the sub-populations examined in the present study. Conclusion These results indicate the Corsican sub-populations useful for the fine mapping of genes contributing to complex diseases.

  15. Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically defined disease in post-menopausal women

    Science.gov (United States)

    The association of coronary heart disease (CHD) with subpopulations of triglyceride (TG)-rich lipoproteins and high-density lipoproteins (HDL) is established in men, but has not been well characterized in women. Plasma HDL subpopulation concentrations, quantified by 2-dimensional gel electrophoresis...

  16. Distinct projection targets define subpopulations of mouse brainstem vagal neurons that express the autism-associated MET receptor tyrosine kinase.

    Science.gov (United States)

    Kamitakahara, Anna; Wu, Hsiao-Huei; Levitt, Pat

    2017-12-15

    Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a MET EGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: (a) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, (b) EGFP+ neurons in the medial DMV projecting to the stomach, and (b) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggests that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. © 2017 Wiley Periodicals, Inc.

  17. Sub-populations of alcohol-dependent patients: differences in psychological functioning between high- and low-frequency alcohol consumers.

    Science.gov (United States)

    Hiltunen, A J; Koechling, U M; Voltaire-Carlsson, A; Borg, S

    1996-07-01

    The purpose of the present study was to examine the processes underlying relapse to drinking using objective biological validation of self-reported recent alcohol consumption, using the ratio of 5-hydroxytryptophol to 5-hydroxyindol-3-ylacetic acid (5-HTOL/5-HIAA), a new biological marker to detect single episodes of drinking, in a sample of 38 male alcohol-dependent patients (DSM-III-R) who were assessed prospectively in terms of their clinical symptomatology over a 6-month treatment period. Results showed that nearly all patients obtained positive 5-HTOL/5-HIAA samples during the course of treatment. However, upon closer inspection, results revealed a bimodal distribution for alcohol intake with high and low frequency of consumption episodes. Results showed that high frequency consumers obtained higher ratings of clinical symptoms as measured by the Comprehensive Psychopathological Rating Scale (CPRS) and by the St Göran's Semi-structured Interview (SGSI) compared to low frequency alcohol consumers on symptoms of inner tension, lack of initiative, risk of relapse (as rated by therapists and as rated by patients themselves), dysphoria, negative craving for alcohol, and positive craving for alcohol. The present results provided evidence for the existence of two sub-populations of alcoholics, those who have frequent lapses and those who have low frequency of sporadic lapses. Further, these two sub-populations were shown to differ with respect to overall psychological functioning, and craving for alcohol. In conclusion, the present findings have important treatment implications in that reliable identification of patients' consumption patterns using biological markers would allow for the design of individually tailored treatment needs.

  18. Major proteins in normal human lymphocyte subpopulations separated by fluorescence-activated cell sorting and analyzed by two-dimensional gel electrophoresis

    DEFF Research Database (Denmark)

    Madsen, P S; Hokland, M; Ellegaard, J

    1988-01-01

    markers were observed in all cell types. All the putative protein markers have been identified in the protein database of human peripheral blood mononuclear cells (PBMCs) (see accompanying article by Celis et al.). Comparison of the overall patterns of protein synthesis of the unsorted PBMCs with those...... of the four subpopulations showed that the synthesis of some major PBMC proteins decreased substantially in the sorted subsets. These proteins are most likely not of monocyte origin, as these cells constituted only about 15% of the total PBMCs. Also, the inhibition does not seem to be due to the addition...

  19. Top IS research on quality of transaction standards: a structured literature review to identify a research gap

    NARCIS (Netherlands)

    Folmer, E.J.A.; Berends, W.; Oude Luttighuis, P.; Hillegersberg, J. van

    2009-01-01

    This paper contains the results of a systematic literature review executed to determine the coverage of transaction standards in top information systems (IS) and management journals. Specifically, it aims to identify a research gap with respect to this topic. The top 25 journals are thoroughly

  20. Structural characterization of POM6 Fab and mouse prion protein complex identifies key regions for prions conformational conversion.

    Science.gov (United States)

    Baral, Pravas Kumar; Swayampakula, Mridula; Aguzzi, Adriano; James, Michael N G

    2018-05-01

    Conversion of the cellular prion protein PrP C into its pathogenic isoform PrP S c is the hallmark of prion diseases, fatal neurodegenerative diseases affecting many mammalian species including humans. Anti-prion monoclonal antibodies can arrest the progression of prion diseases by stabilizing the cellular form of the prion protein. Here, we present the crystal structure of the POM6 Fab fragment, in complex with the mouse prion protein (moPrP). The prion epitope of POM6 is in close proximity to the epitope recognized by the purportedly toxic antibody fragment, POM1 Fab also complexed with moPrP. The POM6 Fab recognizes a larger binding interface indicating a likely stronger binding compared to POM1. POM6 and POM1 exhibit distinct biological responses. Structural comparisons of the bound mouse prion proteins from the POM6 Fab:moPrP and POM1 Fab:moPrP complexes reveal several key regions of the prion protein that might be involved in initiating mis-folding events. The structural data of moPrP:POM6 Fab complex are available in the PDB under the accession number www.rcsb.org/pdb/search/structidSearch.do?structureId=6AQ7. © 2018 Federation of European Biochemical Societies.

  1. A New Approach to Identify Optimal Properties of Shunting Elements for Maximum Damping of Structural Vibration Using Piezoelectric Patches

    Science.gov (United States)

    Park, Junhong; Palumbo, Daniel L.

    2004-01-01

    The use of shunted piezoelectric patches in reducing vibration and sound radiation of structures has several advantages over passive viscoelastic elements, e.g., lower weight with increased controllability. The performance of the piezoelectric patches depends on the shunting electronics that are designed to dissipate vibration energy through a resistive element. In past efforts most of the proposed tuning methods were based on modal properties of the structure. In these cases, the tuning applies only to one mode of interest and maximum tuning is limited to invariant points when based on den Hartog's invariant points concept. In this study, a design method based on the wave propagation approach is proposed. Optimal tuning is investigated depending on the dynamic and geometric properties that include effects from boundary conditions and position of the shunted piezoelectric patch relative to the structure. Active filters are proposed as shunting electronics to implement the tuning criteria. The developed tuning methods resulted in superior capabilities in minimizing structural vibration and noise radiation compared to other tuning methods. The tuned circuits are relatively insensitive to changes in modal properties and boundary conditions, and can applied to frequency ranges in which multiple modes have effects.

  2. Identifying Configurations of Perceived Teacher Autonomy Support and Structure: Associations with Self-Regulated Learning, Motivation and Problem Behavior

    Science.gov (United States)

    Vansteenkiste, Maarten; Sierens, Eline; Goossens, Luc; Soenens, Bart; Dochy, Filip; Mouratidis, Athanasios; Aelterman, Nathalie; Haerens, Leen; Beyers, Wim

    2012-01-01

    Grounded in self-determination theory, the aim of this study was (a) to examine naturally occurring configurations of perceived teacher autonomy support and clear expectations (i.e., a central aspect of teacher structure), and (b) to investigate associations with academic motivation, self-regulated learning, and problem behavior. Based on…

  3. Post-mortem computed tomography angiography utilizing barium sulfate to identify microvascular structures : a preliminary phantom model and case study

    NARCIS (Netherlands)

    Haakma, Wieke; Rohde, Marianne; Kuster, Lidy; Uhrenholt, Lars; Pedersen, Michael; Boel, Lene Warner Thorup

    2016-01-01

    We investigated the use of computer tomography angiography (CTA) to visualize microvascular structures in a vessel-mimicking phantom and post-mortem (PM) bodies. A contrast agent was used based on 22% barium sulfate, 20% polyethylene glycol and 58% distilled water. A vessel-mimicking phantom

  4. Identifying Residual Structure in Intrinsically Disordered Systems : A 2D IR Spectroscopic Study of the GVGXPGVG Peptide

    NARCIS (Netherlands)

    Lessing, Joshua; Roy, Santanu; Reppert, Mike; Baer, Marcel; Marx, Dominik; Jansen, Thomas La Cour; Knoester, Jasper; Tokmakoff, Andrei

    2012-01-01

    The peptide amide-I vibration of a proline turn encodes information on the turn structure. In this study, FTIR, two-dimensional IR spectroscopy and molecular dynamics simulations were employed to characterize the varying turn conformations that exist in the GVGX(L)PGVG family of disordered peptides.

  5. Identifying residual structure in intrinsically disordered systems: a 2D IR spectroscopic study of the GVGXPGVG peptide.

    NARCIS (Netherlands)

    Lessing, J.; Roy, S.; Reppert, M.; Baer, M.; Marx, D.; Jansen, T.L.Th.A.; Knoester, J.; Tokmakoff, A.

    2012-01-01

    The peptide amide-I vibration of a proline turn encodes information on the turn structure. In this study, FTIR, two-dimensional IR spectroscopy and molecular dynamics simulations were employed to characterize the varying turn conformations that exist in the GVGX(L)PGVG family of disordered peptides.

  6. CSI 3.0: a web server for identifying secondary and super-secondary structure in proteins using NMR chemical shifts.

    Science.gov (United States)

    Hafsa, Noor E; Arndt, David; Wishart, David S

    2015-07-01

    The Chemical Shift Index or CSI 3.0 (http://csi3.wishartlab.com) is a web server designed to accurately identify the location of secondary and super-secondary structures in protein chains using only nuclear magnetic resonance (NMR) backbone chemical shifts and their corresponding protein sequence data. Unlike earlier versions of CSI, which only identified three types of secondary structure (helix, β-strand and coil), CSI 3.0 now identifies total of 11 types of secondary and super-secondary structures, including helices, β-strands, coil regions, five common β-turns (type I, II, I', II' and VIII), β hairpins as well as interior and edge β-strands. CSI 3.0 accepts experimental NMR chemical shift data in multiple formats (NMR Star 2.1, NMR Star 3.1 and SHIFTY) and generates colorful CSI plots (bar graphs) and secondary/super-secondary structure assignments. The output can be readily used as constraints for structure determination and refinement or the images may be used for presentations and publications. CSI 3.0 uses a pipeline of several well-tested, previously published programs to identify the secondary and super-secondary structures in protein chains. Comparisons with secondary and super-secondary structure assignments made via standard coordinate analysis programs such as DSSP, STRIDE and VADAR on high-resolution protein structures solved by X-ray and NMR show >90% agreement between those made with CSI 3.0. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. X-ray induction of micronuclei in human lymphocyte subpopulations differentiated by immunoperoxidase staining

    International Nuclear Information System (INIS)

    Ban, Sadayuki; Nakano, Mimako; Cologne, J.B.

    1992-10-01

    In this report we sought to confirm the radiosensitivity of human peripheral blood lymphocyte subpopulations using a micronucleus assay. Mononucleated cells isolated from peripheral blood were irradiated with X rays. After being cultured for 3 days, cells were fixed and stained using the immunoperoxidase staining technique. Lymphocyte subpopulations were characterized by means of the monoclonal antibodies Leu4 (CD3), Leu2a (CD8), and Leu19 (CD56). Dose-response curves were obtained by scoring the number of micronuclei in binucleated cells that reacted with a specific antibody and were then stained. The dose response of CD8 + (suppressor/cytotoxic) cells was quite similar to that of CD3 + (pan T) cells. In comparison, CD56 + (natural killer) cells were significantly less sensitive, although scorable binucleated CD56 + cells made up less than 4 % of the total number of binucleated cells. (author)

  8. Selective proteomic analysis of antibiotic-tolerant cellular subpopulations in pseudomonas aeruginosa biofilms

    DEFF Research Database (Denmark)

    Babin, Brett M.; Atangcho, Lydia; van Eldijk, Mark B.

    2017-01-01

    involved in central carbon metabolism. We differentiated the immediate proteomic response, characterized by an increase in flagellar motility, from the long-term adaptive strategy, which included the upregulation of purine synthesis. This targeted, selective analysis of a bacterial subpopulation...... amino acid tagging (BONCAT) method to enable selective proteomic analysis of a Pseudomonas aeruginosa biofilm subpopulation. Through controlled expression of a mutant methionyl-tRNA synthetase, we targeted BONCAT labeling to cells in the regions of biofilm microcolonies that showed increased tolerance...... demonstrates how the study of proteome dynamics can enhance our understanding of biofilm heterogeneity and antibiotic tolerance. IMPORTANCE Bacterial growth is frequently characterized by behavioral heterogeneity at the single-cell level. Heterogeneity is especially evident in the physiology of biofilms...

  9. REVERSED TREND OF RADIAL DISTRIBUTION OF SUBPOPULATIONS IN THE GLOBULAR CLUSTERS NGC 362 AND NGC 6723

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Dongwook; Lee, Young-Wook; Pasquato, Mario [Center for Galaxy Evolution Research and Department of Astronomy, Yonsei University, Seoul 03722 (Korea, Republic of); Han, Sang-Il; Roh, Dong-Goo, E-mail: dwlim@galaxy.yonsei.ac.kr, E-mail: ywlee2@yonsei.ac.kr [Korea Astronomy and Space Science Institute, Daejeon 34055 (Korea, Republic of)

    2016-12-01

    Most globular clusters (GCs) are now known to host multiple stellar populations with different abundances of light elements. Here we use narrow-band photometry and low-resolution spectroscopy for NGC 362 and NGC 6723 to investigate their chemical properties and radial distributions of subpopulations. We confirm that NGC 362 and NGC 6723 are among the GCs with multiple populations showing bimodal CN distribution and CN–CH anticorrelation without a significant spread in calcium abundance. These two GCs show more centrally concentrated CN-weak, earlier generation stars compared to the CN-strong, later generation stars. These trends are reversed with respect to those found in previous studies for many other GCs. Our findings, therefore, seem contradictory to the current scenario for the formation of multiple stellar populations, but mass segregation acting on the two subpopulations might be a possible solution to explain this reversed radial trend.

  10. Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression.

    Science.gov (United States)

    Willms, Eduard; Cabañas, Carlos; Mäger, Imre; Wood, Matthew J A; Vader, Pieter

    2018-01-01

    Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs) that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and disease.

  11. The concentration of sexual behaviours in the USA: a closer examination of subpopulations.

    Science.gov (United States)

    Leichliter, Jami S; Chesson, Harrell W; Sternberg, Maya; Aral, Sevgi O

    2010-12-01

    To examine the frequency of three sexual behaviours from the most active to the least active members of the population in various subpopulations using measures of inequality. Data from a US national probability sample of the population aged 15-44 years (National Survey of Family Growth) were used. Gini coefficients and Lorenz curves were calculated in order to examine the concentration of three sexual behaviours: vaginal sex acts (past 4 weeks) and number of opposite-sex partners (past 12 months; lifetime). Analyses were conducted separately for men and women and subpopulations of interest (by age, race/ethnicity, educational level and poverty level). The sexual behaviours examined were concentrated within the most active members of the population. This concentration was most pronounced for vaginal sex acts in the past 4 weeks and lifetime opposite-sex partners, with the top 5% of each population accounting for more of the sexual behaviour than the bottom 50% of the population. Sexual behaviours were most concentrated among adolescents, the least educated and the most impoverished. Some subpopulations had similar mean or median numbers of sex acts (or sex partners), but had different degrees of concentration of these behaviours. Finally, the most impoverished men and women had the highest concentration levels for two of the three sexual behaviours (vaginal sex acts, opposite-sex partners in past 12 months). Given that sexual behaviours tended to be highly concentrated in subpopulations that are often at the highest risk of sexually transmitted infections, targeted interventions may be the most efficient method to reduce risk in these groups while minimising potential unintended consequences.

  12. Expressions of Machismo in Colorectal Cancer Screening Among New Mexico Hispanic Subpopulations

    OpenAIRE

    Getrich, Christina M.; Sussman, Andrew L.; Helitzer, Deborah L.; Hoffman, Richard M.; Warner, Teddy D.; Sánchez, Victoria; Solares, Angélica; Rhyne, Robert L.

    2011-01-01

    Although national colorectal cancer (CRC) incidence rates have steadily decreased, the rate for New Mexico Hispanics has been increasing and screening rates are low. We conducted an exploratory qualitative study to determine barriers to CRC screening for New Mexico Hispanics. We found that machismo served as a dynamic influence on men’s health seeking behaviors; however, it was conceptualized differently by two distinct Hispanic subpopulations and therefore appeared to play a different role i...

  13. Exposure subpopulations and peculiarities of individual dose distributions among inhabitants of the Semipalatinsk region

    Energy Technology Data Exchange (ETDEWEB)

    Pivovarov, S. [Institute of Nuclear Physics, National Nuclear Center of Kazakhstan (Kazakhstan)], E-mail: pivov@inp.kz; Rukhin, A.; Seredavina, T.; Sushkova, N. [Institute of Nuclear Physics, National Nuclear Center of Kazakhstan (Kazakhstan); Hill, P. [Forschungszentrum GmbH, Department of Safety and Radiation Protection, Juelich (Germany)], E-mail: p.hill@fz-juelich.de; Peterson, L.E. [Baylor College of Medicine, Houston, TX (United States)], E-mail: peterson.leif@ieee.org

    2007-07-15

    The results of integral dose estimations for inhabitants of four settlements near the former Semipalatinsk nuclear test site obtained by EPR dosimetry on tooth enamel in 2004-2005 years are discussed. It was found that the observed dose distributions have a nonstandard bimodal form with a mode at low doses in the range from 0.3-0.5 Gy, and a tail with higher doses, possibly suggesting two subpopulations. Possible reasons for such high doses are discussed.

  14. Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression

    Directory of Open Access Journals (Sweden)

    Eduard Willms

    2018-04-01

    Full Text Available Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and

  15. Top IS research on quality of transaction standards: a structured literature review to identify a research gap

    OpenAIRE

    Folmer, E.J.A.; Berends, W.; Oude Luttighuis, P.; Hillegersberg, J. van

    2009-01-01

    This paper contains the results of a systematic literature review executed to determine the coverage of transaction standards in top information systems (IS) and management journals. Specifically, it aims to identify a research gap with respect to this topic. The top 25 journals are thoroughly searched and the selected publications are classified in order to make grounded statements. A moderate amount of literature found specifically aims at transaction standards. Hardly any research is found...

  16. Screening of Natural Product Derivatives Identifies Two Structurally Related Flavonoids as Potent Quorum Sensing Inhibitors against Gram-Negative Bacteria

    Directory of Open Access Journals (Sweden)

    Suvi Manner

    2018-05-01

    Full Text Available Owing to the failure of conventional antibiotics in biofilm control, alternative approaches are urgently needed. Inhibition of quorum sensing (QS represents an attractive target since it is involved in several processes essential for biofilm formation. In this study, a compound library of natural product derivatives (n = 3040 was screened for anti-quorum sensing activity using Chromobacterium violaceum as reporter bacteria. Screening assays, based on QS-mediated violacein production and viability, were performed in parallel to identify non-bactericidal QS inhibitors (QSIs. Nine highly active QSIs were identified, while 328 compounds were classified as moderately actives and 2062 compounds as inactives. Re-testing of the highly actives at a lower concentration against C. violaceum, complemented by a literature search, led to the identification of two flavonoid derivatives as the most potent QSIs, and their impact on biofilm maturation in Escherichia coli and Pseudomonas aeruginosa was further investigated. Finally, effects of these leads on swimming and swarming motility of P. aeruginosa were quantified. The identified flavonoids affected all the studied QS-related functions at micromolar concentrations. These compounds can serve as starting points for further optimization and development of more potent QSIs as adjunctive agents used with antibiotics in the treatment of biofilms.

  17. Nanorobotic investigation identifies novel visual, structural and functional correlates of autoimmune pathology in a blistering skin disease model.

    Directory of Open Access Journals (Sweden)

    Kristina Seiffert-Sinha

    Full Text Available There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg 3. We demonstrate that pathogenic (blister-forming anti-Dsg3 antibodies, distinct from non-pathogenic (non-blister forming anti-Dsg3 antibodies, alter the structural and functional properties of keratinocytes in two sequential steps--an initial loss of cell adhesion and a later induction of apoptosis-related signaling pathways, but not full apoptotic cell death. We propose a "2-Hit" model for autoimmune disruption associated with skin-specific pathogenic autoantibodies. These data provide unprecedented details of autoimmune processes at the tissue level and offer a novel conceptual framework for understanding the action of self-reactive antibodies.

  18. Crystal structure of the gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency.

    Directory of Open Access Journals (Sweden)

    Bruno Correia

    Full Text Available Latency-associated nuclear antigen (LANA mediates γ2-herpesvirus genome persistence and regulates transcription. We describe the crystal structure of the murine gammaherpesvirus-68 LANA C-terminal domain at 2.2 Å resolution. The structure reveals an alpha-beta fold that assembles as a dimer, reminiscent of Epstein-Barr virus EBNA1. A predicted DNA binding surface is present and opposite this interface is a positive electrostatic patch. Targeted DNA recognition substitutions eliminated DNA binding, while certain charged patch mutations reduced bromodomain protein, BRD4, binding. Virus containing LANA abolished for DNA binding was incapable of viable latent infection in mice. Virus with mutations at the charged patch periphery exhibited substantial deficiency in expansion of latent infection, while central region substitutions had little effect. This deficiency was independent of BRD4. These results elucidate the LANA DNA binding domain structure and reveal a unique charged region that exerts a critical role in viral latent infection, likely acting through a host cell protein(s.

  19. An integrated structure- and system-based framework to identify new targets of metabolites and known drugs

    KAUST Repository

    Naveed, Hammad; Hameed, Umar Farook Shahul; Harrus, Deborah; Bourguet, William; Arold, Stefan T.; Gao, Xin

    2015-01-01

    Results: Here, we present a novel integrated structure- and system-based approach of drug-target prediction (iDTP) to enable the large-scale discovery of new targets for small molecules, such as pharmaceutical drugs, co-factors and metabolites (collectively called ‘drugs’). For a given drug, our method uses sequence order–independent structure alignment, hierarchical clustering, and probabilistic sequence similarity to construct a probabilistic pocket ensemble (PPE) that captures promiscuous structural features of different binding sites on known targets. A drug’s PPE is combined with an approximation of its delivery profile to reduce false positives. In our cross-validation study, we use iDTP to predict the known targets of eleven drugs, with 63% sensitivity and 81% specificity. We then predicted novel targets for these drugs—two that are of high pharmacological interest, the nuclear receptor PPARγ and the oncogene Bcl-2, were successfully validated through in vitro binding experiments. Our method is broadly applicable for the prediction of protein-small molecule interactions with several novel applications to biological research and drug development.

  20. Versatile action of picomolar gradients of progesterone on different sperm subpopulations.

    Directory of Open Access Journals (Sweden)

    Diego Rafael Uñates

    Full Text Available High step concentrations of progesterone may stimulate various sperm physiological processes, such as priming and the acrosome reaction. However, approaching the egg, spermatozoa face increasing concentrations of the hormone, as it is secreted by the cumulus cells and then passively diffuses along the cumulus matrix and beyond. In this context, several questions arise: are spermatozoa sensitive to the steroid gradients as they undergo priming and the acrosome reaction? If so, what are the functional gradual concentrations of progesterone? Do spermatozoa in different physiological states respond differentially to steroid gradients? To answer these questions, spermatozoa were confronted with progesterone gradients generated by different hormone concentrations (1 pM to 100 µM. Brief exposure to a 10 pM progesterone gradient stimulated priming for the acrosome reaction in one sperm subpopulation, and simultaneously induced the acrosome reaction in a different sperm subpopulation. This effect was not observed in non-capacitated cells or when progesterone was homogeneously distributed. The results suggest a versatile role of the gradual distribution of very low doses of progesterone, which selectively stimulate the priming and the acrosome reaction in different sperm subpopulations.

  1. Heritability of Susceptibility to Ionizing Radiation-Induced Apoptosis of Human Lymphocyte Subpopulations

    International Nuclear Information System (INIS)

    Schmitz, Annette; Bayer, Jan; Dechamps, Nathalie; Goldin, Lynn; Thomas, Gilles

    2007-01-01

    Purpose: To evaluate the heritability of intrinsic radiosensitivity, the induction of apoptosis in lymphocyte subpopulations was determined on samples from related individuals belonging to large kindred families. Methods and Materials: Quiescent lymphocytes from 334 healthy individuals were gamma-irradiated in vitro. Apoptosis was determined 18 h after irradiation by eight-color flow cytometry. Radiosensitivity was quantified from dose-effect curves. Intrafamilial correlations and heritability were computed for 199 father-mother-offspring trios using the programs SOLAR (Sequential Oligogenic Linkage Analysis Routines) and SAGE (Statistical Analysis for Genetic Epidemiology). Segregation analyses were conducted using SAGE. Results: Marked differential susceptibility of naive and memory T lymphocytes was demonstrated. Also, although age and gender were significant covariates, their effects only accounted for a minor part of the inter-individual variation. Parent-offspring and sib-sib correlations were significant for the radiosensitivity of B cells, T4, and T8 and of effector memory T4 and T8 subpopulations. In the T4-effector memory subpopulation, the phenotype showed correlations most consistent with dominant or additive genetic effects, and the results of the segregation analysis were consistent with the contribution of a bi-allelic dominant locus. Conclusions: Heritability was demonstrated for the susceptibility to ionizing radiation-induced apoptosis of lymphocyte populations, and the segregation of the T4-effector memory radiosensitivity phenotype was consistent with a simple mendelian transmission model involving one major gene

  2. Siglec-7 tetramers characterize B-cell subpopulations and leukemic blasts.

    Science.gov (United States)

    Gieseke, Friederike; Mang, Philippa; Viebahn, Susanne; Sonntag, Inga; Kruchen, Anne; Erbacher, Annika; Pfeiffer, Matthias; Handgretinger, Rupert; Müller, Ingo

    2012-08-01

    Cell surface glycosylation has important regulatory functions in the maturation, activation, and homeostasis of lymphocytes. The family of human sialic acid-binding immunoglobulin-like lectins (siglecs) comprises inhibitory as well as activating receptors intimately involved in the regulation of immune responses. Analyses of the interaction between siglecs and glycans are hampered by the low affinity of this interaction. Therefore, we expressed siglec-7 in eukaryotic cells, allowing for glycosylation, and oligomerized the protein in analogy to MHC tetramers. Using this tool, flow cytometric analysis of lymphocytes became possible. Sialic acid-dependent binding of siglec-7 tetramers was confirmed by glycan array analysis and loss of siglec tetramer binding after neuraminidase treatment of lymphocytes. In contrast to most lymphocyte subpopulations, which showed high siglec-7 ligand expression, B-cell subpopulations could be further subdivided according to different siglec-7 ligand expression levels. We also analyzed blasts from acute lymphoblastic leukemias of the B-cell lineage as well as the T-cell lineage, since malignant transformation is often associated with aberrant cell surface glycosylation. While pediatric T-ALL blasts highly expressed siglec-7 ligands, siglec-7 ligands were barely detectable on cALL blasts. Taken together, oligomerization of recombinant soluble siglec-7 enabled flow cytometric identification of physiologic lymphocyte subpopulations and malignant blasts. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Coevolution analysis of Hepatitis C virus genome to identify the structural and functional dependency network of viral proteins

    Science.gov (United States)

    Champeimont, Raphaël; Laine, Elodie; Hu, Shuang-Wei; Penin, Francois; Carbone, Alessandra

    2016-05-01

    A novel computational approach of coevolution analysis allowed us to reconstruct the protein-protein interaction network of the Hepatitis C Virus (HCV) at the residue resolution. For the first time, coevolution analysis of an entire viral genome was realized, based on a limited set of protein sequences with high sequence identity within genotypes. The identified coevolving residues constitute highly relevant predictions of protein-protein interactions for further experimental identification of HCV protein complexes. The method can be used to analyse other viral genomes and to predict the associated protein interaction networks.

  4. Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder.

    Directory of Open Access Journals (Sweden)

    Mark T W Handley

    2010-05-01

    Full Text Available Neuronal calcium sensor-1 (NCS-1 is a Ca(2+ sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1 protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q did not show changes in its affinity for Ca(2+ or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q with the loss of a Ca(2+ -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain.

  5. Phylogenetic analysis and protein structure modelling identifies distinct Ca(2+)/Cation antiporters and conservation of gene family structure within Arabidopsis and rice species.

    Science.gov (United States)

    Pittman, Jon K; Hirschi, Kendal D

    2016-12-01

    The Ca(2+)/Cation Antiporter (CaCA) superfamily is an ancient and widespread family of ion-coupled cation transporters found in nearly all kingdoms of life. In animals, K(+)-dependent and K(+)-indendent Na(+)/Ca(2+) exchangers (NCKX and NCX) are important CaCA members. Recently it was proposed that all rice and Arabidopsis CaCA proteins should be classified as NCX proteins. Here we performed phylogenetic analysis of CaCA genes and protein structure homology modelling to further characterise members of this transporter superfamily. Phylogenetic analysis of rice and Arabidopsis CaCAs in comparison with selected CaCA members from non-plant species demonstrated that these genes form clearly distinct families, with the H(+)/Cation exchanger (CAX) and cation/Ca(2+) exchanger (CCX) families dominant in higher plants but the NCKX and NCX families absent. NCX-related Mg(2+)/H(+) exchanger (MHX) and CAX-related Na(+)/Ca(2+) exchanger-like (NCL) proteins are instead present. Analysis of genomes of ten closely-related rice species and four Arabidopsis-related species found that CaCA gene family structures are highly conserved within related plants, apart from minor variation. Protein structures were modelled for OsCAX1a and OsMHX1. Despite exhibiting broad structural conservation, there are clear structural differences observed between the different CaCA types. Members of the CaCA superfamily form clearly distinct families with different phylogenetic, structural and functional characteristics, and therefore should not be simply classified as NCX proteins, which should remain as a separate gene family.

  6. Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

    Science.gov (United States)

    Flores, África; Herry, Cyril; Maldonado, Rafael; Berrendero, Fernando

    2017-08-01

    Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867. © The Author 2017. Published by Oxford University Press on behalf of CINP.

  7. Comparative Mapping of Soil Physical-Chemical and Structural Parameters at Field Scale to Identify Zones of Enhanced Leaching Risk

    DEFF Research Database (Denmark)

    Nørgaard, Trine; Møldrup, Per; Olsen, Preben

    2013-01-01

    Preferential flow and particle-facilitated transport through macropores contributes significantly to the transport of strongly sorbing substances such as pesticides and phosphorus. The aim of this study was to perform a field-scale characterization of basic soil physical properties like clay...... and organic carbon content and investigate whether it was possible to relate these to derived structural parameters such as bulk density and conservative tracer parameters and to actual particle and phosphorus leaching patterns obtained from laboratory leaching experiments. Sixty-five cylindrical soil columns...... of 20 cm height and 20 cm diameter and bulk soil were sampled from the topsoil in a 15 m  15 m grid in an agricultural loamy field. Highest clay contents and highest bulk densities were found in the northern part of the field. Leaching experiments with a conservative tracer showed fast 5% tracer...

  8. Functional Magnetic Resonance Imaging with Concurrent Urodynamic Testing Identifies Brain Structures Involved in Micturition Cycle in Patients with Multiple Sclerosis.

    Science.gov (United States)

    Khavari, Rose; Karmonik, Christof; Shy, Michael; Fletcher, Sophie; Boone, Timothy

    2017-02-01

    Neurogenic lower urinary tract dysfunction, which is common in patients with multiple sclerosis, has a significant impact on quality of life. In this study we sought to determine brain activity processes during the micturition cycle in female patients with multiple sclerosis and neurogenic lower urinary tract dysfunction. We report brain activity on functional magnetic resonance imaging and simultaneous urodynamic testing in 23 ambulatory female patients with multiple sclerosis. Individual functional magnetic resonance imaging activation maps at strong desire to void and at initiation of voiding were calculated and averaged at Montreal Neuroimaging Institute. Areas of significant activation were identified in these average maps. Subgroup analysis was performed in patients with elicitable neurogenic detrusor overactivity or detrusor-sphincter dyssynergia. Group analysis of all patients at strong desire to void yielded areas of activation in regions associated with executive function (frontal gyrus), emotional regulation (cingulate gyrus) and motor control (putamen, cerebellum and precuneus). Comparison of the average change in activation between previously reported healthy controls and patients with multiple sclerosis showed predominantly stronger, more focal activation in the former and lower, more diffused activation in the latter. Patients with multiple sclerosis who had demonstrable neurogenic detrusor overactivity and detrusor-sphincter dyssynergia showed a trend toward distinct brain activation at full urge and at initiation of voiding respectively. We successfully studied brain activation during the entire micturition cycle in female patients with neurogenic lower urinary tract dysfunction and multiple sclerosis using a concurrent functional magnetic resonance imaging/urodynamic testing platform. Understanding the central neural processes involved in specific parts of micturition in patients with neurogenic lower urinary tract dysfunction may identify areas

  9. Rapid structural and compositional change in an old-growth subtropical forest: using plant traits to identify probable drivers.

    Science.gov (United States)

    Malizia, Agustina; Easdale, Tomás A; Grau, H Ricardo

    2013-01-01

    Recent studies have shown directional changes in old-growth tropical forests, but changes are complex and diverse, and their drivers unclear. Here, we report rapid net structural and compositional changes in an old-growth subtropical forest and we assess the functional nature of these changes to test hypothetical drivers including recovery from past disturbances, reduction in ungulate browsing, CO2 fertilization, and increases in rainfall and temperature. The study relies on 15 years of demographic monitoring within 8 ha of subtropical montane forest in Argentina. Between 1992 and 2007, stem density markedly increased by 50% (12 stems ha(-1) y(-1)) and basal area by 6% (0.13 m(2) ha(-1) y(-1)). Increased stem density resulted from enhanced recruitment of understory treelets (Piper tucumanum, Eugenia uniflora, Allophylus edulis) into small size classes. Among 27 common tree species, net population growth was negatively correlated with maximum tree size and longevity, and positively correlated with leaf size and leaf nutrient content, especially so when initial population size was controlled for. Changes were inconsistent with predictions derived from past disturbances (no increase in shade-tolerant or long-lived late-succesional species), rainfall or temperature increase (no increase in evergreen or deciduous species, respectively). However, the increase in nutrient-rich soft-leaved species was consistent with exclusion of large herbivores two decades before monitoring started; and CO2 fertilization could help explain the disproportionate increase in small stems. Reductions in populations of large vertebrates have been observed in many otherwise undisturbed tropical forests, and our results suggest they can have important structural and functional repercussions in these forests.

  10. Structural Response of the Earth's Crust to an Extra-Terrestrial Source of Stress by Identifying its Characteristic Pattern

    Science.gov (United States)

    Dasgupta, B.

    2016-12-01

    The earth's crust is a geodynamic realm, which is constantly evolving. Due to its dynamic nature, the crust is constantly being subjected to remodelling. The earth's crustal response to stress is a result of isostatic compensation. The crust is also a living proof of yesteryears' dynamics. Extra-terrestrial agents of deformation refers to meteorites, asteroids etc. These are catastrophic events that influence a larger area (considering larger impact bodies). They effect the crust from outside, hence leave behind very specific structural signatures.Consider an extra-terrestrial object impacting the earth's crust. The problem can be broken down into 3 parts: Pre Impact (kinematics of the object and nature of surface of impact); Syn Impact (dissipation of energy and formation of crater); and Post Impact (structural response, geophysical anomalies and effect on biota)Upon impact, the projectile penetrates the earth's crust to a depth of twice its diameter. Shock waves generated due impact propagate in all possible directions. The reflected waves cause complete melting and vaporization of the impact body. At the same time, increased internal energy of the system melts the target rock. Depending on the thickness and density of crustal matter, its' interaction with the mantle is determined. Data collection from such impact sites is the first step towards its theoretical modeling. Integrating geophysical (seismic, magnetic), paleomagnetic, geochemical and geo-chronological data one can determine the kinematic parameters that governed the event. A working model that illustrates the crustal responses to extraterrestrial stress of extreme magnitude cannot be qualitative. Hence the most fundamental thing at this point is quantification of these parameters. The variables form a `mass-energy equation', a simple theorem in Classical Physics. This project is directed to give the equation its shape. The equation will be the foundation on which the simulation model will rest. Mass

  11. Clinical value of Pro-GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC-CIK biological therapy.

    Science.gov (United States)

    He, Lijie; Wang, Jing; Chang, Dandan; Lv, Dandan; Li, Haina; Zhang, Heping

    2018-02-01

    The present study investigated the aptness of assessing the levels of progastrin-releasing peptide (Pro-GRP) in addition to the T lymphocyte subpopulation in lung cancer patients prior to and after therapy for determining immune function. A total of 45 patients with lung cancer were recruited and stratified in to a non-small cell lung cancer (NSCLC) and an SCLC group. Prior to and after treatment by combined biological therapy comprising chemotherapy or chemoradiotherapy followed by three cycles of retransformation of autologous dendritic cells-cytokine-induced killer cells (DC-CIK), the peripheral blood was assessed for populations of CD3 + , CD4 + , CD8 + and regulatory T cells (Treg) by flow cytometry, and for the levels of pro-GRP, carcinoembryonic antigen, neuron-specific enolase and Cyfra 21-1. The results revealed that in NSCLC patients, CD8 + T lymphocytes and Treg populations were decreased, and that CD3 + and CD4 + T lymphocytes as well as the CD4 + /CD8 + ratio were increased after therapy; in SCLC patients, CD3 + , CD4 + and CD8 + T lymphocytes were increased, while Treg cells were decreased after treatment compared with those at baseline. In each group, Pro-GRP was decreased compared with that prior to treatment, and in the SCLC group only, an obvious negative correlation was identified between Pro-GRP and the T lymphocyte subpopulation. Furthermore, a significant correlation between Pro-GRP and Tregs was identified in each group. In conclusion, the present study revealed that the immune function of the patients was improved after biological therapy. The results suggested a significant correlation between Pro-GRP and the T lymphocyte subpopulation in SCLC patients. Detection of Pro-GRP may assist the early clinical diagnosis of SCLC and may also be used to assess the immune regulatory function of patients along with the T lymphocyte subpopulation. Biological therapy with retransformed autologous DC-CIK was indicated to enhance the specific elimination

  12. SiglecF+Gr1hi eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice.

    Science.gov (United States)

    Percopo, Caroline M; Brenner, Todd A; Ma, Michelle; Kraemer, Laura S; Hakeem, Reem M A; Lee, James J; Rosenberg, Helene F

    2017-01-01

    Although eosinophils as a group are readily identified by their unique morphology and staining properties, flow cytometry provides an important means for identification of subgroups based on differential expression of distinct surface Ags. Here, we characterize an eosinophil subpopulation defined by high levels of expression of the neutrophil Ag Gr1 (CD45 + CD11c - SiglecF + Gr1 hi ). SiglecF + Gr1 hi eosinophils, distinct from the canonical SiglecF + Gr1 - eosinophil population, were detected in allergen-challenged wild-type and granule protein-deficient (EPX -/- and MBP-1 -/- ) mice, but not in the eosinophil-deficient ΔdblGATA strain. In contrast to Gr1 + neutrophils, which express both cross-reacting Ags Ly6C and Ly6G, SiglecF + Gr1 hi eosinophils from allergen-challenged lung tissue are uniquely Ly6G + Although indistinguishable from the more-numerous SiglecF + Gr1 - eosinophils under light microscopy, FACS-isolated populations revealed prominent differences in cytokine contents. The lymphocyte-targeting cytokines CXCL13 and IL-27 were identified only in the SiglecF + Gr1 hi eosinophil population (at 3.9 and 4.8 pg/10 6 cells, respectively), as was the prominent proinflammatory mediator IL-13 (72 pg/10 6 cells). Interestingly, bone marrow-derived (SiglecF + ), cultured eosinophils include a more substantial Gr1 + subpopulation (∼50%); Gr1 + bmEos includes primarily a single Ly6C + and a smaller, double-positive (Ly6C + Ly6G + ) population. Taken together, our findings characterize a distinct SiglecF + Gr1 hi eosinophil subset in lungs of allergen-challenged, wild-type and granule protein-deficient mice. SiglecF + Gr1 hi eosinophils from wild-type mice maintain a distinct subset of cytokines, including those active on B and T lymphocytes. These cytokines may facilitate eosinophil-mediated immunomodulatory responses in the allergen-challenged lung as well as in other distinct microenvironments. © Society for Leukocyte Biology.

  13. Using a network-based approach to identify interactions structure for innovation in a low-technology intensive sector

    Energy Technology Data Exchange (ETDEWEB)

    Aouinait, C.; Lepori, B.; Christen, D.; Carlen, C.; Foray, D.

    2016-07-01

    Knowledge transfer in the agricultural network is realized through interactions between stakeholders, inducing innovation development and diffusion. The aim of the paper was to trace interactions in the Swiss apricot sector. Identification of collaborations using face-toface interviews of knowledge producers and knowledge users were conducted. The study showed that informal collaborations are exclusively used to transfer knowledge and create innovation. Personal ties have been established between internal actors of the value chain (e.g. professionals like producers, transformers and wholesalers). External partners like public research organizations have created strong ties with agricultural stakeholders. However, the spatial proximity does not guarantee higher rate of collaborations. The links with the Universities of Applied Sciences, closely located, are sparse. Hence, in order to warrant innovation success, spatial proximity has to be balanced with organizational proximity. Despite the educational background of producers, there are a few connections with universities. Human capital formation and education in the agricultural sector should be examined to design innovation policy. Besides, the public research center for agriculture catalyzes knowledge transfer and facilitates innovation adoption. A suitable ecology of actors through the value chain from research to application is necessary. Furthermore, productive interactions should be investigated to identify the efficiency of knowledge and innovation transfer mechanisms and potential gaps in this process. (Author)

  14. Optimized multiparametric flow cytometric analysis of circulating endothelial cells and their subpopulations in peripheral blood of patients with solid tumors: a technical analysis.

    Science.gov (United States)

    Zhou, Fangbin; Zhou, Yaying; Yang, Ming; Wen, Jinli; Dong, Jun; Tan, Wenyong

    2018-01-01

    Circulating endothelial cells (CECs) and their subpopulations could be potential novel biomarkers for various malignancies. However, reliable enumerable methods are warranted to further improve their clinical utility. This study aimed to optimize a flow cytometric method (FCM) assay for CECs and subpopulations in peripheral blood for patients with solid cancers. An FCM assay was used to detect and identify CECs. A panel of 60 blood samples, including 44 metastatic cancer patients and 16 healthy controls, were used in this study. Some key issues of CEC enumeration, including sample material and anticoagulant selection, optimal titration of antibodies, lysis/wash procedures of blood sample preparation, conditions of sample storage, sufficient cell events to enhance the signal, fluorescence-minus-one controls instead of isotype controls to reduce background noise, optimal selection of cell surface markers, and evaluating the reproducibility of our method, were integrated and investigated. Wilcoxon and Mann-Whitney U tests were used to determine statistically significant differences. In this validation study, we refined a five-color FCM method to detect CECs and their subpopulations in peripheral blood of patients with solid tumors. Several key technical issues regarding preanalytical elements, FCM data acquisition, and analysis were addressed. Furthermore, we clinically validated the utility of our method. The baseline levels of mature CECs, endothelial progenitor cells, and activated CECs were higher in cancer patients than healthy subjects ( P technical issues found in previously published assays and validated the reproducibility and sensitivity of our proposed method. Future work is required to explore the potential of our optimized method in clinical oncologic applications.

  15. Investigation of Pseudomonas aeruginosa quorum-sensing signaling system for identifying multiple inhibitors using molecular docking and structural analysis methodology.

    Science.gov (United States)

    Soheili, Vahid; Bazzaz, Bibi Sedigheh Fazly; Abdollahpour, Nooshin; Hadizadeh, Farzin

    2015-12-01

    Pseudomonas aeruginosa is an opportunistic human pathogen and a common Gram-negative bacterium in hospital-acquired infections. It causes death in many burn victims, cystic-fibrosis and neutropenic-cancer patients. It is known that P. aeruginosa biofilm maturation and production of cell-associated and extracellular virulence factors such as pyocyanin, elastase and rhamnolipids are under the control of a quorum-sensing (QS) system. Among several proteins involved in the Pseudomonas QS mechanism, LasR and PqsE play an important role in its cascade signaling system. They can cause increases in QS factors, biofilm maturation, and the production of virulence factors. Therefore, inhibition of these proteins can reduce the pathogenicity of P. aeruginosa. According to the structure of corresponding auto-inducers bound to these proteins, in silico calculations were performed with some non-steroidal anti-inflammatory drugs (NSAIDs) to estimate possible interactions and find the co-inhibitors of LasR and PqsE. The results showed that oxicams (Piroxicam and Meloxicam) can interact well with active sites of both proteins with the Ki of 119.43 nM and 4.0 μM for Meloxicam and 201.39 nM and 4.88 μM against LasR and PqsE, respectively. These findings suggested that Piroxicam and Meloxicam can be used as potential inhibitors for control of the P. aeruginosa QS signaling system and biofilm formation, and may be used in the design of multiple inhibitors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Optimized multiparametric flow cytometric analysis of circulating endothelial cells and their subpopulations in peripheral blood of patients with solid tumors: a technical analysis

    Directory of Open Access Journals (Sweden)

    Zhou F

    2018-03-01

    Full Text Available Fangbin Zhou,1,2 Yaying Zhou,3 Ming Yang,1 Jinli Wen,3 Jun Dong,4 Wenyong Tan1 1Department of Oncology, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, Shenzhen, People’s Republic of China; 2Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, People’s Republic of China; 3Clinical Medical Research Center, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, Shenzhen, People’s Republic of China; 4Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, People’s Republic of China Background: Circulating endothelial cells (CECs and their subpopulations could be potential novel biomarkers for various malignancies. However, reliable enumerable methods are warranted to further improve their clinical utility. This study aimed to optimize a flow cytometric method (FCM assay for CECs and subpopulations in peripheral blood for patients with solid cancers.Patients and methods: An FCM assay was used to detect and identify CECs. A panel of 60 blood samples, including 44 metastatic cancer patients and 16 healthy controls, were used in this study. Some key issues of CEC enumeration, including sample material and anticoagulant selection, optimal titration of antibodies, lysis/wash procedures of blood sample preparation, conditions of sample storage, sufficient cell events to enhance the signal, fluorescence-minus-one controls instead of isotype controls to reduce background noise, optimal selection of cell surface markers, and evaluating the reproducibility of our method, were integrated and investigated. Wilcoxon and Mann–Whitney U tests were used to determine statistically significant differences.Results: In this validation study, we refined a five-color FCM method to detect CECs and their subpopulations in peripheral blood of patients

  17. Identification of a sub-population of B cells that proliferates after infection with epstein-barr virus

    Directory of Open Access Journals (Sweden)

    Ye Jianjiang

    2011-02-01

    Full Text Available Abstract Background Epstein-Barr virus (EBV-driven B cell proliferation is critical to its subsequent persistence in the host and is a key event in the development of EBV-associated B cell diseases. Thus, inquiry into early cellular events that precede EBV-driven proliferation of B cells is essential for understanding the processes that can lead to EBV-associated B cell diseases. Methods Infection with high titers of EBV of mixed, primary B cells in different stages of differentiation occurs during primary EBV infection and in the setting of T cell-immunocompromise that predisposes to development of EBV-lymphoproliferative diseases. Using an ex vivo system that recapitulates these conditions of infection, we correlated expression of selected B cell-surface markers and intracellular cytokines with expression of EBV latency genes and cell proliferation. Results We identified CD23, CD58, and IL6, as molecules expressed at early times after EBV-infection. EBV differentially infected B cells into two distinct sub-populations of latently infected CD23+ cells: one fraction, marked as CD23hiCD58+IL6- by day 3, subsequently proliferated; another fraction, marked as CD23loCD58+, expressed IL6, a B cell growth factor, but failed to proliferate. High levels of LMP1, a critical viral oncoprotein, were expressed in individual CD23hiCD58+ and CD23loCD58+ cells, demonstrating that reduced levels of LMP1 did not explain the lack of proliferation of CD23loCD58+ cells. Differentiation stage of B cells did not appear to govern this dichotomy in outcome either. Memory or naïve B cells did not exclusively give rise to either CD23hi or IL6-expressing cells; rather memory B cells gave rise to both sub-populations of cells. Conclusions B cells are differentially susceptible to EBV-mediated proliferation despite expression of viral gene products known to be critical for continuous B cell growth. Cellular events, in addition to viral gene expression, likely play a

  18. Flow cytometric analysis of lymphocytes and lymphocyte subpopulations in induced sputum from patients with asthma

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    Yutaro Shiota

    2000-01-01

    Full Text Available Study objectives were to compare the numbers of lymphocytes and lymphocyte subpopulations in induced sputum from asthmatic patients and from healthy subjects, and to determine the effect of inhaled anti-asthmatic steroid therapy on these cell numbers. Hypertonic saline inhalation was used to non-invasively induce sputum samples in 34 patients with bronchial asthma and 21 healthy subjects. The sputum samples were reduced with dithioerythritol and absolute numbers of lymphocytes and lymphocyte subpopulations were assessed by direct immunofluorescence and flow cytometry. To assess the effect of beclomethasone dipropionate (BDP on induced sputum, numbers of lymphocytes and lymphocyte subpopulations in sputum also were evaluated after 4 weeks of BDP inhalation treatment in seven asthmatic patients. An adequate sample was obtained in 85.3% of patients with asthma and in 79.2% of the healthy subjects. Induced sputum from patients with asthma had increased numbers of lymphocytes (P = 0.009; CD4+ cells (P = 0.044; CD4+ cells-bearing interleukin-2 receptor (CD25; P = 0.016; and CD4+ cells bearing human histocompatibility leukocyte antigen (HLA-DR (P = 0.033. CD8+ cells were not increased in asthmatic patients. In patients treated with inhaled steroids, numbers of lymphocytes, CD4+ cells, CD25-bearing CD4+ cells and HLA-DR-bearing CD4+ cells in sputum decreased from pretreatment numbers (P = 0.016, 0.002, 0.003 and 0.002, respectively. Analysis of lymphocytes in induced sputum by flow cytometry is useful in assessing bronchial inflammation, and activated CD4+ lymphocytes may play a key role in the pathogenesis of airway inflammation in bronchial asthma.

  19. The effect of supportive E. coli mastitis treatment on PMN chemiluminescence and subpopulations of T lymphocytes.

    Science.gov (United States)

    Markiewicz, H; Krumrych, W; Gehrke, M

    2013-01-01

    The aim of this field study was to assess the impact of a single i.m. injection of lysozyme dimer and flunixin meglumine in combination with intramammary and systemic antibiotic on chemiluminescence of PMN (polymorphonuclear leucocytes) and subpopulations of lymphocyte T in blood of cows with E. coli mastitis. Examinations were performed on 30 dairy cows affected with naturally occurring acute form of E. coli mastitis. Cows were randomly divided into three groups according to the method of treatment. The first group was treated with approved intramammary antibiotic product, the same antibiotic in i.m. injection and one injection of flunixin meglumine on the first day of therapy. Next group was treated with the same antibiotic and additionally one injection of lysozyme dimer on the first day of therapy. The third one was treated only with an antibiotic and served as a control group. Blood samples were taken before treatment and on days 3 and 7. In samples haematology indices were determined, spontaneous and opsonised zymosan stimulated CL and PMA measurements were performed and the subpopulations of T lymphocyte (CD2(+), CD4(+), CD8(+)) were assayed in whole blood. There was no effect of the applied supportive treatment on the value of morphological blood indices. A significant influence of the time of sample collection on the level of CL and dynamics of lymphocytes T subpopulation was demonstrated. A single injection of flunixin meglumine or lysozyme dimer on the day of the beginning of treatment of E. coli mastitis, does not affect the level of neutrophil chemiluminescence and the percentage of T lymphocytes in the blood of mastitic cows in the analysed period of time.

  20. Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients

    International Nuclear Information System (INIS)

    Sage, Eva K.; Gehrmann, Mathias; Sedelmayr, Michael; Schmid, Thomas E.; Combs, Stephanie E.; Multhoff, Gabriele; Geinitz, Hans; Duma, Marciana N.

    2017-01-01

    Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects. A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period. Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3 + T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT. Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells. (orig.) [de

  1. Subpopulations of Bone Marrow Mesenchymal Stem Cells Exhibit Differential Effects in Delaying Retinal Degeneration.

    Science.gov (United States)

    Li, P; Tian, H; Li, Z; Wang, L; Gao, F; Ou, Q; Lian, C; Li, W; Jin, C; Zhang, J; Xu, J-Y; Wang, J; Zhang, J; Wang, F; Lu, L; Xu, G-T

    2016-01-01

    Bone marrow mesenchymal stem cells (BMSCs) have a therapeutic role in retinal degeneration (RD). However, heterogeneity of BMSCs may be associated with differential therapeutic effects in RD. In order to confirm this hypothesis, two subsets of rat BMSCs, termed rBMSC1 and rBMSC2, were obtained, characterized and functionally evaluated in the treatment of RD of Royal College of Surgeons (RCS) rats. Both subpopulations expressed mesenchymal stem cells (MSC) markers CD29 and CD90, but were negative for hemacyte antigen CD11b and CD45 expression. In comparison with rBMSC2, rBMSC1 showed higher rate of proliferation, stronger colony formation, and increased adipogenic potential, whereas rBMSC2 exhibited higher osteogenic potential. Microarray analysis showed differential gene expression patterns between rBMSC1 and rBMSC2, including functions related to proliferation, differentiation, immunoregulation, stem cell maintenance and division, survival and antiapoptosis. After subretinal transplantation in RCS rats, rBMSC1 showed stronger rescue effect than rBMSC2, including increased b-wave amplitude, restored retinal nuclear layer thickness, and decreased number of apoptotic photoreceptors, whereas the rescue function of rBMSC2 was essentially not better than the control. Histological analysis also demonstrated that rBMSC1 possessed a higher survival rate than rBMSC2 in subretinal space. In addition, treatment of basic fibroblast growth factor, an accompanying event in subretinal injection, triggered more robust increase in secretion of growth factors by rBMSC1 as compared to rBMSC2. Taken together, these results have suggested that the different therapeutic functions of BMSC subpopulations are attributed to their distinct survival capabilities and paracrine functions. The underlying mechanisms responsible for the different functions of BMSC subpopulation may lead to a new strategy for the treatment of RD.

  2. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis for continuous, binary, and count outcomes.

    Science.gov (United States)

    Yip, Wai-Ki; Bonetti, Marco; Cole, Bernard F; Barcella, William; Wang, Xin Victoria; Lazar, Ann; Gelber, Richard D

    2016-08-01

    For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual. Medical research is now focusing more on providing personalized care for patients, which requires investigating how patient characteristics, including novel biomarkers, modify the effect of current treatment modalities. This is known as heterogeneity of treatment effects. A better understanding of the interaction between treatment and patient-specific prognostic factors will enable practitioners to expand the availability of tailored therapies, with the ultimate goal of improving patient outcomes. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement. Here, we extend the Subpopulation Treatment Effect Pattern Plot approach to continuous, binary, and count outcomes, which can be easily modeled using generalized linear models. With this extension of Subpopulation Treatment Effect Pattern Plot, these additional types of treatment effects within subpopulations defined with respect to a covariate of interest can be estimated, and the statistical significance of any observed heterogeneity of treatment effect can be assessed using permutation tests. The desirable feature that commonly used models are applied to well-defined patient subgroups to estimate treatment effects is retained in this extension. We describe a simulation study to confirm that the proper Type I error rate is maintained when there is no treatment heterogeneity, and a power study to show that the statistics have

  3. Raising an Antibody Specific to Breast Cancer Subpopulations Using Phage Display on Tissue Sections

    DEFF Research Database (Denmark)

    Larsen, Simon Asbjørn; Meldgaard, Theresa; Fridriksdottir, Agla Jael Rubner

    2016-01-01

    BACKGROUND/AIM: Primary tumors display a great level of intra-tumor heterogeneity in breast cancer. The current lack of prognostic and predictive biomarkers limits accurate stratification and the ability to predict response to therapy. The aim of the present study was to select recombinant antibody...... fragments specific against breast cancer subpopulations, aiding the discovery of novel biomarkers. MATERIALS AND METHODS: Recombinant antibody fragments were selected by phage display. A novel shadowstick technology enabled the direct selection using tissue sections of antibody fragments specific against...

  4. A SAGE-based screen for genes expressed in sub-populations of neurons in the mouse dorsal root ganglion

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    Garces Alain

    2007-11-01

    Full Text Available Abstract Background The different sensory modalities temperature, pain, touch and muscle proprioception are carried by somatosensory neurons of the dorsal root ganglia. Study of this system is hampered by the lack of molecular markers for many of these neuronal sub-types. In order to detect genes expressed in sub-populations of somatosensory neurons, gene profiling was carried out on wild-type and TrkA mutant neonatal dorsal root ganglia (DRG using SAGE (serial analysis of gene expression methodology. Thermo-nociceptors constitute up to 80 % of the neurons in the DRG. In TrkA mutant DRGs, the nociceptor sub-class of sensory neurons is lost due to absence of nerve growth factor survival signaling through its receptor TrkA. Thus, comparison of wild-type and TrkA mutants allows the identification of transcripts preferentially expressed in the nociceptor or mechano-proprioceptor subclasses, respectively. Results Our comparison revealed 240 genes differentially expressed between the two tissues (P Conclusion We have identified and characterized the detailed expression patterns of three genes in the developing DRG, placing them in the context of the known major neuronal sub-types defined by molecular markers. Further analysis of differentially expressed genes in this tissue promises to extend our knowledge of the molecular diversity of different cell types and forms the basis for understanding their particular functional specificities.

  5. Site-Mutation of Hydrophobic Core Residues Synchronically Poise Super Interleukin 2 for Signaling: Identifying Distant Structural Effects through Affordable Computations

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    Longcan Mei

    2018-03-01

    Full Text Available A superkine variant of interleukin-2 with six site mutations away from the binding interface developed from the yeast display technique has been previously characterized as undergoing a distal structure alteration which is responsible for its super-potency and provides an elegant case study with which to get insight about how to utilize allosteric effect to achieve desirable protein functions. By examining the dynamic network and the allosteric pathways related to those mutated residues using various computational approaches, we found that nanosecond time scale all-atom molecular dynamics simulations can identify the dynamic network as efficient as an ensemble algorithm. The differentiated pathways for the six core residues form a dynamic network that outlines the area of structure alteration. The results offer potentials of using affordable computing power to predict allosteric structure of mutants in knowledge-based mutagenesis.

  6. Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number.

    Science.gov (United States)

    Podhorecka, Monika; Goracy, Aneta; Szymczyk, Agnieszka; Kowal, Malgorzata; Ibanez, Blanca; Jankowska-Lecka, Olga; Macheta, Arkadiusz; Nowaczynska, Aleksandra; Drab-Urbanek, Elzbieta; Chocholska, Sylwia; Jawniak, Dariusz; Hus, Marek

    2017-05-23

    B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration.The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively.The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.

  7. Connective Tissue Growth Factor reporter mice label a subpopulation of mesenchymal progenitor cells that reside in the trabecular bone region.

    Science.gov (United States)

    Wang, Wen; Strecker, Sara; Liu, Yaling; Wang, Liping; Assanah, Fayekah; Smith, Spenser; Maye, Peter

    2015-02-01

    Few gene markers selectively identify mesenchymal progenitor cells inside the bone marrow. We have investigated a cell population located in the mouse bone marrow labeled by Connective Tissue Growth Factor reporter expression (CTGF-EGFP). Bone marrow flushed from CTGF reporter mice yielded an EGFP+ stromal cell population. Interestingly, the percentage of stromal cells retaining CTGF reporter expression decreased with age in vivo and was half the frequency in females compared to males. In culture, CTGF reporter expression and endogenous CTGF expression marked the same cell types as those labeled using Twist2-Cre and Osterix-Cre fate mapping approaches, which previously had been shown to identify mesenchymal progenitors in vitro. Consistent with this past work, sorted CTGF+ cells displayed an ability to differentiate into osteoblasts, chondrocytes, and adipocytes in vitro and into osteoblast, adipocyte, and stromal cell lineages after transplantation into a parietal bone defect. In vivo examination of CTGF reporter expression in bone tissue sections revealed that it marked cells highly localized to the trabecular bone region and was not expressed in the perichondrium or periosteum. Mesenchymal cells retaining high CTGF reporter expression were adjacent to, but distinct from mature osteoblasts lining bone surfaces and endothelial cells forming the vascular sinuses. Comparison of CTGF and Osterix reporter expression in bone tissue sections indicated an inverse correlation between the strength of CTGF expression and osteoblast maturation. Down-regulation of CTGF reporter expression also occurred during in vitro osteogenic differentiation. Collectively, our studies indicate that CTGF reporter mice selectively identify a subpopulation of bone marrow mesenchymal progenitor cells that reside in the trabecular bone region. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Hierarchical super-structure identified by polarized light microscopy, electron microscopy and nanoindentation: Implications for the limits of biological control over the growth mode of abalone sea shells

    Directory of Open Access Journals (Sweden)

    Schneider Andreas S

    2012-09-01

    Full Text Available Abstract Background Mollusc shells are commonly investigated using high-resolution imaging techniques based on cryo-fixation. Less detailed information is available regarding the light-optical properties. Sea shells of Haliotis pulcherina were embedded for polishing in defined orientations in order to investigate the interface between prismatic calcite and nacreous aragonite by standard materialographic methods. A polished thin section of the interface was prepared with a defined thickness of 60 μm for quantitative birefringence analysis using polarized light and LC-PolScope microscopy. Scanning electron microscopy images were obtained for comparison. In order to study structural-mechanical relationships, nanoindentation experiments were performed. Results Incident light microscopy revealed a super-structure in semi-transparent regions of the polished cross-section under a defined angle. This super-structure is not visible in transmitted birefringence analysis due to the blurred polarization of small nacre platelets and numerous organic interfaces. The relative orientation and homogeneity of calcite prisms was directly identified, some of them with their optical axes exactly normal to the imaging plane. Co-oriented "prism colonies" were identified by polarized light analyses. The nacreous super-structure was also visualized by secondary electron imaging under defined angles. The domains of the super-structure were interpreted to consist of crystallographically aligned platelet stacks. Nanoindentation experiments showed that mechanical properties changed with the same periodicity as the domain size. Conclusions In this study, we have demonstrated that insights into the growth mechanisms of nacre can be obtained by conventional light-optical methods. For example, we observed super-structures formed by co-oriented nacre platelets as previously identified using X-ray Photo-electron Emission Microscopy (X-PEEM [Gilbert et al., Journal of the

  9. Using satellite telemetry to define spatial population structure in polar bears in the Norwegian and western Russian Arctic

    Science.gov (United States)

    Mauritzen, Mette; Derocher, Andrew E.; Wiig, Øystein; Belikov, Stanislav; Boltunov, Andrei N.; Garner, Gerald W.

    2002-01-01

    1. Animal populations, defined by geographical areas within a species’ distribution where population dynamics are largely regulated by births and deaths rather than by migration from surrounding areas, may be the correct unit for wildlife management. However, in heterogeneous landscapes varying habitat quality may yield subpopulations with distinct patterns in resource use and demography significant to the dynamics of populations.2. To define the spatial population structure of polar bears Ursus maritimus in the Norwegian and western Russian Arctic, and to assess the existence of a shared population between the two countries, we analysed satellite telemetry data obtained from 105 female polar bears over 12 years.3. Using both cluster analyses and home-range estimation methods, we identified five population units inhabiting areas with different sea-ice characteristics and prey availability.4. The continuous distribution of polar bear positions indicated that the different subpopulations formed one continuous polar bear population in the Norwegian and western Russian Arctic. Hence, Norway and Russia have a shared management responsibility.5. The spatial population structure identified will provide a guide for evaluating geographical patterns in polar bear ecology, the dynamics of polar bear–seal relationships and the effects of habitat alteration due to climate change. The work illustrates the importance of defining population borders and subpopulation structure in understanding the dynamics and management of larger animals.

  10. Sequencing of a patient with balanced chromosome abnormalities and neurodevelopmental disease identifies disruption of multiple high risk loci by structural variation.

    Directory of Open Access Journals (Sweden)

    Jonathon Blake

    Full Text Available Balanced chromosome abnormalities (BCAs occur at a high frequency in healthy and diseased individuals, but cost-efficient strategies to identify BCAs and evaluate whether they contribute to a phenotype have not yet become widespread. Here we apply genome-wide mate-pair library sequencing to characterize structural variation in a patient with unclear neurodevelopmental disease (NDD and complex de novo BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (LINC00299, NUP205, PSMD14 that gave rise to abnormal mRNAs and could be assumed as disease-causing. However, unbiased genome-wide analysis of the sequencing data for cryptic structural variation was key to reveal an additional submicroscopic inversion that truncates the schizophrenia- and bipolar disorder-associated brain transcription factor ZNF804A as an equally likely NDD-driving gene. Deep sequencing of fluorescent-sorted wild-type and derivative chromosomes confirmed the clinically undetected BCA. Moreover, deep sequencing further validated a high accuracy of mate-pair library sequencing to detect structural variants larger than 10 kB, proposing that this approach is powerful for clinical-grade genome-wide structural variant detection. Our study supports previous evidence for a role of ZNF804A in NDD and highlights the need for a more comprehensive assessment of structural variation in karyotypically abnormal individuals and patients with neurocognitive disease to avoid diagnostic deception.

  11. Sequencing of a Patient with Balanced Chromosome Abnormalities and Neurodevelopmental Disease Identifies Disruption of Multiple High Risk Loci by Structural Variation

    Science.gov (United States)

    Blake, Jonathon; Riddell, Andrew; Theiss, Susanne; Gonzalez, Alexis Perez; Haase, Bettina; Jauch, Anna; Janssen, Johannes W. G.; Ibberson, David; Pavlinic, Dinko; Moog, Ute; Benes, Vladimir; Runz, Heiko

    2014-01-01

    Balanced chromosome abnormalities (BCAs) occur at a high frequency in healthy and diseased individuals, but cost-efficient strategies to identify BCAs and evaluate whether they contribute to a phenotype have not yet become widespread. Here we apply genome-wide mate-pair library sequencing to characterize structural variation in a patient with unclear neurodevelopmental disease (NDD) and complex de novo BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (LINC00299, NUP205, PSMD14) that gave rise to abnormal mRNAs and could be assumed as disease-causing. However, unbiased genome-wide analysis of the sequencing data for cryptic structural variation was key to reveal an additional submicroscopic inversion that truncates the schizophrenia- and bipolar disorder-associated brain transcription factor ZNF804A as an equally likely NDD-driving gene. Deep sequencing of fluorescent-sorted wild-type and derivative chromosomes confirmed the clinically undetected BCA. Moreover, deep sequencing further validated a high accuracy of mate-pair library sequencing to detect structural variants larger than 10 kB, proposing that this approach is powerful for clinical-grade genome-wide structural variant detection. Our study supports previous evidence for a role of ZNF804A in NDD and highlights the need for a more comprehensive assessment of structural variation in karyotypically abnormal individuals and patients with neurocognitive disease to avoid diagnostic deception. PMID:24625750

  12. Genetic Diversity and Population Structure of F3:6 Nebraska Winter Wheat Genotypes Using Genotyping-By-Sequencing.

    Science.gov (United States)

    Eltaher, Shamseldeen; Sallam, Ahmed; Belamkar, Vikas; Emara, Hamdy A; Nower, Ahmed A; Salem, Khaled F M; Poland, Jesse; Baenziger, Peter S

    2018-01-01

    The availability of information on the genetic diversity and population structure in wheat ( Triticum aestivum L.) breeding lines will help wheat breeders to better use their genetic resources and manage genetic variation in their breeding program. The recent advances in sequencing technology provide the opportunity to identify tens or hundreds of thousands of single nucleotide polymorphism (SNPs) in large genome species (e.g., wheat). These SNPs can be utilized for understanding genetic diversity and performing genome wide association studies (GWAS) for complex traits. In this study, the genetic diversity and population structure were investigated in a set of 230 genotypes (F 3:6 ) derived from various crosses as a prerequisite for GWAS and genomic selection. Genotyping-by-sequencing provided 25,566 high-quality SNPs. The polymorphism information content (PIC) across chromosomes ranged from 0.09 to 0.37 with an average of 0.23. The distribution of SNPs markers on the 21 chromosomes ranged from 319 on chromosome 3D to 2,370 on chromosome 3B. The analysis of population structure revealed three subpopulations (G1, G2, and G3). Analysis of molecular variance identified 8% variance among and 92% within subpopulations. Of the three subpopulations, G2 had the highest level of genetic diversity based on three genetic diversity indices: Shannon's information index ( I ) = 0.494, diversity index ( h ) = 0.328 and unbiased diversity index (uh) = 0.331, while G3 had lowest level of genetic diversity ( I = 0.348, h = 0.226 and uh = 0.236). This high genetic diversity identified among the subpopulations can be used to develop new wheat cultivars.

  13. Soft sensor for monitoring biomass subpopulations in mammalian cell culture processes.

    Science.gov (United States)

    Kroll, Paul; Stelzer, Ines V; Herwig, Christoph

    2017-11-01

    Biomass subpopulations in mammalian cell culture processes cause impurities and influence productivity, which requires this critical process parameter to be monitored in real-time. For this reason, a novel soft sensor concept for estimating viable, dead and lysed cell concentration was developed, based on the robust and cheap in situ measurements of permittivity and turbidity in combination with a simple model. It could be shown that the turbidity measurements contain information about all investigated biomass subpopulations. The novelty of the developed soft sensor is the real-time estimation of lysed cell concentration, which is directly correlated to process-related impurities such as DNA and host cell protein in the supernatant. Based on data generated by two fed-batch processes the developed soft sensor is described and discussed. The presented soft sensor concept provides a tool for viable, dead and lysed cell concentration estimation in real-time with adequate accuracy and enables further applications with respect to process optimization and control.

  14. Differential enumeration of subpopulations in concentrated frozen and lyophilized cultures of Lactobacillus delbrueckii ssp. bulgaricus.

    Science.gov (United States)

    Shao, Yuyu; Wang, Zhaoxia; Bao, Qiuhua; Zhang, Heping

    2017-11-01

    Differential enumeration of subpopulations in concentrated frozen and lyophilized cultures of Lactobacillus delbrueckii ssp. bulgaricus ND02 derived from 2 propagation procedures was determined. The subpopulations consisted of 3 categories (physiological states): viable cells capable of forming colonies on agar plates (VC+), viable cells incapable of forming colonies on agar plates (VC-), widely referred to as viable but nonculturable (VBNC) cells, and nonviable or dead cells (NVC). Counts of VC+ were recorded using a conventional plate count procedure. A fluorescent vital staining procedure that discriminates between viable (VC+ and VC-) and NVC cells was used to determine the number of viable and nonviable cells. Both propagation procedures had 2 variables: in procedure (P)1, the propagation medium was rich in yeast extract (4.0%) and the pH was maintained at 5.7; in P2, the medium was devoid of yeast extract and the pH was maintained at 5.1. The results showed that post-propagation operations-concentration of cells by centrifugation and subsequent freezing or lyophilization of cell concentrate-induced different degrees of transience from VC+ to VC- states in cells derived from P1 and P2. Compared with cells derived from P2, cells from P1 were more labile to stress associated with centrifugation, freezing, and lyophilization, as revealed by differential counting. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  15. Differential influences of local subpopulations on regional diversity and differentiation for greater sage-grouse (Centrocercus urophasianus)

    Science.gov (United States)

    Row, Jeffery R.; Oyler-McCance, Sara J.; Fedy, Brad C.

    2016-01-01

    The distribution of spatial genetic variation across a region can shape evolutionary dynamics and impact population persistence. Local population dynamics and among-population dispersal rates are strong drivers of this spatial genetic variation, yet for many species we lack a clear understanding of how these population processes interact in space to shape within-species genetic variation. Here, we used extensive genetic and demographic data from 10 subpopulations of greater sage-grouse to parameterize a simulated approximate Bayesian computation (ABC) model and (i) test for regional differences in population density and dispersal rates for greater sage-grouse subpopulations in Wyoming, and (ii) quantify how these differences impact subpopulation regional influence on genetic variation. We found a close match between observed and simulated data under our parameterized model and strong variation in density and dispersal rates across Wyoming. Sensitivity analyses suggested that changes in dispersal (via landscape resistance) had a greater influence on regional differentiation, whereas changes in density had a greater influence on mean diversity across all subpopulations. Local subpopulations, however, varied in their regional influence on genetic variation. Decreases in the size and dispersal rates of central populations with low overall and net immigration (i.e. population sources) had the greatest negative impact on genetic variation. Overall, our results provide insight into the interactions among demography, dispersal and genetic variation and highlight the potential of ABC to disentangle the complexity of regional population dynamics and project the genetic impact of changing conditions.

  16. Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations.

    Science.gov (United States)

    Yoshino, Takayuki; Komatsu, Yoshito; Yamada, Yasuhide; Yamazaki, Kentaro; Tsuji, Akihito; Ura, Takashi; Grothey, Axel; Van Cutsem, Eric; Wagner, Andrea; Cihon, Frank; Hamada, Yoko; Ohtsu, Atsushi

    2015-06-01

    In the international, phase III, randomized, double-blind CORRECT trial, regorafenib significantly prolonged overall survival (OS) versus placebo in patients with metastatic colorectal cancer (mCRC) that had progressed on all standard therapies. This post hoc analysis evaluated the efficacy and safety of regorafenib in Japanese and non-Japanese subpopulations in the CORRECT trial. Patients were randomized 2 : 1 to regorafenib 160 mg once daily or placebo for weeks 1-3 of each 4-week cycle. The primary endpoint was OS. Outcomes were assessed using descriptive statistics. One hundred Japanese and 660 non-Japanese patients were randomized to regorafenib (n = 67 and n = 438) or placebo (n = 33 and n = 222). Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval [CI] 0.43-1.51) and 0.77 (95 % CI 0.62-0.94), respectively. Regorafenib-associated hand-foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable. Regorafenib appears to have comparable efficacy in Japanese and non-Japanese subpopulations, with a manageable adverse-event profile, suggesting that this agent could potentially become a standard of care in patients with mCRC.

  17. An Exponential Regression Model Reveals the Continuous Development of B Cell Subpopulations Used as Reference Values in Children

    Directory of Open Access Journals (Sweden)

    Christoph Königs

    2018-05-01

    Full Text Available B lymphocytes are key players in humoral immunity, expressing diverse surface immunoglobulin receptors directed against specific antigenic epitopes. The development and profile of distinct subpopulations have gained awareness in the setting of primary immunodeficiency disorders, primary or secondary autoimmunity and as therapeutic targets of specific antibodies in various diseases. The major B cell subpopulations in peripheral blood include naïve (CD19+ or CD20+IgD+CD27−, non-switched memory (CD19+ or CD20+IgD+CD27+ and switched memory B cells (CD19+ or CD20+IgD−CD27+. Furthermore, less common B cell subpopulations have also been described as having a role in the suppressive capacity of B cells to maintain self-tolerance. Data on reference values for B cell subpopulations are limited and only available for older age groups, neglecting the continuous process of human B cell development in children and adolescents. This study was designed to establish an exponential regression model to produce continuous reference values for main B cell subpopulations to reflect the dynamic maturation of the human immune system in healthy children.

  18. Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Aman C. Kaushik

    2018-02-01

    Full Text Available GPR142 (G protein receptor 142 is a novel orphan GPCR (G protein coupled receptor belonging to “Class A” of GPCR family and expressed in β cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling, and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

  19. Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

    Science.gov (United States)

    Kaushik, Aman C.; Kumar, Sanjay; Wei, Dong Q.; Sahi, Shakti

    2018-02-01

    GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to ‘Class A’ of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

  20. A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8-Quinolinol Core Structure That Activates p53.

    Science.gov (United States)

    Bechill, John; Zhong, Rong; Zhang, Chen; Solomaha, Elena; Spiotto, Michael T

    2016-01-01

    p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip-Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53. In a multiplexed assay, we coupled p53 targeted degradation with Rb1 targeted degradation in order to identify compounds that prevented p53 degradation while not inhibiting degradation through the SCF complex or other proteolytic machinery. High-throughput screening identified several leads that shared a common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilized p53. Surface plasmon resonance analysis indicated that these compounds bound p53 with a KD of 200 ± 52 nM. Furthermore, these compounds increased p53 nuclear localization and transcription of the p53 target genes PUMA, BAX, p21 and FAS in cancer cells. Although p53-null cells had a 2.5±0.5-fold greater viability compared to p53 wild type cells after treatment with core compounds, loss of p53 did not completely rescue cell viability suggesting that compounds may target both p53-dependent and p53-independent pathways to inhibit cell proliferation. Thus, we present a novel, cell-based high-throughput screen to identify a 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that bound to p53 and increased p53 activity in cancer cells. These compounds may serve as anti-neoplastic agents in part by targeting p53 as well as other potential pathways.

  1. A Novel Methodology for Characterizing Cell Subpopulations in Automated Time-lapse Microscopy

    Directory of Open Access Journals (Sweden)

    Georges Hattab

    2018-02-01

    Full Text Available Time-lapse imaging of cell colonies in microfluidic chambers provides time series of bioimages, i.e., biomovies. They show the behavior of cells over time under controlled conditions. One of the main remaining bottlenecks in this area of research is the analysis of experimental data and the extraction of cell growth characteristics, such as lineage information. The extraction of the cell line by human observers is time-consuming and error-prone. Previously proposed methods often fail because of their reliance on the accurate detection of a single cell, which is not possible for high density, high diversity of cell shapes and numbers, and high-resolution images with high noise. Our task is to characterize subpopulations in biomovies. In order to shift the analysis of the data from individual cell level to cellular groups with similar fluorescence or even subpopulations, we propose to represent the cells by two new abstractions: the particle and the patch. We use a three-step framework: preprocessing, particle tracking, and construction of the patch lineage. First, preprocessing improves the signal-to-noise ratio and spatially aligns the biomovie frames. Second, cell sampling is performed by assuming particles, which represent a part of a cell, cell or group of contiguous cells in space. Particle analysis includes the following: particle tracking, trajectory linking, filtering, and color information, respectively. Particle tracking consists of following the spatiotemporal position of a particle and gives rise to coherent particle trajectories over time. Typical tracking problems may occur (e.g., appearance or disappearance of cells, spurious artifacts. They are effectively processed using trajectory linking and filtering. Third, the construction of the patch lineage consists in joining particle trajectories that share common attributes (i.e., proximity and fluorescence intensity and feature common ancestry. This step is based on patch finding

  2. Ethical Dilemmas in Protecting Susceptible Subpopulations From Environmental Health Risks: Liberty, Utility, Fairness, and Accountability for Reasonableness

    Science.gov (United States)

    Resnik, David B.; MacDougall, D. Robert; Smith, Elise M.

    2018-01-01

    Various U.S. laws, such as the Clean Air Act and the Food Quality Protection Act, require additional protections for susceptible subpopulations who face greater environmental health risks. The main ethical rationale for providing these protections is to ensure that environmental health risks are distributed fairly. In this article, we (1) consider how several influential theories of justice deal with issues related to the distribution of environmental health risks; (2) show that these theories often fail to provide specific guidance concerning policy choices; and (3) argue that an approach to public decision making known as accountability for reasonableness can complement theories of justice in establishing acceptable environmental health risks for the general population and susceptible subpopulations. Since accountability for reasonableness focuses on the fairness of the decision-making process, not the outcome, it does not guarantee that susceptible subpopulations will receive a maximum level of protection, regardless of costs or other morally relevant considerations. PMID:29466133

  3. An approach of radiosensitivity of the CFU-f in the bone marrow and its subpopulation classification

    International Nuclear Information System (INIS)

    Sun Huibin; Liu Ji; Li Ronggui

    1989-01-01

    The cell survival curve of the CFU-f in the guinea-pig bone marrow, which is distinguished according to the cellular density of colony, is assayed. By the analysis of the relative data from the experiment and the observation of the morphology of colony. There are two distinct subpopulations in radiosensitivity and colonial morphology among the CFU-f populations in the guinea-pig bone marrow. The dense cellular colony type subpopulation of the CFU-f: D 0 = 2.17 Gy, N = 1.14; the sparse cellular colony type subpopulation of the CFU-f: D 0 = 4.09 Gy, N = 1.13. The studies may have important implication in acquiring a better understanding of the characteristics of the radiation biology as well as the rule of the radiation injury and recovery of the CFU-f

  4. The catabolite repression control protein Crc plays a role in the development of antimicrobial-tolerant subpopulations in Pseudomonas aeruginosa biofilms

    DEFF Research Database (Denmark)

    Zhang, Lianbo; Chiang, Wen-Chi; Gao, Qingguo

    2012-01-01

    Bacteria form complex surface-attached biofilm communities in nature. Biofilm cells differentiate into subpopulations which display tolerance towards antimicrobial agents. However, the signal transduction pathways regulating subpopulation differentiation in biofilms are largely unelucidated. In t....... In the present study, we show that the catabolite repression control protein Crc regulates the metabolic state of Pseudomonas aeruginosa cells in biofilms, and plays an important role in the development of antimicrobial-tolerant subpopulations in P. aeruginosa biofilms....

  5. Ichthyophonus parasite phylogeny based on ITS rDNA structure prediction and alignment identifies six clades, with a single dominant marine type

    Science.gov (United States)

    Gregg, Jacob; Thompson, Rachel L.; Purcell, Maureen; Friedman, Carolyn S.; Hershberger, Paul

    2016-01-01

    Despite their widespread, global impact in both wild and cultured fishes, little is known of the diversity, transmission patterns, and phylogeography of parasites generally identified as Ichthyophonus. This study constructed a phylogeny based on the structural alignment of internal transcribed spacer (ITS) rDNA sequences to compare Ichthyophonus isolates from fish hosts in the Atlantic and Pacific oceans, and several rivers and aquaculture sites in North America, Europe, and Japan. Structure of the Ichthyophonus ITS1–5.8S–ITS2 transcript exhibited several homologies with other eukaryotes, and 6 distinct clades were identified within Ichthyophonus. A single clade contained a majority (71 of 98) of parasite isolations. This ubiquitous Ichthyophonus type occurred in 13 marine and anadromous hosts and was associated with epizootics in Atlantic herring, Chinook salmon, and American shad. A second clade contained all isolates from aquaculture, despite great geographic separation of the freshwater hosts. Each of the 4 remaining clades contained isolates from single host species. This study is the first to evaluate the genetic relationships among Ichthyophonus species across a significant portion of their host and geographic range. Additionally, parasite infection prevalence is reported in 16 fish species.

  6. Ichthyophonus parasite phylogeny based on ITS rDNA structure prediction and alignment identifies six clades, with a single dominant marine type.

    Science.gov (United States)

    Gregg, Jacob L; Powers, Rachel L; Purcell, Maureen K; Friedman, Carolyn S; Hershberger, Paul K

    2016-07-07

    Despite their widespread, global impact in both wild and cultured fishes, little is known of the diversity, transmission patterns, and phylogeography of parasites generally identified as Ichthyophonus. This study constructed a phylogeny based on the structural alignment of internal transcribed spacer (ITS) rDNA sequences to compare Ichthyophonus isolates from fish hosts in the Atlantic and Pacific oceans, and several rivers and aquaculture sites in North America, Europe, and Japan. Structure of the Ichthyophonus ITS1-5.8S-ITS2 transcript exhibited several homologies with other eukaryotes, and 6 distinct clades were identified within Ichthyophonus. A single clade contained a majority (71 of 98) of parasite isolations. This ubiquitous Ichthyophonus type occurred in 13 marine and anadromous hosts and was associated with epizootics in Atlantic herring, Chinook salmon, and American shad. A second clade contained all isolates from aquaculture, despite great geographic separation of the freshwater hosts. Each of the 4 remaining clades contained isolates from single host species. This study is the first to evaluate the genetic relationships among Ichthyophonus species across a significant portion of their host and geographic range. Additionally, parasite infection prevalence is reported in 16 fish species.

  7. Changes in lymphocyte subpopulations and adhesion/activation molecules following endotoxemia and major surgery

    DEFF Research Database (Denmark)

    Toft, P; Hokland, Marianne; Hansen, Tom Giedsing

    1995-01-01

    Major surgery as well as endotoxin-induced sepsis is accompanied by lymphocytopenia in peripheral blood. The purpose of this study was to investigate the redistribution of lymphocyte subpopulations and adhesion/activation molecules on lymphocytes. Twenty-four rats were included in the investigation....... Eight rats received an intraperitoneal injection of E. coli endotoxin (2 mg kg-1), eight rats had a sham operation performed while eight rats received isotonic saline and served as a control group. Blood samples were obtained by making an incision in the tail before and 2 and 5 h after surgery...... or administration of endotoxin or saline. After isolation of lymphocytes by gradient centrifugation, flow-cytometric immunophenotyping was performed using CD2, CD3, CD4, CD8, CD11/CD18, CD20, CD44 and MHC II monoclonal antibodies. Endotoxemia and surgery were both accompanied by increased serum cortisol...

  8. Effect of radiation on cell-mediated cytotoxicity and lymphocyte subpopulations in patients with ovarian carcinoma

    International Nuclear Information System (INIS)

    Kohorn, E.I.; Mitchell, M.S.; Dwyer, J.M.; Knowlton, A.H.; Klein-Angerer, S.

    1978-01-01

    Lymphocyte subpopulations and cell-mediated cytotoxicity (CMI) were studied during radiation therapy in 16 patients with ovarian carcinoma. The total lymphocyte count became depressed in all patients. The depression was more marked among T cells, while the proportion of B cells remained unaffected. In patients with Stage I and II ovarian cancer, CMI was depressed significantly by radiotherapy after 7 days of treatment, remained low at 14 days but recovered despite continuation of radiation. This depression of CMI occurred at a delivered dose of 1,000 rads with subsequent recovery. Patients with Stage III ovarian cancer given pelvic and abdominal radiation were found to have no consistent depression of CMI, a finding similar to that in Stage III ovarian carcinoma patients given chemotherapy

  9. Survival of Bactericidal Antibiotic Treatment by a Persister Subpopulation of Listeria monocytogenes

    DEFF Research Database (Denmark)

    Knudsen, Gitte Maegaard; Ng, Yin; Gram, Lone

    2013-01-01

    Listeria monocytogenes can cause the serious infection listeriosis, which despite antibiotic treatment has a high mortality. Understanding the response of L. monocytogenes to antibiotic exposure is therefore important to ensure treatment success. Some bacteria survive antibiotic treatment...... by formation of persisters, which are a dormant antibiotic-tolerant subpopulation. The purpose of this study was to determine whether L. monocytogenes can form persisters and how bacterial physiology affects the number of persisters in the population. A stationary-phase culture of L. monocytogenes was adjusted...... that eradication of persisters is possible. Our study adds L. monocytogenes to the list of bacterial species capable of surviving bactericidal antibiotics in a dormant stage, and this persister phenomenon should be borne in mind when developing treatment regimens....

  10. Clonal dominance between subpopulations of mixed small cell lung cancer xenografts implanted ectopically in nude mice

    DEFF Research Database (Denmark)

    Aabo, K; Vindeløv, L L; Spang-Thomsen, M

    1995-01-01

    Clonal evolution of neoplastic cells during solid tumour growth leads to the emergence of new tumour cell subpopulations with diverging phenotypic characteristics which may alter the behaviour of a malignant disease. Cellular interaction was studied in mixed xenografts in nude mice and during...... clone 54B was found to dominate the parent 54A clone when grown as mixed subcutaneous xenografts in nude mice, whereas no dominance was exerted during in vitro growth. The in vivo dominance could not be explained by differences in growth kinetics between the two tumour cell lines, and the interaction...... was not dependent on 54B being in excess in mixed tumours. The dominance was dependent on close in vivo contact as no remote effect on the growth of 54A was found when the dominating 54B cells were growing in the opposite flank of tumour-bearing mice. Irradiation inactivated 54B cells were unable to exert...

  11. An application of the variable-r method to subpopulation growth rates in a 19th century agricultural population

    Directory of Open Access Journals (Sweden)

    Corey Sparks

    2009-07-01

    Full Text Available This paper presents an analysis of the differential growth rates of the farming and non-farming segments of a rural Scottish community during the 19th and early 20th centuries using the variable-r method allowing for net migration. Using this method, I find that the farming population of Orkney, Scotland, showed less variability in their reproduction and growth rates than the non-farming population during a period of net population decline. I conclude by suggesting that the variable-r method can be used in general cases where the relative growth of subpopulations or subpopulation reproduction is of interest.

  12. Effects of habitat fragmentation on the Eurasian badger (Meles meles subpopulations in Denmark

    Directory of Open Access Journals (Sweden)

    Cino Pertoldi

    2001-09-01

    Full Text Available Abstract Genetic variation in five populations of the Eurasian badger from Denmark was screened, using the hyper-variable minisatellite DNA probe 33.15. Very low genetic variability was found within populations. This lack of variability could be related to the fragmentation of the Danish landscape which reduces the effective population size of local populations and the gene flow between different subpopulations. The present paper discusses the possibility of managing the Danish badger subpopulations as a metapopulation.

  13. Ligand-bound Structures and Site-directed Mutagenesis Identify the Acceptor and Secondary Binding Sites of Streptomyces coelicolor Maltosyltransferase GlgE*

    Science.gov (United States)

    Syson, Karl; Stevenson, Clare E. M.; Miah, Farzana; Barclay, J. Elaine; Tang, Minhong; Gorelik, Andrii; Rashid, Abdul M.; Lawson, David M.; Bornemann, Stephen

    2016-01-01

    GlgE is a maltosyltransferase involved in α-glucan biosynthesis in bacteria that has been genetically validated as a target for tuberculosis therapies. Crystals of the Mycobacterium tuberculosis enzyme diffract at low resolution so most structural studies have been with the very similar Streptomyces coelicolor GlgE isoform 1. Although the donor binding site for α-maltose 1-phosphate had been previously structurally defined, the acceptor site had not. Using mutagenesis, kinetics, and protein crystallography of the S. coelicolor enzyme, we have now identified the +1 to +6 subsites of the acceptor/product, which overlap with the known cyclodextrin binding site. The sugar residues in the acceptor subsites +1 to +5 are oriented such that they disfavor the binding of malto-oligosaccharides that bear branches at their 6-positions, consistent with the known acceptor chain specificity of GlgE. A secondary binding site remote from the catalytic center was identified that is distinct from one reported for the M. tuberculosis enzyme. This new site is capable of binding a branched α-glucan and is most likely involved in guiding acceptors toward the donor site because its disruption kinetically compromises the ability of GlgE to extend polymeric substrates. However, disruption of this site, which is conserved in the Streptomyces venezuelae GlgE enzyme, did not affect the growth of S. venezuelae or the structure of the polymeric product. The acceptor subsites +1 to +4 in the S. coelicolor enzyme are well conserved in the M. tuberculosis enzyme so their identification could help inform the design of inhibitors with therapeutic potential. PMID:27531751

  14. Application of a simplified calculation for full-wave microtremor H/ V spectral ratio based on the diffuse field approximation to identify underground velocity structures

    Science.gov (United States)

    Wu, Hao; Masaki, Kazuaki; Irikura, Kojiro; Sánchez-Sesma, Francisco José

    2017-12-01

    Under the diffuse field approximation, the full-wave (FW) microtremor H/ V spectral ratio ( H/ V) is modeled as the square root of the ratio of the sum of imaginary parts of the Green's function of the horizontal components to that of the vertical one. For a given layered medium, the FW H/ V can be well approximated with only surface waves (SW) H/ V of the "cap-layered" medium which consists of the given layered medium and a new larger velocity half-space (cap layer) at large depth. Because the contribution of surface waves can be simply obtained by the residue theorem, the computation of SW H/ V of cap-layered medium is faster than that of FW H/ V evaluated by discrete wavenumber method and contour integration method. The simplified computation of SW H/ V was then applied to identify the underground velocity structures at six KiK-net strong-motion stations. The inverted underground velocity structures were used to evaluate FW H/ Vs which were consistent with the SW H/ Vs of corresponding cap-layered media. The previous study on surface waves H/ Vs proposed with the distributed surface sources assumption and a fixed Rayleigh-to-Love waves amplitude ratio for horizontal motions showed a good agreement with the SW H/ Vs of our study. The consistency between observed and theoretical spectral ratios, such as the earthquake motions of H/ V spectral ratio and spectral ratio of horizontal motions between surface and bottom of borehole, indicated that the underground velocity structures identified from SW H/ V of cap-layered medium were well resolved by the new method.[Figure not available: see fulltext.

  15. Estimating the abundance of the Southern Hudson Bay polar bear subpopulation with aerial surveys

    Science.gov (United States)

    Obbard, Martyn E.; Stapleton, Seth P.; Middel, Kevin R.; Thibault, Isabelle; Brodeur, Vincent; Jutras, Charles

    2015-01-01

    The Southern Hudson Bay (SH) polar bear subpopulation occurs at the southern extent of the species’ range. Although capture–recapture studies indicate abundance was likely unchanged between 1986 and 2005, declines in body condition and survival occurred during the period, possibly foreshadowing a future decrease in abundance. To obtain a current estimate of abundance, we conducted a comprehensive line transect aerial survey of SH during 2011–2012. We stratified the study site by anticipated densities and flew coastal contour transects and systematically spaced inland transects in Ontario and on Akimiski Island and large offshore islands in 2011. Data were collected with double-observer and distance sampling protocols. We surveyed small islands in James Bay and eastern Hudson Bay and flew a comprehensive transect along the Québec coastline in 2012. We observed 667 bears in Ontario and on Akimiski Island and nearby islands in 2011, and we sighted 80 bears on offshore islands during 2012. Mark–recapture distance sampling and sight–resight models yielded an estimate of 860 (SE = 174) for the 2011 study area. Our estimate of abundance for the entire SH subpopulation (943; SE = 174) suggests that abundance is unlikely to have changed significantly since 1986. However, this result should be interpreted cautiously because of the methodological differences between historical studies (physical capture–recapture) and this survey. A conservative management approach is warranted given previous increases in duration of the ice-free season, which are predicted to continue in the future, and previously documented declines in body condition and vital rates.

  16. Estimating abundance of the Southern Hudson Bay polar bear subpopulation using aerial surveys, 2011 and 2012

    Science.gov (United States)

    Obbard, Martyn E.; Middel, Kevin R.; Stapleton, Seth P.; Thibault, Isabelle; Brodeur, Vincent; Jutras, Charles

    2013-01-01

    The Southern Hudson Bay (SH) polar bear subpopulation occurs at the southern extent of the species’ range. Although capture-recapture studies indicate that abundance remained stable between 1986 and 2005, declines in body condition and survival were documented during the period, possibly foreshadowing a future decrease in abundance. To obtain a current estimate of abundance, we conducted a comprehensive line transect aerial survey of SH during 2011–2012. We stratified the study site by anticipated densities and flew coastal contour transects and systematically spaced inland transects in Ontario and on Akimiski Island and large offshore islands in 2011. Data were collected with double observer and distance sampling protocols. We also surveyed small islands in Hudson Bay and James Bay and flew a comprehensive transect along the Québec coastline in 2012. We observed 667 bears in Ontario and on Akimiski Island and nearby islands in 2011, and we sighted 80 bears on offshore islands during 2012. Mark-recapture distance sampling and sightresight models yielded a model-averaged estimate of 868 (SE: 177) for the 2011 study area. Our estimate of abundance for the entire SH subpopulation (951; SE: 177) suggests that abundance has remained unchanged. However, this result should be interpreted cautiously because of the methodological differences between historical studies (physical capture) and this survey. A conservative management approach is warranted given the previous increases in the duration of the ice-free season, which are predicted to continue in the future, and previously documented declines in body condition and vital rates.

  17. Population-level differences in revascularization treatment and outcomes among various United States subpopulations

    Institute of Scientific and Technical Information of China (English)

    Garth Graham; Yang-Yu Karen Xiao; Dan Rappoport; Saima Siddiqi

    2016-01-01

    Despite recent general improvements in health care, significant disparities persist in the cardiovascular care of women and racial/ethnic minorities. This is true even when income, education level, and site of care are taken into consideration. Possible explanations for these disparities include socioeconomic considerations, elements of discrimination and racism that affect socioeconomic status, and access to adequate medical care. Coronary revascularization has become the accepted and recommended treatment for myocardial infarction(MI) today and is one of the most common major medical interventions in the United States, with more than 1 million procedures each year. This review discusses recent data on disparities in co-morbidities and presentation symptoms, care and access to medical resources, and outcomes in revascularization as treatment for acute coronary syndrome, looking especially at women and minority populations in the United States. The data show that revascularization is used less in both female and minority patients. We summarize recent data on disparities in co-morbidities and presentation symptoms related to MI; access to care, medical resources, and treatments; and outcomes in women, blacks, and Hispanics. The picture is complicated among the last group by the many Hispanic/Latino subgroups in the United States. Some differences in outcomes are partially explained by presentation symptoms and co-morbidities and external conditions such as local hospital capacity. Of particular note is the striking differential in both presentation co-morbidities and mortality rates seen in women, compared to men, especially in women ≤ 55 years of age. Surveillance data on other groups in the United States such as American Indians/Alaska Natives and the many Asian subpopulations show disparities in risk factors and co-morbidities, but revascularization as treatment for MI in these populations has not been adequately studied. Significant research is required to

  18. Prevalence of periradicular periodontitis in a Scottish subpopulation found on CBCT images.

    Science.gov (United States)

    Dutta, A; Smith-Jack, F; Saunders, W P

    2014-09-01

    To investigate the prevalence of periradicular periodontitis (PRP) using cone-beam computed tomography (CBCT) scans in a retrospective cross-sectional epidemiological study in a Scottish subpopulation. Of the 319 CBCT scans performed at Dundee Dental Hospital between November 2009 and July 2012, 245 dentate scans of patients over 18 years of age were included and 3595 teeth examined. Odds ratios were calculated, and the association between root filling and posts with PRP was determined. Radiological signs of PRP were detected in 209 teeth (5.8%) in 96 patients (male = 53, female = 43) of which 145 (69.4%) were measurable and 64 (30.6%) appeared as periapical widening. Most lesions were seen in the 46-55-year age group and in maxillary anterior teeth (35.4%); 47.4% (n = 81) of the total root filled teeth (n = 171) had PRP. Of the root filled teeth with lesions, approximately half (50.6%) had an inadequate root filling. Teeth with crowns, but not root filled, accounted for 17.7% of PRP. Periapical changes were detected on a high proportion of teeth with post-retained crowns (70.7%). The presence of a root filling was significantly associated with PRP (z = 17.689 P Scottish subpopulation was 5.8%. The presence of a root filling or a post-retained crown was significantly associated with the presence of PRP as determined by CBCT scans. The prevalence of periradicular disease in root filled teeth remains high in the Scottish population. © 2013 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  19. THE CANDIDATE CLUSTER AND PROTOCLUSTER CATALOG (CCPC). II. SPECTROSCOPICALLY IDENTIFIED STRUCTURES SPANNING 2 <  z  < 6.6

    Energy Technology Data Exchange (ETDEWEB)

    Franck, J. R.; McGaugh, S. S. [Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106 (United States)

    2016-12-10

    The Candidate Cluster and Protocluster Catalog (CCPC) is a list of objects at redshifts z  > 2 composed of galaxies with spectroscopically confirmed redshifts that are coincident on the sky and in redshift. These protoclusters are identified by searching for groups in volumes corresponding to the expected size of the most massive protoclusters at these redshifts. In CCPC1 we identified 43 candidate protoclusters among 14,000 galaxies between 2.74 <  z  < 3.71. Here we expand our search to more than 40,000 galaxies with spectroscopic redshifts z  > 2.00, resulting in an additional 173 candidate structures. The most significant of these are 36 protoclusters with overdensities δ {sub gal} > 7. We also identify three large proto-supercluster candidates containing multiple protoclusters at z  = 2.3, 3.5 and z  = 6.56. Eight candidates with N  ≥ 10 galaxies are found at redshifts z  > 4.0. The last system in the catalog is the most distant spectroscopic protocluster candidate known to date at z  = 6.56.

  20. SuperQuant-assisted comparative proteome analysis of glioblastoma subpopulations allows for identification of potential novel therapeutic targets and cell markers

    DEFF Research Database (Denmark)

    Verano-Braga, Thiago; Gorshkov, Vladimir; Munthe, Sune

    2018-01-01

    Glioblastoma (GBM) is a highly aggressive brain cancer with poor prognosis and low survival rate. Invasive cancer stem-like cells (CSCs) are responsible for tumor recurrence because they escape current treatments. Our main goal was to study the proteome of three GBM subpopulations to identify key...... molecules behind GBM cell phenotypes and potential cell markers for migrating cells. We used SuperQuant-an enhanced quantitative proteome approach-to increase proteome coverage. We found 148 proteins differentially regulated in migrating CSCs and 199 proteins differentially regulated in differentiated cells...... migration. Moreover, our data suggested that microRNA-122 (miR-122) is a potential upstream regulator of GBM phenotypes as miR-122 activation was predicted for differentiated cells while its inhibition was predicted for migrating CSCs. Finally, we validated transferrin (TF) and procollagen-lysine 2...

  1. Emergence of a novel subpopulation of CC398 Staphylococcus aureus infecting animals is a serious hazard for humans

    Directory of Open Access Journals (Sweden)

    Nathalie Laure Van Der Mee-Marquet

    2014-12-01

    Full Text Available Until recently, Staphylococcus aureus from clonal complex (CC398 were mostly described as colonizing asymptomatic raised pigs and pig-farmers. Currently, the epidemiology of the CC398 lineage is becoming more complex. CC398 human-adapted isolates are increasingly being identified in bloodstream infections in humans living in animal-free environments. In addition, CC398 isolates are increasingly responsible for invasive infections in various animals. CC398 isolates that colonize asymptomatic pigs and the isolates that infect humans living in animal-free environments (human-adapted isolates both lack several clinically important S. aureus–associated virulence factors but differ on the basis of their prophage content. Recent findings have provided insight into the influence of a φMR11-like helper prophage on the ability of CC398 isolates to infect humans. To assess the recent spread of the CC398 lineage to various animal species and to investigate the links between the φMR11-like prophage and the emergence of CC398 isolates infecting animals, we studied 277 isolates causing infections in unrelated animals. The prevalence of CC398 isolates increased significantly between 2007 and 2013 (p<0.001; 31.8 % of the animal isolates harbored the φMR11-like prophage. High-density DNA microarray experiments with 37 representative infected-animal isolates positive for φMR11-like DNA established that most infected-animal isolates carried many genetic elements related to antimicrobial resistance and virulence genes, and a φ3 prophage encoding immune-modulating proteins and associated with animal-to-human jumps. Our findings suggest recent clonal expansion and dissemination of a new subpopulation of CC398 isolates, responsible for invasive infections in various animals, with a considerable potential to colonize and infect humans, probably greater than that of human-adapted CC398 isolates, justifying active surveillance.

  2. The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub-populations of rat trigeminal ganglion sensory neurons.

    Science.gov (United States)

    Helley, M P; Abate, W; Jackson, S K; Bennett, J H; Thompson, S W N

    2015-12-03

    The recent discovery that mammalian nociceptors express Toll-like receptors (TLRs) has raised the possibility that these cells directly detect and respond to pathogens with implications for either direct nociceptor activation or sensitization. A range of neuronal TLRs have been identified, however a detailed description regarding the distribution of expression of these receptors within sub-populations of sensory neurons is lacking. There is also some debate as to the composition of the TLR4 receptor complex on sensory neurons. Here we use a range of techniques to quantify the expression of TLR4, TLR7 and some associated molecules within neurochemically-identified sub-populations of trigeminal (TG) and dorsal root (DRG) ganglion sensory neurons. We also detail the pattern of expression and co-expression of two isoforms of lysophosphatidylcholine acyltransferase (LPCAT), a phospholipid remodeling enzyme previously shown to be involved in the lipopolysaccharide-dependent TLR4 response in monocytes, within sensory ganglia. Immunohistochemistry shows that both TLR4 and TLR7 preferentially co-localize with transient receptor potential vallinoid 1 (TRPV1) and purinergic receptor P2X ligand-gated ion channel 3 (P2X3), markers of nociceptor populations, within both TG and DRG. A gene expression profile shows that TG sensory neurons express a range of TLR-associated molecules. LPCAT1 is expressed by a proportion of both nociceptors and non-nociceptive neurons. LPCAT2 immunostaining is absent from neuronal profiles within both TG and DRG and is confined to non-neuronal cell types under naïve conditions. Together, our results show that nociceptors express the molecular machinery required to directly respond to pathogenic challenge independently from the innate immune system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Secondhand smoke exposure in cars and rooms: trend comparisons among subpopulations of nonsmoking U.S. middle and high school students.

    Science.gov (United States)

    McIntire, Russell K; Macy, Jonathan T; Seo, Dong-Chul; Nelson, Ashlyn A; Kolbe, Lloyd J

    2014-06-01

    Young people in the United States are exposed to secondhand smoke (SHS) primarily in 2 settings: homes and cars. Recently, researchers reported that the prevalence of U.S students exposed to SHS in cars decreased from 2000 to 2009; however, comparisons of trends across school levels, gender, and racial/ethnic groups were not assessed. Moreover, no studies have examined trends of exposure to SHS in rooms. We used data from the 2000, 2002, 2004, 2006, and 2009 waves of the National Youth Tobacco Survey, a nationally representative cross-sectional survey of U.S. middle and high school students. For SHS in cars and rooms, we identified exposure trends among nonsmokers from 2000 to 2009 and compared trends across subpopulations with binary logistic regression. We identified significant downward linear trends in SHS in cars and rooms for nearly all measured subpopulations of nonsmoking students from 2000 to 2009. SHS exposure in cars and rooms declined at a significantly greater rate for males than for females. SHS exposure in cars declined at a significantly greater rate for non-Hispanic (NH) Blacks than for NH Whites. SHS exposure in rooms declined at a significantly greater rate for NH Whites than for Hispanics and Native Hawaiians/Pacific Islanders. Although prevalence of exposure to SHS in cars and rooms among nonsmoking U.S. middle and high school students has declined from 2000 to 2009, the rates of decline were not equal across genders and racial/ethnic groups. Identification of these differing rates of exposure can help the public health community advocate for interventions focused on reducing adolescent SHS exposure.

  4. Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: binding mode insights through magnesium complexation and site-directed mutagenesis studies

    DEFF Research Database (Denmark)

    Poongavanam, Vasanthanathan; Corona, Angela; Steinmann, Casper

    2018-01-01

    is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15...... inhibited the RNase H function below 100 μM with three hits exhibiting IC50 values active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 μM and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly...

  5. Distinct DNA methylation epigenotypes in bladder cancer from different Chinese sub-populations and its implication in cancer detection using voided urine

    Directory of Open Access Journals (Sweden)

    Tong Joanna HM

    2011-05-01

    Full Text Available Abstract Background Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Previous studies have identified several tumor-related genes that are hypermethylated in bladder cancer; however the DNA methylation profile of bladder cancer in Taiwan is not fully understood. Methods In this study, we compared the DNA methylation profile of multiple tumor suppressor genes (APC, DAPK, E-cadherin, hMLH1, IRF8, p14, p15, RASSF1A, SFRP1 and SOCS-1 in bladder cancer patients from different Chinese sub-populations including Taiwan (104 cases, Hong Kong (82 cases and China (24 cases by MSP. Two normal human urothelium were also included as control. To investigate the diagnostic potential of using DNA methylation in non-invasive detection of bladder cancer, degree of methylation of DAPK, IRF8, p14, RASSF1A and SFRP1 was also accessed by quantitative MSP in urine samples from thirty bladder cancer patients and nineteen non-cancer controls. Results There were distinct DNA methylation epigenotypes among the different sub-populations. Further, samples from Taiwan and China demonstrated a bimodal distribution suggesting that CpG island methylator phentotype (CIMP is presented in bladder cancer. Moreover, the number of methylated genes in samples from Taiwan and Hong Kong were significantly correlated with histological grade (P SFRP1, IRF8, APC and RASSF1A were significantly associated with increased tumor grade, stage. Methylation of RASSF1A was associated with tumor recurrence. Patients with methylation of APC or RASSF1A were also significantly associated with shorter recurrence-free survival. For methylation detection in voided urine samples of cancer patients, the sensitivity and specificity of using any of the methylated genes (IRF8, p14 or sFRP1 by qMSP was 86.7% and 94.7%. Conclusions Our results indicate that there are distinct methylation epigenotypes among different Chinese sub-populations

  6. Towards Biofilm Spectroscopy - A Novel Microfluidic Approach for Characterizing Biofilm Subpopulation by Microwave-Based Electrical Impedance Spectroscopy

    Science.gov (United States)

    Richter, Christiane; Schneider, Stefan; Rapp, Bastian E.; Schmidt, Sönke; Schüßler, Martin; Jakoby, Rolf; Bruchmann, Julia; Bischer, Moritz; Schwartz, Thomas

    2018-03-01

    In this work three disciplines - microfluidics, microbiology and microwave engineering - are utilized to develop a system for analyzing subpopulations of biofilms and their reaction to antibiotic treatment. We present handling strategies to destabilize a biofilm inside a microfluidic system down to aggregate sizes ofbiofilm effects.

  7. Circulating immune cell subpopulations in pestivirus persistently infected calves and non-infected calves varying in immune status.

    Science.gov (United States)

    Circulating immune cell subpopulations in cattle representing varying stages of immune status categorized as; colostrum deprived (CD), receiving colostrum (COL), colostrum plus vaccination (VAC) and persistently infected with a pestivirus (PI) were compared. The PI calves were infected with a HoBi-...

  8. Circulating immune cell subpopulations in pestivirus persistently infected calves and non-infected calves varying in immune status [Abstract

    Science.gov (United States)

    The circulating immune cell subpopulations in cattle representing varying stages of immune status categorized as; colostrum deprived (CD), receiving colostrum (COL), colostrum plus vaccination (VAC) and persistently infected with a pestivirus (PI) were compared. The PI calves were infected with a H...

  9. Nodal tumor response according to the count of peripheral blood lymphocyte subpopulations during preoperative chemoradiotherapy in locally advanced rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Heo, Jae Sung; Oh, Young Tae; Noh, O Kyu; Chun, Mi Son; Park, Jun Eun; Cho, Sung Ran [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2016-12-15

    The objective of this prospective study was to evaluate the relationship between the circulating lymphocyte subpopulation counts during preoperative chemoradiotherapy (CRT) and tumor response in locally advanced rectal cancer. From August 2015 to June 2016, 10 patients treated with preoperative CRT followed by surgery were enrolled. Patients received conventional fractionated radiotherapy (50.4 Gy) with fluorouracil-based chemotherapy. Surgical resection was performed at 4 to 8 weeks after the completion of preoperative CRT. The absolute blood lymphocyte subpopulation was obtained prior to and after 4 weeks of CRT. We analyzed the association between a tumor response and change in the lymphocyte subpopulation during CRT. Among 10 patients, 2 (20%) had evidence of pathologic complete response. In 8 patients with clinically node positive, 4 (50%) had nodal tumor response. All lymphocyte subpopulation counts at 4 weeks after CRT were significantly lower than those observed during pretreatment (p < 0.01). A high decrease in natural killer (NK) cell, count during CRT (baseline cell count - cell count at 4 weeks) was associated with node down staging (p = 0.034). Our results suggest that the change of lymphocyte subset to preoperative CRT may be a predictive factor for tumor response in rectal cancer.

  10. Microsatellite analysis of genetic diversity and population structure of hermaphrodite ridge gourd (Luffa hermaphrodita).

    Science.gov (United States)

    Pandey, Sudhakar; Ansari, W A; Choudhary, B R; Pandey, Maneesh; Jena, S N; Singh, A K; Dubey, R K; Singh, Bijendra

    2018-01-01

    Out of 103 microsatellite markers used for studying the genetic diversity among local landraces of Luffa species, 56 were found polymorphic, including 38 gSSR and 18 eSSR, respectively. A total of 197 amplification products were obtained. The mean number of alleles per locus was 3.52. The PIC ranged from 0.037 to 0.986, while size of amplified product ranged from 105 to 500 bp. Cucumber-derived SSRs were amplified within L. acutangula (68%), L. aegyptiaca (61.16%), and L. hermaphrodita (60.2%), with an average of 63.12% cross-transferability. The Jaccard's coefficient ranged from 0.66 to 0.97, with an average of 0.81. High genetic variability was observed for node of 1st hermaphrodite flower (6.4-17), days to 1st hermaphrodite flower (38-52.1), days to 1st fruit harvest (43-65), number of fruit per cluster (1-5.9), fruit length (3.9-25 cm), fruit weight (18.4-175 g), number of fruit per plant (20-147.5), and yield per plant (2.2-4.7 kg). Two sub-populations were identified including 21 genotypes (sub-population I) and 06 genotypes (sub-population II), these two sub-populations showed 0.608-0.395% of the ancestral relationship to each other. This study provides information for future exploration, collection, and utilization of Luffa genotypes, as well as the polymorphic markers identified could be available for the study of landmarks in linkages, genomic structures, evolutionary ecology, and marker-assisted selection (MAS) in Luffa species.

  11. Structure-function relationship of a plant NCS1 member - Homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from arabidopsis

    KAUST Repository

    Witz, Sandra

    2014-03-12

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members. 2014 Witz et al.

  12. Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Sage, Eva K.; Gehrmann, Mathias; Sedelmayr, Michael [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); Schmid, Thomas E.; Combs, Stephanie E.; Multhoff, Gabriele [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); HelmholtzZentrum Muenchen, Department of Radiation Sciences (DRS), Institute of Innovate Radiotherapy (iRT), Munich (Germany); Deutsches Konsortium fuer Translationale Krebsforschung (DKTK), Partner Site Munich, Munich (Germany); Geinitz, Hans [Johannes Kepler University, Department of Radiation Oncology, Ordensklinikum Linz, Krankenhaus der Barmherzigen Schwestern and Medical Faculty, Linz (Austria); Duma, Marciana N. [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich (Germany); HelmholtzZentrum Muenchen, Department of Radiation Sciences (DRS), Institute of Innovate Radiotherapy (iRT), Munich (Germany)

    2017-08-15

    Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects. A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period. Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3{sup +} T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT. Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells. (orig.) [German] Die Strahlentherapie (RT) ist eine bewaehrte Behandlung beim primaeren und rezidivierten Prostatakarzinoms. In dieser Studie wurde der Einfluss einer definitiven und Salvage RT auf die Zusammensetzung der Lymphozytensubpopulationen verglichen, um potenzielle Immuneffekte einer RT zu analysieren. In die Studie wurden 33 Prostatakarzinompatienten eingeschlossen

  13. Effects of acupuncture on peripheral T lymphocyte subpopulation and amounts of cerebral catecholamines in mice.

    Science.gov (United States)

    Okumura, M; Toriizuka, K; Iijima, K; Haruyama, K; Ishino, S; Cyong, J C

    1999-01-01

    The aim of this study was to investigate the effects of acupuncture on peripheral lymphocyte subpopulations and cerebral catecholamines. In order to examine the effects of acupuncture, two experiments were performed. Experiment 1: Eighteen female mice (strain; C57BL/6) at the age of 7 weeks were divided three groups, (a) sham operated (control; n=6), (b) ovariectomized (OVX; n=6), and (c) ovariectomized and stimulated by subcutaneous needles on acupuncture point, Shenshu (BL23) at the both sides of the back for 20 days (OVX+Acu; n=6). These animals were sacrificed at 20 days after needle insertion, and the splenic lymphoid cells were examined by two-color flow cytometry, using monoclonal antibodies (mAb) to the cell surface antigens, CD3, CD4, CD8a and NK1.1 (CD56). In the ovariectomized (OVX) group, the peripheral CD4/CD8 ratio was significantly increased and the ratio of natural killer (NK) cells (CD3-NK1.1+; CD3 negative, NK1.1 positive) to T lymphocytes was decreased compared to the sham control group. In the ovariectomized with needle insertion (OVX+Acu) group, the CD4/CD8 ratio was reduced, but the NK cells ratio was not changed compared to the OVX group. Experiment 2: To investigate the acute effects of subcutaneous needle insertion, male C57BL/6 mice (7 weeks old) were used (n=6, each group). The acupuncture points Shen-shu (BL23) on the backs of the male mice were also stimulated by subcutaneous needles for 3 and 7 days. As a result, the CD4/CD8 ratio was significantly decreased at day 3 and day 7, compared to the control group. On the other hand the NK cells ratio and activated T-cells were increased at day 7. The mitogenic activities in the splenic lymphocytes were also increased by acupuncture stimulation at day 3. Catecholamine contents in the hippocampus were measured by high performance liquid chromatography with the electro-chemical detector (ECD-HPLC) method. No significant change was observed in either dopamine contents or norepinephrine; however

  14. Association of CD4+ T cell subpopulations and psychological stress measures in women living with HIV.

    Science.gov (United States)

    Rehm, Kristina E; Konkle-Parker, Deborah

    2017-09-01

    Psychological stress is a known immunomodulator. In individuals with HIV, depression, the most common manifestation of increased psychological stress, can affect immune function with lower CD4+ T cell counts correlating with higher levels of depression. It is unknown how other forms of psychological stress can impact immune markers in people living with HIV. We conducted a cross-sectional study to determine how CD4+ T cell subpopulations correlated with different forms of psychological stress. We recruited 50 HIV-positive women as part of the Women's Interagency HIV Study. We assessed perceived stress, worry, acute anxiety, trait anxiety, and depression through self-report questionnaires and CD4+ T cell subpopulations using flow cytometry. Our sample was 96% African-American with a mean ± SD age and body mass index of 42 ± 8.8 years and 36.6 ± 11.5 kg/m 2 , respectively. The mean ± SD scores on the psychological measures were as follows: Perceived Stress Scale (PSS), 16.5 ± 6.4; Penn State Worry Questionnaire (PSWQ), 47.7 ± 13.8; State-Trait Anxiety Inventory - State (STAIS), 39.1 ± 12.3; State-Trait Anxiety Inventory - Trait (STAIT), 40.2 ± 11.4; Center for Epidemiological Studies Depression Scale (CES-D), 15.6 ± 11.4. The mean + SD values for the immune parameters were as follows: regulatory T cells (Treg), 1.25% ± 0.7; T helper 1 (Th1), 14.9% ± 6.1; T helper 2 (Th2), 3.8% ± 2; Th1/Th2 ratio, 4.6 ± 3; and CD4+ T cell count (cells/mm 3 ), 493 ± 251. Treg levels positively correlated with PSS, STAIS, and STAIT. CD4+ T cell count negatively correlated with PSS, PSWQ, STAIS, STAIT, and CES-D. These data suggest that immune function may be impacted by various forms of psychological stress in HIV-positive women. Interventions that target stress reduction may be useful in improving immune parameters and quality of life.

  15. Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene.

    Science.gov (United States)

    Watanabe, Yousuke; Abe, Hajime; Nakajima, Kota; Ideta-Otsuka, Maky; Igarashi, Katsuhide; Woo, Gye-Hyeong; Yoshida, Toshinori; Shibutani, Makoto

    2018-05-01

    Maternal hexachlorophene (HCP) exposure causes transient disruption of hippocampal neurogenesis in mouse offspring. We examined epigenetically hypermethylated and downregulated genes related to this HCP-induced disrupted neurogenesis. Mated female mice were dietary exposed to 0 or 100 ppm HCP from gestational day 6 to postnatal day (PND) 21 on weaning. The hippocampal dentate gyrus of male offspring was subjected to methyl-capture sequencing and real-time reverse transcription-polymerase chain reaction analyses on PND 21. Validation analyses on methylation identified three genes, Dlx4, Dmrt1, and Plcb4, showing promoter-region hypermethylation. Immunohistochemically, DLX4+, DMRT1+, and PLCB4+ cells in the dentate hilus co-expressed GAD67, a γ-aminobutyric acid (GABA)ergic neuron marker. HCP decreased all of three subpopulations as well as GAD67+ cells on PND 21. PLCB4+ cells also co-expressed the metabotropic glutamate receptor, GRM1. HCP also decreased transcript level of synaptic plasticity-related genes in the dentate gyrus and immunoreactive granule cells for synaptic plasticity-related ARC. On PND 77, all immunohistochemical cellular density changes were reversed, whereas the transcript expression of the synaptic plasticity-related genes fluctuated. Thus, HCP-exposed offspring transiently reduced the number of GABAergic interneurons. Among them, subpopulations expressing DLX4, DMRT1, or PLCB4 were transiently reduced in number through an epigenetic mechanism. Considering the role of the Dlx gene family in GABAergic interneuron migration and differentiation, the decreased number of DLX4+ cells may be responsible for reducing those GABAergic interneurons regulating neurogenesis. The effect on granule cell synaptic plasticity was sustained until the adult stage, and reduced GABAergic interneurons active in GRM1-PLCB4 signaling may be responsible for the suppression on weaning.

  16. Revealing the distinct habitat ranges and hybrid zone of genetic sub-populations within Pseudo-nitzschia pungens (Bacillariophyceae) in the West Pacific area.

    Science.gov (United States)

    Kim, Jin Ho; Wang, Pengbin; Park, Bum Soo; Kim, Joo-Hwan; Patidar, Shailesh Kumar; Han, Myung-Soo

    2018-03-01

    Genetic sub-populations (clades) of cosmopolitan marine diatom Pseudo-nitzschia pungens might have distinct habitats, and their hybrid zone is suspected in higher latitude area of the West Pacific area, however, it is still unrevealed because of technical difficulties and lack of evidences in natural environments. The aim of this study is to investigate the habitat characteristics of each clade of P. pungens on geographical distribution with the habitat temperature ranges of each clade and to reveal their hybrid zone in the West Pacific area. We employed the 137 number of nucleotide sequences of P. pungens and its sampling data (spatial and temporal scale) originated from the West Pacific area, and used field application of qPCR assay for intra-specific level of P. pungens. Only two genotypes, clade I and III, were identified in the West Pacific area. Clade I was distributed from 39 to 32.3°N, and clade III were from 1.4 to 34.4°N. The estimated habitat temperature for the clade I and clade III ranges were 8.1-26.9 °C and 24.2-31.2 °C, respectively. The latitudinal distributions and temperature ranges of each clade were significantly different. The qPCR assay employed, and results suggested that the hybrid zone for clade I and III has been observed in the southern Korean coasts, and clade III might be introduced from the Southern Pacific area. The cell abundances of clade III were strongly related with the higher seawater temperature and warm current force. This study has defined distinct habitat characteristics of genetically different sub-populations of P. pungens, and revealed its hybrid zone in natural environment for the first time. We also provided strong evidences about dispersion of the population of clade III to higher latitude in the West Pacific area. Copyright © 2018. Published by Elsevier B.V.

  17. Activated Protein C Attenuates Severe Inflammation by Targeting VLA-3high Neutrophil Subpopulation in Mice.

    Science.gov (United States)

    Sarangi, Pranita P; Lee, Hyun-Wook; Lerman, Yelena V; Trzeciak, Alissa; Harrower, Eric J; Rezaie, Alireza R; Kim, Minsoo

    2017-10-15

    The host injury involved in multiorgan system failure during severe inflammation is mediated, in part, by massive infiltration and sequestration of hyperactive neutrophils in the visceral organ. A recombinant form of human activated protein C (rhAPC) has shown cytoprotective and anti-inflammatory functions in some clinical and animal studies, but the direct mechanism is not fully understood. Recently, we reported that, during endotoxemia and severe polymicrobial peritonitis, integrin VLA-3 (CD49c/CD29) is specifically upregulated on hyperinflammatory neutrophils and that targeting the VLA-3 high neutrophil subpopulation improved survival in mice. In this article, we report that rhAPC binds to human neutrophils via integrin VLA-3 (CD49c/CD29) with a higher affinity compared with other Arg-Gly-Asp binding integrins. Similarly, there is preferential binding of activated protein C (PC) to Gr1 high CD11b high VLA-3 high cells isolated from the bone marrow of septic mice. Furthermore, specific binding of rhAPC to human neutrophils via VLA-3 was inhibited by an antagonistic peptide (LXY2). In addition, genetically modified mutant activated PC, with a high affinity for VLA-3, shows significantly improved binding to neutrophils compared with wild-type activated PC and significantly reduced neutrophil infiltration into the lungs of septic mice. These data indicate that variants of activated PC have a stronger affinity for integrin VLA-3, which reveals novel therapeutic possibilities. Copyright © 2017 by The American Association of Immunologists, Inc.

  18. BAD-LAMP defines a subset of early endocytic organelles in subpopulations of cortical projection neurons.

    Science.gov (United States)

    David, Alexandre; Tiveron, Marie-Catherine; Defays, Axel; Beclin, Christophe; Camosseto, Voahirana; Gatti, Evelina; Cremer, Harold; Pierre, Philippe

    2007-01-15

    The brain-associated LAMP-like molecule (BAD-LAMP) is a new member of the family of lysosome associated membrane proteins (LAMPs). In contrast to other LAMPs, which show a widespread expression, BAD-LAMP expression in mice is confined to the postnatal brain and therein to neuronal subpopulations in layers II/III and V of the neocortex. Onset of expression strictly parallels cortical synaptogenesis. In cortical neurons, the protein is found in defined clustered vesicles, which accumulate along neurites where it localizes with phosphorylated epitopes of neurofilament H. In primary neurons, BAD-LAMP is endocytosed, but is not found in classical lysosomal/endosomal compartments. Modification of BAD-LAMP by addition of GFP revealed a cryptic lysosomal retention motif, suggesting that the cytoplasmic tail of BAD-LAMP is actively interacting with, or modified by, molecules that promote its sorting away from lysosomes. Analysis of BAD-LAMP endocytosis in transfected HeLa cells provided evidence that the protein recycles to the plasma membrane through a dynamin/AP2-dependent mechanism. Thus, BAD-LAMP is an unconventional LAMP-like molecule and defines a new endocytic compartment in specific subtypes of cortical projection neurons. The striking correlation between the appearance of BAD-LAMP and cortical synatogenesis points towards a physiological role of this vesicular determinant for neuronal function.

  19. Epidemiological differences of lower urinary tract symptoms among female subpopulations and group level interventions

    Directory of Open Access Journals (Sweden)

    Avasarala Atchuta Kameswararao

    2008-01-01

    Full Text Available Objectives: 1 To study the risk factor profiles of lower urinary tract symptoms (LUTS among adolescent girls, housewives and working women and its socioeconomic and quality of life losses. 2 To undertake risk factor modifications using the adolescent girls. Design and Setting: Cross-sectional descriptive study followed by educational intervention. Statistical Methods: Cluster sampling, Proportions, confidence intervals, Chi square and t-Tests and Logistic regression. Materials and Methods: House to house survey was done in two villages and one urban ward. Seventy-five housewives, 75 working women and 180 adolescent girls were asked about the risk factors and losses due to LUTS. Three teams of adolescent girls were utilized to bring about behavioral modifications. Impact was measured through user perspectives obtained from the participants. Results: Risk factors, social, economic and quality of life losses were different among the three female populations. Overall prevalence of LUTS among the three groups is 61(18.5%. Improper anal washing technique, malnutrition, presence of vaginal discharge, use of unsanitary menstrual pads, pinworm infestation and use of bad toilets were the significant causes among girls. Presence of sexually transmitted diseases was a contributing factor among housewives and working women. Prolonged sitting the posture was also contributing to LUTS among working women. Seventy-four per cent of beneficiaries expressed that intervention is useful. Conclusions: The causes for LUTS and their consequences were differing among the three female subpopulations. Specific group level interventions using trained girls were successful.

  20. Msx1 and Msx2 are expressed in sub-populations of vascular smooth muscle cells.

    Science.gov (United States)

    Goupille, Olivier; Saint Cloment, Cécile; Lopes, Miguel; Montarras, Didier; Robert, Benoît

    2008-08-01

    Using an nlacZ reporter gene inserted at the Msx1 and Msx2 loci, we could analyze the expression of these homeogenes in the adult mouse. We observed that Msx genes are prominently expressed in a subset of blood vessels. The Msx2nlacZ allele is mainly expressed in a restricted population of mural cells in peripheral arteries and veins. Msx1nlacZ is expressed to a lesser extent by vascular smooth muscle cells of peripheral arteries, but is highly expressed in arterioles and capillaries, making Msx1 a novel marker for a subpopulation of pericytes. Expression is set up early in developing vessels and maintained throughout life. In addition, expression of both genes is observed in a few endothelial cells of the aorta at fetal stages, and only Msx2 continues to be expressed in this layer at the adult stage. These results suggest major functions for Msx genes in vascular mural cell formation and remodeling. Copyright (c) 2008 Wiley-Liss, Inc.

  1. Validation of revised Epstein's criteria for insignificant prostate cancer prediction in a Greek subpopulation.

    Science.gov (United States)

    Chondros, Κ; Karpathakis, Ν; Heretis, Ι; Mavromanolakis, Ε; Chondros, N; Sofras, F; Mamoulakis, C

    2015-01-01

    Different treatment options for patients with prostate cancer (PCa) are applicable after stratifying patients according to various classification criteria. The purpose of our study is to evaluate the revised Epstein's criteria for insignificant PCa prediction in a Greek subpopulation. During a 4-year-period, 172 Cretan patients were submitted to radical retropubic prostatectomy in our institution. 23 out of them met the revised Epstein's criteria for the presence of clinically insignificant PCa (clinical stage T1c, prostate specific antigen density < 0.15 ng/ml/g, absence of Gleason pattern 4-5, <3 positive biopsy cores, presence of <50% tumor per core) during pre-treatment evaluation and were retrospectively included in the study. Post-surgery outcomes were evaluated including pathological stage, surgical margins and Gleason score upgrade. Organ confined disease and insignificant PCa were predicted with a 74% and 31% accuracy, respectively. These figures are remarkably lower than those derived from similar studies worldwide. Due to the high variation in the revised Epstein's criteria prediction accuracy observed worldwide, the development and implementation of novel tools/nomograms with a greater predictive accuracy is still warranted. Hippokratia 2015, 19 (1): 30-33.

  2. Effect of therapeutic doses of enrofloxacin on circulating lymphocyte subpopulations in pigs

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    Pomorska-Mól Małgorzata

    2015-06-01

    Full Text Available Twenty pigs of similar genetics (PIC were used. Pigs were randomly divided into two groups: experimental (ENRO, n = 10 and control (C, n = 10. From day 0 to day 4, pigs from ENRO group received enrofloxacin at the recommended therapeutic dose. Pigs from C group received PBS instead of enrofloxacin. Blood samples were collected on days 0 (before antibiotic administration, 2, 4 (during antibiotic therapy, 9, and 13 of the study (after enrofloxacin administration. Haematological examination and flow cytometry were used to establish the relative and absolute counts of various leukocyte subsets. Lymphocyte subpopulations were measured by fluorochrom-labelled antibodies according to following definitions: CD3+ (T cells, CD21+ (B cells, CD4+CD8- (helper T cells, Th, CD4-CD8+ (cytolytic T cells, CLT, CD4+CD8+ (cytolytic and memory T cells. The present study revealed the modulating effect of enrofloxacin on the composition of circulating lymphocytes in pigs. Concentration and percentage of CD8+ cells decreased significantly after treatment with enrofloxacin and as a result the absolute CD4/CD8 ratio increased significantly as compared to control group (P < 0.05.These findings should prompt further studies on the practical significance of the results obtained in terms of clinical implications. In view of the results, it cannot be excluded that enrofloxacin may also have immunomodulatory effects on host response to infection.

  3. Increased radiosensitivity of a subpopulation ot T-lymphocyte progenitors from patients with Fanconi's anemia

    International Nuclear Information System (INIS)

    Knox, S.J.; Wilson, F.D.; Greenberg, B.R.; Shifrine, M.; Rosenblatt, L.S.; Reeves, J.D.; Misra, H.

    1981-01-01

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x-irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST (patients, D37 . 198 R; normals, D37 . 309 R, p . 0.057) and colony formation assay (patients, D37 . 53 R; normals, D37 . 109 R, p . 0.016). No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed

  4. Increased radiosensitivity of a subpopulation of T-lymphocyte progenitors from patients with Fanconi's anemia

    International Nuclear Information System (INIS)

    Knox, S.J.; Wilson, F.D.; Greenberg, B.R.; Shifrine, M.; Rosenblatt, L.S.; Reeves, J.D.; Misra, H.

    1981-01-01

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST and colony formation assay. No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed

  5. Clinical trials in hospitalized heart failure patients: targeting interventions to optimal phenotypic subpopulations.

    Science.gov (United States)

    Vaduganathan, Muthiah; Butler, Javed; Roessig, Lothar; Fonarow, Gregg C; Greene, Stephen J; Metra, Marco; Cotter, Gadi; Kupfer, Stuart; Zalewski, Andrew; Sato, Naoki; Filippatos, Gerasimos; Gheorghiade, Mihai

    2015-07-01

    With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

  6. Effect of radiotherapy on lymphocyte subpopulations in patients with carcinoma of the breast and uterine cervix

    International Nuclear Information System (INIS)

    Guha Thakurta, S.; De, M.; Roy Chowdhury, J.

    1983-01-01

    Immune competence was evaluated in 43 patients of carcinoma breast, 77 patients of cancer cervix, as compared to 30 normal healthy women. The study also included 25 women from the two carcinoma groups, who had undergone radiotherapy. A reduction in the white blood cell count, absolute lymphocyte count, active T-cell count and absolute T-cell count were observed in patients with carcinoma of the breast and cervix prior to irradiation. Radiation therapy resulted in a striking reduction of all the three parameters in both the carcinoma groups. Substantial recovery was observed within a year after cessation of therapy. Increased number of peripheral B lymphocytes was observed in carcinoma of the breast as well as the cervix prior to irradiation. At completion of radiation, the number decreased markedly in both groups of patients. Gradual recovery took place within a year. The reduction in lymphocyte numbers and its subpopulations could not be attributed to thymic irradiation, since patients receiving pelvic and mediastinal (including thymic) radiotherapy showed similar changes. (author)

  7. Factors associated with Allergic Rhinitis in Colombian subpopulations aged 1 to 17 and 18 to 59.

    Science.gov (United States)

    Peñaranda, Augusto; Garcia, Elizabeth; Barragán, Ana M; Rondón, Martín A; Pérez, Adriana; Rojas, María X; Caraballo, Luis; Dennis, Rodolfo J

    2016-03-01

    Several studies have shown variations in the prevalence of allergic rhinitis (AR) around the world, and different potential predisposing factors. More studies are needed on risk factors, specifically in developing countries. This study explored the association of several factors and AR among urban residents in six cities of Colombia. A cross-sectional study and a nested case-control study were carried out between 2009 and 2010 involving two Colombian subpopulations: children/adolescents and adults. Cases were affirmative respondents to "In the past 12 months, have you (or your child) had a problem with sneezing or a running or blocked nose, when you (or your child) did not have a cold or the flu?" "Controls" were subjects who never had been diagnosed with asthma, AR or atopic eczema by a physician, and whom did not report any symptoms in the past twelve months. Weighted logistic regression was used to assess the association of different factors with case/control status. Factors associated with AR in children/adolescents were family history of AR, acetaminophen consumption and high socioeconomic status. Among adults, family history of asthma, AR and atopic eczema, and cetaminophen consumption were associated with AR. Consumption of cereals among children/adolescents and eating eggs among adults showed protective associations. Our findings suggest the presence of previously unknown cultural, environmental and family factors associated with the presence of AR in Colombia.

  8. Improving rational thermal comfort prediction by using subpopulation characteristics: A case study at Hermitage Amsterdam.

    Science.gov (United States)

    Kramer, Rick; Schellen, Lisje; Schellen, Henk; Kingma, Boris

    2017-01-01

    This study aims to improve the prediction accuracy of the rational standard thermal comfort model, known as the Predicted Mean Vote (PMV) model, by (1) calibrating one of its input variables "metabolic rate," and (2) extending it by explicitly incorporating the variable running mean outdoor temperature (RMOT) that relates to adaptive thermal comfort. The analysis was performed with survey data ( n = 1121) and climate measurements of the indoor and outdoor environment from a one year-long case study undertaken at Hermitage Amsterdam museum in the Netherlands. The PMVs were calculated for 35 survey days using (1) an a priori assumed metabolic rate, (2) a calibrated metabolic rate found by fitting the PMVs to the thermal sensation votes (TSVs) of each respondent using an optimization routine, and (3) extending the PMV model by including the RMOT. The results show that the calibrated metabolic rate is estimated to be 1.5 Met for this case study that was predominantly visited by elderly females. However, significant differences in metabolic rates have been revealed between adults and elderly showing the importance of differentiating between subpopulations. Hence, the standard tabular values, which only differentiate between various activities, may be oversimplified for many cases. Moreover, extending the PMV model with the RMOT substantially improves the thermal sensation prediction, but thermal sensation toward extreme cool and warm sensations remains partly underestimated.

  9. Genetic variability and effective population size when local extinction and recolonization of subpopulations are frequent

    Science.gov (United States)

    Maruyama, Takeo; Kimura, Motoo

    1980-01-01

    If a population (species) consists of n haploid lines (subpopulations) which reproduce asexually and each of which is subject to random extinction and subsequent replacement, it is shown that, at equilibrium in which mutational production of new alleles and their random extinction balance each other, the genetic diversity (1 minus the sum of squares of allelic frequencies) is given by 2Nev/(1 + 2Nev), where [Formula: see text] in which Ñ is the harmonic mean of the population size per line, n is the number of lines (assumed to be large), λ is the rate of line extinction, and v is the mutation rate (assuming the infinite neutral allele model). In a diploid population (species) consisting of n colonies, if migration takes place between colonies at the rate m (the island model) in addition to extinction and recolonization of colonies, it is shown that effective population size is [Formula: see text] If the rate of colony extinction (λ) is much larger than the migration rate of individuals, the effective population size is greatly reduced compared with the case in which no colony extinctions occur (in which case Ne = nÑ). The stepping-stone type of recolonization scheme is also considered. Bearing of these results on the interpretation of the level of genetic variability at the enzyme level observed in natural populations is discussed from the standpoint of the neutral mutation-random drift hypothesis. PMID:16592920

  10. Prevalence of Asymptomatic Apical Periodontitis and its Association with Coronary Artery Disease in a Brazilian Subpopulation.

    Science.gov (United States)

    Paloma de Oliveira, Bruna; Câmara, Andréa Cruz; Aguiar, Carlos Menezes

    2017-06-01

    The aim of the present study was to determine the prevalence of asymptomatic apical periodontitis (AAP) and its association with coronary artery disease (CAD) in a Brazilian subpopulation, and to examine the correlation of AAP with gender, age and most frequently affected dental elements. The data were collected from medical records of the patients (n = 1346) treated at the Specialization in Endodontics Clinic of the Federal University of Pernambuco in the period between 2003 and 2010. From each patient, the following variables were recorded: gender, age, endodontically compromised teeth, endodontic diseases diagnosed and the history of CAD. The data were analyzed using Pearson's chi-square test adopting a significance level of 5%. AAP was diagnosed in 574 patients (42.6%), corresponding to 641 teeth (40.1%). Both genders (p = 0.082), and all age groups (p = 0.190) were affected similarly. The upper incisors (52.8%, p <0.001) had a higher prevalence of AAP. The patients with AAP showed 1.45 times more chance of exhibiting CAD (p = 0.307). The results pointed out that the prevalence of AAP in this population was high and similar to that observed in other countries. A positive association, but not statistically significant, between AAP and CAD was found.

  11. Prevalence of Asymptomatic Apical Periodontitis and its Association with Coronary Artery Disease in a Brazilian Subpopulation

    Directory of Open Access Journals (Sweden)

    Andréa Cruz Câmara

    2017-01-01

    Full Text Available Objective: The aim of the present study was to determine the prevalence of asymptomatic apical periodontitis (AAP and its association with coronary artery disease (CAD in a Brazilian subpopulation, and to examine the correlation of AAP with gender, age and most frequently affected dental elements. Methods: The data were collected from medical records of the patients (n = 1346 treated at the Specialization in Endodontics Clinic of the Federal University of Pernambuco in the period between 2003 and 2010. From each patient, the following variables were recorded: gender, age, endodontically compromised teeth, endodontic diseases diagnosed and the history of CAD. The data were analyzed using Pearson’s chi-square test adopting a significance level of 5%. Results: AAP was diagnosed in 574 patients (42.6%, corresponding to 641 teeth (40.1%. Both genders (p = 0.082, and all age groups (p = 0.190 were affected similarly. The upper incisors (52.8%, p <0.001 had a higher prevalence of AAP. The patients with AAP showed 1.45 times more chance of exhibiting CAD (p = 0.307. Conclusions: The results pointed out that the prevalence of AAP in this population was high and similar to that observed in other countries. A positive association, but not statistically significant, between AAP and CAD was found.

  12. MLST and Whole-Genome-Based Population Analysis of Cryptococcus gattii VGIII Links Clinical, Veterinary and Environmental Strains, and Reveals Divergent Serotype Specific Sub-populations and Distant Ancestors

    Science.gov (United States)

    Firacative, Carolina; Roe, Chandler C.; Malik, Richard; Ferreira-Paim, Kennio; Escandón, Patricia; Sykes, Jane E.; Castañón-Olivares, Laura Rocío; Contreras-Peres, Cudberto; Samayoa, Blanca; Sorrell, Tania C.; Castañeda, Elizabeth; Lockhart, Shawn R.; Engelthaler, David M.; Meyer, Wieland

    2016-01-01

    The emerging pathogen Cryptococcus gattii causes life-threatening disease in immunocompetent and immunocompromised hosts. Of the four major molecular types (VGI-VGIV), the molecular type VGIII has recently emerged as cause of disease in otherwise healthy individuals, prompting a need to investigate its population genetic structure to understand if there are potential genotype-dependent characteristics in its epidemiology, environmental niche(s), host range and clinical features of disease. Multilocus sequence typing (MLST) of 122 clinical, environmental and veterinary C. gattii VGIII isolates from Australia, Colombia, Guatemala, Mexico, New Zealand, Paraguay, USA and Venezuela, and whole genome sequencing (WGS) of 60 isolates representing all established MLST types identified four divergent sub-populations. The majority of the isolates belong to two main clades, corresponding either to serotype B or C, indicating an ongoing species evolution. Both major clades included clinical, environmental and veterinary isolates. The C. gattii VGIII population was genetically highly diverse, with minor differences between countries, isolation source, serotype and mating type. Little to no recombination was found between the two major groups, serotype B and C, at the whole and mitochondrial genome level. C. gattii VGIII is widespread in the Americas, with sporadic cases occurring elsewhere, WGS revealed Mexico and USA as a likely origin of the serotype B VGIII population and Colombia as a possible origin of the serotype C VGIII population. Serotype B isolates are more virulent than serotype C isolates in a murine model of infection, causing predominantly pulmonary cryptococcosis. No specific link between genotype and virulence was observed. Antifungal susceptibility testing against six antifungal drugs revealed that serotype B isolates are more susceptible to azoles than serotype C isolates, highlighting the importance of strain typing to guide effective treatment to improve the

  13. Genetic structure of Suillus luteus populations in heavy metal polluted and nonpolluted habitats.

    Science.gov (United States)

    Muller, Ludo A H; Vangronsveld, Jaco; Colpaert, Jan V

    2007-11-01

    The genetic structure of populations of the ectomycorrhizal basidiomycete Suillus luteus in heavy metal polluted and nonpolluted areas was studied. Sporocarps were collected at nine different locations and genotyped at four microsatellite loci. Six of the sampling sites were severely contaminated with heavy metals and were dominated by heavy metal-tolerant individuals. Considerable genetic diversity was found within the geographical subpopulations, but no reduction of the genetic diversity, current or historic, was observed in subpopulations inhabiting polluted soils. The genetic differentiation between the geographical subpopulations was low, and no evidence for clustering of subpopulations from polluted soils vs. subpopulations from nonpolluted soils was found. These results indicate that heavy metal pollution has a limited effect on the genetic structure of S. luteus populations, and this may be due to the high frequency of sexual reproduction and extensive gene flow in S. luteus, which allows rapid evolution of the tolerance trait while maintaining high levels of genetic diversity.

  14. Informing conservation management about structural versus functional connectivity: a case-study of Cross River gorillas.

    Science.gov (United States)

    Imong, Inaoyom; Robbins, Martha M; Mundry, Roger; Bergl, Richard; Kühl, Hjalmar S

    2014-10-01

    Connectivity among subpopulations is vital for the persistence of small and fragmented populations. For management interventions to be effective conservation planners have to make the critical distinction between structural connectivity (based on landscape structure) and functional connectivity (which considers both landscape structure and organism-specific behavioral attributes) which can differ considerably within a given context. We assessed spatial and temporal changes in structural and functional connectivity of the Cross River gorilla Gorilla gorilla diehli (CRG) population in a 12,000 km(2) landscape in the Nigeria-Cameroon border region over a 23-year period, comparing two periods: 1987-2000 and 2000-2010. Despite substantial forest connections between occupied areas, genetic evidence shows that only limited dispersal occurs among CRG subpopulations. We used remotely sensed land-cover data and simulated human pressure (using a spatially explicit agent-based model) to assess human impact on connectivity of the CRG population. We calculated cost-weighted distances between areas occupied by gorillas as measures of connectivity (structural based on land-cover only, functional based on both land-cover and simulated human pressure). Whereas structural connectivity decreased by 5% over the 23-year period, functional connectivity decreased by 11%, with both decreasing more during the latter compared to the earlier period. Our results highlight the increasing threat of isolation of CRG subpopulations due to human disturbance, and provide insight into how increasing human influence may lead to functional isolation of wildlife populations despite habitat continuity, a pressing and common issue in tropical Africa often not accounted for when deciding management interventions. In addition to quantifying threats to connectivity, our study provides crucial evidence for management authorities to identify actions that are more likely to be effective for conservation of

  15. Genetic diversity and population structure of Miscanthus sinensis germplasm in China.

    Directory of Open Access Journals (Sweden)

    Hua Zhao

    Full Text Available Miscanthus is a perennial rhizomatous C4 grass native to East Asia. Endowed with great biomass yield, high ligno-cellulose composition, efficient use of radiation, nutrient and water, as well as tolerance to stress, Miscanthus has great potential as an excellent bioenergy crop. Despite of the high potential for biomass production of the allotriploid hybrid M. ×giganteus, derived from M. sacchariflorus and M. sinensis, other options need to be explored to improve the narrow genetic base of M. ×giganteus, and also to exploit other Miscanthus species, including M. sinensis (2n = 2x = 38, as bioenergy crops. In the present study, a large number of 459 M. sinensis accessions, collected from the wide geographical distribution regions in China, were genotyped using 23 SSR markers transferable from Brachypodium distachyon. Genetic diversity and population structure were assessed. High genetic diversity and differentiation of the germplasm were observed, with 115 alleles in total, a polymorphic rate of 0.77, Nei's genetic diversity index (He of 0.32 and polymorphism information content (PIC of 0.26. Clustering of germplasm accessions was primarily in agreement with the natural geographic distribution. AMOVA and genetic distance analyses confirmed the genetic differentiation in the M. sinensis germplasm and it was grouped into five clusters or subpopulations. Significant genetic variation among subpopulations indicated obvious genetic differentiation in the collections, but within-subpopulation variation (83% was substantially greater than the between-subpopulation variation (17%. Considerable phenotypic variation was observed for multiple traits among 300 M. sinensis accessions. Nine SSR markers were found to be associated with heading date and biomass yield. The diverse Chinese M. sinensis germplasm and newly identified SSR markers were proved to be valuable for breeding Miscanthus varieties with desired bioenergy traits.

  16. Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons

    Directory of Open Access Journals (Sweden)

    Luke K. Burke

    2016-03-01

    expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual. Author Video: Author Video Watch what authors say about their articles Keywords: Pro-opiomelanocortin (Pomc, 5-HT2c receptor, Obesity, Energy expenditure, Brown adipose tissue, Hyperinsulinemia, Sexual dimorphism, Hypothalamus

  17. Voluntary Medical Male Circumcision for HIV Prevention: New Mathematical Models for Strategic Demand Creation Prioritizing Subpopulations by Age and Geography.

    Science.gov (United States)

    Hankins, Catherine; Warren, Mitchell; Njeuhmeli, Emmanuel

    2016-01-01

    Over 11 million voluntary medical male circumcisions (VMMC) have been performed of the projected 20.3 million needed to reach 80% adult male circumcision prevalence in priority sub-Saharan African countries. Striking numbers of adolescent males, outside the 15-49-year-old age target, have been accessing VMMC services. What are the implications of overall progress in scale-up to date? Can mathematical modeling provide further insights on how to efficiently reach the male circumcision coverage levels needed to create and sustain further reductions in HIV incidence to make AIDS no longer a public health threat by 2030? Considering ease of implementation and cultural acceptability, decision makers may also value the estimates that mathematical models can generate of immediacy of impact, cost-effectiveness, and magnitude of impact resulting from different policy choices. This supplement presents the results of mathematical modeling using the Decision Makers' Program Planning Tool Version 2.0 (DMPPT 2.0), the Actuarial Society of South Africa (ASSA2008) model, and the age structured mathematical (ASM) model. These models are helping countries examine the potential effects on program impact and cost-effectiveness of prioritizing specific subpopulations for VMMC services, for example, by client age, HIV-positive status, risk group, and geographical location. The modeling also examines long-term sustainability strategies, such as adolescent and/or early infant male circumcision, to preserve VMMC coverage gains achieved during rapid scale-up. The 2016-2021 UNAIDS strategy target for VMMC is an additional 27 million VMMC in high HIV-prevalence settings by 2020, as part of access to integrated sexual and reproductive health services for men. To achieve further scale-up, a combination of evidence, analysis, and impact estimates can usefully guide strategic planning and funding of VMMC services and related demand-creation strategies in priority countries. Mid-course corrections

  18. Voluntary Medical Male Circumcision for HIV Prevention: New Mathematical Models for Strategic Demand Creation Prioritizing Subpopulations by Age and Geography.

    Directory of Open Access Journals (Sweden)

    Catherine Hankins

    Full Text Available Over 11 million voluntary medical male circumcisions (VMMC have been performed of the projected 20.3 million needed to reach 80% adult male circumcision prevalence in priority sub-Saharan African countries. Striking numbers of adolescent males, outside the 15-49-year-old age target, have been accessing VMMC services. What are the implications of overall progress in scale-up to date? Can mathematical modeling provide further insights on how to efficiently reach the male circumcision coverage levels needed to create and sustain further reductions in HIV incidence to make AIDS no longer a public health threat by 2030? Considering ease of implementation and cultural acceptability, decision makers may also value the estimates that mathematical models can generate of immediacy of impact, cost-effectiveness, and magnitude of impact resulting from different policy choices. This supplement presents the results of mathematical modeling using the Decision Makers' Program Planning Tool Version 2.0 (DMPPT 2.0, the Actuarial Society of South Africa (ASSA2008 model, and the age structured mathematical (ASM model. These models are helping countries examine the potential effects on program impact and cost-effectiveness of prioritizing specific subpopulations for VMMC services, for example, by client age, HIV-positive status, risk group, and geographical location. The modeling also examines long-term sustainability strategies, such as adolescent and/or early infant male circumcision, to preserve VMMC coverage gains achieved during rapid scale-up. The 2016-2021 UNAIDS strategy target for VMMC is an additional 27 million VMMC in high HIV-prevalence settings by 2020, as part of access to integrated sexual and reproductive health services for men. To achieve further scale-up, a combination of evidence, analysis, and impact estimates can usefully guide strategic planning and funding of VMMC services and related demand-creation strategies in priority countries. Mid

  19. A sub-population of circulating porcine gammadelta T cells can act as professional antigen presenting cells.

    Science.gov (United States)

    Takamatsu, H-H; Denyer, M S; Wileman, T E

    2002-09-10

    A sub-population of circulating porcine gammadelta T cells express cell surface antigens associated with antigen presenting cells (APCs), and are able to take up soluble antigen very effectively. Functional antigen presentation by gammadelta T cells to memory helper T cells was studied by inbred pig lymphocytes immunised with ovalbumin (OVA). After removing all conventional APCs from the peripheral blood of immunised pigs, the remaining lymphocytes still proliferated when stimulated with OVA. When gammadelta T cells were further depleted, OVA specific proliferation was abolished, but reconstitution with gammadelta T cells restored proliferation. The proliferation was blocked by monoclonal antibodies (mAb) against MHC class II or CD4, and by pre-treatment of gammadelta T cells with chloroquine. These results indicate that a sub-population of circulating porcine gammadelta T cells act as APCs and present antigen via MHC class II.

  20. Differential regulation of amyloid-β-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease

    International Nuclear Information System (INIS)

    Higgins, G.A.; Lewis, D.A.; Bahmanyar, S.; Goldgaber, D.; Gajdusek, D.C.; Young, W.G.; Morrison, J.H.; Wilson, M.C.

    1988-01-01

    The authors have mapped the neuroanatomical distribution of amyloid-β-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-β-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-β-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-β-protein gene expression may be altered in Alzheimer disease

  1. Normative data set identifying properties of the macula across age groups: integration of visual function and retinal structure with microperimetry and spectral-domain optical coherence tomography.

    Science.gov (United States)

    Sabates, Felix N; Vincent, Ryan D; Koulen, Peter; Sabates, Nelson R; Gallimore, Gary

    2011-01-01

    A normative database of functional and structural parameters of the macula from normal subjects was established to identify reference points for the diagnosis of patients with macular disease using microperimetry and scanning laser ophthalmoscope/spectral-domain optical coherence tomography (SD-OCT). This was a community-based, prospective, cross-sectional study of 169 eyes from subjects aged 21 years to 85 years with best-corrected visual acuity of 20/25 or better and without any ocular disease. Full-threshold macular microperimetry combined with the acquisition of structural parameters of the macula with scanning laser ophthalmoscope/SD-OCT was recorded (SD-OCT/scanning laser ophthalmoscope with add-on Microperimetry module; OPKO). Fixation, central, subfield, and mean retinal thickness were acquired together with macular sensitivity function. Thickness and sensitivity as primary outcome measures were mapped and superimposed correlating topographically differentiated macular thickness with sensitivity. Statistical evaluation was performed with age, gender, and ethnicity as covariates. Subfield and mean retinal thickness and sensitivity were measured with macular microperimetry combined with SD-OCT and differentiated by macular topography and subjects' age, gender, and ethnicity. Mean retinal sensitivity and thickness were calculated for 169 healthy eyes (mean age, 48 ± 17 years). A statistically significant decrease in sensitivity was found only in the age group of participants ≥ 70 years and in peripheral portions of the macula in individuals aged ≥60 years and was more pronounced in the area surrounding the fovea than in the center of the macula, while retinal thickness did not change with age. No statistically significant differences in the primary outcome measures or their correlations were found when using gender or ethnicity as a covariate. A database for normal macular thickness and sensitivity was generated with a combined microperimetry SD

  2. Comparison of tumor biology of two distinct cell sub-populations in lung cancer stem cells.

    Science.gov (United States)

    Wang, Jianyu; Sun, Zhiwei; Liu, Yongli; Kong, Liangsheng; Zhou, Shixia; Tang, Junlin; Xing, Hongmei Rosie

    2017-11-14

    Characterization of the stem-like properties of cancer stem cells (CSCs) remain indirect and qualitative, especially the ability of CSCs to undergo asymmetric cell division for self renewal and differentiation, a unique property of cells of stem origin. It is partly due to the lack of stable cellular models of CSCs. In this study, we developed a new approach for CSC isolation and purification to derive a CSC-enriched cell line (LLC-SE). By conducting five consecutive rounds of single cell cloning using the LLC-SE cell line, we obtained two distinct sub-population of cells within the Lewis lung cancer CSCs that employed largely symmetric division for self-renewal (LLC-SD) or underwent asymmetric division for differentiation (LLC-ASD). LLC-SD and LLC-ASD cell lines could be stably passaged in culture and be distinguished by cell morphology, stem cell marker, spheroid formation and subcutaneous tumor initiation efficiency, as well as orthotopic lung tumor growth, progression and survival. The ability LLC-ASD cells to undergo asymmetric division was visualized and quantified by the asymmetric segregation of labeled BrdU and NUMB to one of the two daughter cells in anaphase cell division. The more stem-like LLC-SD cells exhibited higher capacity for tumorigenesis and progression and shorter survival. As few as 10 LLC-SD could initiate subcutaneous tumor growth when transplanted to the athymic mice. Collectively, these observations suggest that the SD-type of cells appear to be on the top of the hierarchical order of the CSCs. Furthermore, they have lead to generated cellular models of CSC self-renewal for future mechanistic investigations.

  3. Defining Subpopulations of Arcuate Nucleus GABA Neurons in Male, Female, and Prenatally Androgenized Female Mice.

    Science.gov (United States)

    Marshall, Christopher J; Desroziers, Elodie; McLennan, Timothy; Campbell, Rebecca E

    2017-01-01

    Arcuate nucleus (ARN) γ-aminobutyric acid (GABA) neurons are implicated in many critical homeostatic mechanisms, from food intake to fertility. To determine the functional relevance of ARN GABA neurons, it is essential to define the neurotransmitters co-expressed with and potentially co-released from ARN GABA neurons. The present study investigated the expression of markers of specific signaling molecules by ARN GABA neurons in brain sections from male, female, and, in some cases, prenatally androgen-treated (PNA) female, vesicular GABA transporter (VGaT)-ires-Cre/tdTomato reporter mice. Immunofluorescence for kisspeptin, β-endorphin, neuropeptide Y (NPY), tyrosine hydroxylase (TH) and neuronal nitric oxide synthase (nNOS) was detected by confocal microscopy, and co-localization with tdTomato VGaT reporter expression throughout the ARN was quantified. GABA neurons rarely co-localized with kisspeptin (95%) co-localized with VGaT across groups. Both TH and nNOS labeling was co-localized with ∼10% of ARN GABA neurons. The proportion of TH neurons co-localized with VGaT was significantly greater in males than either control or PNA females, and the proportion of nNOS neurons co-localizing VGaT was higher in control and PNA females compared with males. These data highlight NPY as a significant subpopulation of ARN GABA neurons, demonstrate no significant impact of PNA on signal co-expression, and, for the first time, show sexually dimorphic co-expression patterns of TH and nNOS with ARN GABA neurons. © 2016 S. Karger AG, Basel.

  4. Prevalence and morphometric analysis of three-rooted mandibular first molars in a Brazilian subpopulation

    Directory of Open Access Journals (Sweden)

    Clarissa Teles Rodrigues

    Full Text Available ABSTRACT The knowledge of the internal anatomy of three-rooted mandibular molars may help clinicians to diagnose and plan the root canal treatment in order to provide adequate therapy when this variation is present. Objectives: To determine the prevalence of three-rooted mandibular molars in a Brazilian population using cone beam computed tomography (CBCT and to analyze the anatomy of mandibular first molars with three roots through micro-CT. Material and Methods: CBCT images of 116 patients were reviewed to determine the prevalence of three-rooted first mandibular molars in a Brazilian subpopulation. Furthermore, with the use of micro-CT, 55 extracted three-rooted mandibular first molars were scanned and reconstructed to assess root length, distance between canal orifices, apical diameter, Vertucci's classification, presence of apical delta, number of foramina and furcations, lateral and accessory canals. The distance between the orifice on the pulp chamber floor and the beginning of the curvature and the angle of canal curvature were analyzed in the distolingual root. Data were compared using the Kruskal-Wallis test (α=0.05. Results: The prevalence of three-rooted mandibular first molars was of 2.58%. Mesial roots showed complex distribution of the root canal system in comparison to the distal roots. The median of major diameters of mesiobuccal, mesiolingual and single mesial canals were: 0.34, 0.41 and 0.60 mm, respectively. The higher values of major diameters were found in the distobuccal canals (0.56 mm and the lower diameters in the distolingual canals (0.29 mm. The lowest orifice distance was found between the mesial canals (MB-ML and the highest distance between the distal root canals (DB-DL. Almost all distal roots had one root canal and one apical foramen with few accessory canals. Conclusions: Distolingual root generally has short length, severe curvature and a single root canal with low apical diameter.

  5. Prevalence and morphometric analysis of three-rooted mandibular first molars in a Brazilian subpopulation

    Science.gov (United States)

    Rodrigues, Clarissa Teles; de Oliveira-Santos, Christiano; Bernardineli, Norberti; Duarte, Marco Antonio Hungaro; Bramante, Clovis Monteiro; Minotti-Bonfante, Paloma Gagliardi; Ordinola-Zapata, Ronald

    2016-01-01

    ABSTRACT The knowledge of the internal anatomy of three-rooted mandibular molars may help clinicians to diagnose and plan the root canal treatment in order to provide adequate therapy when this variation is present. Objectives: To determine the prevalence of three-rooted mandibular molars in a Brazilian population using cone beam computed tomography (CBCT) and to analyze the anatomy of mandibular first molars with three roots through micro-CT. Material and Methods: CBCT images of 116 patients were reviewed to determine the prevalence of three-rooted first mandibular molars in a Brazilian subpopulation. Furthermore, with the use of micro-CT, 55 extracted three-rooted mandibular first molars were scanned and reconstructed to assess root length, distance between canal orifices, apical diameter, Vertucci's classification, presence of apical delta, number of foramina and furcations, lateral and accessory canals. The distance between the orifice on the pulp chamber floor and the beginning of the curvature and the angle of canal curvature were analyzed in the distolingual root. Data were compared using the Kruskal-Wallis test (α=0.05). Results: The prevalence of three-rooted mandibular first molars was of 2.58%. Mesial roots showed complex distribution of the root canal system in comparison to the distal roots. The median of major diameters of mesiobuccal, mesiolingual and single mesial canals were: 0.34, 0.41 and 0.60 mm, respectively. The higher values of major diameters were found in the distobuccal canals (0.56 mm) and the lower diameters in the distolingual canals (0.29 mm). The lowest orifice distance was found between the mesial canals (MB-ML) and the highest distance between the distal root canals (DB-DL). Almost all distal roots had one root canal and one apical foramen with few accessory canals. Conclusions: Distolingual root generally has short length, severe curvature and a single root canal with low apical diameter. PMID:27812625

  6. Quantitative morphological analysis of proliferating and nonproliferating subpopulations of IMR-90 fibroblasts during aging in vitro

    International Nuclear Information System (INIS)

    Pool, T.B.; Heitman, T.O.; Buck, M.A.

    1982-01-01

    Early-, mid- and late-passage cultures (population doubling levels 12, 35, and 51, respectively) of IMR-90 fibroblasts were exposed to 3 H-thymidine for 48 h prior to fixation in situ for morphometric analysis in order to determine quantitatively what ultrastructural changes accompany the loss of proliferative capacity during aging in vitro. Analysis of autoradiographs, both at the light and electron microscopic levels, with an image analyzer followed by ANOVA statistical scrutiny demonstrated that a significant increase in relative cell area, an indicator of cell size, was characteristic of cells unable to incorporate 3 H-TdR at both mid- and late-passage, but not at early-passage levels. Nuclear size also increased significantly with progressive passage level but was not related to proliferative capacity. No significant difference in the area fraction of nucleoli per unit area of nucleus or of mitochondria, Golgi, or lysosomes was seen in either subpopulation at any passage level. Dilated cisternae of rough endoplasmic reticulum in early-passage cells were seen if cells were harvested with trypsin and fixed either before or after centrifugation, but were not seen in labeled or unlabeled cells from any passage level when cultures were fixed in situ. We conclude that a significant increase in cell size is the only significant morphological change associated with the loss of proliferative capacity of IRM-90 fibroblasts. Furthermore, our data indicate that there is no accumulation of secondary lysosomes in human diploid fibroblasts during aging in vitro; we therefore cannot support any hypothesis of aging or proliferative decline that is based mechanistically upon this phenomenon

  7. Relationship and inter observer agreement of tooth and face forms in a Saudi subpopulation.

    Science.gov (United States)

    Habib, Syed Rashid; Shiddi, Ibraheem Al; Al-Sufyani, Mohammed D; Althobaiti, Fahad A

    2015-04-01

    To determine the relationship of tooth form with the face form by different observers and further investigate the inter observer agreement on tooth forms, face forms, their relationship among male Saudis. A comparative cross-sectional study. Department of Prosthodontics, College of Dentistry, King Saud University, Riyadh, KSA, from February till August 2013. Ninety four male participants aged 18 - 35 years were randomly recruited for the study. Full-face and anterior teeth (intraoral) digital photographs in the frontal plane were recorded. The outline tracings of the face and the tooth were obtained using Autocad (version 2010) software. The outline of the tooth was enlarged proportionately, without altering the length to width ratio to fit the face outline. The outlines were then evaluated visually by 6 prosthodontists and results were tabulated. The most common type of face form (49.65%) and tooth form (56.38%) was square tapering. Using the visual method, a good relationship (31.41%), moderate relationship (35.31%), weak relationship (19.68%) and no relationship (13.65%) between the tooth form and face form was found by the observers. Overall kappa for inter observer agreement on face form, tooth form and their relationship was 0.24, 0.17 and 0.26 respectively. The kappa values showed a fair agreement between the observers. The study results indicated that there was no highly defined relationship between the tooth form and face form in the studied Saudi subpopulation. A fair agreement was found between the observers for classifying the tooth forms, face froms and their relationship.

  8. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.

    Science.gov (United States)

    Saito, Takuro; Nishikawa, Hiroyoshi; Wada, Hisashi; Nagano, Yuji; Sugiyama, Daisuke; Atarashi, Koji; Maeda, Yuka; Hamaguchi, Masahide; Ohkura, Naganari; Sato, Eiichi; Nagase, Hirotsugu; Nishimura, Junichi; Yamamoto, Hirofumi; Takiguchi, Shuji; Tanoue, Takeshi; Suda, Wataru; Morita, Hidetoshi; Hattori, Masahira; Honda, Kenya; Mori, Masaki; Doki, Yuichiro; Sakaguchi, Shimon

    2016-06-01

    CD4(+) T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg cells is controversial in colorectal cancers (CRCs), in which FOXP3(+) T cell infiltration indicated better prognosis in some studies. Here we show that CRCs, which are commonly infiltrated by suppression-competent FOXP3(hi) Treg cells, can be classified into two types by the degree of additional infiltration of FOXP3(lo) nonsuppressive T cells. The latter, which are distinguished from FOXP3(+) Treg cells by non-expression of the naive T cell marker CD45RA and instability of FOXP3, secreted inflammatory cytokines. Indeed, CRCs with abundant infiltration of FOXP3(lo) T cells showed significantly better prognosis than those with predominantly FOXP3(hi) Treg cell infiltration. Development of such inflammatory FOXP3(lo) non-Treg cells may depend on secretion of interleukin (IL)-12 and transforming growth factor (TGF)-β by tissues and their presence was correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3(+) T cells contribute in opposing ways to determining CRC prognosis. Depletion of FOXP3(hi) Treg cells from tumor tissues, which would augment antitumor immunity, could thus be used as an effective treatment strategy for CRCs and other cancers, whereas strategies that locally increase the population of FOXP3(lo) non-Treg cells could be used to suppress or prevent tumor formation.

  9. A subpopulation of smooth muscle cells, derived from melanocyte-competent precursors, prevents patent ductus arteriosus.

    Directory of Open Access Journals (Sweden)

    Ichiro Yajima

    Full Text Available BACKGROUND: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA, a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2 and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.

  10. A Subpopulation of Smooth Muscle Cells, Derived from Melanocyte-Competent Precursors, Prevents Patent Ductus Arteriosus

    Science.gov (United States)

    Puig, Isabel; Champeval, Delphine; Kumasaka, Mayuko; Belloir, Elodie; Bonaventure, Jacky; Mark, Manuel; Yamamoto, Hiroaki; Taketo, Mark M.; Choquet, Philippe; Etchevers, Heather C.; Beermann, Friedrich; Delmas, Véronique; Monassier, Laurent; Larue, Lionel

    2013-01-01

    Background Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes. PMID:23382837

  11. Range contraction and increasing isolation of a polar bear subpopulation in an era of sea-ice loss.

    Science.gov (United States)

    Laidre, Kristin L; Born, Erik W; Atkinson, Stephen N; Wiig, Øystein; Andersen, Liselotte W; Lunn, Nicholas J; Dyck, Markus; Regehr, Eric V; McGovern, Richard; Heagerty, Patrick

    2018-02-01

    Climate change is expected to result in range shifts and habitat fragmentation for many species. In the Arctic, loss of sea ice will reduce barriers to dispersal or eliminate movement corridors, resulting in increased connectivity or geographic isolation with sweeping implications for conservation. We used satellite telemetry, data from individually marked animals (research and harvest), and microsatellite genetic data to examine changes in geographic range, emigration, and interpopulation connectivity of the Baffin Bay (BB) polar bear ( Ursus maritimus ) subpopulation over a 25-year period of sea-ice loss. Satellite telemetry collected from n  = 43 (1991-1995) and 38 (2009-2015) adult females revealed a significant contraction in subpopulation range size (95% bivariate normal kernel range) in most months and seasons, with the most marked reduction being a 70% decline in summer from 716,000 km 2 (SE 58,000) to 211,000 km 2 (SE 23,000) ( p  Bears in the 2000s were less likely to leave BB, with significant reductions in the numbers of bears moving into Davis Strait (DS) in winter and Lancaster Sound (LS) in summer. Harvest recoveries suggested both short and long-term fidelity to BB remained high over both periods (83-99% of marked bears remained in BB). Genetic analyses using eight polymorphic microsatellites confirmed a previously documented differentiation between BB, DS, and LS; yet weakly differentiated BB from Kane Basin (KB) for the first time. Our results provide the first multiple lines of evidence for an increasingly geographically and functionally isolated subpopulation of polar bears in the context of long-term sea-ice loss. This may be indicative of future patterns for other polar bear subpopulations under climate change.

  12. Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern Chinese Han subpopulation.

    Science.gov (United States)

    Zhao, Yi; Liu, Xu; Liu, Xia; Su, Yin; Li, Yanmei; Zhang, Xiaoping; Zhu, Lei; Wang, Shiyao; Wang, Tian; Jiang, Quan; Liu, Xiangyuan; Li, Xiaoxia; Huang, Cibo; Jia, Rulin; Lu, Xiaolan; Guo, Jianping; Li, Zhanguo

    2013-04-01

    Several studies have reported STAT4 polymorphism is strongly associated with increased susceptibility to rheumatoid arthritis (RA). However, a study from China showed no association between STAT4 and RA susceptibility in a Chinese Han subpopulation. Since the northern Hans are known to be genetically different from the southern Hans, the aim of this study was to investigate the association of STAT4 polymorphism with RA in a large cohort of a northern Chinese Han subpopulation. 640 RA patients and 662 healthy controls were enrolled. DNA samples were genotyped for STAT4 rs7574865 by direct sequencing. The association of single nucleotide polymorphism (SNP) rs7574865 with RA susceptibility was calculated and the relationship between rs7574865 polymorphism and RA subgroups stratified by clinical features was estimated. We confirmed a significant association of STAT4 rs7574865 polymorphism with RA susceptibility in northern Chinese Han population. The frequency of the minor T allele in RA was significantly higher than in healthy controls (35.2% vs. 31.1%; P = 0.029, OR 1.2 [95% CI 1.02-1.41]). There was also a significant difference in the distribution of the genotypes of SNP rs7574865 between RA patients and healthy controls (P = 0.02). Stratification analyses showed no associations between the genetic risk and clinical/serologic features, but a potential high frequency of TT genotype in a rheumatoid factor-negative subgroup, although it did not reach statistical significance (P = 0.084, OR 2.01 [95% CI 0.91-4.45]). STAT4 rs7574865 is significantly associated with RA susceptibility in northern Chinese Han subpopulations. The genetic differences of Han subpopulations should be considered when genetic susceptibility for diseases is studied. © 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  13. The 2.1 Å resolution structure of cyanopindolol-bound β1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor.

    Directory of Open Access Journals (Sweden)

    Jennifer L Miller-Gallacher

    Full Text Available The β1-adrenoceptor (β1AR is a G protein-coupled receptor (GPCR that is activated by the endogenous agonists adrenaline and noradrenaline. We have determined the structure of an ultra-thermostable β1AR mutant bound to the weak partial agonist cyanopindolol to 2.1 Å resolution. High-quality crystals (100 μm plates were grown in lipidic cubic phase without the assistance of a T4 lysozyme or BRIL fusion in cytoplasmic loop 3, which is commonly employed for GPCR crystallisation. An intramembrane Na+ ion was identified co-ordinated to Asp872.50, Ser1283.39 and 3 water molecules, which is part of a more extensive network of water molecules in a cavity formed between transmembrane helices 1, 2, 3, 6 and 7. Remarkably, this water network and Na+ ion is highly conserved between β1AR and the adenosine A2A receptor (rmsd of 0.3 Å, despite an overall rmsd of 2.4 Å for all Cα atoms and only 23% amino acid identity in the transmembrane regions. The affinity of agonist binding and nanobody Nb80 binding to β1AR is unaffected by Na+ ions, but the stability of the receptor is decreased by 7.5°C in the absence of Na+. Mutation of amino acid side chains that are involved in the co-ordination of either Na+ or water molecules in the network decreases the stability of β1AR by 5-10°C. The data suggest that the intramembrane Na+ and associated water network stabilise the ligand-free state of β1AR, but still permits the receptor to form the activated state which involves the collapse of the Na+ binding pocket on agonist binding.

  14. Nonspecific activation of murine lymphocytes. IV. Proliferation of a distinct, late maturing lymphocyte subpopulation induced by 2-mercaptoethanol

    International Nuclear Information System (INIS)

    Goodman, M.G.; Fidler, J.M.; Weigle, W.O.

    1978-01-01

    The lymphocyte subpopulations that are activated by 2-ME, LPS, poly IC, and PPD were studied in terms of their maturational characteristics. Attempts to stimulate hepatic and splenic lymphoid cells from mice of different ages with these mitogens demonstrated a well ordered sequence for the emergency of mitogen responsiveness in C3H mice: reactivity to LPS and Poly IC was observed early in maturation and was followed by that to PPD, and finally by the development of responsiveness to 2-ME. The same sequence appeared when the mitogen responsiveness of lethally irradiated, fetal liver-reconstituted syngeneic adult recipients was examined. The mitogenic action of 2-ME was dissociated from its ability to enhance lymphocyte reactivity to other mitogens in mice too young to respond to 2-ME as a mitogen. Experiments in which additivity of responses was assayed by adding mitogens to culture singly or conjointly indicated that LPS and Poly IC activate nearly identical B lymphocyte subpopulations, whereas PPD stimulates a subset of cells distinct from that which is responsive to the former two mitogens. The mitogen responsiveness of CBA/N mice, relative to normal CBA/WEHI mice, was shown to decrease as a function of the maturity of the subpopulation of lymphocytes activated. The CBA/N mouse was shown to be unresponsive to stimulation by 2-ME

  15. Viral Transmission Dynamics at Single-Cell Resolution Reveal Transiently Immune Subpopulations Caused by a Carrier State Association.

    Directory of Open Access Journals (Sweden)

    William Cenens

    2015-12-01

    Full Text Available Monitoring the complex transmission dynamics of a bacterial virus (temperate phage P22 throughout a population of its host (Salmonella Typhimurium at single cell resolution revealed the unexpected existence of a transiently immune subpopulation of host cells that emerged from peculiarities preceding the process of lysogenization. More specifically, an infection event ultimately leading to a lysogen first yielded a phage carrier cell harboring a polarly tethered P22 episome. Upon subsequent division, the daughter cell inheriting this episome became lysogenized by an integration event yielding a prophage, while the other daughter cell became P22-free. However, since the phage carrier cell was shown to overproduce immunity factors that are cytoplasmically inherited by the P22-free daughter cell and further passed down to its siblings, a transiently resistant subpopulation was generated that upon dilution of these immunity factors again became susceptible to P22 infection. The iterative emergence and infection of transiently resistant subpopulations suggests a new bet-hedging strategy by which viruses could manage to sustain both vertical and horizontal transmission routes throughout an infected population without compromising a stable co-existence with their host.

  16. Bistable expression of virulence genes in salmonella leads to the formation of an antibiotic-tolerant subpopulation.

    Directory of Open Access Journals (Sweden)

    Markus Arnoldini

    2014-08-01

    Full Text Available Phenotypic heterogeneity can confer clonal groups of organisms with new functionality. A paradigmatic example is the bistable expression of virulence genes in Salmonella typhimurium, which leads to phenotypically virulent and phenotypically avirulent subpopulations. The two subpopulations have been shown to divide labor during S. typhimurium infections. Here, we show that heterogeneous virulence gene expression in this organism also promotes survival against exposure to antibiotics through a bet-hedging mechanism. Using microfluidic devices in combination with fluorescence time-lapse microscopy and quantitative image analysis, we analyzed the expression of virulence genes at the single cell level and related it to survival when exposed to antibiotics. We found that, across different types of antibiotics and under concentrations that are clinically relevant, the subpopulation of bacterial cells that express virulence genes shows increased survival after exposure to antibiotics. Intriguingly, there is an interplay between the two consequences of phenotypic heterogeneity. The bet-hedging effect that arises through heterogeneity in virulence gene expression can protect clonal populations against avirulent mutants that exploit and subvert the division of labor within these populations. We conclude that bet-hedging and the division of labor can arise through variation in a single trait and interact with each other. This reveals a new degree of functional complexity of phenotypic heterogeneity. In addition, our results suggest a general principle of how pathogens can evade antibiotics: Expression of virulence factors often entails metabolic costs and the resulting growth retardation could generally increase tolerance against antibiotics and thus compromise treatment.

  17. The metabolically active subpopulation in Pseudomonas aeruginosa biofilms survives exposure to membrane-targeting antimicrobials via distinct molecular mechanisms

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Pamp, Sünje Johanna; Nilsson, Martin

    2012-01-01

    encoding lipopolysaccharide modification enzymes, as well as on the mexAB-oprM, mexCD-oprJ, and muxABC-opmB genes encoding antimicrobial efflux pumps, but does not depend on the mexPQ-opmE efflux pump genes. Development of chlorhexidine-tolerant subpopulations was found to depend on the mexCD-oprJ genes......, but does not depend on the pmr, mexAB-oprM, mexPQ-opmE, or muxABC-opmB genes. Tolerance to SDS and EDTA in P. aeruginosa biofilms is linked to metabolically active cells, but does not depend on the pmr, mexAB, mexCD, mexPQ, or muxABC genes. Our data suggest that the active subpopulation in P. aeruginosa......-targeting compounds colistin, EDTA, SDS, and chlorhexidine resulted in the same spatial distribution of live and dead bacteria, we investigated whether tolerance to these compounds originated from the same molecular mechanisms. Development of colistin-tolerant subpopulations was found to depend on the pmr genes...

  18. Allelic frequencies and association with carcass traits of six genes in local subpopulations of Japanese Black cattle.

    Science.gov (United States)

    Nishimaki, Takahiro; Ibi, Takayuki; Siqintuya; Kobayashi, Naohiko; Matsuhashi, Tamako; Akiyama, Takayuki; Yoshida, Emi; Imai, Kazumi; Matsui, Mayu; Uemura, Keiichi; Eto, Hisayoshi; Watanabe, Naoto; Fujita, Tatsuo; Saito, Yosuke; Komatsu, Tomohiko; Hoshiba, Hiroshi; Mannen, Hideyuki; Sasazaki, Shinji; Kunieda, Tetsuo

    2016-04-01

    Marker-assisted selection (MAS) is expected to accelerate the genetic improvement of Japanese Black cattle. However, verification of the effects of the genes for MAS in different subpopulations is required prior to the application of MAS. In this study, we investigated the allelic frequencies and genotypic effects for carcass traits of six genes, which can be used in MAS, in eight local subpopulations. These genes are SCD, FASN and SREBP1, which are associated with the fatty acid composition of meat, and NCAPG, MC1R and F11, which are associated with carcass weight, coat color and blood coagulation abnormality, respectively. The frequencies of desirable alleles of SCD and FASN were relatively high and that of NCAPG was relatively low, and NCAPG was significantly associated with several carcass traits, including carcass weight. The proportions of genotypic variance explained by NCAPG to phenotypic variance were 4.83 for carcass weight. We thus confirmed that NCAPG is a useful marker for selection of carcass traits in these subpopulations. In addition, we found that the desirable alleles of six genes showed no negative effects on carcass traits. Therefore, selection using these genes to improve target traits should not have negative impacts on carcass traits. © 2015 Japanese Society of Animal Science.

  19. Effects of cholesterol on progesterone production by goat luteal cell subpopulations at two different stages of the luteal phase.

    Science.gov (United States)

    Arikan, Ş; Kalender, H; Simsek, O

    2010-12-01

    The aim of the present study was to evaluate the effects of cholesterol on progesterone production during long-term culturing of luteal cell subpopulations at early and late luteal stages of the goat corpora lutea. Corpora lutea were collected from Angora goats on days 5 and 15 of the oestrous cycle. Luteal cells were isolated by collagenase digestion. The cells were separated into two distinct subpopulations by Percoll density-gradient centrifugation. Both subpopulations of luteal cells staining positively for 3β-HSD activities (5 × 10(4)  cell/well) were cultured with or without 22(R)-hydroxycholesterol (22R-HC) in serum-free culture medium for periods of up to 7 days. Cells were incubated with serum (10%) for the first 18 h of incubation followed by serum-free medium. Cell treatment (10 and 20 μg/ml) was performed on days 1, 3 and 5. Treatment of cells with both concentrations of 22R-HC resulted in significant (p  0.05) on progesterone production in both fractions of cells throughout 7 days of incubation. Treatment of the cells with cholesterol resulted in 2.5- and 9.0-fold increases in progesterone accumulation on day 3 of incubation. Steroid production was maintained throughout the incubations when cells are incubated in serum-free media treated with cholesterol and ITS premix. Cells collected from higher density of percoll layers produced 2.82 and 2.32 times more progesterone, in comparison to the lover density percoll layer, on days 5 and 15 of the oestrous cycle in untreated cell groups, respectively. Progesterone accumulation was decreased as incubation time advanced in all groups of untreated cells. These results demonstrated that goat luteal cell subpopulations secrete substantial amounts of progesterone in response to cholesterol treatment at least for 7 days, and cholesterol is required as progesterone precursor for maintaining a high-level steroidogenesis during long-life culturing of both cell subpopulations. © 2010 Blackwell

  20. The population genomics of begomoviruses: global scale population structure and gene flow

    Directory of Open Access Journals (Sweden)

    Prasanna HC

    2010-09-01

    Full Text Available Abstract Background The rapidly growing availability of diverse full genome sequences from across the world is increasing the feasibility of studying the large-scale population processes that underly observable pattern of virus diversity. In particular, characterizing the genetic structure of virus populations could potentially reveal much about how factors such as geographical distributions, host ranges and gene flow between populations combine to produce the discontinuous patterns of genetic diversity that we perceive as distinct virus species. Among the richest and most diverse full genome datasets that are available is that for the dicotyledonous plant infecting genus, Begomovirus, in the Family Geminiviridae. The begomoviruses all share the same whitefly vector, are highly recombinogenic and are distributed throughout tropical and subtropical regions where they seriously threaten the food security of the world's poorest people. Results We focus here on using a model-based population genetic approach to identify the genetically distinct sub-populations within the global begomovirus meta-population. We demonstrate the existence of at least seven major sub-populations that can further be sub-divided into as many as thirty four significantly differentiated and genetically cohesive minor sub-populations. Using the population structure framework revealed in the present study, we further explored the extent of gene flow and recombination between genetic populations. Conclusions Although geographical barriers are apparently the most significant underlying cause of the seven major population sub-divisions, within the framework of these sub-divisions, we explore patterns of gene flow to reveal that both host range differences and genetic barriers to recombination have probably been major contributors to the minor population sub-divisions that we have identified. We believe that the global Begomovirus population structure revealed here could

  1. Psychological stress moderates the relationship between running volume and CD4+ T cell subpopulations.

    Science.gov (United States)

    Rehm, K E; Sunesara, I; Tull, M T; Marshall, G D

    2016-01-01

    Endurance-based exercise training can lead to alterations in components of the immune system, but it is unknown how psychological stress (another potent immunomodulator) may impact these changes. The purpose of this study was to determine the moderating role of psychological stress on exercise-induced immune changes. Twenty-nine recreational runners were recruited for this study four weeks before completing a marathon. Each subject reported: weekly training volume (miles/wk) for the week prior to the study visit; completed the Perceived Stress Scale (PSS), the state version of the State-Trait Anxiety Inventory (STAI) and the Penn State Worry Questionnaire (PSWQ); and donated blood for assessment of CD4+ T cell subpopulations and mitogen-induced cytokine production. Participants ran an average of 30 (±13.4) miles (1 mile=1.6 km) per week. Average values (SD) for immune biomarkers were: regulatory T cells (Treg), 3.2% (±1.2%); type 1 regulatory cells (Tr1), 27.1% (±8.3%); T helper 3 (Th3), 1.8% (±0.7%); interferon gamma (IFNγ), 3.1 pg/ml (±1.0); interleukin (IL)-4, 1.4 pg/ml (±1.1); IFNγ/IL-4, 8.6 (±1.2); IL-10, 512 pg/ml (±288). There was a significant relationship between running volume and both Treg cell numbers (slope of the regression line (β)=0.05, p less than 0.001) and IL-10 production β=-10.6, p=0.002), and there was a trending relationship between running volume and Tr1 cell numbers (β=-0.2%, p=0.064). Perceived stress was a trending moderator of the running volume-Treg relationship, whereas worry was a significant moderator of the running volume-IFNγ and running volume-IFNγ/IL-4 relationships. These data indicate that various forms of psychological stress can impact endurance exercise-based changes in certain immune biomarkers. These changes may reflect an increased susceptibility to clinical risks in some individuals.

  2. Cellular variability of RpoS expression underlies subpopulation activation of an integrative and conjugative element.

    Directory of Open Access Journals (Sweden)

    Ryo Miyazaki

    Full Text Available Conjugative transfer of the integrative and conjugative element ICEclc in the bacterium Pseudomonas knackmussii is the consequence of a bistable decision taken in some 3% of cells in a population during stationary phase. Here we study the possible control exerted by the stationary phase sigma factor RpoS on the bistability decision. The gene for RpoS in P. knackmussii B13 was characterized, and a loss-of-function mutant was produced and complemented. We found that, in absence of RpoS, ICEclc transfer rates and activation of two key ICEclc promoters (P(int and P(inR decrease significantly in cells during stationary phase. Microarray and gene reporter analysis indicated that the most direct effect of RpoS is on P(inR, whereas one of the gene products from the P(inR-controlled operon (InrR transmits activation to P(int and other ICEclc core genes. Addition of a second rpoS copy under control of its native promoter resulted in an increase of the proportion of cells expressing the P(int and P(inR promoters to 18%. Strains in which rpoS was replaced by an rpoS-mcherry fusion showed high mCherry fluorescence of individual cells that had activated P(int and P(inR, whereas a double-copy rpoS-mcherry-containing strain displayed twice as much mCherry fluorescence. This suggested that high RpoS levels are a prerequisite for an individual cell to activate P(inR and thus ICEclc transfer. Double promoter-reporter fusions confirmed that expression of P(inR is dominated by extrinsic noise, such as being the result of cellular variability in RpoS. In contrast, expression from P(int is dominated by intrinsic noise, indicating it is specific to the ICEclc transmission cascade. Our results demonstrate how stochastic noise levels of global transcription factors can be transduced to a precise signaling cascade in a subpopulation of cells leading to ICE activation.

  3. Effect of /sup 32/P treatment for polycythaemia vera on blood lymphocyte subpopulations and their functions

    Energy Technology Data Exchange (ETDEWEB)

    Petrini, B.; Wasserman, J.; Stedingk, L.V.; Blomgren, H.; Svedmyr, E.; Schnell, P.O.

    1987-01-01

    The influence of /sup 32/P treatment on the blood lymphocyte population was examined in 16 patiens with polycythaemia vera who had not previously been treated with cytotoxic drugs or irradiation. Before treatment the lymphocyte counts were within the normal range but the expression of certain membrane structures, as detected by monoclonal antibodies directed against total T cells (CD 3 and 5), helper/inducer (CD 4) and suppressor/cytotoxic T cells (CD 8), were slightly reduced. In addition, mitogenic responses of the lymphocytes to PHA and PWM-induced Ig secretion were severely impaired. Following a single oral dose of /sup 32/P (150-305 MBq), which was shown to normalize the production of erythrocytes and/or platelets, the blood lymphocyte counts were reduced by approximately 40% 12 wk after treatment. Subset analysis showed that the proportion of B cells, as identified by monoclonal antibodies (CD 20), was reduced to the highest relative extent. On the other hand, lymphocytes expressing the above T cell markers were somewhat increased. /sup 32/P treatment sharply increased PHA reactivity but it further reduced PWM-induced Ig secretion. The latter observation was in line with the finding that serum concentrations of Ig were reduced following treatment.

  4. Near Identifiability of Dynamical Systems

    Science.gov (United States)

    Hadaegh, F. Y.; Bekey, G. A.

    1987-01-01

    Concepts regarding approximate mathematical models treated rigorously. Paper presents new results in analysis of structural identifiability, equivalence, and near equivalence between mathematical models and physical processes they represent. Helps establish rigorous mathematical basis for concepts related to structural identifiability and equivalence revealing fundamental requirements, tacit assumptions, and sources of error. "Structural identifiability," as used by workers in this field, loosely translates as meaning ability to specify unique mathematical model and set of model parameters that accurately predict behavior of corresponding physical system.

  5. Vulnerability of a low-income community in South Africa to air pollution: Exploring the use of structural equations modelling to identify appropriate interventions

    CSIR Research Space (South Africa)

    John, J

    2012-03-01

    Full Text Available diseases that affect their immune system. Structural equations modelling was used to capture the possible web of relationships between the household traits and a combined respiratory health outcome variable. Specifically, the two traits considered...

  6. Structure-function relationship of a plant NCS1 member - Homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from arabidopsis

    KAUST Repository

    Witz, Sandra; Panwar, Pankaj; Schober, Markus; Deppe, Johannes; Pasha, Farhan Ahmad; Lemieux, M. Joanne; Mö hlmann, Torsten

    2014-01-01

    . Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members. 2014 Witz

  7. Alterations of white matter structural networks in patients with non-neuropsychiatric systemic lupus erythematosus identified by probabilistic tractography and connectivity-based analyses

    Directory of Open Access Journals (Sweden)

    Man Xu

    2017-01-01

    Conclusion: This study reveals an altered topological organization of white matter networks in non-NPSLE patients. Furthermore, this research provides new insights into the structural disruptions underlying the functional and neurocognitive deficits in non-NPSLE patients.

  8. Fast and simple tool for the quantification of biofilm-embedded cells sub-populations from fluorescent microscopic images.

    Directory of Open Access Journals (Sweden)

    Mikhail I Bogachev

    Full Text Available Fluorescent staining is a common tool for both quantitative and qualitative assessment of pro- and eukaryotic cells sub-population fractions by using microscopy and flow cytometry. However, direct cell counting by flow cytometry is often limited, for example when working with cells rigidly adhered either to each other or to external surfaces like bacterial biofilms or adherent cell lines and tissue samples. An alternative approach is provided by using fluorescent microscopy and confocal laser scanning microscopy (CLSM, which enables the evaluation of fractions of cells subpopulations in a given sample. For the quantitative assessment of cell fractions in microphotographs, we suggest a simple two-step algorithm that combines single cells selection and the statistical analysis. To facilitate the first step, we suggest a simple procedure that supports finding the balance between the detection threshold and the typical size of single cells based on objective cell size distribution analysis. Based on a series of experimental measurements performed on bacterial and eukaryotic cells under various conditions, we show explicitly that the suggested approach effectively accounts for the fractions of different cell sub-populations (like the live/dead staining in our samples in all studied cases that are in good agreement with manual cell counting on microphotographs and flow cytometry data. This algorithm is implemented as a simple software tool that includes an intuitive and user-friendly graphical interface for the initial adjustment of algorithm parameters to the microphotographs analysis as well as for the sequential analysis of homogeneous series of similar microscopic images without further user intervention. The software tool entitled BioFilmAnalyzer is freely available online at https://bitbucket.org/rogex/biofilmanalyzer/downloads/.

  9. Subminimal Inhibitory Concentrations of the Disinfectant Benzalkonium Chloride Select for a Tolerant Subpopulation of Escherichia coli with Inheritable Characteristics

    Directory of Open Access Journals (Sweden)

    Solveig Langsrud

    2012-03-01

    Full Text Available Exposure of Escherichia coli to a subminimal inhibitory concentration (25% below MIC of benzalkonium chloride (BC, an antimicrobial membrane-active agent commonly used in medical and food-processing environments, resulted in cell death and changes in cell morphology (filamentation. A small subpopulation (1–5% of the initial population survived and regained similar morphology and growth rate as non-exposed cells. This subpopulation maintained tolerance to BC after serial transfers in medium without BC. To withstand BC during regrowth the cells up regulated a drug efflux associated gene (the acrB gene, member of the AcrAB-TolC efflux system and changed expression of outer membrane porin genes (ompFW and several genes involved in protecting the cell from the osmotic- and oxidative stress. Cells pre-exposed to osmotic- and oxidative stress (sodium chloride, salicylic acid and methyl viologen showed higher tolerance to BC. A control and two selected isolates showing increased BC-tolerance after regrowth in BC was genome sequenced. No common point mutations were found in the BC- isolates but one point mutation in gene rpsA (Ribosomal protein S1 was observed in one of the isolates. The observed tolerance can therefore not solely be explained by the observed point mutation. The results indicate that there are several different mechanisms responsible for the regrowth of a tolerant subpopulation in BC, both BC-specific and general stress responses, and that sub-MIC of BC may select for phenotypic variants in a sensitive E. coli culture.

  10. Fine scale gene flow and individual movements among subpopulations of Centrolene prosoblepon (Anura: Centrolenidae

    Directory of Open Access Journals (Sweden)

    Jeanne M Robertson

    2008-03-01

    Full Text Available Dispersal capabilities determine and maintain local gene flow, and this has implications for population persistence and/or recolonization following environmental perturbations (natural or anthropogenic, disease outbreaks, or other demographic collapses. To predict recolonization and understand dispersal capacity in a stream-breeding frog, we examined individual movement patterns and gene flow among four subpopulations of the Neotropical glassfrog, Centrolene prosoblepon, at a mid-elevation cloud forest site at El Copé, Panama. We measured male movement directly during a two year mark-recapture study, and indirectly with gene flow estimates from mitochondrial DNA sequences (mtDNA. Individuals of this species showed strong site fidelity: over two years, male frogs in all four headwater streams moved very little (mean = 2.33 m; mode = 0 m. Nine individuals changed streams within one or two years, moving 675-1 108 m. For those males moving more than 10 m, movement was biased upstream (p ST = 0.007, p = 0.325 but gene flow was more limited across greater distances (CT = 0.322, p = 0.065, even within the same drainage network. Lowland populations of C. prosoblepon potentially act as an important source of colonists for upland populations in this watershed. Rev. Biol. Trop. 56 (1: 13-26. Epub 2008 March 31.La capacidad de dispersión determina y mantiene el flujo genético local, y esto tiene implicaciones para la persistencia poblacional y/o la recolonización que sigue a perturbaciones ambientales. Examinamos patrones individuales de movimiento y flujo genético entre subpoblaciones de Centrolene prosoblepon (Anura: Centrolenidae en un sitio de elevación media en El Copé, Panamá. Medimos directamente el movimiento de los machos durante un estudio de marcado-recaptura, e indirectamente con estimaciones de flujo genético a partir de secuencias de ADN mitocondrial (mtDNA. Los individuos mostraron fuerte fidelidad a su lugar: por más de dos a

  11. Medication errors versus time of admission in a subpopulation of stroke patients undergoing inpatient rehabilitation complications and considerations.

    Science.gov (United States)

    Pitts, Eric P

    2011-01-01

    This study looked at the medication ordering error frequency and the length of inpatient hospital stay in a subpopulation of stroke patients (n-60) as a function of time of patient admission to an inpatient rehabilitation hospital service. A total of 60 inpatient rehabilitation patients, 30 arriving before 4 pm, and 30 arriving after 4 pm, with as admitting diagnosis of stroke were randomly selected from a larger sample (N=426). There was a statistically significant increase in medication ordering errors and the number of inpatient rehabilitation hospital days in the group of patients who arrived after 4 pm.

  12. A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors

    DEFF Research Database (Denmark)

    Jeon, Jongrye; Dencker, Ditte; Wörtwein, Gitta

    2010-01-01

    AChRs are coexpressed with D(1) dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M(4) mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M(4) mAChRs only in D(1) dopamine....... Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance....

  13. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition

    Directory of Open Access Journals (Sweden)

    Schlichter Rémy

    2008-05-01

    Full Text Available Abstract Background Recent evidence suggests that oxytocin (OT, secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN neurons, produces antinociception and analgesia. The spinal mechanism of OT is, however, still unclear and requires further investigation. We have used patch clamp recording of lamina II neurons in spinal cord slices and immunocytochemistry in order to identify PVN-activated neurons in the superficial layers of the spinal cord and attempted to determine how this neuronal population may lead to OT-mediated antinociception. Results We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II. This OT-specific stimulation of glutamatergic neurons allows the recruitment of all GABAergic interneurons in lamina II which produces a generalized elevation of local inhibition, a phenomenon which might explain the reduction of incoming Aδ and C primary afferent-mediated sensory messages. Conclusion Our results obtained in lamina II of the spinal cord provide the first clear evidence of a specific local neuronal network that is activated by OT release to induce antinociception. This OT-specific pathway might represent a novel and interesting therapeutic target for the management of neuropathic and inflammatory pain.

  14. A subpopulation of mushroom body intrinsic neurons is generated by protocerebral neuroblasts in the tobacco hornworm moth, Manduca sexta (Sphingidae, Lepidoptera)

    Science.gov (United States)

    Farris, Sarah M.; Pettrey, Colleen; Daly, Kevin C.

    2010-01-01

    Subpopulations of Kenyon cells, the intrinsic neurons of the insect mushroom bodies, are typically sequentially generated by dedicated neuroblasts that begin proliferating during embryogenesis. When present, Class III Kenyon cells are thought to be the first born population of neurons by virtue of the location of their cell somata, farthest from the position of the mushroom body neuroblasts. In the adult tobacco hornworm moth Manduca sexta, the axons of Class III Kenyon cells form a separate Y tract and dorsal and ventral lobelet; surprisingly, these distinctive structures are absent from the larval Manduca mushroom bodies. BrdU labeling and immunohistochemical staining reveal that Class III Kenyon cells are in fact born in the mid-larval through adult stages. The peripheral position of their cell bodies is due to their genesis from two previously undescribed protocerebral neuroblasts distinct from the mushroom body neuroblasts that generate the other Kenyon cell types. These findings challenge the notion that all Kenyon cells are produced solely by the mushroom body neuroblasts, and may explain why Class III Kenyon cells are found sporadically across the insects, suggesting that when present, they may arise through de novo recruitment of neuroblasts outside of the mushroom bodies. In addition, lifelong neurogenesis by both the Class III neuroblasts and the mushroom body neuroblasts was observed, raising the possibility that adult neurogenesis may play a role in mushroom body function in Manduca. PMID:21040804

  15. Hydrous ferric oxide: evaluation of Cd-HFO surface complexation models combining Cd(K) EXAFS data, potentiometric titration results, and surface site structures identified from mineralogical knowledge.

    Science.gov (United States)

    Spadini, Lorenzo; Schindler, Paul W; Charlet, Laurent; Manceau, Alain; Vala Ragnarsdottir, K

    2003-10-01

    The surface properties of ferrihydrite were studied by combining wet chemical data, Cd(K) EXAFS data, and a surface structure and protonation model of the ferrihydrite surface. Acid-base titration experiments and Cd(II)-ferrihydrite sorption experiments were performed within 3titration data could be adequately modeled by triple bond Fe- OH(2)(+1/2)-H(+)triple bond Fe-OH(-1/2),logk((int))=-8.29, assuming the existence of a unique intrinsic microscopic constant, logk((int)), and consequently the existence of a single significant type of acid-base reactive functional groups. The surface structure model indicates that these groups are terminal water groups. The Cd(II) data were modeled assuming the existence of a single reactive site. The model fits the data set at low Cd(II) concentration and up to 50% surface coverage. At high coverage more Cd(II) ions than predicted are adsorbed, which is indicative of the existence of a second type of site of lower affinity. This agrees with the surface structure and protonation model developed, which indicates comparable concentrations of high- and low-affinity sites. The model further shows that for each class of low- and high-affinity sites there exists a variety of corresponding Cd surface complex structure, depending on the model crystal faces on which the complexes develop. Generally, high-affinity surface structures have surface coordinations of 3 and 4, as compared to 1 and 2 for low-affinity surface structures.

  16. A multi-sample based method for identifying common CNVs in normal human genomic structure using high-resolution aCGH data.

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    Chihyun Park

    Full Text Available BACKGROUND: It is difficult to identify copy number variations (CNV in normal human genomic data due to noise and non-linear relationships between different genomic regions and signal intensity. A high-resolution array comparative genomic hybridization (aCGH containing 42 million probes, which is very large compared to previous arrays, was recently published. Most existing CNV detection algorithms do not work well because of noise associated with the large amount of input data and because most of the current methods were not designed to analyze normal human samples. Normal human genome analysis often requires a joint approach across multiple samples. However, the majority of existing methods can only identify CNVs from a single sample. METHODOLOGY AND PRINCIPAL FINDINGS: We developed a multi-sample-based genomic variations detector (MGVD that uses segmentation to identify common breakpoints across multiple samples and a k-means-based clustering strategy. Unlike previous methods, MGVD simultaneously considers multiple samples with different genomic intensities and identifies CNVs and CNV zones (CNVZs; CNVZ is a more precise measure of the location of a genomic variant than the CNV region (CNVR. CONCLUSIONS AND SIGNIFICANCE: We designed a specialized algorithm to detect common CNVs from extremely high-resolution multi-sample aCGH data. MGVD showed high sensitivity and a low false discovery rate for a simulated data set, and outperformed most current methods when real, high-resolution HapMap datasets were analyzed. MGVD also had the fastest runtime compared to the other algorithms evaluated when actual, high-resolution aCGH data were analyzed. The CNVZs identified by MGVD can be used in association studies for revealing relationships between phenotypes and genomic aberrations. Our algorithm was developed with standard C++ and is available in Linux and MS Windows format in the STL library. It is freely available at: http://embio.yonsei.ac.kr/~Park/mgvd.php.

  17. Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

    Energy Technology Data Exchange (ETDEWEB)

    Doherty, Kimberly R., E-mail: kimberly.doherty@quintiles.com; Talbert, Dominique R.; Trusk, Patricia B.; Moran, Diarmuid M.; Shell, Scott A.; Bacus, Sarah

    2015-05-15

    Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. - Highlights: • 24 drugs were tested for cardiac liability using an in vitro multi-parameter screen. • Changes in beating activity were the most sensitive in predicting cardiac risk. • Structural effects add in

  18. Identifying structural barriers to an effective HIV response: using the National Composite Policy Index data to evaluate the human rights, legal and policy environment

    Science.gov (United States)

    Gruskin, Sofia; Ferguson, Laura; Alfven, Tobias; Rugg, Deborah; Peersman, Greet

    2013-01-01

    Introduction Attention to the negative effects of structural barriers on HIV efforts is increasing. Reviewing national legal and policy environments with attention to the international human rights commitments of states is a means of assessing and providing focus for addressing these barriers to effective HIV responses. Methods Law and policy data from the 171 countries reporting under the Declaration of Commitment from the 2001 United Nations General Assembly Special Session on HIV/AIDS were analyzed to assess attention to human rights in national legal and policy environments as relevant to the health and rights of key populations such as people who inject drugs, men who have sex with men and sex workers. Results Seventy-eight governments and civil society in 106 countries report the existence of laws and policies which present obstacles to accessing HIV services for key populations. Laws and policies which positively affect access to HIV-related services, in and of themselves constituting structural interventions, were also reported. The dissonance between laws and how this impacts the availability and use of HIV-related services deserve greater attention. Conclusions Recognition of the harms inherent in laws that constitute structural barriers to effective HIV responses and the potential positive role that a supportive legal environment can play suggests the need for legal reform to ensure an enabling regulatory framework within which HIV services can be effectively delivered and used by the populations who need them. Moving beyond laws and policies, further efforts are required to determine how to capture information on the range of structural barriers. Teasing apart the impact of different barriers, as well as the structural interventions put in place to address them, remains complicated. Capturing the impact of policy and legal interventions can ultimately support governments and civil society to ensure the human rights of key populations are protected in

  19. The Crystal Structure of the Drosophila Germline Inducer Oskar Identifies Two Domains with Distinct Vasa Helicase- and RNA-Binding Activities

    Directory of Open Access Journals (Sweden)

    Mandy Jeske

    2015-07-01

    Full Text Available In many animals, the germ plasm segregates germline from soma during early development. Oskar protein is known for its ability to induce germ plasm formation and germ cells in Drosophila. However, the molecular basis of germ plasm formation remains unclear. Here, we show that Oskar is an RNA-binding protein in vivo, crosslinking to nanos, polar granule component, and germ cell-less mRNAs, each of which has a role in germline formation. Furthermore, we present high-resolution crystal structures of the two Oskar domains. RNA-binding maps in vitro to the C-terminal domain, which shows structural similarity to SGNH hydrolases. The highly conserved N-terminal LOTUS domain forms dimers and mediates Oskar interaction with the germline-specific RNA helicase Vasa in vitro. Our findings suggest a dual function of Oskar in RNA and Vasa binding, providing molecular clues to its germ plasm function.

  20. Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.

    Science.gov (United States)

    Yamada, Kazuhiro; Gherasim, Carmen; Banerjee, Ruma; Koutmos, Markos

    2015-12-04

    In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an α+β fold that is structurally reminiscent of the nitro-FMN reductase superfamily. Two of the closest structural relatives of CblD are CblC, a multifunctional enzyme important for cobalamin trafficking, and the activation domain of methionine synthase. CblD, CblC, and the activation domain of methionine synthase share several distinguishing features and, together with two recently described corrinoid-dependent reductive dehalogenases, constitute a new subclass within the nitro-FMN reductase superfamily. We demonstrate that CblD enhances oxidation of cob(II)alamin bound to CblC and that disease-causing mutations in CblD impair the kinetics of this reaction. The striking structural similarity of CblD to CblC, believed to be contiguous in the cobalamin trafficking pathway, suggests the co-option of molecular mimicry as a strategy for achieving its function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Evidence against the existence of specific Schistosoma mansoni subpopulations which are resistant to irradiated vaccine-induced immunity

    International Nuclear Information System (INIS)

    Lewis, F.A.; Hieny, S.; Sher, A.

    1985-01-01

    When mice are immunized with irradiated Schistosoma mansoni cercariae a proportion of the subsequent cercarial challenge always escapes killing and matures to egg-laying adults. This report investigates the possibility that incomplete immunity in this system is governed by a genetically-determined insusceptibility of a particular schistosome subpopulation. To do this the authors tested whether more immunoresistant schistosomes would develop following successive passages of progeny of the resistant worms through immunized mice. Mice were immunized with 500 50 Krad-irradiated cercariae, and challenged with normal cercariae when immunity was at its peak. After five successive passages through snails and immune mice, progeny of those parasites which escaped immune killing were no more refractory to vaccine-induced resistance than the original stock maintained in nonimmune mice. Additionally, the passaged isolates did not differ from the original stock in their ability to induce protection following irradiation. The results indicate that with this model of acquired resistance incomplete immunity is unlikely to be due to a subpopulation of the parasites possessing a genetically-determined insusceptibility to killing

  2. Helper T cell subpopulations from women are more susceptible to the toxic effect of sodium arsenite in vitro

    International Nuclear Information System (INIS)

    Vega, Libia; Montes de Oca, Pavel; Saavedra, Rafael; Ostrosky-Wegman, Patricia

    2004-01-01

    Arsenic is known to produce inhibition as well as induction of proliferative responses in animal and human cells depending on the doses. Despite the amount of information on the immunotoxic effects of arsenic exposure in different animal models, little is known in humans. Arsenic susceptibility of lymphocyte subpopulations (T helper (Th), CD4+; T cytotoxic (Tc), CD8+) and whether arsenic effects are gender related are still to be determined. This work evaluated the in vitro toxicity of sodium arsenite on human T lymphocyte subpopulations from men and women. Peripheral blood mononuclear cells (PBMC) obtained from healthy young men and women were treated with sodium arsenite (0.01, 0.1, and 1 μM). We assessed cell viability, cell proliferation, and the proportion of Th and Tc cells after 48 or 72 h of arsenic exposure in resting and phytohemagglutinin M (PHA)-activated PBMC. We observed that sodium arsenite at 1 μM was more toxic for Th than for Tc cells in PBMC from women. Besides, T lymphocytes from women were more affected by the cell proliferation inhibition induced by arsenic, suggesting that women could be more susceptible to the toxic and immunotoxic effects caused by arsenic exposure

  3. Performance impact of mutation operators of a subpopulation-based genetic algorithm for multi-robot task allocation problems.

    Science.gov (United States)

    Liu, Chun; Kroll, Andreas

    2016-01-01

    Multi-robot task allocation determines the task sequence and distribution for a group of robots in multi-robot systems, which is one of constrained combinatorial optimization problems and more complex in case of cooperative tasks because they introduce additional spatial and temporal constraints. To solve multi-robot task allocation problems with cooperative tasks efficiently, a subpopulation-based genetic algorithm, a crossover-free genetic algorithm employing mutation operators and elitism selection in each subpopulation, is developed in this paper. Moreover, the impact of mutation operators (swap, insertion, inversion, displacement, and their various combinations) is analyzed when solving several industrial plant inspection problems. The experimental results show that: (1) the proposed genetic algorithm can obtain better solutions than the tested binary tournament genetic algorithm with partially mapped crossover; (2) inversion mutation performs better than other tested mutation operators when solving problems without cooperative tasks, and the swap-inversion combination performs better than other tested mutation operators/combinations when solving problems with cooperative tasks. As it is difficult to produce all desired effects with a single mutation operator, using multiple mutation operators (including both inversion and swap) is suggested when solving similar combinatorial optimization problems.

  4. Does the sex difference in competitiveness decrease in selective sub-populations? A test with intercollegiate distance runners.

    Science.gov (United States)

    Deaner, Robert O; Lowen, Aaron; Rogers, William; Saksa, Eric

    2015-01-01

    Sex differences in some preferences and motivations are well established, but it is unclear whether they persist in selective sub-populations, such as expert financial decision makers, top scientists, or elite athletes. We addressed this issue by studying competitiveness in 1,147 varsity intercollegiate distance runners. As expected, across all runners, men reported greater competitiveness with two previously validated instruments, greater competitiveness on a new elite competitiveness scale, and greater training volume, a known correlate of competitiveness. Among faster runners, the sex difference decreased for one measure of competitiveness but did not decrease for the two other competitiveness measures or either measure of training volume. Across NCAA athletic divisions (DI, DII, DIII), the sex difference did not decrease for any competitiveness or training measure. Further analyses showed that these sex differences could not be attributed to women suffering more injuries or facing greater childcare responsibilities. However, women did report greater commitment than men to their academic studies, suggesting a sex difference in priorities. Therefore, policies aiming to provide men and women with equal opportunities to flourish should acknowledge that sex differences in some kinds of preferences and motivation may persist even in selective sub-populations.

  5. Definite vs adjuvant radiotherapy. Comparative effects on lymphocyte subpopulations in patients with head and neck squamous carcinoma

    International Nuclear Information System (INIS)

    Wolf, G.T.; Amendola, B.E.; Diaz, R.; Lovett, E.J. III; Hammerschmidt, R.M.; Peterson, K.A.

    1985-01-01

    The recent association of alterations in T-lymphocyte subpopulations and impaired cellular immunity prompted an investigation of the effects of radiotherapy (RT) on serial levels of lymphocyte subsets in 30 patients with head and neck squamous carcinoma. Percentage and absolute levels of T3, T4, T6, T8, T10, T11, and Leu 7 cells were measured before, during, and after RT at monthly intervals for six months and compared with levels in 40 normal subjects. Sixteen patients received curative and 14 postoperative adjuvant RT. Before treatment, mean subset levels were similar among the patient and normal groups except for elevated Leu 7 (natural killer) cells in patients with stage I and II disease. There were profound decreases in absolute levels of each subpopulation during and after RT. The percentage of T4 (helper/inducer) cells decreased, whereas that of T8 (cytotoxic/suppressor) and Leu 7 cells tended to increase. Compared with normal values, the mean T4/T8 ratio decreased significantly by six months after RT, when absolute levels of the subsets had rebounded to pretreatment levels in the definitive RT group but remained profoundly decreased in the adjuvant group. The differing recovery patterns suggest that factors other than RT may contribute to persistent immunosuppression following RT

  6. IgE to penicillins with different specificities can be identified by a multiepitope macromolecule: Bihaptenic penicillin structures and IgE specificities.

    Science.gov (United States)

    Ariza, A; Barrionuevo, E; Mayorga, C; Montañez, M I; Perez-Inestrosa, E; Ruiz-Sánchez, A; Rodríguez-Guéant, R M; Fernández, T D; Guéant, J L; Torres, M J; Blanca, M

    2014-04-01

    Quantitation of specific IgE by immunoassay is a recommended in vitro test for the diagnosis of immediate hypersensitivity reactions to betalactams (BLs), particularly when skin test results are negative. IgE antibodies that recognize the common nuclear structure of all BLs or the specific side chain structure can be mainly distinguished by immunoassays. The aim of this study was to develop an immunoassay system to detect IgE antibodies with different specificities. Cellulose discs conjugated with benzylpenicillin (BP), amoxicillin (AX) or both drugs, with poly-l-lysine (PLL) as carrier molecule, were used as solid phases in the radioallergosorbent test (RAST). Direct and inhibition radioimmunoassay studies were made to verify the structures recognized by serum IgE antibodies from penicillin-allergic patients. Our results indicated that the addition of both haptens did not decrease the capacity to capture IgE when serum specific to either BP or AX was used, at least in terms of sensitivity. In addition, the inclusion of two haptens improved significantly the levels of IgE detection in patients who recognized both BP and AX. Therefore, the use of a solid phase with a carrier molecule conjugated with two determinants (AX and BP) is helpful to recognize IgE antibodies against either of these determinants and is useful for screening sera with different specificities. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Structures of the Apo and FAD-bound forms of 2-hydroxybiphenyl 3-monooxygenase (HbpA) locate activity hotspots identified by using directed evolution.

    Science.gov (United States)

    Jensen, Chantel N; Mielke, Tamara; Farrugia, Joseph E; Frank, Annika; Man, Henry; Hart, Sam; Turkenburg, Johan P; Grogan, Gideon

    2015-04-13

    The FAD-dependent monooxygenase HbpA from Pseudomonas azelaica HBP1 catalyses the hydroxylation of 2-hydroxybiphenyl (2HBP) to 2,3-dihydroxybiphenyl (23DHBP). HbpA has been used extensively as a model for studying flavoprotein hydroxylases under process conditions, and has also been subjected to directed-evolution experiments that altered its catalytic properties. The structure of HbpA has been determined in its apo and FAD-complex forms to resolutions of 2.76 and 2.03 Å, respectively. Comparisons of the HbpA structure with those of homologues, in conjunction with a model of the reaction product in the active site, reveal His48 as the most likely acid/base residue to be involved in the hydroxylation mechanism. Mutation of His48 to Ala resulted in an inactive enzyme. The structures of HbpA also provide evidence that mutants achieved by directed evolution that altered activity are comparatively remote from the substrate-binding site. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Cation-Poor Complex Metallic Alloys in Ba(Eu)-Au-Al(Ga) Systems: Identifying the Keys that Control Structural Arrangements and Atom Distributions at the Atomic Level.

    Science.gov (United States)

    Smetana, Volodymyr; Steinberg, Simon; Mudryk, Yaroslav; Pecharsky, Vitalij; Miller, Gordon J; Mudring, Anja-Verena

    2015-11-02

    Four complex intermetallic compounds BaAu(6±x)Ga(6±y) (x = 1, y = 0.9) (I), BaAu(6±x)Al(6±y) (x = 0.9, y = 0.6) (II), EuAu6.2Ga5.8 (III), and EuAu6.1Al5.9 (IV) have been synthesized, and their structures and homogeneity ranges have been determined by single crystal and powder X-ray diffraction. Whereas I and II originate from the NaZn13-type structure (cF104-112, Fm3̅c), III (tP52, P4/nbm) is derived from the tetragonal Ce2Ni17Si9-type, and IV (oP104, Pbcm) crystallizes in a new orthorhombic structure type. Both I and II feature formally anionic networks with completely mixed site occupation by Au and triel (Tr = Al, Ga) atoms, while a successive decrease of local symmetry from the parental structures of I and II to III and, ultimately, to IV correlates with increasing separation of Au and Tr on individual crystallographic sites. Density functional theory-based calculations were employed to determine the crystallographic site preferences of Au and the respective triel element to elucidate reasons for the atom distribution ("coloring scheme"). Chemical bonding analyses for two different "EuAu6Tr6" models reveal maximization of the number of heteroatomic Au-Tr bonds as the driving force for atom organization. The Fermi levels fall in broad pseudogaps for both models allowing some electronic flexibility. Spin-polarized band structure calculations on the "EuAu6Tr6" models hint to singlet ground states for europium and long-range magnetic coupling for both EuAu6.2Ga5.8 (III) and EuAu6.1Al5.9 (IV). This is substantiated by experimental evidence because both compounds show nearly identical magnetic behavior with ferromagnetic transitions at TC = 6 K and net magnetic moments of 7.35 μB/f.u. at 2 K. The effective moments of 8.3 μB/f.u., determined from Curie-Weiss fits, point to divalent oxidation states for europium in both III and IV.

  9. Energetics of the rearrangement of neutral and ionized perfluorocyclopropane to perfluoropropylene. Use of infrared multiphoton dissociation spectra to identify structural isomers of molecular ions

    International Nuclear Information System (INIS)

    Bomse, D.S.; Berman, D.W.; Beauchamp, J.L.

    1981-01-01

    Infrared photodissociation spectroscopy is used to compare the structure of gas-phase C 3 F 6 + ions obtained by electron-impact ionization of two isomeric precursors: perfluoropropylene and perfluorocyclopropane. Photodissociation spectra are obtained by observing the extent of multiphoton dissociation as the CO 2 laser is tuned across the 925 to 1080 cm -1 wavelength range. Ions are formed, stored, and detected with the use of techniques of ion cyclotron resonance spectroscopy. Infrared multiphoton excitation is effected by using low-power, continuous-wave laser radiation. The fingerprint spectrum of the molecular ion of perfluorocyclopropane is identical with that obtained from perfluoropropylene, indicating rearrangement of the former to the latter. Photodissociation kinetics indicate that the entire perfluorocyclopropane molecular ion population isomerizes to the more stable perfluoropropylene structure. Thermochemistry of C 3 F 6 and C 3 F 6 + isomers is discussed. Comparisons are made with the analogous C 3 H 6 system. Photoionization mass spectroscopy results yield ΔH/sub f/(c-C 3 F 6 ) = -233.8 kcal/mol. 4 figures

  10. The Rome II and Rome III criteria identify the same subtype-populations in irritable bowel syndrome

    DEFF Research Database (Denmark)

    Engsbro, A L; Simrén, M; Bytzer, P

    2012-01-01

    For comparing trials using different classifications for irritable bowel syndrome (IBS) subtypes, it is important to know whether these identify the same sub-populations. Our aim was to determine the agreement between Rome II and Rome III subtypes, and to explore whether agreement depends...

  11. Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability.

    Science.gov (United States)

    Ring, Caroline L; Pearce, Robert G; Setzer, R Woodrow; Wetmore, Barbara A; Wambaugh, John F

    2017-09-01

    The thousands of chemicals present in the environment (USGAO, 2013) must be triaged to identify priority chemicals for human health risk research. Most chemicals have little of the toxicokinetic (TK) data that are necessary for relating exposures to tissue concentrations that are believed to be toxic. Ongoing efforts have collected limited, in vitro TK data for a few hundred chemicals. These data have been combined with biomonitoring data to estimate an approximate margin between potential hazard and exposure. The most "at risk" 95th percentile of adults have been identified from simulated populations that are generated either using standard "average" adult human parameters or very specific cohorts such as Northern Europeans. To better reflect the modern U.S. population, we developed a population simulation using physiologies based on distributions of demographic and anthropometric quantities from the most recent U.S. Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES) data. This allowed incorporation of inter-individual variability, including variability across relevant demographic subgroups. Variability was analyzed with a Monte Carlo approach that accounted for the correlation structure in physiological parameters. To identify portions of the U.S. population that are more at risk for specific chemicals, physiologic variability was incorporated within an open-source high-throughput (HT) TK modeling framework. We prioritized 50 chemicals based on estimates of both potential hazard and exposure. Potential hazard was estimated from in vitro HT screening assays (i.e., the Tox21 and ToxCast programs). Bioactive in vitro concentrations were extrapolated to doses that produce equivalent concentrations in body tissues using a reverse dosimetry approach in which generic TK models are parameterized with: 1) chemical-specific parameters derived from in vitro measurements and predicted from chemical structure; and 2) with

  12. Impact of Soil Salinity on the Structure of the Bacterial Endophytic Community Identified from the Roots of Caliph Medic (Medicago truncatula).

    Science.gov (United States)

    Yaish, Mahmoud W; Al-Lawati, Abbas; Jana, Gerry Aplang; Vishwas Patankar, Himanshu; Glick, Bernard R

    2016-01-01

    In addition to being a forage crop, Caliph medic (Medicago truncatula) is also a model legume plant and is used for research focusing on the molecular characterization of the interaction between rhizobia and plants. However, the endophytic microbiome in this plant is poorly defined. Endophytic bacteria play a role in supplying plants with the basic requirements necessary for growth and development. Moreover, these bacteria also play a role in the mechanism of salinity stress adaptation in plants. As a prelude to the isolation and utilization of these bacteria in Caliph medic farming, 41 bacterial OTUs were identified in this project from within the interior of the roots of this plant by pyrosequencing of the small ribosomal subunit gene (16S rDNA) using a cultivation-independent approach. In addition, the differential abundance of these bacteria was studied following exposure of the plants to salinity stress. About 29,064 high-quality reads were obtained from the sequencing of six libraries prepared from control and salinity-treated tissues. Statistical analysis revealed that the abundance of ~70% of the OTUs was significantly (p ≤ 0.05) altered in roots that were exposed to salinity stress. Sequence analysis showed a similarity between some of the identified species and other, known, growth-promoting bacteria, marine and salt-stressed soil-borne bacteria, and nitrogen-fixing bacterial isolates. Determination of the amendments to the bacterial community due to salinity stress in Caliph medic provides a crucial step toward developing an understanding of the association of these endophytes, under salt stress conditions, in this model plant. To provide direct evidence regarding their growth promoting activity, a group of endophytic bacteria were isolated from inside of plant roots using a cultivation-dependent approach. Several of these isolates were able to produce ACC-deaminase, ammonia and IAA; and to solubilize Zn+2 and PO4-3. This data is consistent with the

  13. Impact of Soil Salinity on the Structure of the Bacterial Endophytic Community Identified from the Roots of Caliph Medic (Medicago truncatula.

    Directory of Open Access Journals (Sweden)

    Mahmoud W Yaish

    Full Text Available In addition to being a forage crop, Caliph medic (Medicago truncatula is also a model legume plant and is used for research focusing on the molecular characterization of the interaction between rhizobia and plants. However, the endophytic microbiome in this plant is poorly defined. Endophytic bacteria play a role in supplying plants with the basic requirements necessary for growth and development. Moreover, these bacteria also play a role in the mechanism of salinity stress adaptation in plants. As a prelude to the isolation and utilization of these bacteria in Caliph medic farming, 41 bacterial OTUs were identified in this project from within the interior of the roots of this plant by pyrosequencing of the small ribosomal subunit gene (16S rDNA using a cultivation-independent approach. In addition, the differential abundance of these bacteria was studied following exposure of the plants to salinity stress. About 29,064 high-quality reads were obtained from the sequencing of six libraries prepared from control and salinity-treated tissues. Statistical analysis revealed that the abundance of ~70% of the OTUs was significantly (p ≤ 0.05 altered in roots that were exposed to salinity stress. Sequence analysis showed a similarity between some of the identified species and other, known, growth-promoting bacteria, marine and salt-stressed soil-borne bacteria, and nitrogen-fixing bacterial isolates. Determination of the amendments to the bacterial community due to salinity stress in Caliph medic provides a crucial step toward developing an understanding of the association of these endophytes, under salt stress conditions, in this model plant. To provide direct evidence regarding their growth promoting activity, a group of endophytic bacteria were isolated from inside of plant roots using a cultivation-dependent approach. Several of these isolates were able to produce ACC-deaminase, ammonia and IAA; and to solubilize Zn+2 and PO4-3. This data is

  14. Structure of proton-proton events at high center-of-mass energy with an identified particle of large transverse momentum

    International Nuclear Information System (INIS)

    Hanke, P.

    1977-01-01

    At the CERN-ISR events of pp-collisions, in which particles of large transverse momentum psub(T) are produced, were studied at √S = 52 GeV center-of-mass energy, using the 'Split-Field'-magnetspectrometer. The lorentz-invariant production cross-section of positive particles with high psub(T) was measured in the fragmentation region (average* approximately 20 0 ). In the same kinematical region the pion-fraction of produced particles for both charges was determined. In these events the effect of 'strangeness'-conservation on the dynamics of additionally produced particles was investigated. The comparison of events with negative pions and events with heavier particles - mainly kaons - at high psub(T) indicates, that the compensation of transverse momentum does not depend on the 'strangeness' of the particle at high psub(T). The quantum-number conservation rather influences the particle-content from the hadronic rest inside longitudinal phase-space. This was shown by reconstruction of decay-vertices of neutral kaons. The results obtained can be interpreted by 'constituent'-models of the proton-structure. (orig.) [de

  15. Identifying Structure-Property Relationships Through DREAM.3D Representative Volume Elements and DAMASK Crystal Plasticity Simulations: An Integrated Computational Materials Engineering Approach

    Science.gov (United States)

    Diehl, Martin; Groeber, Michael; Haase, Christian; Molodov, Dmitri A.; Roters, Franz; Raabe, Dierk

    2017-05-01

    Predicting, understanding, and controlling the mechanical behavior is the most important task when designing structural materials. Modern alloy systems—in which multiple deformation mechanisms, phases, and defects are introduced to overcome the inverse strength-ductility relationship—give raise to multiple possibilities for modifying the deformation behavior, rendering traditional, exclusively experimentally-based alloy development workflows inappropriate. For fast and efficient alloy design, it is therefore desirable to predict the mechanical performance of candidate alloys by simulation studies to replace time- and resource-consuming mechanical tests. Simulation tools suitable for this task need to correctly predict the mechanical behavior in dependence of alloy composition, microstructure, texture, phase fractions, and processing history. Here, an integrated computational materials engineering approach based on the open source software packages DREAM.3D and DAMASK (Düsseldorf Advanced Materials Simulation Kit) that enables such virtual material development is presented. More specific, our approach consists of the following three steps: (1) acquire statistical quantities that describe a microstructure, (2) build a representative volume element based on these quantities employing DREAM.3D, and (3) evaluate the representative volume using a predictive crystal plasticity material model provided by DAMASK. Exemplarily, these steps are here conducted for a high-manganese steel.

  16. Quantitative structure-activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries.

    Science.gov (United States)

    Pham-The, H; Casañola-Martin, G; Diéguez-Santana, K; Nguyen-Hai, N; Ngoc, N T; Vu-Duc, L; Le-Thi-Thu, H

    2017-03-01

    Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0.83 to 0.90. Various aspects related to the comparison of modelling techniques, applicability domain and descriptor interpretations were discussed. Finally, consensus predictions of these models were used for screening HDAC2 inhibitors from four chemical libraries whose bioactivities against HDAC1, HDAC3, HDAC6 and HDAC8 have been known. According to the results of virtual screening assays, structures of some hits with pair-isoform-selective activity (between HDAC2 and other HDACs) were revealed. This study illustrates the power of ML-based QSAR approaches for the screening and discovery of potent, isoform-selective HDACIs.

  17. Identifying compositional and structural changes in spongy and subchondral bone from the hip joints of patients with osteoarthritis using Raman spectroscopy

    Science.gov (United States)

    Buchwald, Tomasz; Niciejewski, Krzysztof; Kozielski, Marek; Szybowicz, Mirosław; Siatkowski, Marcin; Krauss, Hanna

    2012-01-01

    Raman microspectroscopy was used to examine the biochemical composition and molecular structure of extracellular matrix in spongy and subchondral bone collected from patients with clinical and radiological evidence of idiopathic osteoarthritis of the hip and from patients who underwent a femoral neck fracture, as a result of trauma, without previous clinical and radiological evidence of osteoarthritis. The objectives of the study were to determine the levels of mineralization, carbonate accumulation and collagen quality in bone tissue. The subchondral bone from osteoarthritis patients in comparison with control subject is less mineralized due to a decrease in the hydroxyapatite concentration. However, the extent of carbonate accumulation in the apatite crystal lattice increases, most likely due to deficient mineralization. The alpha helix to random coil band area ratio reveals that collagen matrix in subchondral bone is more ordered in osteoarthritis disease. The hydroxyapatite to collagen, carbonate apatite to hydroxyapatite and alpha helix to random coil band area ratios are not significantly changed in the differently loaded sites of femoral head. The significant differences also are not visible in mineral and organic constituents' content in spongy bone beneath the subchondral bone in osteoarthritis disease.

  18. Cell context-dependent dual effects of EFEMP1 stabilizes subpopulation equilibrium in responding to changes of in vivo growth environment.

    Science.gov (United States)

    Hu, Yuanjie; Ke, Chao; Ru, Ning; Chen, Yumay; Yu, Liping; Siegel, Eric R; Linskey, Mark E; Wang, Ping; Zhou, Yi-Hong

    2015-10-13

    Conflicting functions of EFEMP1 in cancer have been reported. Using two syngeneic glioma cell lines (U251 and U251-NS) carrying two different principal cell subpopulations that express high or low EGFR, and that are able to interconvert via mis-segregation of chromosome 7 (Chr7), we studied EFEMP1's cell-context-dependent functions in regulating subpopulation equilibrium, here defined by the percentage of cells carrying different copies of Chr7. We found that EFEMP1 attenuated levels of EGFR and cellular respiration in high-EGFR-expressing cells, but increased levels of NOTCH1, MMP2, cell invasiveness, and both oxidative phosphorylation and glycolytic respiration in low-EGFR-expressing cells. Consistently, EFEMP1 suppressed intracranial xenograft formation in U251 and promoted its formation in U251-NS. Interestingly, subpopulation equilibria in xenografts of U251-NS without EFEMP1 overexpression were responsive to inoculum size (1, 10 and 100 thousand cells), which may change the tumor-onset environment. It was not observed in xenografts of U251-NS with EFEMP1 overexpression. The anti-EGFR function of EFEMP1 suppressed acceleration of growth of U251-NS, but not the subpopulation equilibrium, when serially passed under a different (serum-containing adherent) culture condition. Overall, the data suggest that the orthotopic environment of the brain tumor supports EFEMP1 in carrying out both its anti-EGFR and pro-invasive/cancer stem cell-transforming functions in the two glioma cell subpopulations during formation of a single tumor, where EFEMP1 stabilizes the subpopulation equilibrium in response to alterations of the growth environment. This finding implies that EFEMP1 may restrain cancer plasticity in coping with ever-changing tumor microenvironments and/or therapeutic-intervention stresses.

  19. Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART.

    Directory of Open Access Journals (Sweden)

    Jose Manuel Vazquez-Guillen

    Full Text Available Although Structured Treatment Interruptions (STI are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM's at levels under limit of detection of conventional genotyping (<20% of quasispecies could increase the risk of virologic failure. In this work, we analyzed the protease and reverse transcriptase regions of the pol gene by ultra-deep sequencing in pediatric patients under STI with the aim of determining the presence of high- and low-abundance DRM's in the viral rebounds generated by the STI. High-abundance mutations in protease and high- and low-abundance mutations in reverse transcriptase were detected but no one of these are directly associated with resistance to antiretroviral drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM's during STI.

  20. Preparation and in vivo evaluation of radioiodinated closo-decaborate(2-) derivatives to identify structural components that provide low retention in tissues

    International Nuclear Information System (INIS)

    Wilbur, D. Scott; Chyan, M.-K.; Hamlin, Donald K.; Perry, Matthew A.

    2010-01-01

    Introduction: In vivo deastatination of 211 At-labeled biomolecules can severely limit their use in endoradiotherapy. Our studies have shown that the use of closo-decaborate(2-) moiety for 211 At-labeling of biomolecules provides high in vivo stability towards deastatination. However, data from those studies have also been suggestive that some astatinated closo-decaborate(2-) catabolites may be retained in tissues. In this study, we investigated the in vivo distributions of several structurally simple closo-decaborate(2-) derivatives to gain information on the effects of functional groups if catabolites are released into the blood system from the carrier biomolecule. Methods: Thirteen closo-decaborate(2-) derivatives were synthesized and radioiodinated for evaluation. Tissue concentrations of the radioiodinated compounds were obtained in groups of five mice at 1 and 4 h postinjection (pi). Dual-label ( 125 I and 131 I) experiments permitted evaluation of two compounds in each set of mice. Results: All of the target compounds were readily synthesized. Radioiodination reactions were conducted with chloramine-T and Na[ 125/131 I]I in water to give high yields (75-96%) of the desired compounds. Biodistribution data at 1 and 4 h pi (representing catabolites released into the blood system) showed small differences in tissue concentrations for some compounds, but large differences for others. The results indicate that formal (overall) charge on the compounds could not be used as a predictor of tissue localization or retention. However, derivatives containing carboxylate groups generally had lower tissue concentrations. Acid cleavable hydrazone functionalities appeared to be the best candidates for further study. Conclusions: Further studies incorporating hydrazone functionalities into pendant groups for biomolecule radiohalogenation are warranted.

  1. CONTENTS OF LYMPHOCYTE SUB-POPULATIONS IN THE CHILDREN WITH ACUTE LEUKEMIA AND LYMPHOMAS DEPENDENT ON INFECTIOUS COMPLICATION AND NEUTROPENIA

    Directory of Open Access Journals (Sweden)

    M. V. Peshikova

    2005-01-01

    Full Text Available Abstract. The aim of the present work was to evaluate the contents of some lymphocyte sub-populations in peripheral blood of the children with tumors of hematopoietic and lymphoid tissues, depending on infectious complication of cytostatic therapy and neutropenia. In all children undergoing cytostatic therapy for acute lympho-blastic leukemia and non-B cell non-Hodgkinґs lymphomas, we found significant decrease in the numbers of CD95 lymphocytes, absolute amounts of natural killer cells (CD16, CD56-lymphocytes and activated lymphocytes (СD11b, HLA-DR-cells, irrespective of neutrophile numbers in their blood and infectious complications. However, absolute number of CD25- lymphocytes was significantly decreased in the children with neutropenia. Relative contents of CD16, CD56, СD11b, HLA-DR, CD25-lymphocytes did not significantly differ from those in healthy children, or they were found to be significantly increased.

  2. Impact of Pneumococcal Conjugate Vaccines on Pneumonia Hospitalizations in High- and Low-Income Subpopulations in Brazil

    DEFF Research Database (Denmark)

    Warren, Joshua L.; Shioda, Kayoko; Kürüm, Esra

    2017-01-01

    Background Pneumococcal conjugate vaccines (PCVs) are being used worldwide. A key question is whether the impact of PCVs on pneumonia is similar in low- and high-income populations. However, most low-income countries, where the burden of disease is greatest, lack reliable data that can be used...... to evaluate the impact. Data from middle-income countries that have both low- and high-income subpopulations can provide a proxy measure for the impact of the vaccine in low-income countries. Methods We evaluated the impact of PCV10 on hospitalizations for all-cause pneumonia in Brazil, a middle......-income country with localities that span a broad range of human development index (HDI) levels. We used complementary time series and spatiotemporal methods (synthetic controls and hierarchical Bayesian spatial regression) to test whether the decline in pneumonia hospitalizations associated with vaccine...

  3. Data in support of dyslipidemia-associated alterations in B cell subpopulations frequency and phenotype during experimental atherosclerosis

    Directory of Open Access Journals (Sweden)

    Héctor Rincón-Arévalo

    2016-06-01

    Full Text Available Cardiovascular diseases are the most common cause of death in the world, atherosclerosis being its main underlying disease. Information about the role of B cells during atherosclerotic process is scarce, but both proatherogenic and atheroprotective properties have been described in the immunopathology of this disease. Frequency and phenotype of B cell subpopulations were studied in wild type and apolipoprotein-E-deficient (apoE−/− mice fed or not with high-fat diet (HFD, by flow cytometry. Here, we provide the information about the materials, methods, analysis and additional information related to our study published in Atherosclerosis (DOI: 10.1016/j.atherosclerosis.2015.12.022, article reference: ATH14410 [1]. The data contained in this article shows and supports that mice with advanced atherosclerosis have a variety of alterations in frequency and phenotype of B cell subsets, most of which associated with dyslipidemia.

  4. Data in support of dyslipidemia-associated alterations in B cell subpopulations frequency and phenotype during experimental atherosclerosis

    Science.gov (United States)

    Rincón-Arévalo, Héctor; Castaño, Diana; Villa-Pulgarín, Janny; Rojas, Mauricio; Vásquez, Gloria; Correa, Luis A.; Ramírez-Pineda, José R.; Yassin, Lina M.

    2016-01-01

    Cardiovascular diseases are the most common cause of death in the world, atherosclerosis being its main underlying disease. Information about the role of B cells during atherosclerotic process is scarce, but both proatherogenic and atheroprotective properties have been described in the immunopathology of this disease. Frequency and phenotype of B cell subpopulations were studied in wild type and apolipoprotein-E-deficient (apoE−/−) mice fed or not with high-fat diet (HFD), by flow cytometry. Here, we provide the information about the materials, methods, analysis and additional information related to our study published in Atherosclerosis (DOI: 10.1016/j.atherosclerosis.2015.12.022, article reference: ATH14410) [1]. The data contained in this article shows and supports that mice with advanced atherosclerosis have a variety of alterations in frequency and phenotype of B cell subsets, most of which associated with dyslipidemia. PMID:27081674

  5. A Subpopulation of the K562 Cells Are Killed by Curcumin Treatment after G2/M Arrest and Mitotic Catastrophe.

    Directory of Open Access Journals (Sweden)

    Macario Martinez-Castillo

    Full Text Available Curcumin is extensively investigated as a good chemo-preventive agent in the development of many cancers and particularly in leukemia, including treatment of chronic myelogenous leukemia and it has been proposed as an adjuvant for leukemia therapies. Human chronic myeloid leukemia cells (K562, were treated with 20 μM of curcumin, and we found that a subpopulation of these cells were arrested and accumulate in the G2/M phase of the cell cycle. Characterization of this cell subpopulation showed that the arrested cells presented nuclear morphology changes resembling those described for mitotic catastrophe. Mitotic cells displayed abnormal chromatin organization, collapse of the mitotic spindle and abnormal chromosome segregation. Then, these cells died in an apoptosis dependent manner and showed diminution in the protein levels of BCL-2 and XIAP. Moreover, our results shown that a transient activation of the nuclear factor κB (NFκB occurred early in these cells, but decreased after 6 h of the treatment, explaining in part the diminution of the anti-apoptotic proteins. Additionally, P73 was translocated to the cell nuclei, because the expression of the C/EBPα, a cognate repressor of the P73 gene, was decreased, suggesting that apoptosis is trigger by elevation of P73 protein levels acting in concert with the diminution of the two anti-apoptotic molecules. In summary, curcumin treatment might produce a P73-dependent apoptotic cell death in chronic myelogenous leukemia cells (K562, which was triggered by mitotic catastrophe, due to sustained BAX and survivin expression and impairment of the anti-apoptotic proteins BCL-2 and XIAP.

  6. The osteogenic differentiation of SSEA-4 sub-population of human adipose derived stem cells using silicate nanoplatelets.

    Science.gov (United States)

    Mihaila, Silvia M; Gaharwar, Akhilesh K; Reis, Rui L; Khademhosseini, Ali; Marques, Alexandra P; Gomes, Manuela E

    2014-11-01

    How to surpass in vitro stem cell differentiation, reducing cell manipulation, and lead the in situ regeneration process after transplantation, remains to be unraveled in bone tissue engineering (bTE). Recently, we showed that the combination of human bone marrow stromal cells with bioactive silicate nanoplatelets (sNPs) promotes the osteogenic differentiation without the use of standard osteogenic inductors. Even more, using SSEA-4(+) cell-subpopulations (SSEA-4(+)hASCs) residing within the adipose tissue, as a single-cellular source to obtain relevant cell types for bone regeneration, was also proposed. Herein, sNPs were used to promote the osteogenic differentiation of SSEA-4(+)hASCs. The interactions between SSEA-4(+)hASCs and sNPs, namely the internalization pathway and effect on cells osteogenic differentiation, were evaluated. SNPs below 100 μg/mL showed high cytocompatibility and fast internalization via clathrin-mediated pathway. SNPs triggered an overexpression of osteogenic-related markers (RUNX2, osteopontin, osteocalcin) accompanied by increased alkaline phosphatase activity and deposition of a predominantly collagen-type I matrix. Consequently, a robust matrix mineralization was achieved, covering >90% of the culturing surface area. Overall, we demonstrated the high osteogenic differentiation potential of SSEA-4(+)hASCs, further enhanced by the addition of sNPs in a dose dependent manner. This strategy endorses the combination of an adipose-derived cell-subpopulation with inorganic compounds to achieve bone matrix-analogs with clinical relevance. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Effects of low dose rate fission neutron irradiation on the lymphocyte subpopulations of peripheral blood in rats

    International Nuclear Information System (INIS)

    Jiang Dingwen; Lei Chengxiang; Shen Xianrong; Ma Li; Yang Yifang; Peng Wulin; Dai Shourong

    2008-01-01

    Objective: To evaluate the effects of long-term, low dose rate fission neutron irradiation on lymphocyte subpopulations in peripheral blood of rats. Methods: Ninety-six rats were randomly divided into control group and irradiated group exposed to low dose rate fission neutron ( 252 Cf,0.35 mGy/h) for 20.5 h every day. At days 14,28,42,56 and 70 d after irradiation and 35 d after stopping irradiation, After 8 rats of each group were killed, WBC and lymphocyte subpopulations of CD4 + CD3 + , CD8 + CD3 + and CD45RA + /CD161α + in peripheral blood were estimated respectively. Results: Compared with the control group, WBC was reduced significantly at dose of 0.3, 0.4 and 0.5 Gy (P + CD3 - was evidently higher compared with control group at doses of 0.1,0.3, 0.4 and 0.5 Gy and 35 d after stopping irradiation (P + CD3 - was obviously higher compared with control group at dose of 0.2 and 0.3 Gy (P + CD3 + at dose of 0.1 Gy (P + CD3 + at doses of 0.1 and 0.2 Gy (P + CD45RA - ) was increased significantly at doses of 0.2-0.3 Gy, and peripheral blood B cells(CD161α - CD45RA + ) was reduced remarkably at doses of 0.1-0.5 Gy and 35 d after stopping irradiation compared with the control group. Conclusions: Long-term irradiation with low dose rate fission neutron could make TCR (T-cell-receptor) mutant, therefore, WBC, B cells in peripheral blood significantly reduced and NK cells increased. These changes may could not recover at 35 d after Stopping irradiation. (authors)

  8. [Common variable immunodeficiency: Clinical and immunological characterization of patients and homogeneous subgroup definition by means of B lymphocyte subpopulation typing].

    Science.gov (United States)

    Vélez, Alejandra Catalina; Castaño, Diana María; Gómez, Rubén Darío; Orrego, Julio César; Moncada, Marcela; Franco, José Luis

    2015-01-01

    Common variable immunodeficiency is a heterogeneous syndrome characterized by recurrent infections, hypogammaglobulinemia and defective production of specific antibodies. Abnormalities in peripheral blood lymphocyte subpopulations, in particular of B lymphocytes, allow the classification of patients into homogeneous groups. To perform a clinical and immunological characterization and to evaluate lymphocyte subpopulations of twelve Colombian patients with common variable immunodeficiency in order to define homogeneous groups. We reviewed medical records and evaluated serum immunoglobulins (Ig), lymphoproliferation, delayed hypersensitivity and used flow cytometry to quantify peripheral blood total lymphocyte and B cell populations. All patients had recurrent respiratory and/or gastrointestinal infections, while some also had infections affecting other systems. All patients had abnormally low serum IgG levels, while IgA and IgM levels were reduced in nine and ten patients, respectively. Lymphoproliferation to mitogen was lower in patients than in healthy controls but lymphoproliferation to specific antigen was normal in all. Flow cytometry revealed high numbers of T cells in three patients, while seven had a low CD4+/CD8+ ratio and four had reduced NK cells . Eleven patients had normal B cell counts, and eight of them also showed decreased memory B lymphocytes, and four had increased transitional or CD21 low B lymphocytes. Lymphocyte typing allowed assigning all but one patient to homogeneous groups according to international classification schemes, indicating the necessity of including more criteria until an ideal classification is achieved. This study will lead to a better medical monitoring of common variable immunodeficiency patients in groups at high risk of developing clinical complications.

  9. A structured proteomic approach identifies 14-3-3Sigma as a novel and reliable protein biomarker in panel based differential diagnostics of liver tumors.

    Science.gov (United States)

    Reis, Henning; Pütter, Carolin; Megger, Dominik A; Bracht, Thilo; Weber, Frank; Hoffmann, Andreas-C; Bertram, Stefanie; Wohlschläger, Jeremias; Hagemann, Sascha; Eisenacher, Martin; Scherag, André; Schlaak, Jörg F; Canbay, Ali; Meyer, Helmut E; Sitek, Barbara; Baba, Hideo A

    2015-06-01

    Hepatocellular carcinoma (HCC) is a major lethal cancer worldwide. Despite sophisticated diagnostic algorithms, the differential diagnosis of small liver nodules still is difficult. While imaging techniques have advanced, adjuvant protein-biomarkers as glypican3 (GPC3), glutamine-synthetase (GS) and heat-shock protein 70 (HSP70) have enhanced diagnostic accuracy. The aim was to further detect useful protein-biomarkers of HCC with a structured systematic approach using differential proteome techniques, bring the results to practical application and compare the diagnostic accuracy of the candidates with the established biomarkers. After label-free and gel-based proteomics (n=18 HCC/corresponding non-tumorous liver tissue (NTLT)) biomarker candidates were tested for diagnostic accuracy in immunohistochemical analyses (n=14 HCC/NTLT). Suitable candidates were further tested for consistency in comparison to known protein-biomarkers in HCC (n=78), hepatocellular adenoma (n=25; HCA), focal nodular hyperplasia (n=28; FNH) and cirrhosis (n=28). Of all protein-biomarkers, 14-3-3Sigma (14-3-3S) exhibited the most pronounced up-regulation (58.8×) in proteomics and superior diagnostic accuracy (73.0%) in the differentiation of HCC from non-tumorous hepatocytes also compared to established biomarkers as GPC3 (64.7%) and GS (45.4%). 14-3-3S was part of the best diagnostic three-biomarker panel (GPC3, HSP70, 14-3-3S) for the differentiation of HCC and HCA which is of most important significance. Exclusion of GS and inclusion of 14-3-3S in the panel (>1 marker positive) resulted in a profound increase in specificity (+44.0%) and accuracy (+11.0%) while sensitivity remained stable (96.0%). 14-3-3S is an interesting protein biomarker with the potential to further improve the accuracy of differential diagnostic process of hepatocellular tumors. This article is part of a Special Issue entitled: Medical Proteomics. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. United in Diversity : A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry

    OpenAIRE

    Viereckel, Thomas

    2017-01-01

    The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this ...

  11. Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

    International Nuclear Information System (INIS)

    Yue, Dongli; Zhang, Zhen; Li, Jieyao; Chen, Xinfeng; Ping, Yu; Liu, Shasha; Shi, Xiaojuan; Li, Lifeng; Wang, Liping; Huang, Lan; Zhang, Bin; Sun, Yan

    2015-01-01

    Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells. - Highlights: • Esophageal cancer sphere-forming cells possess cancer stem cell properties. • Sphere-forming cells enhance TGF-β1 pathway activity. • TGF-β 1 inhibitor suppresses the migration and invasion of sphere-forming cells

  12. Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yue, Dongli; Zhang, Zhen; Li, Jieyao; Chen, Xinfeng [Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China (China); Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China); Ping, Yu; Liu, Shasha [Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China (China); School of Life Sciences, Zhengzhou University, Zhengzhou 450000 (China); Shi, Xiaojuan; Li, Lifeng [Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China (China); Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China); Wang, Liping [Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China); Huang, Lan [Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China (China); Zhang, Bin [Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou 450052, Henan, PR China (China); Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 (United States); Sun, Yan [Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China); Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences (China); and others

    2015-08-01

    Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells. - Highlights: • Esophageal cancer sphere-forming cells possess cancer stem cell properties. • Sphere-forming cells enhance TGF-β1 pathway activity. • TGF-β 1 inhibitor suppresses the migration and invasion of sphere-forming cells.

  13. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.

    Science.gov (United States)

    Carbognin, Luisa; Sperduti, Isabella; Brunelli, Matteo; Marcolini, Lisa; Nortilli, Rolando; Pilotto, Sara; Zampiva, Ilaria; Merler, Sara; Fiorio, Elena; Filippi, Elisa; Manfrin, Erminia; Pellini, Francesca; Bonetti, Franco; Pollini, Giovanni Paolo; Tortora, Giampaolo; Bria, Emilio

    2016-03-22

    The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67. At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology. Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.

  14. Effects of Intrauterine Growth Restriction During Late Pregnancy on the Development of the Ovine Fetal Thymus and the T-Lymphocyte Subpopulation.

    Science.gov (United States)

    Liu, Yingchun; He, Shan; Zhang, Yuan; Xia, Wei; Li, Ming; Zhang, Chongzhi; Gao, Feng

    2015-07-01

    The retarded development of fetal thymus in intrauterine growth restriction (IUGR) from maternal undernutrition during late pregnancy destroys the tridimensional structure and modifies the development of fetal T lymphocytes. The mechanisms, however, remain unclear. The objective of this study was to investigate the effect of IUGR during late pregnancy on the development of the ovine fetal thymus and the T-lymphocyte subpopulation. Eighteen time-mated ewes with singleton fetuses were allocated to three groups at day 90 of pregnancy: restricted group 1 (RG1, 0.18 MJ ME/BW(0.75) /day, n = 6), restricted group 2 (RG2, 0.33 MJ ME/BW(0.75) /day, n = 6) and a control group (CG, ad libitum, 0.67 MJ ME/BW(0.75) /day, n = 6). Fetuses were recovered at slaughter on day 140. Fetuses in RG1 exhibited decreased (P restricted groups. In addition, there was reduced mRNA expression (P < 0.05) of T-cell receptor, apoptosis antigen 1 ligand, and RAG2 in the RG1 group. In contrast, increases in glutathione peroxidase, malondialdehyde, caspase-3, Cytochrome c, and CD4(+) T cells were observed (P < 0.05), and higher mRNA expressions (P < 0.05) of protein 53, Bcl-2 associated X protein (Bax), and apoptosis antigen 1 (Fas) were found in RG1 fetuses; and thymuses of RG2 fetuses had increased caspase-3, and expression of Fas and Bax (P < 0.05), relative to control fetuses. These results indicate that reduced cell proliferation, oxidative stress, and increased cell apoptosis were the potential mechanisms for impaired development and microenvironment of IUGR fetal thymus, and for modifying the maturation of CD4(+) CD8(+) thymocytes underlying their reduced numbers . © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Structuralism.

    Science.gov (United States)

    Piaget, Jean

    Provided is an overview of the analytical method known as structuralism. The first chapter discusses the three key components of the concept of a structure: the view of a system as a whole instead of so many parts; the study of the transformations in the system; and the fact that these transformations never lead beyond the system but always…

  16. Identifying Likely Transmission Pathways within a 10-Year Community Outbreak of Tuberculosis by High-Depth Whole Genome Sequencing.

    Directory of Open Access Journals (Sweden)

    Alexander C Outhred

    Full Text Available Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways.We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24-locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants.Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade.Whole genome sequencing, with analysis of single-nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster.

  17. Identifying the distinct features of geometric structures for hole trapping to generate radicals on rutile TiO₂(110) in photooxidation using density functional theory calculations with hybrid functional.

    Science.gov (United States)

    Wang, Dong; Wang, Haifeng; Hu, P

    2015-01-21

    Using density functional theory calculations with HSE 06 functional, we obtained the structures of spin-polarized radicals on rutile TiO2(110), which is crucial to understand the photooxidation at the atomic level, and further calculate the thermodynamic stabilities of these radicals. By analyzing the results, we identify the structural features for hole trapping in the system, and reveal the mutual effects among the geometric structures, the energy levels of trapped hole states and their hole trapping capacities. Furthermore, the results from HSE 06 functional are compared to those from DFT + U and the stability trend of radicals against the number of slabs is tested. The effect of trapped holes on two important steps of the oxygen evolution reaction, i.e. water dissociation and the oxygen removal, is investigated and discussed.

  18. Travel patterns and characteristics of low-income subpopulation in New York state

    Energy Technology Data Exchange (ETDEWEB)

    Reuscher, Tim [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hwang, Ho-Ling [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Lim, Hyeonsup [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2017-10-01

    Studies have shown that people residing in poverty face more mobility challenges in their daily travels as compared to those living in higher income households. In many cities, the lack of a public transportation systems and investments in low-income areas are making it difficult for those living in poverty to access jobs, goods, and services (schools, groceries, health cares, etc. In this study, Oak Ridge National Laboratory was tasked by the New York State (NYS) Department of Transportation to conduct a detailed examination of the travel behaviors and identify patterns and trends of the low-income residents within NYS. The 2009 National Household Travel Survey data was used as the primary information source to analyze subjects associated with poverty and mobility, as well as to address questions such as are there differences in traveler demographics between the low-income population and those of others who live in various NYS regions (e.g., New York City, other urban areas of NYS)? How do they compare with the population at large (e.g., rest of the country) or with findings from previous years (i.e., trend)? Are there any regional differences (e.g., urban versus rural)? Do any unique travel characteristics or patterns exist within the low-income group? Through this study, various key findings on low-income population sizes, household characteristics, travel patterns, and mobility limitations were identified and summarized in this report.

  19. EXPRESSION OF CALCIUM-BINDING PROTEINS IN THE NEUROTROPHIN-3-DEPENDENT SUBPOPULATION OF RAT EMBRYONIC DORSAL-ROOT GANGLION-CELLS IN CULTURE

    NARCIS (Netherlands)

    COPRAY, JCVM; MANTINGHOTTER, IJ; BROUWER, N

    1994-01-01

    In this study we have examined the calcium-binding protein expression in rat embryonic (E16) dorsal root ganglia (DRG) neurons in vitro in the presence of neurotrophin-3 (NT-3). A comparison was made with the expression of calcium-binding proteins in DRG subpopulations that depended in vitro on

  20. Growth kinetics and in vivo radiosensitivity in nude mice of two subpopulations derived from a single human small cell carcinoma of the lung

    DEFF Research Database (Denmark)

    Spang-Thomsen, M; Clerici, M; Engelholm, S A

    1986-01-01

    , and by the cell cycle distribution changes monitored by FCM. The results showed that the tumors differed in the in vivo radiosensitivity despite similarities in the growth kinetics. The results support the concept that difference in sensitivity among tumor subpopulations is an important reason for therapeutic...

  1. Travel patterns and characteristics of foreign-born sub-population in New York state

    Energy Technology Data Exchange (ETDEWEB)

    Chin, Shih-Miao [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hwang, Ho-Ling [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Reuscher, Tim [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wilson, Daniel W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2017-10-01

    According to the 2010 Census, over 22% of total New York State (NYS) residents were foreign-born and over one in three persons living in New York City (NYC) were foreign-born. Foreign-born and their dependents impact local economies in many different ways, including purchasing power, transportation service needs, business sales and receipts generated, and workforce. To allow better policy decision making and program planning of transportation developments and investments in NYS, a clear understanding of the foreign-born population’s travel characteristics and behaviors, as well as their unique transportation service needs, are necessary. This report documents the characteristics of the foreign-born population and identified differences in travel behaviors and mobility issues between foreign-born residents of NYS and their U.S.-born counterparts.

  2. A feasibility study for enrichment of highly aggressive cancer subpopulations by their biophysical properties via dielectrophoresis enhanced with synergistic fluid flow.

    Science.gov (United States)

    Douglas, Temple Anne; Cemazar, Jaka; Balani, Nikita; Sweeney, Daniel C; Schmelz, Eva M; Davalos, Rafael V

    2017-06-01

    A common problem with cancer treatment is the development of treatment resistance and tumor recurrence that result from treatments that kill most tumor cells yet leave behind aggressive cells to repopulate. Presented here is a microfluidic device that can be used to isolate tumor subpopulations to optimize treatment selection. Dielectrophoresis (DEP) is a phenomenon where particles are polarized by an electric field and move along the electric field gradient. Different cell subpopulations have different DEP responses depending on their bioelectrical phenotype, which, we hypothesize, correlate with aggressiveness. We have designed a microfluidic device in which a region containing posts locally distorts the electric field created by an AC voltage and forces cells toward the posts through DEP. This force is balanced with a simultaneous drag force from fluid motion that pulls cells away from the posts. We have shown that by adjusting the drag force, cells with aggressive phenotypes are influenced more by the DEP force and trap on posts while others flow through the chip unaffected. Utilizing single-cell trapping via cell-sized posts coupled with a drag-DEP force balance, we show that separation of similar cell subpopulations may be achieved, a result that was previously impossible with DEP alone. Separated subpopulations maintain high viability downstream, and remain in a native state, without fluorescent labeling. These cells can then be cultured to help select a therapy that kills aggressive subpopulations equally or better than the bulk of the tumor, mitigating resistance and recurrence. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. The Nordic back pain subpopulation program: predicting outcome among chiropractic patients in Finland

    Directory of Open Access Journals (Sweden)

    Pekkarinen Harri

    2008-11-01

    Full Text Available Abstract Background In a previous Swedish study it was shown that it is possible to predict which chiropractic patients with persistent LBP will not report definite improvement early in the course of treatment, namely those with LBP for altogether at least 30 days in the past year, who had leg pain, and who did not report definite general improvement by the second treatment. The objectives of this study were to investigate if the predictive value of this set of variables could be reproduced among chiropractic patients in Finland, and if the model could be improved by adding some new potential predictor variables. Methods The study was a multi-centre prospective outcome study with internal control groups, carried out in private chiropractic practices in Finland. Chiropractors collected data at the 1st, 2nd and 4th visits using standardized questionnaires on new patients with LBP and/or radiating leg pain. Status at base-line was identified in relation to pain and disability, at the 2nd visit in relation to disability, and "definitely better" at the 4th visit in relation to a global assessment. The Swedish questionnaire was used including three new questions on general health, pain in other parts of the spine, and body mass index. Results The Swedish model was reproduced in this study sample. An alternative model including leg pain (yes/no, improvement at 2nd visit (yes/no and BMI (underweight/normal/overweight or obese was also identified with similar predictive values. Common throughout the testing of various models was that improvement at the 2nd visit had an odds ratio of approximately 5. Additional analyses revealed a dose-response in that 84% of those patients who fulfilled none of these (bad criteria were classified as "definitely better" at the 4th visit, vs. 75%, 60% and 34% of those who fulfilled 1, 2 or all 3 of the criteria, respectively. Conclusion When treating patients with LBP, at the first visits, the treatment strategy should be

  4. Identifying the Relevant Local Population for Environmental Impact Assessments of Mobile Marine Fauna

    Directory of Open Access Journals (Sweden)

    Delphine B. H. Chabanne

    2017-05-01

    Full Text Available Environmental impact assessments must be addressed at a scale that reflects the biological organization for the species affected. It can be challenging to identify the relevant local wildlife population for impact assessment for those species that are continuously distributed and highly mobile. Here, we document the existence of local communities of Indo-Pacific bottlenose dolphins (Tursiops aduncus inhabiting coastal and estuarine waters of Perth, Western Australia, where major coastal developments have been undertaken or are proposed. Using sighting histories from a 4-year photo-identification study, we investigated fine-scale, social community structure of dolphins based on measures of social affinity, and network (Half-Weight Index—HWI, preferred dyadic association tests, and Lagged Association Rates—LAR, home ranges, residency patterns (Lagged Identification Rates—LIR, and genetic relatedness. Analyses revealed four socially and spatially distinct, mixed-sex communities. The four communities had distinctive social patterns varying in strength, site fidelity, and residency patterns. Overlap in home ranges and relatedness explained little to none of the association patterns between individuals, suggesting complex local social structures. The study demonstrated that environmental impact assessments for mobile, continuously distributed species must evaluate impacts in light of local population structure, especially where proposed developments may affect core habitats of resident communities or sub-populations. Here, the risk of local extinction is particularly significant for an estuarine community because of its small size, limited connectivity with adjacent communities, and use of areas subject to intensive human use. In the absence of information about fine-scale population structure, impact assessments may fail to consider the appropriate biological context.

  5. T cell subpopulations in lymph nodes may not be predictive of patient outcome in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Yoon Han-Seung

    2011-08-01

    Full Text Available Abstract Background The immune response has been proposed to be an important factor in determining patient outcome in colorectal cancer (CRC. Previous studies have concentrated on characterizing T cell populations in the primary tumour where T cells with regulatory effect (Foxp3+ Tregs have been identified as both enhancing and diminishing anti-tumour immune responses. No previous studies have characterized the T cell response in the regional lymph nodes in CRC. Methods Immunohistochemistry was used to analyse CD4, CD8 or Foxp3+ T cell populations in the regional lymph nodes of patients with stage II CRC (n = 31, with (n = 13 or without (n = 18 cancer recurrence after 5 years of follow up, to determine if the priming environment for anti-tumour immunity was associated with clinical outcome. Results The proportions of CD4, CD8 or Foxp3+ cells in the lymph nodes varied widely between and within patients, and there was no association between T cell populations and cancer recurrence or other clinicopathological characteristics. Conclusions These data indicate that frequency of these T cell subsets in lymph nodes may not be a useful tool for predicting patient outcome.

  6. Dissection of a circulating CD3+ CD20+ T cell subpopulation in patients with psoriasis.

    Science.gov (United States)

    Niu, J; Zhai, Z; Hao, F; Zhang, Y; Song, Z; Zhong, H

    2018-05-01

    CD3 + CD20 + T cells are a population of CD3 + T cells that express CD20 and identified in healthy donors and autoimmune diseases. However, the nature and role of these cells in patients with psoriasis remain unclear. In this study, we aimed to investigate the level, phenotype, functional and clinical relevance of CD3 + CD20 + T cells in the peripheral blood of patients with psoriasis. We found that a small subset of CD3 + T cells expressed CD20 molecule in the peripheral blood of patients with psoriasis, and their levels were similar to those in healthy donors. Circulating CD3 + CD20 + T cells in patients with psoriasis were enriched in CD4 + cells and displayed an activated effector phenotype, as these cells contained fewer CD45RA + -naive and CCR7 + cells with increased activity than those of CD3 + T cells lacking CD20. In addition, compared with healthy donors, circulating CD3 + CD20 + T cells in patients with psoriasis produced more cytokines, interleukin (IL)-17A, tumour necrosis factor (TNF)-α and IL-21, but not IL-4 and IFN-γ. Furthermore, a significantly positive correlation was found between the levels of IL-17A, TNF-α and IL-21-production CD3 + CD20 + T cells with Psoriasis Area and Severity Index scores. Our findings suggest that CD3 + CD20 + T cells may play a role in the pathogenesis of psoriasis. © 2018 British Society for Immunology.

  7. Recreational Drug Use and T Lymphocyte Subpopulations in HIV-uninfected and HIV-infected Men

    Science.gov (United States)

    Chao, Chun; Jacobson, Lisa P; Tashkin, Donald; Martínez-Maza, Otoniel; Roth, Michael D; Margolick, Joseph B; Chmiel, Joan S; Rinaldo, Charles; Zhang, Zuo-Feng; Detels, Roger

    2009-01-01

    The effects of recreational drugs on CD4 and CD8 T cells in humans are not well understood. We conducted a longitudinal analysis of men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study to define associations between self-reported use of marijuana, cocaine, poppers and amphetamines, and CD4 and CD8 T cell parameters in both HIV-uninfected and HIV-infected MSM. For the HIV-infected MSM, we used clinical and laboratory data collected semiannually before 1996 to avoid potential effects of antiretroviral treatment. A regression model that allowed random intercepts and slopes as well as autoregressive covariance structure for within subject errors was used. Potential confounders adjusted for included length of follow-up, demographics, tobacco smoking, alcohol use, risky sexual behaviors, history of sexually transmitted infections, and antiviral therapy. We found no clinically meaningful associations between use of marijuana, cocaine, poppers, or amphetamines and CD4 and CD8 T cell counts, percentages, or rates of change in either HIV-uninfected or -infected men. The regression coefficients were of minimum magnitude despite some reaching statistical significance. No threshold effect was detected for frequent (at least weekly) or continuous substance use in the previous year. These results indicate that use of these substances does not adversely affect the numbers and percentages of circulating CD4 or CD8 T cells in either HIV-uninfected or -infected MSM. PMID:18180115

  8. The functional and anatomical dissection of somatosensory subpopulations using mouse genetics

    Directory of Open Access Journals (Sweden)

    Claire E Le Pichon

    2014-04-01

    Full Text Available The word somatosensation comes from joining the Greek word for body (soma with a word for perception (sensation. Somatosensory neurons comprise the largest sensory system in mammals and have nerve endings coursing throughout the skin, viscera, muscle, and bone. Their cell bodies reside in a chain of ganglia adjacent to the dorsal spinal cord (the dorsal root ganglia and at the base of the skull (the trigeminal ganglia. While the neuronal cell bodies are intermingled within the ganglia, the somatosensory system is in reality composed of numerous sub-systems, each specialized to detect distinct stimuli, such as temperature and touch. Historically, somatosensory neurons have been classified using a diverse host of anatomical and physiological parameters, such as the size of the cell body, degree of myelination, histological labeling with markers, specialization of the nerve endings, projection patterns in the spinal cord and brainstem, receptive tuning, and conduction velocity of their action potentials. While useful, the picture that emerged was one of heterogeneity, with many markers at least partially overlapping. More recently, by capitalizing on advances in molecular techniques, researchers have identified specific ion channels and sensory receptors expressed in subsets of sensory neurons. These studies have proved invaluable as they allow genetic access to small subsets of neurons for further molecular dissection. Data being generated from transgenic mice favor the model whereby an array of dedicated neurons is responsible for selectively encoding different modalities. Here we review the current knowledge of the different sensory neuron subtypes in the mouse, the markers used to study them, and the neurogenetic strategies used to define their anatomical projections and functional roles.

  9. Travel Patterns and Characteristics of Elderly Subpopulation in New York State

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Ho-Ling [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wilson, Daniel W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Reuscher, Tim [Macrosys, Arlington, VA (United States); Yang, Jianjiang [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Taylor, Rob D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Chin, Shih-Miao [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-03-01

    With the increasing demographic shift towards a larger population of elderly (individuals 65 years and older), it is essential for policy makers and planners to have an understanding of transportation issues that affect the elderly. These issues include livability of the community, factors impacting travel behavior and mobility, transportation safety, etc. In this study, Oak Ridge National Laboratory was tasked by the New York State (NYS) Department of Transportation to conduct a detailed examination of travel behaviors, and identify patterns and trends of the elderly within NYS. The National Household Travel Survey (NHTS) was used as the primary data source to analyze subjects and address questions such as: Are there differences in traveler demographics between the elderly population and those of younger age groups who live in various NYS regions; e.g., New York City, other urban areas of NYS, or other parts of the country? How do they compare with the population at large? Are there any regional differences (e.g., urban versus rural)? Gender differences? Do any unique travel characteristics or patterns exist within the elderly group? In addition to analysis of NHTS data, roadway travel safety concerns associated with elderly travelers were also investigated in this study. Specifically, data on accidents involving the elderly (including drivers, passengers, and others) as captured in the Fatal Analysis Reporting System (FARS) database was analyzed to examine elderly driver and elderly pedestrian travel safety issues in NYS. The analyses of these data sets provide a greater understanding of the elderly within NYS and their associated transportation issues. Through this study, various key findings on elderly population size, household characteristics, and travel patterns were produced and are report herein this report.

  10. Modification of the effect of ambient air pollution on pediatric asthma emergency visits: susceptible subpopulations

    Science.gov (United States)

    Strickland, Matthew J; Klein, Mitchel; Flanders, W Dana; Chang, Howard H; Mulholland, James A; Tolbert, Paige E; Darrow, Lyndsey A

    2016-01-01

    Background Children may have differing susceptibility to ambient air pollution concentrations depending on various background characteristics of the children. Methods Using emergency department (ED) data linked with birth records from Atlanta, Georgia, we identified ED visits for asthma or wheeze among children aged 2–16 years from 1 January 2002 through 30 June 2010 (n=109,758). We stratified by preterm delivery, term low birth weight, maternal race, Medicaid status, maternal education, maternal smoking, delivery method, and history of a bronchiolitis ED visit. Population-weighted daily average concentrations were calculated for 1-hour maximum carbon monoxide and nitrogen dioxide; 8-hour maximum ozone; and 24-hour average particulate matter less than 10 microns in diameter, particulate matter less than 2.5 microns in diameter (PM2.5), and the PM2.5 components sulfate, nitrate, ammonium, elemental carbon, and organic carbon, using measurements from stationary monitors. Poisson time-series models were used to estimate rate ratios for associations between three-day moving average pollutant concentrations and daily ED visit counts and to investigate effect-measure modification by the stratification factors. Results Associations between pollutant concentrations and asthma exacerbations were larger among children born preterm and among children born to African American mothers. Stratification by race and preterm status together suggested that both factors affected susceptibility. The largest estimated effect size (for an interquartile-range increase in pollution) was observed for ozone among preterm births to African American mothers: rate ratio=1.138 (95% confidence interval=1.077–1.203). In contrast, the rate ration for the ozone association among full-term births to mothers of other races was 1.025 (0.970–1.083). Conclusions Results support the hypothesis that children vary in their susceptibility to ambient air pollutants. PMID:25192402

  11. Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage.

    Directory of Open Access Journals (Sweden)

    Rebecca Williams

    Full Text Available BACKGROUND: Articular cartilage displays a poor repair capacity. The aim of cell-based therapies for cartilage defects is to repair damaged joint surfaces with a functional replacement tissue. Currently, chondrocytes removed from a healthy region of the cartilage are used but they are unable to retain their phenotype in expanded culture. The resulting repair tissue is fibrocartilaginous rather than hyaline, potentially compromising long-term repair. Mesenchymal stem cells, particularly bone marrow stromal cells (BMSC, are of interest for cartilage repair due to their inherent replicative potential. However, chondrocyte differentiated BMSCs display an endochondral phenotype, that is, can terminally differentiate and form a calcified matrix, leading to failure in long-term defect repair. Here, we investigate the isolation and characterisation of a human cartilage progenitor population that is resident within permanent adult articular cartilage. METHODS AND FINDINGS: Human articular cartilage samples were digested and clonal populations isolated using a differential adhesion assay to fibronectin. Clonal cell lines were expanded in growth media to high population doublings and karyotype analysis performed. We present data to show that this cell population demonstrates a restricted differential potential during chondrogenic induction in a 3D pellet culture system. Furthermore, evidence of high telomerase activity and maintenance of telomere length, characteristic of a mesenchymal stem cell population, were observed in this clonal cell population. Lastly, as proof of principle, we carried out a pilot repair study in a goat in vivo model demonstrating the ability of goat cartilage progenitors to form a cartilage-like repair tissue in a chondral defect. CONCLUSIONS: In conclusion, we propose that we have identified and characterised a novel cartilage progenitor population resident in human articular cartilage which will greatly benefit future cell

  12. Insights into the state of radiation protection among a subpopulation of Indian dental practitioners.

    Science.gov (United States)

    Binnal, Almas; Rajesh, Gururaghavendran; Denny, Ceena; Ahmed, Junaid; Nayak, Vijayendra

    2013-12-01

    Radiographs is an integral part of patient management in dentistry, despite their detrimental effects. As the literature pertaining to radiation protection among Indian dental practitioners is sparse, exploring such protection is needed. All private dental practitioners in Mangalore, India were included in the study. A structured, pre-tested, self-administered questionnaire was employed to assess the knowledge, attitudes, practices, previous training, perceptions towards the need to spread awareness, and willingness to gain and implement knowledge about radiation hazards and protection. Information regarding each respondent's age, gender, education, and type and duration of practice was collected. Overall, 87 out of 120 practitioners participated in the study. The mean knowledge, attitude, and practice scores were 9.54±2.54, 59.39±7.01, and 5.80±3.19, respectively. Overall, 25.3% of the respondents had undergone training in radiation protection, 98.9% perceived a need to spread awareness, and 94.3% were willing to improve their knowledge. Previous training showed a significant correlation with age, sex, and duration of practice; attitude was significantly correlated with education and type of practice; and knowledge scores showed a significant correlation with type of practice. Although the knowledge and practices of respondents were poor, they had a positive attitude and were willing to improve their knowledge. Age, sex, and duration of practice were associated with previous training; education and type of practice with attitude scores; and type of practice with knowledge scores. The findings of this study suggest a policy is needed to ensure the adherence of dental practitioners to radiation protection guidelines.

  13. Insights into the state of radiation protection among a subpopulation of Indian dental practitioners

    International Nuclear Information System (INIS)

    Binnal, Almas; Rajesh, Gururaghavendran; Denny, Ceena; Ahmed, Junaid; Nayak, Vijayendra

    2013-01-01

    Radiographs is an integral part of patient management in dentistry, despite their detrimental effects. As the literature pertaining to radiation protection among Indian dental practitioners is sparse, exploring such protection is needed. All private dental practitioners in Mangalore, India were included in the study. A structured, pre-tested, self-administered questionnaire was employed to assess the knowledge, attitudes, practices, previous training, perceptions towards the need to spread awareness, and willingness to gain and implement knowledge about radiation hazards and protection. Information regarding each respondent's age, gender, education, and type and duration of practice was collected. Overall, 87 out of 120 practitioners participated in the study. The mean knowledge, attitude, and practice scores were 9.54±2.54, 59.39±7.01, and 5.80±3.19, respectively. Overall, 25.3% of the respondents had undergone training in radiation protection, 98.9% perceived a need to spread awareness, and 94.3% were willing to improve their knowledge. Previous training showed a significant correlation with age, sex, and duration of practice; attitude was significantly correlated with education and type of practice; and knowledge scores showed a significant correlation with type of practice. Although the knowledge and practices of respondents were poor, they had a positive attitude and were willing to improve their knowledge. Age, sex, and duration of practice were associated with previous training; education and type of practice with attitude scores; and type of practice with knowledge scores. The findings of this study suggest a policy is needed to ensure the adherence of dental practitioners to radiation protection guidelines.

  14. Insights into the state of radiation protection among a subpopulation of Indian dental practitioners

    Energy Technology Data Exchange (ETDEWEB)

    Binnal, Almas; Rajesh, Gururaghavendran; Denny, Ceena; Ahmed, Junaid; Nayak, Vijayendra [Manipal College of Dental Sciences, Manipal University, Mangalore (India)

    2013-12-15

    Radiographs is an integral part of patient management in dentistry, despite their detrimental effects. As the literature pertaining to radiation protection among Indian dental practitioners is sparse, exploring such protection is needed. All private dental practitioners in Mangalore, India were included in the study. A structured, pre-tested, self-administered questionnaire was employed to assess the knowledge, attitudes, practices, previous training, perceptions towards the need to spread awareness, and willingness to gain and implement knowledge about radiation hazards and protection. Information regarding each respondent's age, gender, education, and type and duration of practice was collected. Overall, 87 out of 120 practitioners participated in the study. The mean knowledge, attitude, and practice scores were 9.54±2.54, 59.39±7.01, and 5.80±3.19, respectively. Overall, 25.3% of the respondents had undergone training in radiation protection, 98.9% perceived a need to spread awareness, and 94.3% were willing to improve their knowledge. Previous training showed a significant correlation with age, sex, and duration of practice; attitude was significantly correlated with education and type of practice; and knowledge scores showed a significant correlation with type of practice. Although the knowledge and practices of respondents were poor, they had a positive attitude and were willing to improve their knowledge. Age, sex, and duration of practice were associated with previous training; education and type of practice with attitude scores; and type of practice with knowledge scores. The findings of this study suggest a policy is needed to ensure the adherence of dental practitioners to radiation protection guidelines.

  15. METHAMPHETAMINE-INDUCED CELL DEATH: SELECTIVE VULNERABILITY IN NEURONAL SUBPOPULATIONS OF THE STRIATUM IN MICE

    Science.gov (United States)

    ZHU, J. P. Q.; XU, W.; ANGULO, J. A.

    2010-01-01

    Methamphetamine (METH) is an illicit and potent psychostimulant, which acts as an indirect dopamine agonist. In the striatum, METH has been shown to cause long lasting neurotoxic damage to dopaminergic nerve terminals and recently, the degeneration and death of striatal cells. The present study was undertaken to identify the type of striatal neurons that undergo apoptosis after METH. Male mice received a single high dose of METH (30 mg/kg, i.p.) and were killed 24 h later. To demonstrate that METH induces apoptosis in neurons, we combined terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining with immunohistofluorescence for the neuronal marker neuron-specific nuclear protein (NeuN). Staining for TUNEL and NeuN was colocalized throughout the striatum. METH induces apoptosis in approximately 25% of striatal neurons. Cell counts of TUNEL-positive neurons in the dorsomedial, ventromedial, dorsolateral and ventrolateral quadrants of the striatum did not reveal anatomical preference. The type of striatal neuron undergoing cell death was determined by combining TUNEL with immunohistofluorescence for selective markers of striatal neurons: dopamine- and cAMP-regulated phosphoprotein, of apparent Mr 32,000, parvalbumin, choline acetyltransferase and somatostatin (SST). METH induces apoptosis in approximately 21% of dopamine- and cAMP-regulated phosphoprotein, of apparent Mr 32,000-positive neurons (projection neurons), 45% of GABA-parvalbumin-positive neurons in the dorsal striatum, and 29% of cholinergic neurons in the dorsal–medial striatum. In contrast, the SST-positive interneurons were refractory to METH-induced apoptosis. Finally, the amount of cell loss determined with Nissl staining correlated with the amount of TUNEL staining in the striatum of METH-treated animals. In conclusion, some of the striatal projection neurons and the GABA-parvalbumin and cholinergic interneurons were removed by apoptosis in the aftermath of METH. This

  16. Electrophysiological and pharmacological evidence for the existence of distinct subpopulations of nigrostriatal dopaminergic neuron in the rat.

    Science.gov (United States)

    Shepard, P D; German, D C

    1988-11-01

    The electrophysiological and pharmacological properties of dopaminergic neurons were systematically examined throughout the anterior-posterior extent of the substantia nigra zona compacta in the rat. Cells were characterized in terms of their (1) firing pattern, (2) firing rate, (3) antidromic response properties, and (4) inhibition in firing rate following dopaminergic agonist administration. These properties were then related to the cell's position within one of four anterior-posterior segments of the nucleus. There were three types of neuronal discharge pattern encountered; irregular, burst and regular. Cells which exhibited different firing patterns exhibited different firing rates and anatomical locations within the substantia nigra zona compacta. All neurons were antidromically activated from the striatum, however, the burst- and regular-firing cells exhibited significantly faster estimated conduction velocities than irregular-firing cells. The irregular-firing cells were most sensitive to dopaminergic autoreceptor agonists whereas the burst-firing cells were most sensitive to an indirect-acting dopaminergic agonist. These experiments provide both electrophysiological and pharmacological evidence to indicate that nigrostriatal dopaminergic neurons are composed of distinct subpopulations which are characterized by their firing pattern.

  17. Sequential appearance of thymocyte subpopulations and T cell antigen receptor gene messages in the mouse thymus after sublethal irradiation

    International Nuclear Information System (INIS)

    Tomooka, S.; Matsuzaki, G.; Kishihara, K.; Tanaka, K.; Yoshikai, Y.; Taniguchi, K.; Himeno, K.; Nomoto, K.

    1987-01-01

    The sequential differentiation patterns of thymocyte were observed with cell surface phenotypes and the expression of T cell antigen receptor in 800 rad irradiated adult mice. Thymus was severely reduced in size and cell number by day 5 after whole body irradiation and rapidly recovered from day 7 to day 14. Surface marker analysis on day 5 after irradiation showed thymocytes with Thy-1low L3T4+/Lyt-2- dominantly existed and suggested that these cells were radioresistant-survived cells. On the other hand, thymocytes on day 7 were composed of a large number of Thy-1high L3T4+/Lyt-2+ blast-like cells and a relatively high proportion of Thy-1high L3T4-/Lyt-2- cells which expressed a large amount of gamma-chain gene messages but scarcely any alpha- and beta-chain gene messages similar to the fetal thymocytes. On day 14, thymocytes were composed mostly of Thy-1high H-2low L3T4+/Lyt-2+ subpopulation which expressed a remarkably low level of gamma-chain gene messages, and high levels of alpha- and beta-chain transcripts analogous to those of normal adult thymus. Taken together, intrathymic radioresistent stem cells for T thymocytes seem to proliferate and differentiate after irradiation with the same pattern as was seen in a fetal thymus development

  18. Hair Mercury Levels in Six Iranian Sub-populations for Estimation of Methylmercury Exposure: A Mini-review

    Directory of Open Access Journals (Sweden)

    Abbas Esmaili-Sari

    2012-01-01

    Full Text Available Background: Mercury is widespread and persistent in the environment. One organicform of mercury, Methylmercury (MeHg, can accumulate in the food chain in aquaticecosystems and lead to high concentrations of MeHg in fish, which, when consumed byhumans, can result in an increased risk of adverse effects. Currently, the Joint FAO/WHOExpert Committee on Food Additives (JECFA has established provisional tolerableweekly intakes (PTWIs for total mercury at 5 μg/kg body weight and for methylmercury at1.6 μg/kg body weight. Mercury concentration in blood or hair has been widely used forestimation of methylmercury exposure.Materials and Methods: In this review article, we calculated methylmercury exposurefrom hair mercury levels among six subpopulations (i.e. students, dentists, dental nurses,women with amalgam fillings, pregnant women in Mahshahr, and Women of a port town,Mahshahr, Iran. Some of the experiments had been performed by this group in previousyears.Results: The mean exposure level (μg/kg bw/day in three Iranian groups (dentists,pregnant women, and women in Mahshahr was higher than RfD and PTWIs.Conclusion: As people are exposed to methylmercury mainly through their diet,especially from fish and other marine species, pregnant women should reduce fishconsumption, especially predatory fish, and dentists should use preventive measures (likemasks and gloves.

  19. Evaluation of T-lymphocyte subpopulations in actinic keratosis, in situ and invasive squamous cell carcinoma of the skin.

    Science.gov (United States)

    Stravodimou, Aristea; Tzelepi, Vassiliki; Papadaki, Helen; Mouzaki, Athanasia; Georgiou, Sophia; Melachrinou, Maria; Kourea, Eleni P

    2018-05-01

    Tumor infiltrating lymphocytes (TILs) represent important regulators of carcinogenesis. Cutaneous invasive squamous cell carcinoma (inSCC) develops through precursor lesions, namely in situ squamous cell carcinoma (isSCC) and actinic keratosis (AK), representing a natural model of carcinogenesis. The study evaluates TIL subpopulations in inSCC and its precursors by comparing 2 semiquantitative scoring systems, and assesses the presence of regulatory T-cells (Tregs) in these lesions. Paraffin sections from 33 cases of AK, 19 isSCCs and 34 inSCCs with adjacent precursor lesions or normal skin (NS) were immunostained for CD3, CD4, CD8 and Foxp3. TIL subgroups were evaluated by the semiquantitative Klintrup-Mäkinen (K-M) score, and by a more detailed modification of this system. Treg counts were assessed by image analysis quantification. An increase of all TIL subpolulations from precursor lesions toward inSCC was shown by both scoring systems. Treg counts progressively increased from NS to AK and isSCC, but decreased in inSCC. Tregs were more numerous in pT2 and around indolent inSCCs compared to T1 and aggressive subtypes. T-cells and cytotoxic T-cells progressively increase in cutaneous squamous cell carcinogenesis, while Treg counts diminish in inSCC. The K-M score is an appropriate, easily applicable TIL scoring system in cutaneous inSCC. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Hoogsteen, Ilse J., E-mail: i.hoogsteen@rther.umcn.nl [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Marres, Henri A.M.; Hoogen, Franciscus J.A. van den [Department of Otorhinolaryngology/Head-Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Rijken, Paul F.J.W.; Lok, Jasper; Bussink, Johan; Kaanders, Johannes H.A.M. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands)

    2012-11-01

    Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

  1. George’s Island, Labrador - A high-density predator-free refuge for a woodland caribou subpopulation?

    Directory of Open Access Journals (Sweden)

    Rebecca A. Jeffery

    2007-04-01

    Full Text Available The movement patterns and demographic parameters were measured for caribou (Rangifer tarandus caribou on George’s Island (Labrador, Canada to determine if the population is separate from the Mealy Mountain Caribou Herd. Movements between George’s Island caribou and nearby Mealy Mountain caribou were examined through satellite telemetry (April 2005 to April 2006. Demographic information was collected through aerial classification surveys. The predator-free island is currently maintaining a density of 22.5-26.5 caribou/km2. Female survival appears high and the recruitment rate in late fall-early spring was 19.0-29.2% calves. Mainland caribou moved very little throughout the year, travelling no more than 53.7 km on average from their initial collaring locations. Also, satellite data indicated no mixing between animals on George’s Island and the mainland. The elevated caribou density and high proportion of calves suggest that George’s Island could at times be acting as a predator-free recruitment area and that George’s Island may be a subpopulation from which animals disperse to the mainland.

  2. Distribution of smile line, gingival angle and tooth shape among the Saudi Arabian subpopulation and their association with gingival biotype.

    Science.gov (United States)

    AlQahtani, Nabeeh A; Haralur, Satheesh B; AlMaqbol, Mohammad; AlMufarrij, Ali Jubran; Al Dera, Ahmed Ali; Al-Qarni, Mohammed

    2016-04-01

    To determine the occurrence of smile line and maxillary tooth shape in the Saudi Arabian subpopulation, and to estimate the association between these parameters with gingival biotype. On the fulfillment of selection criteria, total 315 patients belong to Saudi Arabian ethnic group were randomly selected. Two frontal photographs of the patients were acquired. The tooth morphology, gingival angle, and smile line classification were determined with ImageJ image analyzing software. The gingival biotype was assessed by probe transparency method. The obtained data were analyzed with SPSS 19 (IBM Corporation, New York, USA) software to determine the frequency and association between other parameters and gingival biotype. Among the clinical parameters evaluated, the tapering tooth morphology (56.8%), thick gingival biotype (53%), and average smile line (57.5%) was more prevalent. The statistically significant association was found between thick gingival biotype and the square tooth, high smile line. The high gingival angle was associated with thin gingival biotype. The study results indicate the existence of an association between tooth shape, smile line, and gingival angle with gingival biotype.

  3. Expression profile of vesicular nucleotide transporter (VNUT, SLC17A9) in subpopulations of rat dorsal root ganglion neurons.

    Science.gov (United States)

    Nishida, Kentaro; Nomura, Yuka; Kawamori, Kanako; Moriyama, Yoshinori; Nagasawa, Kazuki

    2014-09-05

    ATP plays an important role in the signal transduction between sensory neurons and satellite cells in dorsal root ganglia (DRGs). In primary cultured DRG neurons, ATP is known to be stored in lysosomes via a vesicular nucleotide transporter (VNUT), and to be released into the intercellular space through exocytosis. DRGs consist of large-, medium- and small-sized neurons, which play different roles in sensory transmission, but there is no information on the expression profiles of VNUT in DRG subpopulations. Here, we obtained detailed expression profiles of VNUT in isolated rat DRG tissues. On immunohistochemical analysis, VNUT was found in DRG neurons, and was predominantly expressed by the small- and medium-sized DRG ones, as judged upon visual inspection, and this was compatible with the finding that the number of VNUT-positive DRG neurons in IB4-positive cells was greater than that in NF200-positive ones. These results suggest that VNUT play a role in ATP accumulation in DRG neurons, especially in small- and medium-sized ones, and might be involved in ATP-mediated nociceptive signaling in DRGs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. A Retrospective Study on Genetic Heterogeneity within Treponema Strains: Subpopulations Are Genetically Distinct in a Limited Number of Positions.

    Directory of Open Access Journals (Sweden)

    Darina Čejková

    Full Text Available Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares. A set of 10 treponemal genome sequences including those of 4 Treponema pallidum ssp. pallidum (TPA strains (Nichols, DAL-1, Mexico A, SS14, 4 T. p. ssp. pertenue (TPE strains (CDC-2, Gauthier, Samoa D, Fribourg-Blanc, 1 T. p. ssp. endemicum (TEN strain (Bosnia A and one strain (Cuniculi A of Treponema paraluisleporidarum ecovar Cuniculus (TPLC were examined with respect to the presence of nucleotide intrastrain heterogeneous sites.The number of identified intrastrain heterogeneous sites in individual genomes ranged between 0 and 7. Altogether, 23 intrastrain heterogeneous sites (in 17 genes were found in 5 out of 10 investigated treponemal genomes including TPA strains Nichols (n = 5, DAL-1 (n = 4, and SS14 (n = 7, TPE strain Samoa D (n = 1, and TEN strain Bosnia A (n = 5. Although only one heterogeneous site was identified among 4 tested TPE strains, 16 such sites were identified among 4 TPA strains. Heterogeneous sites were mostly strain-specific and were identified in four tpr genes (tprC, GI, I, K, in genes involved in bacterial motility and chemotaxis (fliI, cheC-fliY, in genes involved in cell structure (murC, translation (prfA, general and DNA metabolism (putative SAM dependent methyltransferase, topA, and in seven hypothetical genes.Heterogeneous sites likely represent both the selection of adaptive changes during infection of the host as well as an ongoing diversifying evolutionary process.

  5. A Retrospective Study on Genetic Heterogeneity within Treponema Strains: Subpopulations Are Genetically Distinct in a Limited Number of Positions.

    Science.gov (United States)

    Čejková, Darina; Strouhal, Michal; Norris, Steven J; Weinstock, George M; Šmajs, David

    2015-01-01

    Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares. A set of 10 treponemal genome sequences including those of 4 Treponema pallidum ssp. pallidum (TPA) strains (Nichols, DAL-1, Mexico A, SS14), 4 T. p. ssp. pertenue (TPE) strains (CDC-2, Gauthier, Samoa D, Fribourg-Blanc), 1 T. p. ssp. endemicum (TEN) strain (Bosnia A) and one strain (Cuniculi A) of Treponema paraluisleporidarum ecovar Cuniculus (TPLC) were examined with respect to the presence of nucleotide intrastrain heterogeneous sites. The number of identified intrastrain heterogeneous sites in individual genomes ranged between 0 and 7. Altogether, 23 intrastrain heterogeneous sites (in 17 genes) were found in 5 out of 10 investigated treponemal genomes including TPA strains Nichols (n = 5), DAL-1 (n = 4), and SS14 (n = 7), TPE strain Samoa D (n = 1), and TEN strain Bosnia A (n = 5). Although only one heterogeneous site was identified among 4 tested TPE strains, 16 such sites were identified among 4 TPA strains. Heterogeneous sites were mostly strain-specific and were identified in four tpr genes (tprC, GI, I, K), in genes involved in bacterial motility and chemotaxis (fliI, cheC-fliY), in genes involved in cell structure (murC), translation (prfA), general and DNA metabolism (putative SAM dependent methyltransferase, topA), and in seven hypothetical genes. Heterogeneous sites likely represent both the selection of adaptive changes during infection of the host as well as an ongoing diversifying evolutionary process.

  6. Identifying hidden sexual bridging communities in Chicago.

    Science.gov (United States)

    Youm, Yoosik; Mackesy-Amiti, Mary Ellen; Williams, Chyvette T; Ouellet, Lawrence J

    2009-07-01

    Bridge populations can play a central role in the spread of human immunodeficiency virus (HIV) by providing transmission links between higher and lower prevalence populations. While social network methods are well suited to the study of bridge populations, analyses tend to focus on dyads (i.e., risk between drug and/or sex partners) and ignore bridges between distinct subpopulations. This study takes initial steps toward moving the analysis of sexual network linkages beyond individual and risk group levels to a community level in which Chicago's 77 community areas are examined as subpopulations for the purpose of identifying potential bridging communities. Of particular interest are "hidden" bridging communities; that is, areas with above-average levels of sexual ties with other areas but whose below-average AIDS prevalence may hide their potential importance for HIV prevention. Data for this analysis came from the first wave of recruiting at the Chicago Sexual Acquisition and Transmission of HIV Cooperative Agreement Program site. Between August 2005 through October 2006, respondent-driven sampling was used to recruit users of heroin, cocaine, or methamphetamine, men who have sex with men regardless of drug use, the sex partners of these two groups, and sex partners of the sex partners. In this cross-sectional study of the sexual transmission of HIV, participants completed a network-focused computer-assisted self-administered interview, which included questions about the geographic locations of sexual contacts with up to six recent partners. Bridging scores for each area were determined using a matrix representing Chicago's 77 community areas and were assessed using two measures: non-redundant ties and flow betweenness. Bridging measures and acquired immunodeficiency syndrome (AIDS) case prevalence rates were plotted for each community area on charts representing four conditions: below-average bridging and AIDS prevalence, below-average bridging and above

  7. Population structure of Helicobacter pylori among ethnic groups in Malaysia: recent acquisition of the bacterium by the Malay population.

    Science.gov (United States)

    Tay, Chin Yen; Mitchell, Hazel; Dong, Quanjiang; Goh, Khean-Lee; Dawes, Ian W; Lan, Ruiting

    2009-06-19

    Helicobacter pylori is a major gastric bacterial pathogen. This pathogen has been shown to follow the routes of human migration by their geographical origin and currently the global H. pylori population has been divided into six ancestral populations, three from Africa, two from Asia and one from Europe. Malaysia is made up of three major ethnic populations, Malay, Chinese and Indian, providing a good population for studying recent H. pylori migration and admixture. Seventy eight H. pylori isolates, including 27 Chinese, 35 Indian and 16 Malay isolates from Malaysia were analysed by multilocus sequence typing (MLST) of seven housekeeping genes and compared with the global MLST data. STRUCTURE analysis assigned the isolates to previously identified H. pylori ancestral populations, hpEastAsia, hpAsia2 and hpEurope, and revealed a new subpopulation, hspIndia, within hpAsia2. Statistical analysis allowed us to identify population segregation sites that divide the H. pylori populations and the subpopulations. The majority of Malay isolates were found to be grouped together with Indian isolates. The majority of the Malay and Indian H. pylori isolates share the same origin while the Malaysian Chinese H. pylori is distinctive. The Malay population, known to have a low infection rate of H. pylori, was likely to be initially H. pylori free and gained the pathogen only recently from cross infection from other populations.

  8. Population structure of Helicobacter pylori among ethnic groups in Malaysia: recent acquisition of the bacterium by the Malay population

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    Dawes Ian W

    2009-06-01

    Full Text Available Abstract Background Helicobacter pylori is a major gastric bacterial pathogen. This pathogen has been shown to follow the routes of human migration by their geographical origin and currently the global H. pylori population has been divided into six ancestral populations, three from Africa, two from Asia and one from Europe. Malaysia is made up of three major ethnic populations, Malay, Chinese and Indian, providing a good population for studying recent H. pylori migration and admixture. Results Seventy eight H. pylori isolates, including 27 Chinese, 35 Indian and 16 Malay isolates from Malaysia were analysed by multilocus sequence typing (MLST of seven housekeeping genes and compared with the global MLST data. STRUCTURE analysis assigned the isolates to previously identified H. pylori ancestral populations, hpEastAsia, hpAsia2 and hpEurope, and revealed a new subpopulation, hspIndia, within hpAsia2. Statistical analysis allowed us to identify population segregation sites that divide the H. pylori populations and the subpopulations. The majority of Malay isolates were found to be grouped together with Indian isolates. Conclusion The majority of the Malay and Indian H. pylori isolates share the same origin while the Malaysian Chinese H. pylori is distinctive. The Malay population, known to have a low infection rate of H. pylori, was likely to be initially H. pylori free and gained the pathogen only recently from cross infection from other populations.

  9. Genome re-sequencing of semi-wild soybean reveals a complex Soja population structure and deep introgression.

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    Jie Qiu

    Full Text Available Semi-wild soybean is a unique type of soybean that retains both wild and domesticated characteristics, which provides an important intermediate type for understanding the evolution of the subgenus Soja population in the Glycine genus. In this study, a semi-wild soybean line (Maliaodou and a wild line (Lanxi 1 collected from the lower Yangtze regions were deeply sequenced while nine other semi-wild lines were sequenced to a 3-fold genome coverage. Sequence analysis revealed that (1 no independent phylogenetic branch covering all 10 semi-wild lines was observed in the Soja phylogenetic tree; (2 besides two distinct subpopulations of wild and cultivated soybean in the Soja population structure, all semi-wild lines were mixed with some wild lines into a subpopulation rather than an independent one or an intermediate transition type of soybean domestication; (3 high heterozygous rates (0.19-0.49 were observed in several semi-wild lines; and (4 over 100 putative selective regions were identified by selective sweep analysis, including those related to the development of seed size. Our results suggested a hybridization origin for the semi-wild soybean, which makes a complex Soja population structure.

  10. Sex Venue-Based Network Analysis to Identify HIV Prevention Dissemination Targets for Men Who Have Sex with Men.

    Science.gov (United States)

    Patel, Rupa R; Luke, Douglas A; Proctor, Enola K; Powderly, William G; Chan, Philip A; Mayer, Kenneth H; Harrison, Laura C; Dhand, Amar

    2018-01-01

    The aim of this study was to identify sex venue-based networks among men who have sex with men (MSM) to inform HIV preexposure prophylaxis (PrEP) dissemination efforts. Using a cross-sectional design, we interviewed MSM about the venues where their recent sexual partners were found. Venues were organized into network matrices grouped by condom use and race. We examined network structure, central venues, and network subgroups. Among 49 participants, the median age was 27 years, 49% were Black and 86% reported condomless anal sex (ncAS). Analysis revealed a map of 54 virtual and physical venues with an overlap in the ncAS and with condom anal sex (cAS) venues. In the ncAS network, virtual and physical locations were more interconnected. The ncAS venues reported by Blacks were more diffusely organized than those reported by Whites. The network structures of sex venues for at-risk MSM differed by race. Network information can enhance HIV prevention dissemination efforts among subpopulations, including PrEP implementation.

  11. Deciphering the Structural Requirements of Nucleoside Bisubstrate Analogues for Inhibition of MbtA in Mycobacterium tuberculosis: A FB-QSAR Study and Combinatorial Library Generation for Identifying Potential Hits.

    Science.gov (United States)

    Maganti, Lakshmi; Das, Sanjit Kumar; Mascarenhas, Nahren Manuel; Ghoshal, Nanda

    2011-10-01

    The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade. Inhibitors of aryl acid adenylating enzyme known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. The ability to identify fragments that interact with a biological target is a key step in fragment based drug design (FBDD). To expand the boundaries of quantitative structure activity relationship (QSAR) paradigm, we have proposed a Fragment Based QSAR methodology, referred here in as FB-QSAR, for deciphering the structural requirements of a series of nucleoside bisubstrate analogs for inhibition of MbtA, a key enzyme involved in siderophore biosynthetic pathway. For the development of FB-QSAR models, statistical techniques such as stepwise multiple linear regression (SMLR), genetic function approximation (GFA) and GFAspline were used. The predictive ability of the generated models was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. To aid the creation of novel antituberculosis compounds, a bioisosteric database was enumerated using the combichem approach endorsed mining in a lead-like chemical space. The generated library was screened using an integrated in-silico approach and potential hits identified. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Visualization and modeling of sub-populations of compositional data: statistical methods illustrated by means of geochemical data from fumarolic fluids

    Science.gov (United States)

    Pawlowsky-Glahn, Vera; Buccianti, Antonella

    In the investigation of fluid samples of a volcanic system, collected during a given period of time, one of the main goals is to discover cause-effect relationships that allow us to explain changes in the chemical composition. They might be caused by physicochemical factors, such as temperature, pressure, or non-conservative behavior of some chemical constituents (addition or subtraction of material), among others. The presence of subgroups of observations showing different behavior is evidence of unusually complex situations, which might render even more difficult the analysis and interpretation of observed phenomena. These cases require appropriate statistical techniques as well as sound a priori hypothesis concerning underlying geological processes. The purpose of this article is to present the state of the art in the methodology for a better visualization of compositional data, as well as for detecting statistically significant sub-populations. The scheme of this article is to present first the application, and then the underlying methodology, with the aim of the first motivating the second. Thus, the first part has the goal to illustrate how to understand and interpret results, whereas the second is devoted to expose how to perform a study of this kind. The case study is related to the chemical composition of a fumarole of Vulcano Island (southern Italy), called F14. The volcanic activity at Vulcano Island is subject to a continuous program of geochemical surveillance from 1978 up to now and the large data set of observations contains the main chemical composition of volcanic gases as well as trace element concentrations in the condensates of fumarolic gases. Out of the complete set of measured components, the variables H2S, HF and As, determined in samples collected from 1978 to 1993 (As is not available in recent samples) are used to characterize two groups in the original population, which proved to be statistically distinct. The choice of the variables is

  13. Analysis of the numbers of B, T and subpopulation lymphocytes in patients with breast cancer submitted to a different radiotherapy schedules

    International Nuclear Information System (INIS)

    Andrade, J.M. de.

    1989-01-01

    The behaviour of T and B lymphocytes subpopulations was evaluated in patients with breast cancer submitted to 3 different schedules of radiotherapy. The assays were carried out before and immediately after the end of treatment. T lymphocytes and the helper/inducer (CD 4 ) and suppressor/cytotoxic (CD 8 ) subpopulations were counted by indirect immunofluorescence with monoclonal antibodies of the OKT series. The number of B lymphocytes was obtained by direct immunofluorescence with fluorescein-conjugated anti-human Ig antibodies. The patients were divided into 3 groups: irradiation of the breast only; irradiation of the lymph-draining areas; irradiation of the breast, of the lymph-draining area and of the sternal area. (author)

  14. Subpopulations of lymphocytes and their bearing on the radiation dose-response of the human lymphocyte (cell survival, mitogenic stimulation and chromosome aberration frequency)

    International Nuclear Information System (INIS)

    Schwartz, J.L.

    1979-01-01

    To determine whether in the lymphocyte the frequency of chromosome aberrations might be influenced by a differential radiation response of the varying types of cells, as well as interactions among them, subpopulations were separated on the basis of differences in cell surface receptors. The subpopulations, namely, T and B lymphocytes and three T subsets, T-M, T-G, T-null, were found to differ in radiosensitivity as measured by survival in culture and mitotic index after PHA stimulation. All the populations studied are represented to varying degrees among the mitotic cells of unirradiated samples 48 hours after PHA stimulation. At increasing doses of 6 Co gamma rays (50, 100, 250, 500 rads), however, their proportions change both as a direct result of irradiation, such as cell killing, and as an indirect effect, such as the reduction in suppressor cell action

  15. Evaluation of the effects of Ramadan fasting on lymphocyte subpopulations in a two‐year follow‐up

    Directory of Open Access Journals (Sweden)

    Zahra Siadat

    2014-03-01

    Full Text Available Today, the intractions of the immune system of the immune system, nutrition, and nervous system are one of the main research areas of interest in immunology and disease treatment. Due to changes in the mood, behavior, and diet of an individual during fasting period, the body's internal homeostasis is affected. The aim of the present study was to evaluate the effects of Ramadan fasting on lymphocyte subgroups, which are the main specific immune cells in the body. For this purpose, in years 1999 and 2000, thirty‐eight healthy Muslims (9 females and 29 males, within the age range of 17 to 51 years (mean age=35.4 years, were assessed before the start and one day before the end of Ramadan. The pre‐Lymphocytic subpopulations analysis was conducted using flow cytometery. The results showed that the percentage of total lymphocytes was 25.82% and 26.23% in the pre‐ and late‐Ramadan periods, respectively; the observed difference was insignificant. However, the absolute lymphocyte counts were 2.3×103 and 2.1×103 mm3 before and late Ramadan, respectively, and the difference was considered significant (P‐value=0.06. The percentage of CD3+ cells (T cells was 70.12% before Ramadan and 70.25% late Ramadan, and the absolute lymphocyte counts were 1.6×103 and 1.5×103 mm3, respectively; therefore, the differences were not significant. Regarding the subgroups of CD4+cells (TH, the percentage ratios of the cells were 53.46% and 52.8% in the pre‐ and late Ramadan periods, and the absolute counts were 0.087×103 and 0.081×103 mm3, respectively; however, the differences were not significant in this cell subgroup. The percentage of CD8+ (TC cells was 37.7% before Ramadan and 37.8% late Ramadan, and the absolute counts were 0.6×103 and 0.54×103 mm3 in the pre‐ and late‐Ramadan periods, respectively; therefore, the differences were considered insignificant. In addition, the percentage ratios of Blymphocytes cells were 14.56 % and 14.74% in the pre

  16. Evaluation of the Effects of Ramadan Fasting on Lymphocyte subpopulations in a Two‐year Follow‐up

    Directory of Open Access Journals (Sweden)

    Zahra Siadat

    2014-03-01

    Full Text Available Today, the intractions of the immune system of the immune system, nutrition, and nervous system are one of the main research areas of interest in immunology and disease treatment. Due to changes in the mood, behavior, and diet of an individual during fasting period, the body's internal homeostasis is affected. The aim of the present study was to evaluate the effects of Ramadan fasting on lymphocyte subgroups, which are the main specific immune cells in the body. For this purpose, in years 1999 and 2000, thirty‐eight healthy Muslims (9 females and 29 males, within the age range of 17 to 51 years (mean age=35.4 years, were assessed before the start and one day before the end of Ramadan. The pre‐Lymphocytic subpopulations analysis was conducted using flow cytometery. The results showed that the percentage of total lymphocytes was 25.82% and 26.23% in the pre‐ and late‐Ramadan periods, respectively; the observed difference was insignificant. However, the absolute lymphocyte counts were 2.3×103 and 2.1×103 mm3 before and late Ramadan, respectively, and the difference was considered significant (P‐value=0.06. The percentage of CD3+ cells (T cells was 70.12% before Ramadan and 70.25% late Ramadan, and the absolute lymphocyte counts were 1.6×103 and 1.5×103 mm3, respectively; therefore, the differences were not significant. Regarding the subgroups of CD4+cells (TH, the percentage ratios of the cells were 53.46% and 52.8% in the pre‐ and late Ramadan periods, and the absolute counts were 0.087×103 and 0.081×103 mm3, respectively; however, the differences were not significant in this cell subgroup. The percentage of CD8+ (TC cells was 37.7% before Ramadan and 37.8% late Ramadan, and the absolute counts were 0.6×103 and 0.54×103 mm3 in the pre‐ and late‐Ramadan periods, respectively; therefore, the differences were considered insignificant. In addition, the percentage ratios of Blymphocytes cells were 14.56 % and 14.74% in the pre

  17. TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation.

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    Orla M Casey

    Full Text Available Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi/EpCAM(+ basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium.

  18. Morphological switch to a resistant subpopulation in response to viral infection in the bloom-forming coccolithophore Emiliania huxleyi.

    Science.gov (United States)

    Frada, Miguel José; Rosenwasser, Shilo; Ben-Dor, Shifra; Shemi, Adva; Sabanay, Helena; Vardi, Assaf

    2017-12-01

    Recognizing the life cycle of an organism is key to understanding its biology and ecological impact. Emiliania huxleyi is a cosmopolitan marine microalga, which displays a poorly understood biphasic sexual life cycle comprised of a calcified diploid phase and a morphologically distinct biflagellate haploid phase. Diploid cells (2N) form large-scale blooms in the oceans, which are routinely terminated by specific lytic viruses (EhV). In contrast, haploid cells (1N) are resistant to EhV. Further evidence indicates that 1N cells may be produced during viral infection. A shift in morphology, driven by meiosis, could therefore constitute a mechanism for E. huxleyi cells to escape from EhV during blooms. This process has been metaphorically coined the 'Cheshire Cat' (CC) strategy. We tested this model in two E. huxleyi strains using a detailed assessment of morphological and ploidy-level variations as well as expression of gene markers for meiosis and the flagellate phenotype. We showed that following the CC model, production of resistant cells was triggered during infection. This led to the rise of a new subpopulation of cells in the two strains that morphologically resembled haploid cells and were resistant to EhV. However, ploidy-level analyses indicated that the new resistant cells were diploid or aneuploid. Thus, the CC strategy in E. huxleyi appears to be a life-phase switch mechanism involving morphological remodeling that is decoupled from meiosis. Our results highlight the adaptive significance of morphological plasticity mediating complex host-virus interactions in marine phytoplankton.

  19. Total lymphocyte count and subpopulation lymphocyte counts in relation to dietary intake and nutritional status of peritoneal dialysis patients.

    Science.gov (United States)

    Grzegorzewska, Alicja E; Leander, Magdalena

    2005-01-01

    Dietary deficiency causes abnormalities in circulating lymphocyte counts. For the present paper, we evaluated correlations between total and subpopulation lymphocyte counts (TLC, SLCs) and parameters of nutrition in peritoneal dialysis (PD) patients. Studies were carried out in 55 patients treated with PD for 22.2 +/- 11.4 months. Parameters of nutritional status included total body mass, lean body mass (LBM), body mass index (BMI), and laboratory indices [total protein, albumin, iron, ferritin, and total iron binding capacity (TIBC)]. The SLCs were evaluated using flow cytometry. Positive correlations were seen between TLC and dietary intake of niacin; TLC and CD8 and CD16+56 counts and energy delivered from protein; CD4 count and beta-carotene and monounsaturated fatty acids 17:1 intake; and CD19 count and potassium, copper, vitamin A, and beta-carotene intake. Anorexia negatively influenced CD19 count. Serum albumin showed correlations with CD4 and CD19 counts, and LBM with CD19 count. A higher CD19 count was connected with a higher red blood cell count, hemoglobin, and hematocrit. Correlations were observed between TIBC and TLC and CD3 and CD8 counts, and between serum Fe and TLC and CD3 and CD4 counts. Patients with a higher CD19 count showed a better clinical-laboratory score, especially less weakness. Patients with a higher CD4 count had less expressed insomnia. Quantities of ingested vitamins and minerals influence lymphocyte counts in the peripheral blood of PD patients. Evaluation of TLC and SLCs is helpful in monitoring the effectiveness of nutrition in these patients.

  20. Frailty in Older Adults Is Associated With Plasma Concentrations of Inflammatory Mediators but Not With Lymphocyte Subpopulations

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    Diego Marcos-Pérez

    2018-05-01

    Full Text Available Frailty denotes a multidimensional syndrome that gives rise to vulnerability to stressors and leads to an increase of the age-related decline of different physiological systems and cognitive abilities. Aging-related alterations of the immune system may compromise its competence culminating in a chronic low-grade inflammation state. Thus, it has been proposed that frailty is associated with alterations in the concentration of pro-inflammatory molecules and in different lymphocyte subpopulations. To provide further support to the validity of that hypothesis, we conducted a cross-sectional study in a population of Spanish older adults (N = 259, aged 65 and over classified according to their frailty status. Biomarkers analyzed included percentages of several lymphocyte subsets and several inflammation mediators, namely concentrations of interleukin 6 (IL6, C-reactive protein (CRP, tumor necrosis factor α (TNFα, and 75 kDa soluble TNFα receptor II (sTNF-RII. Reference ranges for the inflammation mediators were established for the first time in robust older adults. A significant increase in the CD4+/CD8+ ratio and a significant decrease in the % CD19+ cells were observed in the frail group. Progressive increases with frailty severity were obtained in all inflammatory mediator concentrations, especially notable for IL6 and sTNF-RII. Area under the receiver-operating characteristic curve obtained for sTNF-RII (0.90, 95% CI 0.85–0.94, P < 0.001 indicates a high accuracy in the predictive value of this biomarker for frailty. Although results from the current study revealed limited strength associations between frailty and the lymphocyte subsets assessed, data obtained for the inflammatory mediators provide further support to involvement of inflammaging in frailty status in older adults.