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Sample records for subpopulation structure identified

  1. Subpopulation structure of caribou (Rangifer tarandus L.) in arctic and subarctic Canada.

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    Nagy, John A; Johnson, Deborah L; Larter, Nicholas C; Campbell, Mitch W; Derocher, Andrew E; Kelly, Allicia; Dumond, Mathieu; Allaire, Danny; Croft, Bruno

    2011-09-01

    Effective management and conservation of species, subspecies, or ecotypes require an understanding of how populations are structured in space. We used satellite-tracking locations and hierarchical and fuzzy clustering to quantify subpopulations within the behaviorally different barren-ground caribou (Rangifer tarandus groenlandicus), Dolphin and Union island caribou (R. t. groenlandicus x pearyi), and boreal (R. t. caribou) caribou ecotypes in the Northwest Territories and Nunavut, Canada. Using a novel approach, we verified that the previously recognized Cape Bathurst, Bluenose-West, Bluenose-East, Bathurst, Beverly, Qamanirjuaq, and Lorillard barren-ground subpopulations were robust and that the Queen Maude Gulf and Wager Bay barren-ground subpopulations were organized as individuals. Dolphin and Union island and boreal caribou formed one and two distinct subpopulation, respectively, and were organized as individuals. Robust subpopulations were structured by strong annual spatial affiliation among females; subpopulations organized as individuals were structured by migratory connectivity, barriers to movement, and/or habitat discontinuity. One barren-ground subpopulation used two calving grounds, and one calving ground was used by two barren-ground subpopulations, indicating that these caribou cannot be reliably assigned to subpopulations solely by calving-ground use. They should be classified by annual spatial affiliation among females. Annual-range size and path lengths varied significantly among ecotypes, including mountain woodland caribou (R. t. caribou), and reflected behavioral differences. An east-west cline in annual-range sizes and path lengths among migratory barren-ground subpopulations likely reflected differences in subpopulation size and habitat conditions and further supported the subpopulation structure identified.

  2. Identifying the relative priorities of subpopulations for containing infectious disease spread.

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    Xia, Shang; Liu, Jiming; Cheung, William

    2013-01-01

    In response to the outbreak of an emerging infectious disease, e.g., H1N1 influenza, public health authorities will take timely and effective intervention measures to contain disease spread. However, due to the scarcity of required resources and the consequent social-economic impacts, interventions may be suggested to cover only certain subpopulations, e.g., immunizing vulnerable children and the elderly as well as closing schools or workplaces for social distancing. Here we are interested in addressing the question of how to identify the relative priorities of subpopulations for two measures of disease intervention, namely vaccination and contact reduction, especially when these measures are implemented together at the same time. We consider the measure of vaccination that immunizes susceptible individuals in different age subpopulations and the measure of contact reduction that cuts down individuals' effective contacts in different social settings, e.g., schools, households, workplaces, and general communities. In addition, we construct individuals' cross-age contact frequency matrix by inferring basic contact patterns respectively for different social settings from the socio-demographical census data. By doing so, we present a prioritization approach to identifying the target subpopulations that will lead to the greatest reduction in the number of disease transmissions. We calculate the relative priorities of subpopulations by considering the marginal effects of reducing the reproduction number for the cases of vaccine allocation by age and contact reduction by social setting. We examine the proposed approach by revisiting the real-world scenario of the 2009 Hong Kong H1N1 influenza epidemic and determine the relative priorities of subpopulations for age-specific vaccination and setting-specific contact reduction. We simulate the influenza-like disease spread under different settings of intervention. The results have shown that the proposed approach can improve

  3. Identifying the relative priorities of subpopulations for containing infectious disease spread.

    Directory of Open Access Journals (Sweden)

    Shang Xia

    Full Text Available In response to the outbreak of an emerging infectious disease, e.g., H1N1 influenza, public health authorities will take timely and effective intervention measures to contain disease spread. However, due to the scarcity of required resources and the consequent social-economic impacts, interventions may be suggested to cover only certain subpopulations, e.g., immunizing vulnerable children and the elderly as well as closing schools or workplaces for social distancing. Here we are interested in addressing the question of how to identify the relative priorities of subpopulations for two measures of disease intervention, namely vaccination and contact reduction, especially when these measures are implemented together at the same time. We consider the measure of vaccination that immunizes susceptible individuals in different age subpopulations and the measure of contact reduction that cuts down individuals' effective contacts in different social settings, e.g., schools, households, workplaces, and general communities. In addition, we construct individuals' cross-age contact frequency matrix by inferring basic contact patterns respectively for different social settings from the socio-demographical census data. By doing so, we present a prioritization approach to identifying the target subpopulations that will lead to the greatest reduction in the number of disease transmissions. We calculate the relative priorities of subpopulations by considering the marginal effects of reducing the reproduction number for the cases of vaccine allocation by age and contact reduction by social setting. We examine the proposed approach by revisiting the real-world scenario of the 2009 Hong Kong H1N1 influenza epidemic and determine the relative priorities of subpopulations for age-specific vaccination and setting-specific contact reduction. We simulate the influenza-like disease spread under different settings of intervention. The results have shown that the proposed

  4. Normozoospermic versus teratozoospermic domestic cats: differential testicular volume, sperm morphometry, and subpopulation structure during epididymal maturation.

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    Gutiérrez-Reinoso, Miguel Angel; García-Herreros, Manuel

    2016-01-01

    Teratozoospermia (sperm morphometric traits, and potential differences regarding the sperm subpopulational structure during epididymal sperm maturation in teratozoospermic feline donors. Epididymal sperm samples were collected from the caput (R1), corpus (R2), and cauda (R3) epididymidis in two donor groups (N: normozoospermic; T: teratozoospermic). Aliquots were assessed for concentration, viability, motility, and acrosomal integrity. Sperm morphometric descriptors from CASA-Morph analysis were analyzed by the Principal Component Analysis (PCA) and clustering analyses. Irrespective of the group analyzed, PCA revealed two Principal Components (PCs) for each epididymal region explaining more than the 93% of the variance. Surprisingly, the number of subpopulations remained constant in regions R1-R2-R3 irrespective of the donor group analyzed. However, the distribution of these subpopulations was found to be structurally different and strongly influenced by the epididymal region and the donor group. In conclusion, testicular morphometry and the sperm subpopulation structure were different in N and T donors. The alterations in subpopulations during epididymal maturation could be used as a potential clinical indicator of teratozoospermic individuals since an important influence of teratozoospermia on sperm subpopulation structure has been demonstrated.

  5. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate

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    Zvelebil Marketa

    2008-12-01

    Full Text Available Abstract Background Understanding the molecular control of cell lineages and fate determination in complex tissues is key to not only understanding the developmental biology and cellular homeostasis of such tissues but also for our understanding and interpretation of the molecular pathology of diseases such as cancer. The prerequisite for such an understanding is detailed knowledge of the cell types that make up such tissues, including their comprehensive molecular characterisation. In the mammary epithelium, the bulk of the tissue is composed of three cell lineages, namely the basal/myoepithelial, luminal epithelial estrogen receptor positive and luminal epithelial estrogen receptor negative cells. However, a detailed molecular characterisation of the transcriptomic differences between these three populations has not been carried out. Results A whole transcriptome analysis of basal/myoepithelial cells, luminal estrogen receptor negative cells and luminal estrogen receptor positive cells isolated from the virgin mouse mammary epithelium identified 861, 326 and 488 genes as highly differentially expressed in the three cell types, respectively. Network analysis of the transcriptomic data identified a subpopulation of luminal estrogen receptor negative cells with a novel potential role as non-professional immune cells. Analysis of the data for potential paracrine interacting factors showed that the basal/myoepithelial cells, remarkably, expressed over twice as many ligands and cell surface receptors as the other two populations combined. A number of transcriptional regulators were also identified that were differentially expressed between the cell lineages. One of these, Sox6, was specifically expressed in luminal estrogen receptor negative cells and functional assays confirmed that it maintained mammary epithelial cells in a differentiated luminal cell lineage. Conclusion The mouse mammary epithelium is composed of three main cell types with

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

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    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.

  7. No Evidence of Population Structure across Three Isolated Subpopulations of Russula brevipes in an Oak/Pine Woodland

    National Research Council Canada - National Science Library

    Sarah E. Bergemann; Greg W. Douhan; Matteo Garbelotto; Steven L. Miller

    2006-01-01

    .... $\\bullet$ To examine genetic structure over a more localized scale, basidiocarps of Russula brevipes from three subpopulations, separated by distances of 230-1090 m, were collected over two consecutive years...

  8. Effects of subpopulation structure on probability calculations of DNA profiles from forensic PCR analysis.

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    Gallo, J C; Thomas, E; Novick, G E; Herrera, R J

    1997-01-01

    DNA typing for forensic identification is a two-step process. The first step involves determining the profiles of samples collected at the crime scene and comparing them with the profiles obtained from suspects and the victims. In the case of a match that includes the suspect as the potential source of the material collected at the crime scene, the last step in the process is to answer the question, what is the likelihood that someone in addition to the suspect could match the profile of the sample studied? This likelihood is calculated by determining the frequency of the suspect's profile in the relevant population databases. The design of forensic databases and the criteria for comparison has been addressed by the NRC report of 1996 (National Research Council, 1996). However, the fact that geographical proximity, migrational patterns, and even cultural and social practices have effects on subpopulation structure establishes the grounds for further study into its effects on the calculation of probability of occurrence values. The issue becomes more relevant in the case of discrete polymorphic markers that show higher probability of occurrence in the reference populations, where several orders of magnitude difference between the databases may have an impact on the jury. In this study, we calculated G values for all possible pairwise comparisons of allelic frequencies in the different databases from the races or subpopulations examined. In addition, we analyzed a set of 24 unrelated Caucasian, 37 unrelated African-American, and 96 unrelated Sioux/Chippewa individuals for seven polymorphic loci (DQA1, LDLR, GYPA, HBGG, D7S8, GC, and D1S80). All three sets of individuals where sampled from Minnesota. The probability of occurrence for all seven loci were calculated with respect to nine different databases: Caucasian, Arabic, Korean, Sioux/Chippewa, Navajo, Pueblo, African American, Southeastern Hispanic, and Southwestern Hispanic. Analysis of the results demonstrated

  9. Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data

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    2013-01-01

    Background Ineffective risk stratification can delay diagnosis of serious disease in patients with hematuria. We applied a systems biology approach to analyze clinical, demographic and biomarker measurements (n = 29) collected from 157 hematuric patients: 80 urothelial cancer (UC) and 77 controls with confounding pathologies. Methods On the basis of biomarkers, we conducted agglomerative hierarchical clustering to identify patient and biomarker clusters. We then explored the relationship between the patient clusters and clinical characteristics using Chi-square analyses. We determined classification errors and areas under the receiver operating curve of Random Forest Classifiers (RFC) for patient subpopulations using the biomarker clusters to reduce the dimensionality of the data. Results Agglomerative clustering identified five patient clusters and seven biomarker clusters. Final diagnoses categories were non-randomly distributed across the five patient clusters. In addition, two of the patient clusters were enriched with patients with 'low cancer-risk' characteristics. The biomarkers which contributed to the diagnostic classifiers for these two patient clusters were similar. In contrast, three of the patient clusters were significantly enriched with patients harboring 'high cancer-risk" characteristics including proteinuria, aggressive pathological stage and grade, and malignant cytology. Patients in these three clusters included controls, that is, patients with other serious disease and patients with cancers other than UC. Biomarkers which contributed to the diagnostic classifiers for the largest 'high cancer- risk' cluster were different than those contributing to the classifiers for the 'low cancer-risk' clusters. Biomarkers which contributed to subpopulations that were split according to smoking status, gender and medication were different. Conclusions The systems biology approach applied in this study allowed the hematuric patients to cluster naturally on

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

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    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).

  11. Identifying sub-populations via unsupervised cluster analysis on multi-edge similarity graphs.

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    Ingalhalikar, Madhura; Smith, Alex R; Bloy, Luke; Gur, Ruben; Roberts, Timothy P L; Verma, Ragini

    2012-01-01

    Pathologies like autism and schizophrenia are a broad set of disorders with multiple etiologies in the same diagnostic category. This paper presents a method for unsupervised cluster analysis using multi-edge similarity graphs that combine information from different modalities. The method alleviates the issues with traditional supervised classification methods that use diagnostic labels and are therefore unable to exploit or elucidate the underlying heterogeneity of the dataset under analysis. The framework introduced in this paper has the ability to employ diverse features that define different aspects of pathology obtained from different modalities to create a multi-edged graph on which clustering is performed. The weights on the multiple edges are optimized using a novel concept of 'holding power' that describes the certainty with which a subject belongs to a cluster. We apply the technique to two separate clinical populations of autism spectrum disorder (ASD) and schizophrenia (SCZ), where the multi-edged graph for each population is created by combining information from structural networks and cognitive scores. For the ASD-control population the method clusters the data into two classes and the SCZ-control population is clustered into four. The two classes in ASD agree with underlying diagnostic labels with 92% accuracy and the SCZ clustering agrees with 78% accuracy, indicating a greater heterogeneity in the SCZ population.

  12. Population genetic analysis of Propionibacterium acnes identifies a subpopulation and epidemic clones associated with acne.

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    Hans B Lomholt

    Full Text Available The involvement of Propionibacterium acnes in the pathogenesis of acne is controversial, mainly owing to its dominance as an inhabitant of healthy skin. This study tested the hypothesis that specific evolutionary lineages of the species are associated with acne while others are compatible with health. Phylogenetic reconstruction based on nine housekeeping genes was performed on 210 isolates of P. acnes from well-characterized patients with acne, various opportunistic infections, and from healthy carriers. Although evidence of recombination was observed, the results showed a basically clonal population structure correlated with allelic variation in the virulence genes tly and camp5, with pulsed field gel electrophoresis (PFGE- and biotype, and with expressed putative virulence factors. An unexpected geographically and temporal widespread dissemination of some clones was demonstrated. The population comprised three major divisions, one of which, including an epidemic clone, was strongly associated with moderate to severe acne while others were associated with health and opportunistic infections. This dichotomy correlated with previously observed differences in in vitro inflammation-inducing properties. Comparison of five genomes representing acne- and health-associated clones revealed multiple both cluster- and strain-specific genes that suggest major differences in ecological preferences and redefines the spectrum of disease-associated virulence factors. The results of the study indicate that particular clones of P. acnes play an etiologic role in acne while others are associated with health.

  13. Morphometry and subpopulation structure of Holstein bull spermatozoa: variations in ejaculates and cryopreservation straws

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    Valverde, Anthony; Arenán, Héctor; Sancho, María; Contell, Jesús; Yániz, Jesús; Fernández, Alejandro; Soler, Carles

    2016-01-01

    Sperm quality is evaluated for the calculation of sperm dosage in artificial reproductive programs. The most common parameter used is motility, but morphology has a higher potential as a predictor of genetic quality. Morphometry calculations from CASA-Morph technology improve morphological evaluation and allow mathematical approaches to the problem. Semen from 28 Holstein bulls was collected by artificial vagina, and several ejaculates were studied. After general evaluation, samples were diluted, packaged in 0.25 ml straws, and stored in liquid nitrogen. Two straws per sample were thawed, and slides were processed and stained with Diff-Quik. Samples were analyzed by a CASA-Morph system for eight morphometric parameters. In addition to the “classical” statistical approach, based on variance analysis (revealing differences between animals, ejaculates, and straws), principal component (PC) analysis showed that the variables were grouped into PC1, related to size, and PC2 to shape. Subpopulation structure analysis showed four groups, namely, big, small, short, and narrow from their dominant characteristics, representing 31.0%, 27.3%, 24.1%, and 17.7% of the total population, respectively. The distributions varied between animals and ejaculates, but between straws, there were no differences in only four animals. This modern approach of considering an ejaculate sperm population as divided into subpopulations reflecting quantifiable parameters generated by CASA-Morph systems technology opens a new view on sperm function. This is the first study applying this approach to evaluate different ejaculates and straws from the same individual. More work must be done to improve seminal dose calculations in assisted reproductive programs. PMID:27678464

  14. Genetic structure and variation of Petrosimonia sibirica subpopulations in oasis-desert transitional zone in Fukang, Xinjiang

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    Wang, Yiling; Xu, Li; Yan, Guiqin; Gu, Fengxue; Pan, Xiaoling; Yue, Ming; Zhao, Guifang

    2003-07-01

    Population genetic structure and genetic diversity were studied using RAPD in five samples of Petrosimonia sibirica in Fukang, XinJiang. The results showed that amplification of 14 random primers detected 76 of 77 loci were polymorphic. The mean proportion of ploymorphic loci (P) of P. sibirica was 98.7%. It showed the higher genetic diversity existed in the subpopulations of P. sibirica. Furthermore, the study discussed the Shannon information index (HPOP/HSP =0.6933), Nei gene diversity index (HS/HT=0.6948) and gene differentiation index (GST=0.3052). The analysis presented that the ratio of molecular variation was over 30% among subpopulations and about 70% within subpopulations. Therefore the genetic differentiation had happened among subpopulations of P. sibirica. On the other hand, the gene flow of P. sibirica (Nm=1.138) was less than that of cosmopolite species (Nm=1.881), and much lower than that of of Caragana spp. populations over Maowusu sandy grassland (Nm=5.9529). Additionally, through the correlation analysis, the relationship between the genetic distance of P. sibirica and latitude, longitude and altitude was not significant. It showed the geographical difference was not one of the potential factors, which affected the genetic differentiation of P. sibirica. At the same time, the soluble salt in soil of the oasis desert transitional zone might play a role in maintaining the genetic diversity of P. sibirica. The paper indicated that the mean proportion of ploymorphic loci (P)and Nei gene diversity index (H) of P. sibirica had the remarkably negative relationship (pgenetic variation existed within the subpopulations, the genetic differentiation occurred among subpopulations. The natural selection may have a determinate effect on keeping the genetic variation and differentiation of the subpopulations of P. sibirica.

  15. Lectin from Griffonia simplicifolia identifies an immature-appearing subpopulation of sensory hair cells in the avian utricle.

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    Warchol, M E

    2001-03-01

    The sensory hair cells of the inner ear are coated with a variety of glycoproteins and glycolipids which can be identified by the binding of specific lectins. The present study examined the binding patterns of three lectins-Wheat Germ Agglutinin, Peanut Agglutinin, and lectin from Griffonia simplicifolia (Isoform B(4))-in the avian utricle. Each of the lectins exhibited a distinct pattern of hair cell labeling. Wheat Germ Agglutinin (WGA) appeared to label the ciliary bundles of all sensory hair cells. In contrast, the binding of Peanut Agglutinin (PNA) was mainly confined to the ciliary bundles of extrastriolar hair cells. Finally, lectin from Griffonia simplicifolia (GS-IB(4)) labeled a subpopulation of hair cells in all regions of the chick utricle. Those bundles were much smaller than the majority of ciliary bundles labeled by either WGA or PNA, and the density of GS-IB(4)-labeled bundles in the normal mature utricle was relatively low. Increased densities of GS-IB(4)-labeled hair cells were observed in the embryonic utricle and during the process of hair cell regeneration. The observations suggest that GS-IB(4) labels a glycoprotein that is expressed preferentially on the ciliary bundles of immature hair cells.

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

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    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

  17. CD24 expression identifies teratogen-sensitive fetal neural stem cell subpopulations: evidence from developmental ethanol exposure and orthotopic cell transfer models.

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    Tingling, Joseph D; Bake, Shameena; Holgate, Rhonda; Rawlings, Jeremy; Nagsuk, Phillips P; Chandrasekharan, Jayashree; Schneider, Sarah L; Miranda, Rajesh C

    2013-01-01

    Ethanol is a potent teratogen. Its adverse neural effects are partly mediated by disrupting fetal neurogenesis. The teratogenic process is poorly understood, and vulnerable neurogenic stages have not been identified. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures. We used flow cytometry and qRT-PCR to screen fetal mouse-derived neurosphere cultures for ethanol-sensitive neural stem cell (NSC) subpopulations, to study NSC renewal and differentiation. The identity of vulnerable NSC populations was validated in vivo, using a maternal ethanol exposure model. Finally, the effect of ethanol exposure on the ability of vulnerable NSC subpopulations to integrate into the fetal neurogenic environment was assessed following ultrasound guided, adoptive transfer. Ethanol decreased NSC mRNAs for c-kit, Musashi-1and GFAP. The CD24(+) NSC population, specifically the CD24(+)CD15(+) double-positive subpopulation, was selectively decreased by ethanol. Maternal ethanol exposure also resulted in decreased fetal forebrain CD24 expression. Ethanol pre-exposed CD24(+) cells exhibited increased proliferation, and deficits in cell-autonomous and cue-directed neuronal differentiation, and following orthotopic transplantation into naïve fetuses, were unable to integrate into neurogenic niches. CD24(depleted) cells retained neurosphere regeneration capacity, but following ethanol exposure, generated increased numbers of CD24(+) cells relative to controls. Neuronal lineage committed CD24(+) cells exhibit specific vulnerability, and ethanol exposure persistently impairs this population's cell-autonomous differentiation capacity. CD24(+) cells may additionally serve as quorum sensors within neurogenic niches; their loss, leading to compensatory NSC activation, perhaps depleting renewal capacity. These data collectively advance a mechanistic hypothesis for teratogenesis leading to microencephaly.

  18. Cell surface marker profiling of human tracheal basal cells reveals distinct subpopulations, identifies MST1/MSP as a mitogenic signal, and identifies new biomarkers for lung squamous cell carcinomas.

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    Van de Laar, Emily; Clifford, Monica; Hasenoeder, Stefan; Kim, Bo Ram; Wang, Dennis; Lee, Sharon; Paterson, Josh; Vu, Nancy M; Waddell, Thomas K; Keshavjee, Shaf; Tsao, Ming-Sound; Ailles, Laurie; Moghal, Nadeem

    2014-12-31

    The large airways of the lungs (trachea and bronchi) are lined with a pseudostratified mucociliary epithelium, which is maintained by stem cells/progenitors within the basal cell compartment. Alterations in basal cell behavior can contribute to large airway diseases including squamous cell carcinomas (SQCCs). Basal cells have traditionally been thought of as a uniform population defined by basolateral position, cuboidal cell shape, and expression of pan-basal cell lineage markers like KRT5 and TP63. While some evidence suggests that basal cells are not all functionally equivalent, few heterogeneously expressed markers have been identified to purify and study subpopulations. In addition, few signaling pathways have been identified that regulate their cell behavior. The goals of this work were to investigate tracheal basal cell diversity and to identify new signaling pathways that regulate basal cell behavior. We used flow cytometry (FACS) to profile cell surface marker expression at a single cell level in primary human tracheal basal cell cultures that maintain stem cell/progenitor activity. FACS results were validated with tissue staining, in silico comparisons with normal basal cell and lung cancer datasets, and an in vitro proliferation assay. We identified 105 surface markers, with 47 markers identifying potential subpopulations. These subpopulations generally fell into more (~ > 13%) or less abundant (~ markers in the total population, and immunostaining of large airway tissue suggested that some of these markers are relevant in vivo. 24 markers were enriched in lung SQCCs relative to adenocarcinomas, with four markers having prognostic significance in SQCCs. We also identified 33 signaling receptors, including the MST1R/RON growth factor receptor, whose ligand MST1/MSP was mitogenic for basal cells. This work provides the largest description to date of molecular diversity among human large airway basal cells. Furthermore, these markers can be used to further

  19. Griffonia simplicifolia isolectin B4 identifies a specific subpopulation of angiogenic blood vessels following contusive spinal cord injury in the adult mouse.

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    Benton, Richard L; Maddie, Melissa A; Minnillo, Danielle R; Hagg, Theo; Whittemore, Scott R

    2008-03-01

    After traumatic spinal cord injury (SCI), disruption and plasticity of the microvasculature within injured spinal tissue contribute to the pathological cascades associated with the evolution of both primary and secondary injury. Conversely, preserved vascular function most likely results in tissue sparing and subsequent functional recovery. It has been difficult to identify subclasses of damaged or regenerating blood vessels at the cellular level. Here, adult mice received a single intravenous injection of the Griffonia simplicifolia isolectin B4 (IB4) at 1-28 days following a moderate thoracic (T9) contusion. Vascular binding of IB4 was maximally observed 7 days following injury, a time associated with multiple pathologic aspects of the intrinsic adaptive angiogenesis, with numbers of IB4 vascular profiles decreasing by 21 days postinjury. Quantitative assessment of IB4 binding shows that it occurs within the evolving lesion epicenter, with affected vessels expressing a temporally specific dysfunctional tight junctional phenotype as assessed by occludin, claudin-5, and ZO-1 immunoreactivities. Taken together, these results demonstrate that intravascular lectin delivery following SCI is a useful approach not only for observing the functional status of neovascular formation but also for definitively identifying specific subpopulations of reactive spinal microvascular elements. Copyright 2007 Wiley-Liss, Inc.

  20. Using cluster analysis to identify a homogeneous subpopulation of women with polycystic ovarian morphology in a population of non-hyperandrogenic women with regular menstrual cycles.

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    Dewailly, D; Alebić, M Š; Duhamel, A; Stojanović, N

    2014-11-01

    Can cluster analysis can be used to identify a homogeneous subpopulation of women with polycystic ovarian morphology (PCOM) within a very large population of control women in a non-subjective way? Identification and exclusion of the cluster corresponding to women with PCOM from controls improved the diagnostic power of serum anti-Müllerian hormone (AMH) level and follicle number per ovary (FNPO) in discriminating between women with or without polycystic ovary syndrome (PCOS). There is disagreement as to whether women with PCOM should be excluded from the control population when establishing FNPO and AMH diagnostic thresholds for the definition of PCOS and how to identify such women. It has been demonstrated that cluster analysis can detect women with PCOM within the control population through a set of classifying variables among which the most relevant was AMH. The adequacy of this approach has not been confirmed in other clinical settings. This was a retrospective study using clinical and laboratory data derived from the computerized database. The data were collected from March 2011 to May 2013. The study included 893 patients referred for routine infertility evaluation and treatment. The patients were divided into three groups: (i) the control group (n = 621) included women with regular menstrual cycles and no signs of hyperandrogenism (HA), (ii) the full-blown PCOS group (n = 95) consisted of women who were diagnosed as having PCOS based on the presence of both HA and oligo/amenorrhoea (OA), (iii) the mild PCOS group included women with only two items of the Rotterdam classification, i.e. PCOM at ultrasonography according to the FNPO threshold of 12 or more and either OA (n = 110) or HA (n = 67). After exclusion of women with PCOM from the controls, the AMH threshold of 28 pmol/l with specificity 97.5% and sensitivity 84.2% [area under the curve (AUC) 0.948 (95% confidence interval (CI) 0.915-0.982)] and FNPO threshold of 12 with specificity 92.5% and

  1. Identifying complete RNA structural ensembles including pseudoknots.

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    Gupta, Aditi; Rahman, Reazur; Li, Kejie; Gribskov, Michael

    2012-02-01

    The close relationship between RNA structure and function underlines the significance of accurately predicting RNA structures from sequence information. Structural topologies such as pseudoknots are of particular interest due to their ubiquity and direct involvement in RNA function, but identifying pseudoknots is a computationally challenging problem and existing heuristic approaches usually perform poorly for RNA sequences of even a few hundred bases. We survey the performance of pseudoknot prediction methods on a data set of full-length RNA sequences representing varied sequence lengths, and biological RNA classes such as RNase P RNA, Group I Intron, tmRNA and tRNA. Pseudoknot prediction methods are compared with minimum free energy and suboptimal secondary structure prediction methods in terms of correct base-pairs, stems and pseudoknots and we find that the ensemble of suboptimal structure predictions succeeds in identifying correct structural elements in RNA that are usually missed in MFE and pseudoknot predictions. We propose a strategy to identify a comprehensive set of non-redundant stems in the suboptimal structure space of a RNA molecule by applying heuristics that reduce the structural redundancy of the predicted suboptimal structures by merging slightly varying stems that are predicted to form in local sequence regions. This reduced-redundancy set of structural elements consistently outperforms more specialized approaches.in data sets. Thus, the suboptimal folding space can be used to represent the structural diversity of an RNA molecule more comprehensively than optimal structure prediction approaches alone.

  2. 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...

  3. Effects of dilution and centrifugation on the survival of spermatozoa and the structure of motile sperm cell subpopulations in refrigerated Catalonian donkey semen.

    Science.gov (United States)

    Miró, J; Taberner, E; Rivera, M; Peña, A; Medrano, A; Rigau, T; Peñalba, A

    2009-11-01

    The aim of this work was to study the effects of dilution and centrifugation (i.e., two methods of reducing the influence of the seminal plasma) on the survival of spermatozoa and the structure of motile sperm cell subpopulations in refrigerated Catalonian donkey (Equus asinus) semen. Fifty ejaculates from nine Catalonian jackasses were collected. Gel-free semen was diluted 1:1, 1:5 or 1:10 with Kenney extender. Another sample of semen was diluted 1:5, centrifuged, and then resuspended with Kenney extender until a final dilution of 25x10(6) sperm/ml was achieved (C). After 24 h, 48 h or 72 h of refrigerated storage at 5 degrees C, aliquots of these semen samples were incubated at 37 degrees C for 5 min. The percentage of viable sperm was determined by staining with eosin-nigrosin. The motility characteristics of the spermatozoa were examined using the CASA system (Microptic, Barcelona, Spain). At 24h, more surviving spermatozoa were seen in the more diluted and in the centrifuged semen samples (1:1 48.71%; 1:5 56.58%, 1:10 62.65%; C 72.40%). These differences were maintained at 48 h (1:1 34.31%, 1:5 40.56%, 1:10 48.52%, C 66.30%). After 72 h, only the C samples showed a survival rate of above 25%. The four known donkey motile sperm subpopulations were maintained by refrigeration. However, the percentage of motile sperms in each subpopulation changed with dilution. Only the centrifuged samples, and only at 24h, showed exactly the same motile sperm subpopulation proportions as recorded for fresh sperm. However, the 1:10 dilutions at 24 and 48 h, and the centrifuged semen at 48 h, showed few variations compared to fresh sperm. These results show that the elimination of seminal plasma increases the survival of spermatozoa and the maintenance of motility patterns. The initial sperm concentration had a significant (P<0.05) influence on centrifugation efficacy, but did not influence the number of spermatozoa damaged by centrifugation. In contrast, the percentage of live

  4. 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.

  5. Assessing the Viability of Tiger Subpopulations in a Fragmented Landscape

    National Research Council Canada - National Science Library

    Matthew Linkie; Guillaume Chapron; Deborah J. Martyr; Jeremy Holden; Nigel Leader-Williams

    2006-01-01

    .... This study aimed to provide such information for tigers in the Kerinci Seblat (KS) region, Sumatra, by identifying and assessing subpopulation viability under different management strategies. 2...

  6. Human corneal epithelial subpopulations

    DEFF Research Database (Denmark)

    Søndergaard, Chris Bath

    2013-01-01

    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......-free EpiLife medium, using a range of physiologically relevant oxygen concentrations (2%, 5%, 10%, 15% and 20%). Using immunocytochemistry and advanced fluorescence microscopy, cells were characterized regarding growth, cell cycle distribution, colony-forming efficiency (CFE), phenotypes...... was not dependent on the system used for propagation (Bath et al. 2013a). Laser capture microdissection was used to isolate cellular subpopulations in situ from the spatially defined differentiation pathway in human corneal epithelium according to an optimized protocol for maintenance of expression profiles...

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

    Directory of Open Access Journals (Sweden)

    Ernest Diez Benavente

    2017-09-01

    Full Text Available 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.

  8. 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.

  9. 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.

  10. Structure formation cosmic rays: Identifying observational constraints

    OpenAIRE

    Prodanović T.; Fields B.D.

    2005-01-01

    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 react...

  11. Risk managment in LSF structures (identifying, assessment ...

    African Journals Online (AJOL)

    Light Steel Frame System that is briefly called LSF is a building system which is used for implying of short-rise and mid-rise buildings (up to 5 floors). ... Despite the relatively significant growth of LSF structures during the last decade in our country, the studies in this field have been still done neither in our country nor in ...

  12. [Study of interaction of wild soybean subpopulations (Glycine soja) in the valley of the Tsukanovka river in the south of Far East of Russia].

    Science.gov (United States)

    Tikhonov, A V; Martynov, V V; Dorokhov, D B

    2011-01-01

    A comparative study of the genetic structure of natural and anthropogenic populations of G. soja gives significant information about formation of different populations, and allows developing measures for preservation of unique natural gene bank of wild soybean, the species closely related to cultivated soybean. In this study, ISSR markers were used to carry out a comparative analysis of genetic structure of natural and anthropogenic subpopulations of G. soja for studying possible mutual influence of subpopulations of anthropogenic and natural phytocenosis on the formation of their genetic diversity and to study genetic structure of natural subpopulations of wild soybean in the contact places between the two types ofcenoses. As a result, the characteristics that describe the genetic diversity of studied populations have been identified and the important role of an interaction between subpopulations of different phytocenoses on formation of the spatial genetic structure of population in the valley of Tsukanovka river has been demonstrated.

  13. Structure formation cosmic rays: Identifying observational constraints

    Directory of Open Access Journals (Sweden)

    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

  14. Identifying Quantum Structures in the Ellsberg Paradox

    CERN Document Server

    Aerts, Diederik; Tapia, Jocelyn

    2013-01-01

    Empirical evidence has confirmed that quantum effects systematically occur 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 their '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, indicating that genuine quantum effects occur in the decision processes of the participants in the experiment. 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'.

  15. Identifying community structure in complex networks

    Science.gov (United States)

    Shao, Chenxi; Duan, Yubing

    2015-07-01

    A wide variety of applications could be formulated to resolve the problem of finding all communities from a given network, ranging from social and biological network analysis to web mining and searching. In this study, we propose the concept of virtual attractive strength between each pair of node in networks, and then give the definition of community structure based on the proposed attractive strength. Furthermore, we present a community detection method by moving vertices to the clusters that produce the largest attractive strengths to them until the division of network reaches unchanged. Experimental results on synthetic and real networks indicate that the proposed approach has favorite effectiveness and fast convergence speed, which provides an efficient method for exploring and analyzing complex systems.

  16. Identifying the structural discontinuities of human interactions

    CERN Document Server

    Grauwin, Sebastian; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabasi, Albert-Laszlo; Ratti, Carlo

    2015-01-01

    The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. In the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls and uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylize the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models, thus increasing our ability to predict social activiti...

  17. Housekeeping Gene Sequencing and Multilocus Variable-Number Tandem-Repeat Analysis To Identify Subpopulations within Pseudomonas syringae pv. maculicola and Pseudomonas syringae pv. tomato That Correlate with Host Specificity

    Science.gov (United States)

    Gironde, S.

    2012-01-01

    Pseudomonas syringae pv. maculicola causes bacterial spot on Brassicaceae worldwide, and for the last 10 years severe outbreaks have been reported in the Loire Valley, France. P. syringae pv. maculicola resembles P. syringae pv. tomato in that it is also pathogenic for tomato and causes the same types of symptoms. We used a collection of 106 strains of P. syringae to characterize the relationships between P. syringae pv. maculicola and related pathovars, paying special attention to P. syringae pv. tomato. Phylogenetic analysis of gyrB and rpoD gene sequences showed that P. syringae pv. maculicola, which causes diseases in Brassicaceae, forms six genetic lineages within genomospecies 3 of P. syringae strains as defined by L. Gardan et al. (Int. J. Syst. Bacteriol. 49[Pt 2]:469–478, 1999), whereas P. syringae pv. tomato forms two distinct genetic lineages. A multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) conducted with eight minisatellite loci confirmed the genetic structure obtained with rpoD and gyrB sequence analyses. These results provide promising tools for fine-scale epidemiological studies on diseases caused by P. syringae pv. maculicola and P. syringae pv. tomato. The two pathovars had distinct host ranges; only P. syringae pv. maculicola strains were pathogenic for Brassicaceae. A subpopulation of P. syringae pv. maculicola strains that are pathogenic for Pto-expressing tomato plants were shown to lack avrPto1 and avrPtoB or to contain a disrupted avrPtoB homolog. Taking phylogenetic and pathological features into account, our data suggest that the DC3000 strain belongs to P. syringae pv. maculicola. This study shows that P. syringae pv. maculicola and P. syringae pv. tomato appear multiclonal, as they did not diverge from a single common ancestral group within the ancestral P. syringae genomospecies 3, and suggests that pathovar specificity within P. syringae may be due to independent genetic events. PMID:22389364

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

    Directory of Open Access Journals (Sweden)

    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

  19. Disentangling subpopulations in single-molecule FRET and ALEX experiments with photon distribution analysis.

    Science.gov (United States)

    Tomov, Toma E; Tsukanov, Roman; Masoud, Rula; Liber, Miran; Plavner, Noa; Nir, Eyal

    2012-03-07

    Among the advantages of the single-molecule approach when used to study biomolecular structural dynamics and interaction is its ability to distinguish between and independently observe minor subpopulations. In a single-molecule Förster resonance energy transfer (FRET) and alternating laser excitation diffusion experiment, the various populations are apparent in the resultant histograms. However, because histograms are calculated based on the per-burst mean FRET and stoichiometry ratio and not on the internal photon distribution, much of the acquired information is lost, thereby reducing the capabilities of the method. Here we suggest what to our knowledge is a novel statistical analysis tool that significantly enhances these capabilities, and we use it to identify and isolate static and dynamic subpopulations. Based on a kernel density estimator and a proper photon distribution analysis, for each individual burst, we calculate scores that reflect properties of interest. Specifically, we determine the FRET efficiency and brightness ratio distributions and use them to reveal 1), the underlying structure of a two-state DNA-hairpin and a DNA hairpin that is bound to DNA origami; 2), a minor doubly labeled dsDNA subpopulation concealed in a larger singly labeled dsDNA; and 3), functioning DNA origami motors concealed within a larger subpopulation of defective motors. Altogether, these findings demonstrate the usefulness of the proposed approach. The method was developed and tested using simulations, its rationality is described, and a computer algorithm is provided. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  20. 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.

  1. Identifying the risks in LSF structures (designing, implementation ...

    African Journals Online (AJOL)

    ... optimum use of building materials and proper construction techniques. In this article, we try to study LSF structures from the design and implementation stage to the operation one and identify its risks exactly and finally offer a solution for each risk. Keywords: Lsf structures; risk management; identifying risk; classifying risk.

  2. Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties.

    Directory of Open Access Journals (Sweden)

    Paloma Bragado

    Full Text Available Head and neck squamous carcinoma (HNSCC tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin surface levels and aldehyde dehydrogenase (ALDH activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu and NSG (NOD.Cg-Prkdc(scid Il2rg(tm1Wjl/SzJ mice and chicken embryo chorioallantoic membrane (CAM assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49f(high/ALDH1A1(high/H3K4/K27me3(low subpopulation (CD49f+ of tumor cells. A strikingly similar CD49f(high/H3K27me3(low subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49f(high/ALDH(high, label retaining cells (LRC proliferated immediately in vivo, with time the CD49f(low/ALDH(low, non-LRC (NLRC tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49f(high/ALDH(high, label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2 phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f- cells can "reprogram" and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a "moving target" and their eradication might require

  3. Analysis of Marker-Defined HNSCC Subpopulations Reveals a Dynamic Regulation of Tumor Initiating Properties

    Science.gov (United States)

    Bragado, Paloma; Estrada, Yeriel; Sosa, Maria Soledad; Avivar-Valderas, Alvaro; Cannan, David; Genden, Eric; Teng, Marita; Ranganathan, Aparna C.; Wen, Huei-Chi; Kapoor, Avnish; Bernstein, Emily; Aguirre-Ghiso, Julio A.

    2012-01-01

    Head and neck squamous carcinoma (HNSCC) tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs) in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin) surface levels and aldehyde dehydrogenase (ALDH) activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu) and NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice and chicken embryo chorioallantoic membrane (CAM) assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49fhigh/ALDH1A1high/H3K4/K27me3low subpopulation (CD49f+) of tumor cells. A strikingly similar CD49fhigh/H3K27me3low subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49fhigh/ALDHhigh, label retaining cells (LRC) proliferated immediately in vivo, with time the CD49flow/ALDHlow, non-LRC (NLRC) tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49fhigh/ALDHhigh, label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f− cells can “reprogram” and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a “moving target” and their eradication might require more

  4. Structural parameter identifiability analysis for dynamic reaction networks

    DEFF Research Database (Denmark)

    Davidescu, Florin Paul; Jørgensen, Sten Bay

    2008-01-01

    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...... 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...

  5. Estimating and Identifying Unspecified Correlation Structure for Longitudinal Data

    OpenAIRE

    Hu, Jianhua; Wang, Peng; Qu, Annie

    2014-01-01

    Identifying correlation structure is important to achieving estimation efficiency in analyzing longitudinal data, and is also crucial for drawing valid statistical inference for large size clustered data. In this paper, we propose a nonparametric method to estimate the correlation structure, which is applicable for discrete longitudinal data. We utilize eigenvector-based basis matrices to approximate the inverse of the empirical correlation matrix and determine the number of basis matrices vi...

  6. Effectiveness of a structured checklist of risk factors in identifying ...

    African Journals Online (AJOL)

    Background: Gestational diabetes mellitus (GDM) is associated with increased risk of mortality and morbidity for pregnant women and newborns. Identifying pregnant women with risk factors for GDM based on the clinical suspicion is a popular approach. However, the effectiveness of the use of a structured checklist of risk ...

  7. Identifying multiple influential spreaders via local structural similarity

    Science.gov (United States)

    Liu, J.-G.; Wang, Z.-Y.; Guo, Q.; Guo, L.; Chen, Q.; Ni, Y.-Z.

    2017-07-01

    Identifying the nodes with largest spreading influence is of significance for information diffusion, product exposure and contagious disease detection. In this letter, based on the local structural similarity, we present a method (LSS) to identify the multiple influential spreaders. Firstly, we choose the node with the largest degree as the first spreader. Then the new spreaders would be selected if they belong to the first- or second-order-neighbor node set of the spreaders and their local structural similarities with other spreaders are smaller than the threshold parameter r. Comparing with the susceptible-infected-recovered model, the experimental results for four empirical networks show that the spreading influences of spreaders selected by the local structural similarity method are larger than that of the color method, the degree, betweenness and closeness centralities. The further experimental results for the Barabàsi-Albert and random networks show that the LSS method could identify the multiple influential spreaders more accurately, which suggests that the local structural property plays a more important role than the distance for identifying multiple influential spreaders.

  8. 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.

  9. Identifying local structural states in atomic imaging by computer vision.

    Science.gov (United States)

    Laanait, Nouamane; Ziatdinov, Maxim; He, Qian; Borisevich, Albina

    2017-01-01

    The availability of atomically resolved imaging modalities enables an unprecedented view into the local structural states of materials, which manifest themselves by deviations from the fundamental assumptions of periodicity and symmetry. Consequently, approaches that aim to extract these local structural states from atomic imaging data with minimal assumptions regarding the average crystallographic configuration of a material are indispensable to advances in structural and chemical investigations of materials. Here, we present an approach to identify and classify local structural states that is rooted in computer vision. This approach introduces a definition of a structural state that is composed of both local and nonlocal information extracted from atomically resolved images, and is wholly untethered from the familiar concepts of symmetry and periodicity. Instead, this approach relies on computer vision techniques such as feature detection, and concepts such as scale invariance. We present the fundamental aspects of local structural state extraction and classification by application to simulated scanning transmission electron microscopy images, and analyze the robustness of this approach in the presence of common instrumental factors such as noise, limited spatial resolution, and weak contrast. Finally, we apply this computer vision-based approach for the unsupervised detection and classification of local structural states in an experimental electron micrograph of a complex oxides interface, and a scanning tunneling micrograph of a defect-engineered multilayer graphene surface.

  10. Identifying duplicate crystal structures: XTALCOMP, an open-source solution

    Science.gov (United States)

    Lonie, David C.; Zurek, Eva

    2012-03-01

    We describe the implementation of XTALCOMP, an efficient, reliable, and open-source library that tests if two crystal descriptions describe the same underlying structure. The algorithm has been tested and found to correctly identify duplicate structures in spite of the "real-world" difficulties that arise from working with numeric crystal representations: degenerate unit cell lattices, numerical noise, periodic boundaries, and the lack of a canonical coordinate origin. The library is portable, open, and not dependent on any external packages. A web interface to the algorithm is publicly accessible at http://xtalopt.openmolecules.net/xtalcomp/xtalcomp.html. Program summaryProgram title: XtalComp Catalogue identifier: AEKV_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKV_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: "New" (3-clause) BSD [1] No. of lines in distributed program, including test data, etc.: 3148 No. of bytes in distributed program, including test data, etc.: 21 860 Distribution format: tar.gz Programming language: C++ Computer: No restrictions Operating system: All operating systems with a compliant C++ compiler. Classification: 7.8 Nature of problem: Computationally identifying duplicate crystal structures taken from the output of modern solid state calculations is a non-trivial exercise for many reasons. The translation vectors in the description are not unique — they may be transformed into linear combinations of themselves and continue to describe the same extended structure. The coordinates and cell parameters contain numerical noise. The periodic boundary conditions at the unit cell faces, edges, and corners can cause very small displacements of atomic coordinates to result in very different representations. The positions of all atoms may be uniformly translated by an arbitrary vector without modifying the underlying structure. Additionally, certain

  11. Demographic and traditional knowledge perspectives on the current status of Canadian polar bear subpopulations.

    Science.gov (United States)

    York, Jordan; Dowsley, Martha; Cornwell, Adam; Kuc, Miroslaw; Taylor, Mitchell

    2016-05-01

    Subpopulation growth rates and the probability of decline at current harvest levels were determined for 13 subpopulations of polar bears (Ursus maritimus) that are within or shared with Canada based on mark-recapture estimates of population numbers and vital rates, and harvest statistics using population viability analyses (PVA). Aboriginal traditional ecological knowledge (TEK) on subpopulation trend agreed with the seven stable/increasing results and one of the declining results, but disagreed with PVA status of five other declining subpopulations. The decline in the Baffin Bay subpopulation appeared to be due to over-reporting of harvested numbers from outside Canada. The remaining four disputed subpopulations (Southern Beaufort Sea, Northern Beaufort Sea, Southern Hudson Bay, and Western Hudson Bay) were all incompletely mark-recapture (M-R) sampled, which may have biased their survival and subpopulation estimates. Three of the four incompletely sampled subpopulations were PVA identified as nonviable (i.e., declining even with zero harvest mortality). TEK disagreement was nonrandom with respect to M-R sampling protocols. Cluster analysis also grouped subpopulations with ambiguous demographic and harvest rate estimates separately from those with apparently reliable demographic estimates based on PVA probability of decline and unharvested subpopulation growth rate criteria. We suggest that the correspondence between TEK and scientific results can be used to improve the reliability of information on natural systems and thus improve resource management. Considering both TEK and scientific information, we suggest that the current status of Canadian polar bear subpopulations in 2013 was 12 stable/increasing and one declining (Kane Basin). We do not find support for the perspective that polar bears within or shared with Canada are currently in any sort of climate crisis. We suggest that monitoring the impacts of climate change (including sea ice decline) on polar bear

  12. Retrieving composition and sizes of oceanic particle subpopulations from the volume scattering function.

    Science.gov (United States)

    Zhang, Xiaodong; Twardowski, Michael; Lewis, Marlon

    2011-03-20

    For a particle population with known size, composition, structure, and shape distributions, its volume scattering function (VSF) can be estimated from first principles through a governing relationship, the Fredholm linear integral equation of the first kind. Inverting the Fredholm equation to derive the composition and size distribution of particles from measured VSFs remains challenging because 1) the solution depends on the kernel function, and 2) the kernel function needs to be constructed to avoid singularity. In this study, a thorough review of the earlier and current inversion techniques is provided. An inversion method based on nonnegative least squares is presented and evaluated using the VSFs measured by a prototype volume scattering meter at the LEO-15 site off the New Jersey coast. The kernel function was built by a compilation of individual subpopulations, each of which follows a lognormal size distribution and whose characteristic size and refractive index altogether cover the entire ranges of natural variability of potential marine particles of the region. Sensitivity analyses were conducted to ensure the kernel function being constructed is neither singular nor pathological. A total of 126 potential subpopulations were identified, among which 11 are common in more than half of the inversions and only five consistently present (>90% of measurements). These five subpopulations can be interpreted as small colloidal type particles of sizes around 0.02 μm, submicrometer detritus-type particles (n(r)=1.02, r(mode)=0.2 μm), two micrometer-sized subpopulations with one relatively soft (n(r)=1.04 and r(mode)=1.6 μm) and the other relatively refringent (n(r)=1.10 and r(mode)=3.2 μm), and bubbles of relatively large sizes (n(r)=0.75 and r(mode)=10 μm). Reconstructed PSDs feature a bimodal shape, with the smaller peak dominated by the colloidal subpopulations and the larger particles closely approximated by a power-law function. The Junge

  13. Estimating and Identifying Unspecified Correlation Structure for Longitudinal Data.

    Science.gov (United States)

    Hu, Jianhua; Wang, Peng; Qu, Annie

    2015-04-01

    Identifying correlation structure is important to achieving estimation efficiency in analyzing longitudinal data, and is also crucial for drawing valid statistical inference for large size clustered data. In this paper, we propose a nonparametric method to estimate the correlation structure, which is applicable for discrete longitudinal data. We utilize eigenvector-based basis matrices to approximate the inverse of the empirical correlation matrix and determine the number of basis matrices via model selection. A penalized objective function based on the difference between the empirical and model approximation of the correlation matrices is adopted to select an informative structure for the correlation matrix. The eigenvector representation of the correlation estimation is capable of reducing the risk of model misspecification, and also provides useful information on the specific within-cluster correlation pattern of the data. We show that the proposed method possesses the oracle property and selects the true correlation structure consistently. The proposed method is illustrated through simulations and two data examples on air pollution and sonar signal studies.

  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. SPIV Measurements for Identifying Turbulence Structure in Swirling Jets

    Science.gov (United States)

    Demillard, Eric; Nikoueeyan, Pourya; Naughton, Jonathan

    2015-11-01

    Swirling jets are of interest because they can enhance and control mixing and combustion. Several past studies have considered the turbulence statistics in swirling jets for a range of swirl number, and this behavior is now well characterized. However, there has been no attempt to date to link the statistical results to the turbulent structure in the jet. To address this, Stereoscopic Particle Image Velocimetry (SPIV) is being performed to capture instantaneous velocity fields. The resulting planes of three-component velocities are to be used in conjunction with Proper Orthogonal Decomposition (POD) to reconstruct turbulence structure. Using the POD results, comparisons can be made between the turbulence structure in the swirling jets to that of their non-swirling counterparts. Critical to this analysis are accurate two-point statistics that only result if proper care is taken during experiment setup. Errors can arise from misalignment of the laser sheet with the calibration plane, the selection of viewing angles and object distances for both cameras, and the improper selection of dual-image acquisition parameters. This work thus identifies the requirements for successful execution of SPIV measurements in swirling jets to be used for POD analysis.

  16. 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

    to determine the dynamic proteomic response of the tolerant subpopulation to supra-MIC treatment with the fluoroquinolone antibiotic ciprofloxacin. The adaptive response included the upregulation of proteins required for sensing and repairing DNA damage and substantial changes in the expression of enzymes...... 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......, in which distinct cellular subpopulations can respond differently to stresses, including subpopulations of pathogenic biofilms that are more tolerant to antibiotics. Global proteomic analysis affords insights into cellular physiology but cannot identify proteins expressed in a particular subpopulation...

  17. The input-output relationship approach to structural identifiability analysis.

    Science.gov (United States)

    Bearup, Daniel J; Evans, Neil D; Chappell, Michael J

    2013-02-01

    Analysis of the identifiability of a given model system is an essential prerequisite to the determination of model parameters from physical data. However, the tools available for the analysis of non-linear systems can be limited both in applicability and by computational intractability for any but the simplest of models. The input-output relation of a model summarises the input-output structure of the whole system and as such provides the potential for an alternative approach to this analysis. However for this approach to be valid it is necessary to determine whether the monomials of a differential polynomial are linearly independent. A simple test for this property is presented in this work. The derivation and analysis of this relation can be implemented symbolically within Maple. These techniques are applied to analyse classical models from biomedical systems modelling and those of enzyme catalysed reaction schemes. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. A Simple Model for Identifying Critical Structures in Atrial Fibrillation

    CERN Document Server

    Christensen, Kim; Peters, Nicholas S

    2014-01-01

    Atrial fibrillation (AF) is the most common abnormal heart rhythm and the single biggest cause of stroke. Ablation, destroying regions of the atria, is applied largely empirically and can be curative but with a disappointing clinical success rate. We design a simple model of activation wavefront propagation on a structure mimicking the branching network architecture of heart muscle and show how AF emerges spontaneously as age-related parameters change. We identify regions responsible for the initiation and maintenance of AF, the ablation of which terminates AF. The simplicity of the model allows us to calculate analytically the risk of arrhythmia. This analytical result allows us to locate the transition in parameter space and highlights that the transition from regular to fibrillatory behaviour is a finite-size effect present in systems of any size. These clinically testable predictions might inform ablation therapies and arrhythmic risk assessment.

  19. Morphometric and kinematic sperm subpopulations in split ejaculates of normozoospermic men

    Directory of Open Access Journals (Sweden)

    Pilar Santolaria

    2016-01-01

    Full Text Available This study was designed to analyze the sperm kinematic and morphometric subpopulations in the different fractions of the ejaculate in normozoospermic men. Ejaculates from eight normozoospermic men were collected by masturbation in three fractions after 3-5 days of sexual abstinence. Analyses of sperm motility by computer-assisted sperm analysis (CASA-Mot, and of sperm morphometry by computer-assisted sperm morphometry analysis (CASA-Morph using fluorescence were performed. Clustering and discriminant procedures were performed to identify sperm subpopulations in the kinematic and morphometric data obtained. Clustering procedures resulted in the classification of spermatozoa into three kinematic subpopulations (slow with low ALH [35.6% of all motile spermatozoa], with circular trajectories [32.0%], and rapid with high ALH [32.4%], and three morphometric subpopulations (large-round [33.9% of all spermatozoa], elongated [32.0%], and small [34.10%]. The distribution of kinematic sperm subpopulations was different among ejaculate fractions (P < 0.001, with higher percentages of spermatozoa exhibiting slow movements with low ALH in the second and third portions, and with a more homogeneous distribution of kinematic sperm subpopulations in the first portion. The distribution of morphometric sperm subpopulations was also different among ejaculate fractions (P < 0.001, with more elongated spermatozoa in the first, and of small spermatozoa in the third, portion. It is concluded that important variations in the distribution of kinematic and morphometric sperm subpopulations exist between ejaculate fractions, with possible functional implications.

  20. 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 < 0.001) in the distribution of the seven subpopulations as well as in the incidence of abnormal pleiomorphisms (58.6 %, 49.8 %, 35.1 %, 66.4 %, and 55.1 %, P < 0.05) among the five donors tested. Our results indicated that differences among individuals related to the incidence of pleiomorphisms, and sperm subpopulational structure was not related to the captivity conditions or the sperm collection method, since all individuals were studied under identical conditions. In conclusion, the combination of 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.

  1. 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...

  2. An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force.

    Science.gov (United States)

    Whitlock, Evelyn P; Eder, Michelle; Thompson, Jamie H; Jonas, Daniel E; Evans, Corinne V; Guirguis-Blake, Janelle M; Lin, Jennifer S

    2017-03-02

    Guideline developers and other users of systematic reviews need information about whether a medical or preventive intervention is likely to benefit or harm some patients more (or less) than the average in order to make clinical practice recommendations tailored to these populations. However, guidance is lacking on how to include patient subpopulation considerations into the systematic reviews upon which guidelines are often based. In this article, we describe methods developed to consistently consider the evidence for relevant subpopulations in systematic reviews conducted to support primary care clinical preventive service recommendations made by the U.S. Preventive Services Task Force (USPSTF). Our approach is grounded in our experience conducting systematic reviews for the USPSTF and informed by a review of existing guidance on subgroup analysis and subpopulation issues. We developed and refined our approach based on feedback from the Subpopulation Workgroup of the USPSTF and pilot testing on reviews being conducted for the USPSTF. This paper provides processes and tools for incorporating evidence-based identification of important sources of potential heterogeneity of intervention effects into all phases of systematic reviews. Key components of our proposed approach include targeted literature searches and key informant interviews to identify the most important subpopulations a priori during topic scoping, a framework for assessing the credibility of subgroup analyses reported in studies, and structured investigation of sources of heterogeneity of intervention effects. Further testing and evaluation are necessary to refine this proposed approach and demonstrate its utility to the producers and users of systematic reviews beyond the context of the USPSTF. Gaps in the evidence on important subpopulations identified by routinely applying this process in systematic reviews will also inform future research needs.

  3. T and B Lymphocyte Subpopulations

    Science.gov (United States)

    Seeger, Robert C.; Stiehm, E. Richard

    1975-01-01

    Reviewed are diagnostic tests of symphocyte subgroups which identify immuno deficiency disorders (such as DiGeorge's Syndrome) and malignant cells in lymphoproliferative disorders (such as lumphoid leukemia). (CL)

  4. 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 recent development of data analytic tools rooted around the Multi-Group Latent Class Analysis (MGLCA) has enabled the examination of heterogeneous datasets in a cross-cultural context. Although the MGLCA is considered as an established and popular cross-cultural data analysis approach......, 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...

  5. 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...

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Structures in Transitional Taylor-Couette Flows Identified using POD

    Science.gov (United States)

    Balabani, Stavroula; Imomoh, Eboshogwe; Dusting, Jonathan

    2009-11-01

    The flow in the gap between concentric cylinders, or Taylor-Couette flow, has been used to study transition to turbulence for decades, and is also utilised for various biotechnological and industrial processes. Transitional flow states depend highly on vessel geometry; they are also three-dimensional and often time dependent limiting the use of experimental techniques for their characterisation. In this talk the transition to turbulence in a Taylor-Couette flow is studied by means of time resolved PIV velocity fields and Proper Orthogonal Decomposition (POD). It is found that for the particular geometry studied the transition to turbulence occurs via a quasi periodic regime characterised by a fast moving azimuthal wave (FMAW). Aspects of the FMAW structure, such as a series of co-rotating vortices that increase in strength away from the endwalls, are also revealed by spatially resolved POD.

  12. Identifying and modeling the structural discontinuities of human interactions

    Science.gov (United States)

    Grauwin, Sebastian; Szell, Michael; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabási, Albert-László; Ratti, Carlo

    2017-04-01

    The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. Along the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls - both, mobile and landline - and in either case uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylizes the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models. This increases our ability to understand, model and predict social activities and to plan the development of infrastructures across multiple scales.

  13. Identifying and modeling the structural discontinuities of human interactions.

    Science.gov (United States)

    Grauwin, Sebastian; Szell, Michael; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabási, Albert-László; Ratti, Carlo

    2017-04-26

    The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. Along the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls - both, mobile and landline - and in either case uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylizes the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models. This increases our ability to understand, model and predict social activities and to plan the development of infrastructures across multiple scales.

  14. Subpopulation-proteomics in prokaryotic populations.

    Science.gov (United States)

    Jahn, Michael; Seifert, Jana; von Bergen, Martin; Schmid, Andreas; Bühler, Bruno; Müller, Susann

    2013-02-01

    Clonal microbial cells do not behave in an identical manner and form subpopulations during cultivation. Besides varying micro-environmental conditions, cell inherent features like cell cycle dependent localization and concentration of regulatory proteins as well as epigenetic properties are well accepted mechanisms creating cell heterogeneity. Another suspected reason is molecular noise on the transcriptional and translational level. A promising tool to unravel reasons for cell heterogeneity is the combination of cell sorting and subpopulation proteomics. This review summarizes recent developments in prokaryotic single-cell analytics and provides a workflow for selection of single cells, low cell number mass spectrometry, and proteomics evaluation. This approach is useful for understanding the dependency of individual cell decisions on inherent protein profiles. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. A slow-cycling subpopulation of melanoma cells with highly invasive properties

    DEFF Research Database (Denmark)

    Perego, M; Maurer, M; Wang, J X

    2017-01-01

    as label-retaining cells (LRC), with strong invasive properties. We demonstrate through live imaging that LRC are leaving the primary tumor mass at a very early stage and disseminate to peripheral organs. Through global proteome analyses, we identified the secreted protein SerpinE2/protease nexin-1......Melanoma is a heterogeneous tumor with different subpopulations showing different proliferation rates. Slow-cycling cells were previously identified in melanoma, but not fully biologically characterized. Using the label-retention method, we identified a subpopulation of slow-cycling cells, defined...

  16. 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.

  17. Emergence of bursting activity in connected neuronal sub-populations.

    Directory of Open Access Journals (Sweden)

    Marta Bisio

    Full Text Available Uniform and modular primary hippocampal cultures from embryonic rats were grown on commercially available micro-electrode arrays to investigate network activity with respect to development and integration of different neuronal populations. Modular networks consisting of two confined active and inter-connected sub-populations of neurons were realized by means of bi-compartmental polydimethylsiloxane structures. Spontaneous activity in both uniform and modular cultures was periodically monitored, from three up to eight weeks after plating. Compared to uniform cultures and despite lower cellular density, modular networks interestingly showed higher firing rates at earlier developmental stages, and network-wide firing and bursting statistics were less variable over time. Although globally less correlated than uniform cultures, modular networks exhibited also higher intra-cluster than inter-cluster correlations, thus demonstrating that segregation and integration of activity coexisted in this simple yet powerful in vitro model. Finally, the peculiar synchronized bursting activity shown by confined modular networks preferentially propagated within one of the two compartments ('dominant', even in cases of perfect balance of firing rate between the two sub-populations. This dominance was generally maintained during the entire monitored developmental frame, thus suggesting that the implementation of this hierarchy arose from early network development.

  18. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

    NARCIS (Netherlands)

    Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Teumer, Alexander; Chen, Ming-Huei; Leening, Maarten J. G.; Voelker, Uwe; Grossmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Doerthe; Smith, Albert Vernon; Sundstrom, Johan; Minelli, Cosetta; Ruggiero, Daniela; Lyytikainen, Leo-Pekka; Tiller, Daniel; Smith, J. Gustav; Monnereau, Claire; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Benjamin, Emelia J.; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kahonen, Mika; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Leosdottir, Margret; Lin, Honghuang; Lindgren, Cecilia M.; Loley, Christina; MacRae, Calum A.; Mascalzoni, Deborah; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Mueller, Christian; Mueller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rivadeneira, Fernando; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L.; Samdarshi, Tandaw E.; Schmidt, Helena; Sharp, Andrew S. P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Thom, Simon; Toeglhofer, Anna M.; Uitterlinden, Andre G.; Wachter, Rolf; Voelzke, Henry; Ziegler, Andreas; Muenzel, Thomas; Maerz, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W. V.; Melander, Olle; Russ, Martin; Lehtimaki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Doerr, Marcus

    2017-01-01

    BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS

  19. The Gulliver Effect: The Impact of Error in an Elephantine Subpopulation on Estimates for Lilliputian Subpopulations

    Science.gov (United States)

    Micceri, Theodore; Parasher, Pradnya; Waugh, Gordon W.; Herreid, Charlene

    2009-01-01

    An extensive review of the research literature and a study comparing over 36,000 survey responses with archival true scores indicated that one should expect a minimum of at least three percent random error for the least ambiguous of self-report measures. The Gulliver Effect occurs when a small proportion of error in a sizable subpopulation exerts…

  20. 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.

  1. 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

  2. Morphometric and kinematic sperm subpopulations in split ejaculates of normozoospermic men

    Science.gov (United States)

    Santolaria, Pilar; Soler, Carles; Recreo, Pilar; Carretero, Teresa; Bono, Araceli; Berné, José M; Yániz, Jesús L

    2016-01-01

    This study was designed to analyze the sperm kinematic and morphometric subpopulations in the different fractions of the ejaculate in normozoospermic men. Ejaculates from eight normozoospermic men were collected by masturbation in three fractions after 3–5 days of sexual abstinence. Analyses of sperm motility by computer-assisted sperm analysis (CASA-Mot), and of sperm morphometry by computer-assisted sperm morphometry analysis (CASA-Morph) using fluorescence were performed. Clustering and discriminant procedures were performed to identify sperm subpopulations in the kinematic and morphometric data obtained. Clustering procedures resulted in the classification of spermatozoa into three kinematic subpopulations (slow with low ALH [35.6% of all motile spermatozoa], with circular trajectories [32.0%], and rapid with high ALH [32.4%]), and three morphometric subpopulations (large-round [33.9% of all spermatozoa], elongated [32.0%], and small [34.10%]). The distribution of kinematic sperm subpopulations was different among ejaculate fractions (P functional implications. PMID:27624985

  3. Structural identifiability of a model for the acetic acid fermentation process.

    Science.gov (United States)

    Jiménez-Hornero, Jorge E; Santos-Dueñas, Inés M; Garci A-Garci A, Isidoro

    2008-12-01

    Modelling has proved an essential tool for addressing research into biotechnological processes, particularly with a view to their optimization and control. Parameter estimation via optimization approaches is among the major steps in the development of biotechnology models. In fact, one of the first tasks in the development process is to determine whether the parameters concerned can be unambiguously determined and provide meaningful physical conclusions as a result. The analysis process is known as 'identifiability' and presents two different aspects: structural or theoretical identifiability and practical identifiability. While structural identifiability is concerned with model structure alone, practical identifiability takes into account both the quantity and quality of experimental data. In this work, we discuss the theoretical identifiability of a new model for the acetic acid fermentation process and review existing methods for this purpose.

  4. State-dependent propagation of neuronal sub-population in spontaneous synchronized bursts.

    Directory of Open Access Journals (Sweden)

    Yuichiro eYada

    2016-03-01

    Full Text Available Repeating stable spatiotemporal patterns emerge in synchronized spontaneous activity in neuronal networks. The repertoire of such patterns can serve as memory, or a reservoir of information, in a neuronal network; moreover, the variety of patterns may represent the network memory capacity. However, a neuronal substrate for producing a repertoire of patterns in synchronization remains elusive. We herein hypothesize that state-dependent propagation of a neuronal sub-population is the key mechanism. By combining high-resolution measurement with a 4,096-channel complementary metal-oxide semiconductor microelectrode array and dimensionality reduction with non-negative matrix factorization, we investigated synchronized bursts of dissociated rat cortical neurons at approximately three weeks in vitro. We found that bursts had a repertoire of repeating spatiotemporal patterns, and different patterns shared a partially similar sequence of sub-population, supporting the idea of sequential structure of neuronal sub-populations during synchronized activity. We additionally found that similar spatiotemporal patterns tended to appear successively and periodically, suggesting a state-dependent fluctuation of propagation, which has been overlooked in existing literature. Thus, such a state-dependent property within the sequential sub-population structure is a plausible neural substrate for performing a repertoire of stable patterns during synchronized activity.

  5. Identifying coherent structures and vortex clusters in Taylor-Couette turbulence

    NARCIS (Netherlands)

    Arza, Vamsi Spandan; Ostilla-Monico, Rodolfo; Lohse, Detlef; Verzicco, Roberto

    2016-01-01

    The nature of the underlying structures in Taylor-Couette (TC) flow, the flow between two co-axial and independently rotating cylinders is investigated by two methods. First, the quadrant analysis technique for identifying structures with intense radial-azimuthal stresses (also referred to as 'Q's)

  6. 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.

  7. Identifying key nodes based on improved structural holes in complex networks

    Science.gov (United States)

    Yu, Hui; Cao, Xi; Liu, Zun; Li, Yongjun

    2017-11-01

    Identifying key nodes in complex networks is of theoretical and practical significance. Local metrics such as degree centrality is simplest but cannot effectively identify the important bridging nodes. Global metrics such as betweenness and closeness centrality can better identify important nodes, but they are often restricted by the unknown topology and cannot be conveniently applied in large-scale networks. In this paper, we propose an effective ranking method based on an Improved Structural Holes (ISH) to identify the important nodes. ISH method only uses the degree of nodes and the nearest neighborhood information rather than considering the global structure of a network. Our experimental results on five complex networks show that the proposed method can effectively identify the key nodes in complex networks and can also be applied in large-scale or unconnected networks.

  8. 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.

  9. 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...... 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...

  10. 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.

  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. 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

    BACKGROUND: Within the last decade a large number of noncoding RNA genes have been identified, but this may only be the tip of the iceberg. Using comparative genomics a large number of sequences that have signals concordant with conserved RNA secondary structures have been discovered in the human...

  13. Identifying Key Structural Features of IrOx Water Splitting Catalysts.

    Science.gov (United States)

    Willinger, Elena; Massué, Cyriac; Schlögl, Robert; Willinger, Marc Georg

    2017-08-30

    Hydrogen production by electrocatalytic water splitting will play a key role in the realization of a sustainable energy supply. Owing to their relatively high stability and activity, iridium (hydr)oxides have been identified as the most promising catalysts for the oxidation of water. Comprehensive spectroscopic and theoretical studies on the basis of rutile IrO2 have provided insight about the electronic structure of the active X-ray amorphous phase. However, due to the absence of long-range order and missing information about the local arrangement of structural units, our present understanding of the active phase is very unsatisfying. In this work, using a combination of real-space atomic scale imaging with atomic pair distribution function analysis and local measurements of the electronic structure, we identify key structural motifs that are associated with high water splitting activity. Comparison of two X-ray amorphous phases with distinctively different electrocatalytic performance reveals that high activity is linked to the ratio between corner- and edge-sharing IrO6 octahedra. We show that the active and stable phase consists of single unit cell sized hollandite-like structural domains that are cross-linked through undercoordinated oxygen/iridium atoms. In the less active phase, the presence of the rutile phase structural motif results in a faster structural collapse and deactivation. The presented results provide insight into the structure-activity relationship and promote a rational synthesis of X-ray amorphous IrOx hydroxides that contain a favorable arrangement of structural units for improved performance in catalytic water splitting.

  14. Integrated sequence-structure motifs suffice to identify microRNA precursors.

    Directory of Open Access Journals (Sweden)

    Xiuqin Liu

    Full Text Available BACKGROUND: Upwards of 1200 miRNA loci have hitherto been annotated in the human genome. The specific features defining a miRNA precursor and deciding its recognition and subsequent processing are not yet exhaustively described and miRNA loci can thus not be computationally identified with sufficient confidence. RESULTS: We rendered pre-miRNA and non-pre-miRNA hairpins as strings of integrated sequence-structure information, and used the software Teiresias to identify sequence-structure motifs (ss-motifs of variable length in these data sets. Using only ss-motifs as features in a Support Vector Machine (SVM algorithm for pre-miRNA identification achieved 99.2% specificity and 97.6% sensitivity on a human test data set, which is comparable to previously published algorithms employing combinations of sequence-structure and additional features. Further analysis of the ss-motif information contents revealed strongly significant deviations from those of the respective training sets, revealing important potential clues as to how the sequence and structural information of RNA hairpins are utilized by the miRNA processing apparatus. CONCLUSION: Integrated sequence-structure motifs of variable length apparently capture nearly all information required to distinguish miRNA precursors from other stem-loop structures.

  15. Multiparametric characterization of neuronal subpopulations in the ventrolateral preoptic nucleus.

    Science.gov (United States)

    Dubourget, Romain; Sangare, Aude; Geoffroy, Hélène; Gallopin, Thierry; Rancillac, Armelle

    2017-04-01

    The characterization of neuronal properties is a necessary first step toward understanding how the ventrolateral preoptic nucleus (VLPO) neuronal network regulates slow-wave sleep (SWS). Indeed, the electrophysiological heterogeneity of VLPO neurons suggests the existence of subtypes that could differently contribute in SWS induction and maintenance. The aim of the present study was to define cell classes in the VLPO using an unsupervised clustering classification method. Electrophysiological features extracted from 289 neurons recorded in whole-cell patch-clamp allowed the identification of three main classes of VLPO neurons subdivided into five distinct subpopulations (cluster 1, 2a, 2b, 3a and 3b). The high occurrence of a low-threshold calcium spike (LTS) was one of the most distinctive features of cluster 1 and 3. Since sleep-promoting neurons are generally identified by their ability to generate an LTS and by their inhibitory response to noradrenaline (NA), 189 neurons from our dataset were also tested for this neurotransmitter. Neurons from cluster 3 were the most frequently inhibited by NA. Biocytin labeling and Neurolucida reconstructions of 112 neurons furthermore revealed a small dendritic arbor of cluster 3b neurons compared, in particular, to cluster 2b neurons. Altogether, we performed an exhaustive characterization of VLPO neuronal subtypes that is a crucial step toward a better understanding of the neuronal network within the VLPO and thereby sleep physiology.

  16. Identification of drug-resistant subpopulations in canine hemangiosarcoma.

    Science.gov (United States)

    Khammanivong, A; Gorden, B H; Frantz, A M; Graef, A J; Dickerson, E B

    2016-09-01

    Canine hemangiosarcoma is a rapidly progressive disease that is poorly responsive to conventional chemotherapy. Despite numerous attempts to advance treatment options and improve outcomes, drug resistance remains a hurdle to successful therapy. To address this problem, we used recently characterized progenitor cell populations derived from canine hemangiosarcoma cell lines and grown as non-adherent spheres to identify potential drug resistance mechanisms as well as drug-resistant cell populations. Cells from sphere-forming cultures displayed enhanced resistance to chemotherapy drugs, expansion of dye-excluding side populations and altered ATP-binding cassette (ABC) transporter expression. Invasion studies demonstrated variability between cell lines as well as between sphere and monolayer cell populations. Collectively, our results suggest that sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs. Our approach represents a new tool for the study of drug resistance in hemangiosarcoma, which could alter approaches for treating this disease. © 2014 John Wiley & Sons Ltd.

  17. Tracking Functional Tumor Cell Subpopulations of Malignant Glioma by Phasor Fluorescence Lifetime Imaging Microscopy of NADH

    Directory of Open Access Journals (Sweden)

    Andrew L. Trinh

    2017-12-01

    Full Text Available Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC subpopulation relative to the tumor mass-forming cell (TMC subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis, EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment.

  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. Restricted Gene Flow among Hospital Subpopulations of Enterococcus faecium

    Science.gov (United States)

    Willems, Rob J. L.; Top, Janetta; van Schaik, Willem; Leavis, Helen; Bonten, Marc; Sirén, Jukka; Hanage, William P.; Corander, Jukka

    2012-01-01

    ABSTRACT Enterococcus faecium has recently emerged as an important multiresistant nosocomial pathogen. Defining population structure in this species is required to provide insight into the existence, distribution, and dynamics of specific multiresistant or pathogenic lineages in particular environments, like the hospital. Here, we probe the population structure of E. faecium using Bayesian-based population genetic modeling implemented in Bayesian Analysis of Population Structure (BAPS) software. The analysis involved 1,720 isolates belonging to 519 sequence types (STs) (491 for E. faecium and 28 for Enterococcus faecalis). E. faecium isolates grouped into 13 BAPS (sub)groups, but the large majority (80%) of nosocomial isolates clustered in two subgroups (2-1 and 3-3). Phylogenetic and eBURST analysis of BAPS groups 2 and 3 confirmed the existence of three separate hospital lineages (17, 18, and 78), highlighting different evolutionary trajectories for BAPS 2-1 (lineage 78) and 3-3 (lineage 17 and lineage 18) isolates. Phylogenomic analysis of 29 E. faecium isolates showed agreement between BAPS assignment of STs and their relative positions in the phylogenetic tree. Odds ratio calculation confirmed the significant association between hospital isolates with BAPS 3-3 and lineages 17, 18, and 78. Admixture analysis showed a scarce number of recombination events between the different BAPS groups. For the E. faecium hospital population, we propose an evolutionary model in which strains with a high propensity to colonize and infect hospitalized patients arise through horizontal gene transfer. Once adapted to the distinct hospital niche, this subpopulation becomes isolated, and recombination with other populations declines. PMID:22807567

  20. 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.

  1. Biochemical phenotypes to discriminate microbial subpopulations and improve outbreak detection.

    Directory of Open Access Journals (Sweden)

    Alicia Galar

    Full Text Available Clinical microbiology laboratories worldwide constitute an invaluable resource for monitoring emerging threats and the spread of antimicrobial resistance. We studied the growing number of biochemical tests routinely performed on clinical isolates to explore their value as epidemiological markers.Microbiology laboratory results from January 2009 through December 2011 from a 793-bed hospital stored in WHONET were examined. Variables included patient location, collection date, organism, and 47 biochemical and 17 antimicrobial susceptibility test results reported by Vitek 2. To identify biochemical tests that were particularly valuable (stable with repeat testing, but good variability across the species or problematic (inconsistent results with repeat testing, three types of variance analyses were performed on isolates of K. pneumonia: descriptive analysis of discordant biochemical results in same-day isolates, an average within-patient variance index, and generalized linear mixed model variance component analysis.4,200 isolates of K. pneumoniae were identified from 2,485 patients, 32% of whom had multiple isolates. The first two variance analyses highlighted SUCT, TyrA, GlyA, and GGT as "nuisance" biochemicals for which discordant within-patient test results impacted a high proportion of patient results, while dTAG had relatively good within-patient stability with good heterogeneity across the species. Variance component analyses confirmed the relative stability of dTAG, and identified additional biochemicals such as PHOS with a large between patient to within patient variance ratio. A reduced subset of biochemicals improved the robustness of strain definition for carbapenem-resistant K. pneumoniae. Surveillance analyses suggest that the reduced biochemical profile could improve the timeliness and specificity of outbreak detection algorithms.The statistical approaches explored can improve the robust recognition of microbial subpopulations with

  2. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

    Science.gov (United States)

    Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Chen, Ming-Huei; Leening, Maarten J.G.; Völker, Uwe; Großmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Dörthe; Lyytikäinen, Leo-Pekka; Tiller, Daniel; Smith, J. Gustav; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco M, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kähönen, Mika; investigators, KNHI; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Lindgren, Cecilia M.; Loley, Christina; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Müller, Christian; Müller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L.; Samdarshi, Tandaw E.; Sharp, Andrew S.P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Töglhofer, Anna M.; Uitterlinden, André G.; Völzke, Henry; Ziegler, Andreas; Münzel, Thomas; März, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W.V.; Melander, Olle; Lehtimäki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Dörr, Marcus

    2017-01-01

    BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING. For detailed information per study, see Acknowledgments. PMID:28394258

  3. Lithospheric Structure in Central California: Towards Identifying the Tectonic Origin of the Isabella Anomaly

    Science.gov (United States)

    Dougherty, S. L.; Clayton, R. W.

    2015-12-01

    The tectonic origin of the Isabella high-velocity anomaly in the upper mantle beneath California's southern Great Valley is unclear. Previous low-resolution seismic imaging studies of the region have been unable to identify the structural connection between this upper mantle anomaly and the overlying lithosphere. The two dominant hypotheses attribute the Isabella anomaly to a fossil slab or the foundered lithospheric root of the Sierra Nevada batholith. The Central California Seismic Experiment (CCSE) is designed to distinguish between these hypotheses. We present results from the CCSE, which consists of 44 broadband seismometers currently deployed in a quasi-linear array spanning from the Pacific coast, across the Great Valley, to the Sierra Nevada foothills, at an approximate latitude of 36°N. Forward modeling of the 2D structure of the crust is performed using local earthquakes recorded by the CCSE and a finite-difference algorithm to provide constraints on the geometry and velocity of the seismic structure of the Great Valley. This sedimentary basin is suggested to be filled with very low velocity material at shallow depths and partially underlain by a high-velocity ophiolite body. Hence, a well-constrained basin structure will be important in correcting surface wave tomography and receiver function images. The impact of the Great Valley basin structure on body waves is evident by an observed delay in P-wave arrival times on the radial component relative to the vertical component for stations located within the basin. Surface waves along the CCSE array also show a distinct slowing by the valley at periods <10 sec. Data from teleseismic events recorded by the CCSE reveal scattered waves arriving tens of seconds after the S-wave, which we will interpret in terms of the lithospheric structure of the region by identifying the source location(s) of the scatterer(s). We may also gain insights into the structural connection between the Isabella anomaly and the

  4. 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.

  5. 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.

  6. Tactile perception: do distinct subpopulations explain differences in mislocalization rates of stimuli across fingertips?

    Science.gov (United States)

    Warren, Jay P; Tillery, Stephen I Helms

    2011-11-07

    In a previous study we were able to demonstrate that the Cutaneous Rabbit Effect (CRE) could be induced across fingertips using a form of the reduced rabbit paradigm and electrotactile stimuli. The CRE, as used here, is an illusory phenomenon where two stimuli are rapidly at a site and then a stimulus is presented to a nearby site. The perception of the second of the stimuli is not at its presented location but at a site between the first and last stimuli. In this experiment, though the overall population did perceive the mislocalized stimuli as the CRE would predict, some subjects were very infrequently observed to mislocalize stimuli due to the CRE or other effects. Here we further examine this phenomena, attempting to identify whether a subpopulation exists that rarely mislocalizes stimuli on their fingertips. To test for this subpopulation, we reexamined the collected data from the previously published experiment and other unpublished data relating to that study. By examining these data for rates of mislocalization utilizing our previous metric we identified that there is a perceptual subpopulation that very infrequently misidentifies the location of a fingertip stimulus. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  7. Exploring methods for identifying related patient safety events using structured and unstructured data.

    Science.gov (United States)

    Fong, Allan; Hettinger, A Zachary; Ratwani, Raj M

    2015-12-01

    Most healthcare systems have implemented patient safety event reporting systems to identify safety hazards. Searching the safety event data to find related patient safety reports and identify trends is challenging given the complexity and quantity of these reports. Structured data elements selected by the event reporter may be inaccurate and the free-text narrative descriptions are difficult to analyze. In this paper we present and explore methods for utilizing both the unstructured free-text and structured data elements in safety event reports to identify and rank similar events. We evaluate the results of three different free-text search methods, including a unique topic modeling adaptation, and structured element weights, using a patient fall use case. The various search techniques and weight combinations tended to prioritize different aspects of the event reports leading to different search and ranking results. These search and prioritization methods have the potential to greatly improve patient safety officers, and other healthcare workers, understanding of which safety event reports are related. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. 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.

    2014-01-01

    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. PMID:25275860

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

    Directory of Open Access Journals (Sweden)

    Christian Lohse

    2014-10-01

    Full Text Available 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.

  10. 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.

  11. Identifying ligands at orphan GPCRs: current status using structure-based approaches.

    Science.gov (United States)

    Ngo, Tony; Kufareva, Irina; Coleman, James Lj; Graham, Robert M; Abagyan, Ruben; Smith, Nicola J

    2016-10-01

    GPCRs are the most successful pharmaceutical targets in history. Nevertheless, the pharmacology of many GPCRs remains inaccessible as their endogenous or exogenous modulators have not been discovered. Tools that explore the physiological functions and pharmacological potential of these 'orphan' GPCRs, whether they are endogenous and/or surrogate ligands, are therefore of paramount importance. Rates of receptor deorphanization determined by traditional reverse pharmacology methods have slowed, indicating a need for the development of more sophisticated and efficient ligand screening approaches. Here, we discuss the use of structure-based ligand discovery approaches to identify small molecule modulators for exploring the function of orphan GPCRs. These studies have been buoyed by the growing number of GPCR crystal structures solved in the past decade, providing a broad range of template structures for homology modelling of orphans. This review discusses the methods used to establish the appropriate signalling assays to test orphan receptor activity and provides current examples of structure-based methods used to identify ligands of orphan GPCRs. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc. © 2016 The British Pharmacological Society.

  12. Crystal structure of a novel prolidase from Deinococcus radiodurans identifies new subfamily of bacterial prolidases.

    Science.gov (United States)

    Are, Venkata N; Jamdar, Sahayog N; Ghosh, Biplab; Goyal, Venuka Durani; Kumar, Ashwani; Neema, Sanchit; Gadre, Rekha; Makde, Ravindra D

    2017-12-01

    Xaa-Pro peptidases (XPP) are dinuclear peptidases of MEROPS M24B family that hydrolyze Xaa-Pro iminopeptide bond with a trans-proline at the second position of the peptide substrate. XPPs specific towards dipeptides are called prolidases while those that prefer longer oligopeptides are called aminopeptidases P. Though XPPs are strictly conserved in bacterial and archaeal species, the structural and sequence features that distinguish between prolidases and aminopeptidases P are not always clear. Here, we report 1.4 Å resolution crystal structure of a novel XPP from Deinococcus radiodurans (XPPdr). XPPdr forms a novel dimeric structure via unique dimer stabilization loops of N-terminal domains such that their C-terminal domains are placed far apart from each other. This novel dimerization is also the consequence of a different orientation of N-terminal domain in XPPdr monomer than those in other known prolidases. The enzymatic assays show that it is a prolidase with broad substrate specificity. Our structural, mutational, and molecular dynamics simulation analyses show that the conserved Arg46 of N-terminal domain is important for the dipeptide selectivity. Our BLAST search found XPPdr orthologs with conserved sequence motifs which correspond to unique structural features of XPPdr, thus identify a new subfamily of bacterial prolidases. © 2017 Wiley Periodicals, Inc.

  13. Identifying large scale structures at 1 AU using fluctuations and wavelets

    Science.gov (United States)

    Niembro, T.; Lara, A.

    2016-12-01

    The solar wind (SW) is inhomogeneous and it is dominated for two types of flows: one quasi-stationary and one related to large scale transients (such as coronal mass ejections and co-rotating interaction regions). The SW inhomogeneities can be study as fluctuations characterized by a wide range of length and time scales. We are interested in the study of the characteristic fluctuations caused by large scale transient events. To do so, we define the vector space F with the normalized moving monthly/annual deviations as the orthogonal basis. Then, we compute the norm in this space of the solar wind parameters (velocity, magnetic field, density and temperature) fluctuations using WIND data from August 1992 to August 2015. This norm gives important information about the presence of a large structure disturbance in the solar wind and by applying a wavelet transform to this norm, we are able to determine, without subjectivity, the duration of the compression regions of these large transient structures and, even more, to identify if the structure corresponds to a single or complex (or merged) event. With this method we have automatically detected most of the events identified and published by other authors.

  14. Eastern Mediterranean Sea Spatial and Temporal Variability of Thermohaline Structure and Circulation Identified from Observational (T, S) Profiles

    Science.gov (United States)

    2015-12-01

    MEDITERRANEAN SEA SPATIAL AND TEMPORAL VARIABILITY OF THERMOHALINE STRUCTURE AND CIRCULATION IDENTIFIED FROM OBSERVATIONAL (T, S) PROFILES by Nuri...MEDITERRANEAN SEA SPATIAL AND TEMPORAL VARIABILITY OF THERMOHALINE STRUCTURE AND CIRCULATION IDENTIFIED FROM OBSERVATIONAL (T, S) PROFILES 5. FUNDING NUMBERS...variability of thermohaline structure and circulation were investigated. Surface depth shows high seasonal temperature variability through the year

  15. Statistical machine learning to identify traumatic brain injury (TBI) from structural disconnections of white matter networks.

    Science.gov (United States)

    Mitra, Jhimli; Shen, Kai-Kai; Ghose, Soumya; Bourgeat, Pierrick; Fripp, Jurgen; Salvado, Olivier; Pannek, Kerstin; Taylor, D Jamie; Mathias, Jane L; Rose, Stephen

    2016-04-01

    Identifying diffuse axonal injury (DAI) in patients with traumatic brain injury (TBI) presenting with normal appearing radiological MRI presents a significant challenge. Neuroimaging methods such as diffusion MRI and probabilistic tractography, which probe the connectivity of neural networks, show significant promise. We present a machine learning approach to classify TBI participants primarily with mild traumatic brain injury (mTBI) based on altered structural connectivity patterns derived through the network based statistical analysis of structural connectomes generated from TBI and age-matched control groups. In this approach, higher order diffusion models were used to map white matter connections between 116 cortical and subcortical regions. Tracts between these regions were generated using probabilistic tracking and mean fractional anisotropy (FA) measures along these connections were encoded in the connectivity matrices. Network-based statistical analysis of the connectivity matrices was performed to identify the network differences between a representative subset of the two groups. The affected network connections provided the feature vectors for principal component analysis and subsequent classification by random forest. The validity of the approach was tested using data acquired from a total of 179 TBI patients and 146 controls participants. The analysis revealed altered connectivity within a number of intra- and inter-hemispheric white matter pathways associated with DAI, in consensus with existing literature. A mean classification accuracy of 68.16%±1.81% and mean sensitivity of 80.0%±2.36% were achieved in correctly classifying the TBI patients evaluated on the subset of the participants that was not used for the statistical analysis, in a 10-fold cross-validation framework. These results highlight the potential for statistical machine learning approaches applied to structural connectomes to identify patients with diffusive axonal injury. Copyright

  16. Jury-Contestant Bipartite Competition Network: Identifying Biased Scores and Their Impact on Network Structure Inference

    CERN Document Server

    Jeon, Gyuhyeon

    2016-01-01

    A common form of competition is one where judges grade contestants' performances which are then compiled to determine the final ranking of the contestants. Unlike in another common form of competition where two contestants play a head-to-head match to produce a winner as in football or basketball, the objectivity of judges are prone to be questioned, potentially undermining the public's trust in the fairness of the competition. In this work we show, by modeling the judge--contestant competition as a weighted bipartite network, how we can identify biased scores and measure their impact on our inference of the network structure. Analyzing the prestigious International Chopin Piano Competition of 2015 with a well-publicized scoring controversy as an example, we show that even a single statistically uncharacteristic score can be enough to gravely distort our inference of the community structure, demonstrating the importance of detecting and eliminating biases. In the process we also find that there does not exist...

  17. Higher-Order Spectral Analysis to Identify Quadratic Nonlinearities in Fluid-Structure Interaction

    Directory of Open Access Journals (Sweden)

    Imran Akhtar

    2018-01-01

    Full Text Available Hydrodynamic forces on a structure are the manifestation of fluid-structure interaction. Since this interaction is nonlinear, these forces consist of various frequencies: fundamental, harmonics, excitation, sum, and difference of these frequencies. To analyze this phenomenon, we perform numerical simulations of the flow past stationary and oscillating cylinders at low Reynolds numbers. We compute the pressure, integrate it over the surface, and obtain the lift and drag coefficients for the two configurations: stationary and transversely oscillating cylinders. Higher-order spectral analysis is performed to investigate the nonlinear interaction between the forces. We confirmed and investigated the quadratic coupling between the lift and drag coefficients and their phase relationship. We identify additional frequencies and their corresponding energy present in the flow field that appear as the manifestation of quadratic nonlinear interaction.

  18. Combining structured and unstructured data to identify a cohort of ICU patients who received dialysis.

    Science.gov (United States)

    Abhyankar, Swapna; Demner-Fushman, Dina; Callaghan, Fiona M; McDonald, Clement J

    2014-01-01

    To develop a generalizable method for identifying patient cohorts from electronic health record (EHR) data-in this case, patients having dialysis-that uses simple information retrieval (IR) tools. We used the coded data and clinical notes from the 24,506 adult patients in the Multiparameter Intelligent Monitoring in Intensive Care database to identify patients who had dialysis. We used SQL queries to search the procedure, diagnosis, and coded nursing observations tables based on ICD-9 and local codes. We used a domain-specific search engine to find clinical notes containing terms related to dialysis. We manually validated the available records for a 10% random sample of patients who potentially had dialysis and a random sample of 200 patients who were not identified as having dialysis based on any of the sources. We identified 1844 patients that potentially had dialysis: 1481 from the three coded sources and 1624 from the clinical notes. Precision for identifying dialysis patients based on available data was estimated to be 78.4% (95% CI 71.9% to 84.2%) and recall was 100% (95% CI 86% to 100%). Combining structured EHR data with information from clinical notes using simple queries increases the utility of both types of data for cohort identification. Patients identified by more than one source are more likely to meet the inclusion criteria; however, including patients found in any of the sources increases recall. This method is attractive because it is available to researchers with access to EHR data and off-the-shelf IR tools. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Identifying dynamic characteristics of structures to estimate the performance of a smart wireless MA system

    Science.gov (United States)

    Heo, Gwanghee; Lee, WooSang; Lee, Giu; Lee, Donggi

    2005-05-01

    In this paper, a smart wireless MEMS-based accelerometer(MA) system has been designed and experimented for smart monitoring system of civil structures. In order to estimate the performance of a smart wireless MA system(SWMAS), dynamic characteristics of our model structure need to be identified. This system thus employed a high-performance AVR microcontroller, a wireless modem, and MA for multiplex communication capability and real time duplex communication. Various performance and experimental tests have been carried out to evaluate whether this system is suitable for monitoring system of civil structures. First, we examined its sensitivity, resolution, and noise, specifically to evaluate the performance of the smart wireless MA system. The results of experiments enabled us to estimate performance of the MA in SWMAS in comparison to the value of data sheet from MA. Second, characteristics of model structure were analyzed by the ambient vibration test based on the NExT combined with ERA. Finally, this analysis was compared to the one that was made by FE results, and the comparison proved that a smart wireless MA system was fitted in smart monitoring system effectively.

  20. 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.

  1. Mononuclear phagocyte subpopulations in the mouse kidney.

    Science.gov (United States)

    George, James F; Lever, Jeremie M; Agarwal, Anupam

    2017-04-01

    Mononuclear phagocytes are the most common cells in the kidney associated with immunity and inflammation. Although the presence of these cells in the kidney has been known for decades, the study of mononuclear phagocytes in the context of kidney function and dysfunction is still at an early stage. The purpose of this review is to summarize the present knowledge regarding classification of these cells in the mouse kidney and to identify relevant questions that would further advance the field and potentially lead to new opportunities for treatment of acute kidney injury and other kidney diseases.

  2. Identifying structural variation in haploid microbial genomes from short-read resequencing data using breseq.

    Science.gov (United States)

    Barrick, Jeffrey E; Colburn, Geoffrey; Deatherage, Daniel E; Traverse, Charles C; Strand, Matthew D; Borges, Jordan J; Knoester, David B; Reba, Aaron; Meyer, Austin G

    2014-11-29

    Mutations that alter chromosomal structure play critical roles in evolution and disease, including in the origin of new lifestyles and pathogenic traits in microbes. Large-scale rearrangements in genomes are often mediated by recombination events involving new or existing copies of mobile genetic elements, recently duplicated genes, or other repetitive sequences. Most current software programs for predicting structural variation from short-read DNA resequencing data are intended primarily for use on human genomes. They typically disregard information in reads mapping to repeat sequences, and significant post-processing and manual examination of their output is often required to rule out false-positive predictions and precisely describe mutational events. We have implemented an algorithm for identifying structural variation from DNA resequencing data as part of the breseq computational pipeline for predicting mutations in haploid microbial genomes. Our method evaluates the support for new sequence junctions present in a clonal sample from split-read alignments to a reference genome, including matches to repeat sequences. Then, it uses a statistical model of read coverage evenness to accept or reject these predictions. Finally, breseq combines predictions of new junctions and deleted chromosomal regions to output biologically relevant descriptions of mutations and their effects on genes. We demonstrate the performance of breseq on simulated Escherichia coli genomes with deletions generating unique breakpoint sequences, new insertions of mobile genetic elements, and deletions mediated by mobile elements. Then, we reanalyze data from an E. coli K-12 mutation accumulation evolution experiment in which structural variation was not previously identified. Transposon insertions and large-scale chromosomal changes detected by breseq account for ~25% of spontaneous mutations in this strain. In all cases, we find that breseq is able to reliably predict structural variation

  3. Abnormalities of stromal structure in the bullous keratopathy cornea identified by second harmonic generation imaging microscopy.

    Science.gov (United States)

    Morishige, Naoyuki; Yamada, Norihiro; Zhang, Xu; Morita, Yukiko; Yamada, Naoyuki; Kimura, Kazuhiro; Takahara, Atsushi; Sonoda, Koh-Hei

    2012-07-27

    To identify structural alterations in collagen lamellae and the transdifferentiation of keratocytes into myofibroblasts in the corneal stroma of bullous keratopathy (BK) patients and to examine the relation of such changes to the duration of stromal edema or the underlying cause of BK. Six normal human corneas and 16 BK corneas were subjected to second harmonic generation (SHG) imaging microscopy to allow three-dimensional (3-D) reconstruction of collagen lamellae. Expression of α-smooth muscle actin (αSMA) was examined by immunofluorescence analysis and conventional laser confocal microscopy. Collagen lamellae were interwoven at the anterior stroma and uniformly aligned at the posterior stroma, whereas αSMA was not detected throughout the entire stroma of the normal cornea. Nine (56%) and 7 (44%) of the 16 BK corneas showed abnormal collagen structure at the anterior and posterior stroma, respectively. Expression of αSMA was detected in the anterior or posterior stroma of 7 (44%) and 6 (38%) of the 16 BK corneas, respectively. Disorganization of collagen lamellae and myofibroblastic transdifferentiation were detected only in corneas with a duration of stromal edema of at least 12 months. Corneas with BK as a result of birth injury showed abnormal collagen structure at the posterior stroma, whereas those with BK resulting from laser iridotomy did not. Changes in the structure of the entire stroma were detected in BK corneas with a duration of stromal edema of at least 12 months, suggesting that such changes may be progressive. In addition, the underlying cause of BK may influence structural changes at the posterior stroma.

  4. 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.

  5. Damage Detection of Structures Identified with Deterministic-Stochastic Models Using Seismic Data

    Directory of Open Access Journals (Sweden)

    Ming-Chih Huang

    2014-01-01

    Full Text Available A deterministic-stochastic subspace identification method is adopted and experimentally verified in this study to identify the equivalent single-input-multiple-output system parameters of the discrete-time state equation. The method of damage locating vector (DLV is then considered for damage detection. A series of shaking table tests using a five-storey steel frame has been conducted. Both single and multiple damage conditions at various locations have been considered. In the system identification analysis, either full or partial observation conditions have been taken into account. It has been shown that the damaged stories can be identified from global responses of the structure to earthquakes if sufficiently observed. In addition to detecting damage(s with respect to the intact structure, identification of new or extended damages of the as-damaged counterpart has also been studied. This study gives further insights into the scheme in terms of effectiveness, robustness, and limitation for damage localization of frame systems.

  6. 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.

  7. 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.

  8. A consensus secondary structure of ITS2 in the chlorophyta identified by phylogenetic reconstruction.

    Science.gov (United States)

    Caisová, Lenka; Marin, Birger; Melkonian, Michael

    2013-07-01

    The definition of species plays a pivotal role in biology. It has been proposed that Compensatory Base Changes (CBCs) in the fast-evolving Internal Transcribed Spacer 2 (ITS2) correlate with speciation and thus can be used to distinguish species. The applicability of CBC - based species concepts using ITS2, however, rests on the homology of the investigated ITS2 positions. We studied the ITS2 molecule of 147 strains of Chlorophyceae (Chlorophyta, Viridiplantae) including 26 new sequences in the order Chaetophorales, and compared their secondary structures to ITS2 in the sister class Ulvophyceae, represented by the order Ulvales. Using a phylogenetic/comparative approach, it was possible to identify 1) the first consensus structure model of the ITS2 molecule that can be applied to two classes of green algae [Ulvophyceae (Ulvales), Chlorophyceae] and 2) landmarks (the spacer regions separating the ITS2 Helices) for more robust prediction of the secondary structures in green algae. Moreover, we found that CBCs in homologous positions in these 147 strains (representing 115 validly described species) are either completely absent or mostly associated with internal branches representing higher order taxonomic levels (genera, families, orders). As reported for the Ulvales, CBCs are not diagnostic at the species level in the dataset used. Copyright © 2013 Elsevier GmbH. All rights reserved.

  9. 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.

  10. Use of structured decision making to identify monitoring variables and management priorities for salt marsh ecosystems

    Science.gov (United States)

    Neckles, Hilary A.; Lyons, James E.; Guntenspergen, Glenn R.; Shriver, W. Gregory; Adamowicz, Susan C.

    2015-01-01

    Most salt marshes in the USA have been degraded by human activities, and coastal managers are faced with complex choices among possible actions to restore or enhance ecosystem integrity. We applied structured decision making (SDM) to guide selection of monitoring variables and management priorities for salt marshes within the National Wildlife Refuge System in the northeastern USA. In general, SDM is a systematic process for decomposing a decision into its essential elements. We first engaged stakeholders in clarifying regional salt marsh decision problems, defining objectives and attributes to evaluate whether objectives are achieved, and developing a pool of alternative management actions for achieving objectives. Through this process, we identified salt marsh attributes that were applicable to monitoring National Wildlife Refuges on a regional scale and that targeted management needs. We then analyzed management decisions within three salt marsh units at Prime Hook National Wildlife Refuge, coastal Delaware, as a case example of prioritizing management alternatives. Values for salt marsh attributes were estimated from 2 years of baseline monitoring data and expert opinion. We used linear value modeling to aggregate multiple attributes into a single performance score for each alternative, constrained optimization to identify alternatives that maximized total management benefits subject to refuge-wide cost constraints, and used graphical analysis to identify the optimal set of alternatives for the refuge. SDM offers an efficient, transparent approach for integrating monitoring into management practice and improving the quality of management decisions.

  11. Typical structural elements of seismicity and impact crater morphology identified in GIS ENDDB digital models.

    Science.gov (United States)

    Mikheeva, Anna

    2014-05-01

    The subject database of the ENDDB system (Earth's Natural Disasters Database) is a combination of the EISC catalog (Earth's impact structures Catalog [1]) and seismological data of more than 60 earthquake catalogs (EC). ENDDB geographic subsystem uses the NASA ASTER GDEM data arrays to obtain a high-resolution (1 arc-second) shaded relief model, as well as the digital mapping technology, which consists in shading surface points according to their brightness controlled by the illumination angle. For example, the identifying impact craters by means of ENDDB begins with selecting the optimum base colors of the image, the parameters of illumination and shadow depth for constructing a shaded model on a regular grid of values. This procedure allows obtaining precise 3D images of the terrain and gravity patterns, and, moreover, furnishes data for recognizing standard morphological elements according to which impact structures can be visually detected. For constructing a shaded gravity anomaly with the ENDDB tools, Global marine gravity data (of models V16.1 and V18.1 [2]) are embedded into the system. These models, which are arrays of gravity pixel values, are of the resolution increased from the equator to the poles, being 30 arc-seconds per point on average. This resolution is the same as in the more recent V21.1 model. Due to these data, new morphological elements typical of impact structures, which are expressed in the shaded elevation and gravity models (identified using the ENDDB visualization tools) was found and compared in hundreds of craters from the EISC-catalog: tail-shaped asymmetry of relief, heart-shaped geometry of craters, and tail-shaped gravity lows [3] and so on. New diagnostic criteria associated with typical morphological elements revealed with advanced image processing technologies are very important to confirm the impact origin for many potential craters. The basic hypothesis of the impact-explosive tectonics [4] is that meteorite craters on the

  12. 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

  13. Identifying the stored energy of a hyperelastic structure by using an attenuated Landweber method

    Science.gov (United States)

    Seydel, Julia; Schuster, Thomas

    2017-12-01

    We consider the nonlinear inverse problem of identifying the stored energy function of a hyperelastic material from full knowledge of the displacement field as well as from surface sensor measurements. The displacement field is represented as a solution of Cauchy’s equation of motion, which is a nonlinear elastic wave equation. Hyperelasticity means that the first Piola-Kirchhoff stress tensor is given as the gradient of the stored energy function. We assume that a dictionary of suitable functions is available. The aim is to recover the stored energy with respect to this dictionary. The considered inverse problem is of vital interest for the development of structural health monitoring systems which are constructed to detect defects in elastic materials from boundary measurements of the displacement field, since the stored energy encodes the mechanical properties of the underlying structure. In this article we develop a numerical solver using the attenuated Landweber method. We show that the parameter-to-solution map satisfies the local tangential cone condition. This result can be used to prove local convergence of the attenuated Landweber method in the case that the full displacement field is measured. In our numerical experiments we demonstrate how to construct an appropriate dictionary and show that our method is well suited to localize damages in various situations.

  14. 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

    2016-10-01

    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.

  15. Multi-Scale Compositionality: Identifying the Compositional Structures of Social Dynamics Using Deep Learning

    Science.gov (United States)

    Peng, Huan-Kai; Marculescu, Radu

    2015-01-01

    Objective Social media exhibit rich yet distinct temporal dynamics which cover a wide range of different scales. In order to study this complex dynamics, two fundamental questions revolve around (1) the signatures of social dynamics at different time scales, and (2) the way in which these signatures interact and form higher-level meanings. Method In this paper, we propose the Recursive Convolutional Bayesian Model (RCBM) to address both of these fundamental questions. The key idea behind our approach consists of constructing a deep-learning framework using specialized convolution operators that are designed to exploit the inherent heterogeneity of social dynamics. RCBM’s runtime and convergence properties are guaranteed by formal analyses. Results Experimental results show that the proposed method outperforms the state-of-the-art approaches both in terms of solution quality and computational efficiency. Indeed, by applying the proposed method on two social network datasets, Twitter and Yelp, we are able to identify the compositional structures that can accurately characterize the complex social dynamics from these two social media. We further show that identifying these patterns can enable new applications such as anomaly detection and improved social dynamics forecasting. Finally, our analysis offers new insights on understanding and engineering social media dynamics, with direct applications to opinion spreading and online content promotion. PMID:25830775

  16. East Sea Spatial and Temporal Variability of Thermohaline Structure and Circulation Identified From Observational (T, S) Profiles

    Science.gov (United States)

    2015-12-01

    VARIABILITY OF THERMOHALINE STRUCTURE AND CIRCULATION IDENTIFIED FROM OBSERVATIONAL (T, S) PROFILES by Hyewon Choi December 2015 Thesis Advisor...the gridded data, seasonal and inter-annual variability of thermohaline structure and circulation of the East Sea were analyzed. Found was a low...unlimited EAST SEA SPATIAL AND TEMPORAL VARIABILITY OF THERMOHALINE STRUCTURE AND CIRCULATION IDENTIFIED FROM OBSERVATIONAL (T, S) PROFILES Hyewon Choi

  17. 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.

  18. Somal size of prefrontal cortical pyramidal neurons in schizophrenia: differential effects across neuronal subpopulations.

    Science.gov (United States)

    Pierri, Joseph N; Volk, Christine L E; Auh, Sungyoung; Sampson, Allan; Lewis, David A

    2003-07-15

    Cognitive dysfunction in schizophrenia may be related to morphologic abnormalities of pyramidal neurons in the dorsal prefrontal cortex (dPFC) and the largest pyramidal neurons in deep layer 3 may be most affected. Immunoreactivity (IR) for the nonphosphorylated epitopes of neurofilament protein (NNFP) identifies a subset of large dPFC deep layer 3 pyramidal neurons. We tested the hypotheses that the average size of NNFP-IR neurons is smaller in schizophrenia and that the decrease in size of these neurons is greater than that observed in the general population of deep layer 3 pyramidal neurons. We estimated the mean somal volume of NNFP-IR neurons in deep layer 3 of 9 in 13 matched pairs of control and schizophrenia subjects and compared the differences in somal size of NNFP-IR neurons to the differences in size of all deep layer 3 pyramidal neurons identified in Nissl-stained material. In subjects with schizophrenia, the somal volume of NNFP-IR neurons was nonsignificantly decreased by 6.6%, whereas that of the Nissl-stained pyramidal neurons was significantly decreased by 14.2%. These results suggest that the NNFP-IR subpopulation of dPFC pyramidal neurons are not preferentially affected in schizophrenia. Thus, a subpopulation of dPFC deep layer 3 pyramidal neurons, other than those identified by NNFP-IR, may be selectively vulnerable in schizophrenia.

  19. Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases.

    Science.gov (United States)

    Grunert, Marcel; Dorn, Cornelia; Cui, Huanhuan; Dunkel, Ilona; Schulz, Kerstin; Schoenhals, Sophia; Sun, Wei; Berger, Felix; Chen, Wei; Sperling, Silke R

    2016-10-01

    For the majority of congenital heart diseases (CHDs), the full complexity of the causative molecular network, which is driven by genetic, epigenetic, and environmental factors, is yet to be elucidated. Epigenetic alterations are suggested to play a pivotal role in modulating the phenotypic expression of CHDs and their clinical course during life. Candidate approaches implied that DNA methylation might have a developmental role in CHD and contributes to the long-term progress of non-structural cardiac diseases. The aim of the present study is to define the postnatal epigenome of two common cardiac malformations, representing epigenetic memory, and adaption to hemodynamic alterations, which are jointly relevant for the disease course. We present the first analysis of genome-wide DNA methylation data obtained from myocardial biopsies of Tetralogy of Fallot (TOF) and ventricular septal defect patients. We defined stringent sets of differentially methylated regions between patients and controls, which are significantly enriched for genomic features like promoters, exons, and cardiac enhancers. For TOF, we linked DNA methylation with genome-wide expression data and found a significant overlap for hypermethylated promoters and down-regulated genes, and vice versa. We validated and replicated the methylation of selected CpGs and performed functional assays. We identified a hypermethylated novel developmental CpG island in the promoter of SCO2 and demonstrate its functional impact. Moreover, we discovered methylation changes co-localized with novel, differential splicing events among sarcomeric genes as well as transcription factor binding sites. Finally, we demonstrated the interaction of differentially methylated and expressed genes in TOF with mutated CHD genes in a molecular network. By interrogating DNA methylation and gene expression data, we identify two novel mechanism contributing to the phenotypic expression of CHDs: aberrant methylation of promoter CpG islands

  20. 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.

  1. Practical implementation of the corrected force analysis technique to identify the structural parameter and load distributions

    Science.gov (United States)

    Leclère, Quentin; Ablitzer, Frédéric; Pézerat, Charles

    2015-09-01

    The paper aims to combine two objectives of the Force Analysis Technique (FAT): vibration source identification and material characterization from the same set of measurement. Initially, the FAT was developed for external load location and identification. It consists in injecting measured vibration displacements in the discretized equation of motion. Two developments exist: FAT and CFAT (Corrected Force Analysis Technique) where two finite difference schemes are used. Recently, the FAT was adapted for the identification of elastic and damping properties in a structure. The principal interests are that the identification is local and allows mapping of material characteristics, the identification can be made at all frequencies, especially in medium and high frequency domains. The paper recalls the development of FAT and CFAT on beams and plates and how it can be possible to extract material characteristics in areas where no external loads are applied. Experimental validations are shown on an aluminum plate with arbitrary boundary conditions, excited by a point force and where a piece of foam is glued on a sub-surface of the plate. Contactless measurements were made using a scanning laser vibrometer. The results of FAT and CFAT are compared and discussed for material property identifications in the regions with and without foam. The excitation force identification is finally made by using the identified material properties. CFAT gives excellent results comparable to a direct measurement obtained by a piezoelectric sensor. The relevance of the corrected scheme is then underlined for both source identification and material characterization from the same measurements.

  2. 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

    2017-10-23

    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]; Mage = 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 (χ2 = 66.09, df = 28, p medicinal cannabis and other subpopulations of cannabis users.

  3. 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.

  4. Enhanced generation of induced pluripotent stem cells from a subpopulation of human fibroblasts.

    Directory of Open Access Journals (Sweden)

    James A Byrne

    Full Text Available BACKGROUND: The derivation of induced pluripotent stem cells (iPSCs provides new possibilities for basic research and novel cell-based therapies. Limitations, however, include our current lack of understanding regarding the underlying mechanisms and the inefficiency of reprogramming. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report identification and isolation of a subpopulation of human dermal fibroblasts that express the pluripotency marker stage specific embryonic antigen 3 (SSEA3. Fibroblasts that expressed SSEA3 demonstrated an enhanced iPSC generation efficiency, while no iPSC derivation was obtained from the fibroblasts that did not express SSEA3. Transcriptional analysis revealed NANOG expression was significantly increased in the SSEA3 expressing fibroblasts, suggesting a possible mechanistic explanation for the differential reprogramming. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this study is the first to identify a pluripotency marker in a heterogeneous population of human dermal fibroblasts, to isolate a subpopulation of cells that have a significantly increased propensity to reprogram to pluripotency and to identify a possible mechanism to explain this differential reprogramming. This discovery provides a method to significantly increase the efficiency of reprogramming, enhancing the feasibility of the potential applications based on this technology, and a tool for basic research studies to understand the underlying reprogramming mechanisms.

  5. 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....

  6. Using multilevel models to identify drivers of landscape-genetic structure among management areas.

    Science.gov (United States)

    Dudaniec, Rachael Y; Rhodes, Jonathan R; Worthington Wilmer, Jessica; Lyons, Mitchell; Lee, Kristen E; McAlpine, Clive A; Carrick, Frank N

    2013-07-01

    Landscape genetics offers a powerful approach to understanding species' dispersal patterns. However, a central obstacle is to account for ecological processes operating at multiple spatial scales, while keeping research outcomes applicable to conservation management. We address this challenge by applying a novel multilevel regression approach to model landscape drivers of genetic structure at both the resolution of individuals and at a spatial resolution relevant to management (i.e. local government management areas: LGAs) for the koala (Phascolartos cinereus) in Australia. Our approach allows for the simultaneous incorporation of drivers of landscape-genetic relationships operating at multiple spatial resolutions. Using microsatellite data for 1106 koalas, we show that, at the individual resolution, foliage projective cover (FPC) facilitates high gene flow (i.e. low resistance) until it falls below approximately 30%. Out of six additional land-cover variables, only highways and freeways further explained genetic distance after accounting for the effect of FPC. At the LGA resolution, there was significant variation in isolation-by-resistance (IBR) relationships in terms of their slopes and intercepts. This was predominantly explained by the average resistance distance among LGAs, with a weaker effect of historical forest cover. Rates of recent landscape change did not further explain variation in IBR relationships among LGAs. By using a novel multilevel model, we disentangle the effect of landscape resistance on gene flow at the fine resolution (i.e. among individuals) from effects occurring at coarser resolutions (i.e. among LGAs). This has important implications for our ability to identify appropriate scale-dependent management actions. © 2013 John Wiley & Sons Ltd.

  7. B-cell subpopulations from normal human secondary lymphoid tissues with specific gene expression profiles and phenotypes

    DEFF Research Database (Denmark)

    Johnsen, Hans Erik; Schmitz, Alexander; Perez Andres, Martin

    In order to improve insights into the B-cell biology and thereby B-cell myelomagenesis we have established a MSCNET standard for multiparametric flow cytometry (MFC) and cell sorting (FACS) for subsequent genetic analysis. The material analysed was fresh tonsils, blood and bone marrow. The method...... and single gene expression analysis (qRT-PCR) for transcription factors as well as global gene expression profiling (GEP; GeneChip Human Exon 1.0 ST Array). For example for tonsils, based on the immunophenotypic presentation (including CD3/44/CXCR4 in the panel), B-cell subsets were identified and sorted......-cell subpopulations identified have distinct gene expression profiles reflecting their functions but also revealing genes with subpopulation specific exon splicing. In conclusion a combination of surface markers expressed antigens and gene expression analysis of B cell subsets confirm a strong methodology to be used...

  8. Genomic epidemiology of Lineage 4 Mycobacterium tuberculosis subpopulations in New York City and New Jersey, 1999-2009.

    Science.gov (United States)

    Brown, Tyler S; Narechania, Apurva; Walker, John R; Planet, Paul J; Bifani, Pablo J; Kolokotronis, Sergios-Orestis; Kreiswirth, Barry N; Mathema, Barun

    2016-11-21

    Whole genome sequencing (WGS) has rapidly become an important research tool in tuberculosis epidemiology and is likely to replace many existing methods in public health microbiology in the near future. WGS-based methods may be particularly useful in areas with less diverse Mycobacterium tuberculosis populations, such as New York City, where conventional genotyping is often uninformative and field epidemiology often difficult. This study applies four candidate strategies for WGS-based identification of emerging M. tuberculosis subpopulations, employing both phylogenomic and population genetics methods. M. tuberculosis subpopulations in New York City and New Jersey can be distinguished via phylogenomic reconstruction, evidence of demographic expansion and subpopulation-specific signatures of selection, and by determination of subgroup-defining nucleotide substitutions. These methods identified known historical outbreak clusters and previously unidentified subpopulations within relatively monomorphic M. tuberculosis endemic clone groups. Neutrality statistics based on the site frequency spectrum were less useful for identifying M. tuberculosis subpopulations, likely due to the low levels of informative genetic variation in recently diverged isolate groups. In addition, we observed that isolates from New York City endemic clone groups have acquired multiple non-synonymous SNPs in virulence- and growth-associated pathways, and relatively few mutations in drug resistance-associated genes, suggesting that overall pathoadaptive fitness, rather than the acquisition of drug resistance mutations, has played a central role in the evolutionary history and epidemiology of M. tuberculosis subpopulations in New York City. Our results demonstrate that some but not all WGS-based methods are useful for detection of emerging M. tuberculosis clone groups, and support the use of phylogenomic reconstruction in routine tuberculosis laboratory surveillance, particularly in areas with

  9. 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...... substrate uptake, CO2 production, and NH3 uptake for biomass growth. The structural identifiability was studied using the Taylor series method and a recently proposed generalization method. It showed that combining respirometric and titrimetric data allows structural identifiability of one extra parameter...... combination, the biomass yield, Y-H, compared to estimation on separate data sets, on condition that the nitrogen fraction in biomass (i(XB)) is known. However, data from short-term batch substrate degradation experiments were not sufficiently informative to allow practical identification of all structurally...

  10. Identifying blue whiting (Micromesistius poutassou) stock structure in the Northeast Atlantic by otolith shape analysis

    DEFF Research Database (Denmark)

    Mahe, Kélig; Oudard, Clémence; Mille, Tiphaine

    2016-01-01

    Information on stock identification and spatial stock structure provide a basis for understanding fish population dynamics and improving fisheries management. In this study, otolith shape analysis was used to study the stock structure of blue whiting (Micromesistius poutassou) in the northeast At...

  11. Genetic Characterization Indicates that a Specific Subpopulation of Pseudomonas aeruginosa Is Associated with Keratitis Infections▿

    Science.gov (United States)

    Stewart, Rosalind M. K.; Wiehlmann, Lutz; Ashelford, Kevin E.; Preston, Stephanie J.; Frimmersdorf, Eliane; Campbell, Barry J.; Neal, Timothy J.; Hall, Neil; Tuft, Stephen; Kaye, Stephen B.; Winstanley, Craig

    2011-01-01

    Pseudomonas aeruginosa is a common opportunistic bacterial pathogen that causes a variety of infections in humans. Populations of P. aeruginosa are dominated by common clones that can be isolated from diverse clinical and environmental sources. To determine whether specific clones are associated with corneal infection, we used a portable genotyping microarray system to analyze a set of 63 P. aeruginosa isolates from patients with corneal ulcers (keratitis). We then used population analysis to compare the keratitis isolates to a wider collection of P. aeruginosa from various nonocular sources. We identified various markers in a subpopulation of P. aeruginosa associated with keratitis that were in strong disequilibrium with the wider P. aeruginosa population, including oriC, exoU, katN, unmodified flagellin, and the carriage of common genomic islands. The genome sequencing of a keratitis isolate (39016; representing the dominant serotype O11), which was associated with a prolonged clinical healing time, revealed several genomic islands and prophages within the accessory genome. The PCR amplification screening of all 63 keratitis isolates, however, provided little evidence for the shared carriage of specific prophages or genomic islands between serotypes. P. aeruginosa twitching motility, due to type IV pili, is implicated in corneal virulence. We demonstrated that 46% of the O11 keratitis isolates, including 39016, carry a distinctive pilA, encoding the pilin of type IV pili. Thus, the keratitis isolates were associated with specific characteristics, indicating that a subpopulation of P. aeruginosa is adapted to cause corneal infection. PMID:21227987

  12. Chemical communication of antibiotic resistance by a highly resistant subpopulation of bacterial cells.

    Directory of Open Access Journals (Sweden)

    Omar M El-Halfawy

    Full Text Available The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB and also other bactericidal antibiotics. Here, we report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling also identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of polymyxin B than the rest of the cells in the culture, and can protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low-molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to polymyxin B. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. We propose that putrescine and YceI resemble "danger" infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species.

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

    Science.gov (United States)

    Sloma, Michael F; Mathews, David H

    2016-12-01

    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. © 2016 Sloma and Mathews; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  14. Emergent patterns in interacting neuronal sub-populations

    Science.gov (United States)

    Kamal, Neeraj Kumar; Sinha, Sudeshna

    2015-05-01

    We investigate an ensemble of coupled model neurons, consisting of groups of varying sizes and intrinsic dynamics, ranging from periodic to chaotic, where the inter-group coupling interaction is effectively like a dynamic signal from a different sub-population. We observe that the minority group can significantly influence the majority group. For instance, when a small chaotic group is coupled to a large periodic group, the chaotic group de-synchronizes. However, counter-intuitively, when a small periodic group couples strongly to a large chaotic group, it leads to complete synchronization in the majority chaotic population, which also spikes at the frequency of the small periodic group. It then appears that the small group of periodic neurons can act like a pacemaker for the whole network. Further, we report the existence of varied clustering patterns, ranging from sets of synchronized clusters to anti-phase clusters, governed by the interplay of the relative sizes and dynamics of the sub-populations. So these results have relevance in understanding how a group can influence the synchrony of another group of dynamically different elements, reminiscent of event-related synchronization/de-synchronization in complex networks.

  15. Trypanosoma cruzi: effect of parasite subpopulation on murine pregnancy outcome.

    Science.gov (United States)

    Solana, María Elisa; Celentano, Ana María; Tekiel, Valeria; Jones, Marta; González Cappa, Stella Maris

    2002-02-01

    C3H/HeN female mice infected with distinct Trypanosoma cruzi subpopulations (RA strain [pantropic/reticulotropic] and K98 clone of the CA-I strain [myotropic]) show differences both in inflammatory compromise of the genital tract and in the outcome of pregnancy. The group of mice infected with the K98 clone show lymphomononuclear infiltrates in pelvian fat and in uterus interstitium, coexisting with the presence of T. cruzi DNA, and show moderate oophoritis, perioophoritis, and vasculitis. However, neither parasite DNA nor inflammatory foci were detected in the uterus, and only mild oophoritis was observed among RA-infected mice at mating time. Independently from the parasite subpopulation, females developed estrous 30 days postinoculation (PI), and at the same time, parasite counts were similar for K98 and for RA-infected mice. However, fertility was significantly diminished in K98-infected females. On day 14 of gestation, fetal resorptions increased in this group and cannot be attributed to hormonal disbalance because similar serum progesterone levels were found in all groups. At this time (44 days PI), parasitemia was higher in K98- than in RA-infected mice. However, resorptions were not triggered by massive infection because polymerase chain reaction failed to prove parasite DNA in resorbing fetuses. In contrast with K98 females, RA-infected mice delivered T. cruzi-infected newborns.

  16. Use of structured and unstructured data to identify contraceptive use in women veterans.

    Science.gov (United States)

    Womack, Julie A; Scotch, Matthew; Leung, Sylvia N; Skanderson, Melissa; Bathulapalli, Harini; Haskell, Sally G; Brandt, Cynthia A

    2013-01-01

    Contraceptive use among women Veterans may not be adequately captured using administrative and pharmacy codes. Clinical progress notes may provide a useful alternative. The objectives of this study were to validate the use of administrative and pharmacy codes to identify contraceptive use in Veterans Health Administration data, and to determine the feasibility and validity of identifying contraceptive use in clinical progress notes. The study included women Veterans who participated in the Women Veterans Cohort Study, enrolled in the Veterans Affairs Connecticut Health Care System, completed a baseline survey, and had clinical progress notes from one year prior to survey completion. Contraceptive ICD-9-CM codes, V-codes, CPT codes, and pharmacy codes were identified. Progress notes were annotated to identify contraceptive use. Self-reported contraceptive use was identified from a baseline survey of health habits and healthcare practices and utilization. Sensitivity, specificity, and positive predictive value were calculated comparing administrative and pharmacy contraceptive codes and progress note-based contraceptive information to self-report survey data. Results showed that administrative and pharmacy codes were specific but not sensitive for identifying contraceptive use. For example, oral contraceptive pill codes were highly specific (1.00) but not sensitive (0.41). Data from clinical progress notes demonstrated greater sensitivity and comparable specificity. For example, for oral contraceptive pills, progress notes were both specific (0.85) and sensitive (0.73). Results suggest that the best approach for identifying contraceptive use, through either administrative codes or progress notes, depends on the research question.

  17. 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.

  18. A fast virtual screening approach to identify structurally diverse inhibitors of trypanothione reductase.

    Science.gov (United States)

    Maccari, Giorgio; Jaeger, Timo; Moraca, Francesca; Biava, Mariangela; Flohé, Leopold; Botta, Maurizio

    2011-09-15

    Trypanothione reductase (TryR) is one of the favorite targets for those designing drugs for the treatment of Chagas disease. We present the application of a fast virtual screening approach for designing hit compounds active against TryR. Our protocol combines information derived from structurally known inhibitors and from the TryR receptor structure. Five structurally diverse hit compounds active against TryR and holding promise for the treatment of Chagas disease are reported. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. 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.

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

    OpenAIRE

    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 pop...

  1. 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

  2. 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

  3. 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

    2016-01-01

    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

  4. Retrospective Validation of a Structure-Based Virtual Screening Protocol to Identify Ligands for Estrogen Receptor Alpha and Its Application to Identify the Alpha-Mangostin Binding Pose

    Directory of Open Access Journals (Sweden)

    Agustina Setiawati

    2014-07-01

    Full Text Available The publicly available enhanced data of ligands and decoys for estrogen receptor alpha (ERα which were recently published has made the retrospective validation of a structure-based virtual screening (SBVS protocol to identify ligands for ERα possible. In this article, we present the retrospective validation of an SBVS protocol using PLANTS molecular docking software version 1.2 (PLANTS1.2 as the backbone software. The protocol shows better enrichment factor at 1% false positives (EF1% value and the Area Under Curve (AUC value of the Receiver Operator Characteristic (ROC compared to the original published protocol. Moreover, in all 1000 iterative attempts the protocol could reproduce the co-crystal pose of 4-hydroxitamoxifen in ERα binding pocket. It shows that the protocol is not only able to identify potent ligands for ERα but also able to be employed in examining binding pose of known ligand. Thence, the protocol was successfully employed to examine the binding poses of α-mangostin, an ERα ligand found in the Garcinia mangostana, L. pericarp.

  5. 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.

  6. Exploitation of speculation markers to identify the structure of biomedical scientific writing.

    Science.gov (United States)

    Grabar, Natalia; Hamon, Thierry

    2009-11-14

    The motivation of this work is to study the use of speculation markers within scientific writing: this may be useful for discovering whether these markers are regularly spread across biomedical articles and then for establishing the logical structure of articles. To achieve these objectives, we compute associations between article sections and speculation markers. We use machine learning algorithms to show that there are strong and interesting associations between speculation markers and article structure. For instance, strong markers, which strongly influence the presentation of knowledge, are specific to Results, Discussion and Abstract; while non strong markers appear with higher regularity within Material and Methods. Our results indicate that speculation is governed by observable usage rules within scientific articles and can help their structuring.

  7. Identifying dynamic membrane structures with atomic-force microscopy and confocal imaging.

    Science.gov (United States)

    Timmel, Tobias; Schuelke, Markus; Spuler, Simone

    2014-04-01

    Combining the biological specificity of fluorescence microscopy with topographical features revealed by atomic force microscopy (AFM) provides new insights into cell biology. However, the lack of systematic alignment capabilities especially in scanning-tip AFM has limited the combined application approach as AFM drift leads to increasing image mismatch over time. We present an alignment correction method using the cantilever tip as a reference landmark. Since the precise tip position is known in both the fluorescence and AFM images, exact re-alignment becomes possible. We used beads to demonstrate the validity of the method in a complex artificial sample. We then extended this method to biological samples to depict membrane structures in fixed and living human fibroblasts. We were able to map nanoscale membrane structures, such as clathrin-coated pits, to their respective fluorescent spots. Reliable alignment between fluorescence signals and topographic structures opens possibilities to assess key biological processes at the cell surface such as endocytosis and exocytosis.

  8. Methods for Identifying Ligands that Target Nucleic Acid Molecules and Nucleic Acid Structural Motifs

    Science.gov (United States)

    Disney, Matthew D. (Inventor); Childs-Disney, Jessica L. (Inventor)

    2017-01-01

    Disclosed are methods for identifying a nucleic acid (e.g., RNA, DNA, etc.) motif which interacts with a ligand. The method includes providing a plurality of ligands immobilized on a support, wherein each particular ligand is immobilized at a discrete location on the support; contacting the plurality of immobilized ligands with a nucleic acid motif library under conditions effective for one or more members of the nucleic acid motif library to bind with the immobilized ligands; and identifying members of the nucleic acid motif library that are bound to a particular immobilized ligand. Also disclosed are methods for selecting, from a plurality of candidate ligands, one or more ligands that have increased likelihood of binding to a nucleic acid molecule comprising a particular nucleic acid motif, as well as methods for identifying a nucleic acid which interacts with a ligand.

  9. A Bayesian approach to identifying structural nonlinearity using free-decay response: Application to damage detection in composites

    Science.gov (United States)

    Nichols, J.M.; Link, W.A.; Murphy, K.D.; Olson, C.C.

    2010-01-01

    This work discusses a Bayesian approach to approximating the distribution of parameters governing nonlinear structural systems. Specifically, we use a Markov Chain Monte Carlo method for sampling the posterior parameter distributions thus producing both point and interval estimates for parameters. The method is first used to identify both linear and nonlinear parameters in a multiple degree-of-freedom structural systems using free-decay vibrations. The approach is then applied to the problem of identifying the location, size, and depth of delamination in a model composite beam. The influence of additive Gaussian noise on the response data is explored with respect to the quality of the resulting parameter estimates.

  10. Embryonic Stem Cell-Like Subpopulations in Venous Malformation

    Directory of Open Access Journals (Sweden)

    Elysia M. S. Tan

    2017-10-01

    Full Text Available BackgroundVenous malformation (VM consists of a network of ectatic anomalous thin-walled venous channels. A role for an activating TIE2 mutation in the development of the dilated luminal vessels in VM, and its proposed involvement of embryonic stem cells (ESCs, led us to investigate the expression of ESC markers in subcutaneous VM (SCVM and intramuscular VM (IMVM.MethodsFormalin-fixed paraffin-embedded sections of SCVM from seven patients and IMVM samples from seven patients were analyzed for the expression of Nanog, pSTAT3, OCT4, SOX2, SALL4, and CD44, using 3,3′-diaminobenzidine (DAB immunohistochemical (IHC staining. All these samples did not express lymphatic marker D2-40. NanoString mRNA analysis and RT-PCR were performed on snap-frozen samples of SCVM (n = 3 and IMVM (n = 3 from the respective original cohorts of patients included in DAB IHC staining. To confirm co-expression of two proteins, immunofluorescent (IF IHC staining on two representative samples of IMVM and SCVM samples from the original cohorts of patients included for DAB IHC staining was performed.ResultsDAB IHC staining demonstrated expression of all of the above ESC markers in both SCVM and IMVM samples. IF IHC staining showed that these markers were localized to the endothelium within these lesions and that Nanog, pSTAT3, SOX2, and CD44 were also expressed by cells outside of the endothelium. NanoString mRNA analysis confirmed transcription activation of pSTAT3, OCT4, and CD44. RT-qPCR confirmed transcription activation of Nanog, SOX2, and SALL4.ConclusionOur findings support the presence of two ESC-like subpopulations, one within and one outside of the endothelium, of both SCVM and IMVM. Given that the endothelial ESC-like subpopulation expresses the more primitive marker, OCT4, it is exciting to speculate that they give rise to the non-endothelial subpopulation.

  11. Density dependence in an age-structured population of great tits: identifying the critical age classes

    NARCIS (Netherlands)

    Gamelon, M.; Grotan, V.; Engen, S.; Bjørkvoll, E.; Visser, M.E.; Sæther, Bernt-Erik

    2016-01-01

    Classical approaches for the analyses of density dependence assume that all the individuals in a population equally respond and equally contribute to density dependence. However, in age-structured populations, individuals of different ages may differ in their responses to changes in population size

  12. Identifying Atomic Structure as a Threshold Concept: Student Mental Models and Troublesomeness

    Science.gov (United States)

    Park, Eun Jung; Light, Gregory

    2009-01-01

    Atomic theory or the nature of matter is a principal concept in science and science education. This has, however, been complicated by the difficulty students have in learning the concept and the subsequent construction of many alternative models. To understand better the conceptual barriers to learning atomic structure, this study explores the…

  13. 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 importance of considering regional differences in studies of population structure, even when strong isolation-by-distance influences the genetic population structure of species.

  14. Identifying and characterising the different structural length scales in liquids and glasses: an experimental approach.

    Science.gov (United States)

    Salmon, Philip S; Zeidler, Anita

    2013-10-07

    The structure of several network-forming liquids and glasses is considered, where a focus is placed on the detailed information that is made available by using the method of neutron diffraction with isotope substitution (NDIS). In the case of binary network glass-forming materials with the MX2 stoichiometry (e.g. GeO2, GeSe2, ZnCl2), two different length scales at distances greater than the nearest-neighbour distance manifest themselves by peaks in the measured diffraction patterns. The network properties are influenced by a competition between the ordering on these "intermediate" and "extended" length scales, which can be manipulated by changing the chemical identity of the atomic constituents or by varying state parameters such as the temperature and pressure. The extended-range ordering, which describes the decay of the pair-correlation functions at large-r, can be represented by making a pole analysis of the Ornstein-Zernike equations, an approach that can also be used to describe the large-r behaviour of the pair-correlation functions for liquid and amorphous metals where packing constraints are important. The first applications are then described of the NDIS method to measure the detailed structure of aerodynamically-levitated laser-heated droplets of "fragile" glass-forming liquid oxides (CaAl2O4 and CaSiO3) at high-temperatures (~2000 K) and the structure of a "strong" network-forming glass (GeO2) under pressures ranging from ambient to ~8 GPa. The high-temperature experiments show structural changes on multiple length scales when the oxides are vitrified. The high-pressure experiment offers insight into the density-driven mechanisms of network collapse in GeO2 glass, and parallels are drawn with the high-pressure behaviour of silica glass. Finally, the hydrogen-bonded network of water is considered, where the first application of the method of oxygen NDIS is used to measure the structures of light versus heavy water and a difference of approximately equal

  15. 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 aim of this study was to enhance the understanding of cultural and sample differences in the assessment of attachment by examining the factor structure of the Experiences in Close Relationships-Revised (ECR-R). The ECR-R is a self-report measure of adult roman- tic attachment dimensions....... 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...

  16. Simulation Study for Transfer of Antibiotic Resistance via Mutator Subpopulation

    DEFF Research Database (Denmark)

    Philipsen, Kirsten Riber; Christiansen, Lasse Engbo; Aarestrup, Frank Møller

    Evolution of antibiotic resistance in bacterial populations is an increasing problem having fatal consequences for treatment of diseases. Therefore it is very important to understand this evolution. Traditionally evolution is considered to happen by single point mutations, where each mutant must...... have a growth advantage over the parent strain and grow to a sufficient number before a second mutation can occur. However, when multiple mutations are necessary for development of resistance, single mutations occurring with a normal mutation rate can not always explain the observed resistance. We...... introduce an alternative hypothesis by which a subpopulation of mutators drives the evolution process. Resistance is acquired by a subpoplution of mutators, for which the mutation rate is much higher than the wild-type. If the resistance is located on a transferable plasmid it can subsequently...

  17. Chronic stress, leukocyte subpopulations, and humoral response to latent viruses

    Energy Technology Data Exchange (ETDEWEB)

    McKinnon, W.; Weisse, C.S.; Reynolds, C.P.; Bowles, C.A.; Baum, A. (Uniformed Services Univ. of the Health Sciences, Bethesda, MD (USA))

    1989-01-01

    Psychological stress has been shown to affect immune system status and function, but most studies of this relationship have focused on acute stress and/or laboratory situations. The present study compared total numbers of leukocytes and lymphocyte subpopulations (determined by flow cytometry) and antibody titers to latent and nonlatent viruses among a group of chronically stressed individuals living near the damaged Three Mile Island (TMI) nuclear power plant with those of a demographically comparable control group. Urinary catecholamine and cortisol levels were also examined. Residents of the TMI area exhibited greater numbers of neutrophils, which were positively correlated with epinephrine levels. The TMI group also exhibited fewer B lymphocytes, T-suppressor/cytotoxic lymphocytes, and natural killer cells. Antibody titers to herpes simplex were significantly different across groups as well, whereas titers to nonlatent rubella virus as well as IgG and IgM levels were comparable.

  18. Aberrations in lymphocyte subpopulations and function during psychological stress.

    Science.gov (United States)

    Dorian, B; Garfinkel, P; Brown, G; Shore, A; Gladman, D; Keystone, E

    1982-10-01

    Eight trainees in psychiatry taking their final oral fellowship examinations were compared with 16 controls to determine the effect of stress on their immune system. Two measures of stress were utilized to distinguish the highly stressed subjects from those minimally stressed. T cell subpopulations, B cell numbers, mitogen reactivity, natural killer cell activity, plaque forming cell responsiveness, antigen specific T suppressor cell activity, and hormone levels were studied 2 weeks before and 2 weeks after the exam. The results demonstrated transiently elevated numbers of T and B lymphocytes but impaired plaque forming cell and mitogen responsiveness in the highly stressed group prior to their exam which normalized later. The results support the concept that stress may significantly alter the immune response in man.

  19. Subpoblaciones con perfiles epidemiológicos y de riesgo singulares en La Habana, Cuba: diabetes, hipertensión y tabaquismo Subpopulations with particular epidemiologic profiles and risks in Havana, Cuba: diabetes, hypertension, and tobacco-related illnesses

    Directory of Open Access Journals (Sweden)

    Georgia Díaz-Perera

    2012-07-01

    described. The determining factor in defining this group is the subjective perception of their economic situation. The families in this group have the highest household density of diabetes, hypertension, and tobacco-related illnesses and are distributed among all the facilities visited. On average, the subpopulation consisted of smaller families and have between two and three years less schooling, a more negative perception of their economic situation, and an older average age, when compared to the study group as a whole. CONCLUSIONS: Subpopulations were identified with higher proportions of the disease burden and with particular risk profiles. These subpopulations exhibit certain features consistent with trends in the social structure of Cuban families that have been evolving over the past two decades.

  20. A substrate-bound structure of cyanobacterial biliverdin reductase identifies stacked substrates as critical for activity

    OpenAIRE

    Takao, Haruna; Hirabayashi, Kei; Nishigaya, Yuki; Kouriki, Haruna; Nakaniwa, Tetsuko; Hagiwara, Yoshinori; Harada, Jiro; Sato, Hideaki; Yamazaki, Toshimasa; Sakakibara, Yoichi; Suiko, Masahito; Asada, Yujiro; Takahashi, Yasuhiro; Yamamoto, Ken; Fukuyama, Keiichi

    2017-01-01

    Biliverdin reductase catalyses the last step in haem degradation and produces the major lipophilic antioxidant bilirubin via reduction of biliverdin, using NAD(P)H as a cofactor. Despite the importance of biliverdin reductase in maintaining the redox balance, the molecular details of the reaction it catalyses remain unknown. Here we present the crystal structure of biliverdin reductase in complex with biliverdin and NADP+. Unexpectedly, two biliverdin molecules, which we designated the proxim...

  1. Enzymatic Degradation Identifies Components Responsible for the Structural Properties of the Vitreous Body

    Science.gov (United States)

    Filas, Benjamen A.; Zhang, Qianru; Okamoto, Ruth J.; Shui, Ying-Bo; Beebe, David C.

    2014-01-01

    Purpose. Vitreous degeneration contributes to several age-related eye diseases, including retinal detachment, macular hole, macular traction syndrome, and nuclear cataracts. Remarkably little is understood about the molecular interactions responsible for maintaining vitreous structure. The purpose of this study was to measure the structural properties of the vitreous body after enzymatic degradation of selected macromolecules. Methods. Mechanical properties of plugs of bovine and porcine vitreous were analyzed using a rheometer. Oscillatory and extensional tests measured vitreous stiffness and adhesivity, respectively. Major structural components of the vitreous were degraded by incubation overnight in collagenase, trypsin, or hyaluronidase, singly or in combination. Vitreous bodies were also incubated in hyper- or hypotonic saline. Effects of these treatments on the mechanical properties of the vitreous were measured by rheometry. Results. Enzymatic digestion of each class of macromolecules decreased the stiffness of bovine vitreous by approximately half (P vitreous (P vitreous and increased adhesivity. Collagen degradation resulted in the opposite effect, whereas digestion of proteins and proteoglycans with trypsin did not alter behavior relative to controls. Osmotic perturbations and double-enzyme treatments further implicated hyaluronan and hyaluronan-associated water as a primary regulator of adhesivity and material behavior in extension. Conclusions. Collagen, hyaluronan, and proteoglycans act synergistically to maintain vitreous stiffness. Hyaluronan is a key mediator of vitreous adhesivity, and mechanical damping is an important factor influencing dynamic vitreous behavior. PMID:24222300

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

    Science.gov (United States)

    Holme, Petter; Huss, Mikael; Lee, Sang Hoon

    2011-05-06

    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.

  4. 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.

  5. Identifying the factor structure of the SOCRATES in a sample of Latino adolescents.

    Science.gov (United States)

    Burrow-Sanchez, Jason J

    2014-03-01

    The Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) is a frequently used measure to assess client motivation to change an alcohol use problem. The factor structure of this measure has most extensively been studied in samples of adult clients with alcohol use disorders with very little research conducted with adolescents or ethnic minority participants. The purpose of the current study is to determine if the factor structure of the SOCRATES (Version 8A-Alcohol) found in prior research can be generalized to a sample of Latino adolescents with substance use disorders. Latino adolescents (N = 106) were administered the SOCRATES and assessed for alcohol use at a pretreatment baseline assessment as part of a larger study. Competing factor models were tested and results via confirmatory factor analysis indicated that a 14-item two factor model best fit the data for the Latino adolescents in this sample. In addition, scores on the Taking Steps factor predicted alcohol use variables. Implications for these results and suggestions for further research are discussed.

  6. Identifying Driver Nodes in the Human Signaling Network Using Structural Controllability Analysis.

    Science.gov (United States)

    Liu, Xueming; Pan, Linqiang

    2015-01-01

    Cell signaling governs the basic cellular activities and coordinates the actions in cell. Abnormal regulations in cell signaling processing are responsible for many human diseases, such as diabetes and cancers. With the accumulation of massive data related to human cell signaling, it is feasible to obtain a human signaling network. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis to biological networks. In this work, we apply structural controllability to a human signaling network and detect driver nodes, providing a systematic analysis of the role of different proteins in controlling the human signaling network. We find that the proteins in the upstream of the signaling information flow and the low in-degree proteins play a crucial role in controlling the human signaling network. Interestingly, inputting different control signals on the regulators of the cancer-associated genes could cost less than controlling the cancer-associated genes directly in order to control the whole human signaling network in the sense that less drive nodes are needed. This research provides a fresh perspective for controlling the human cell signaling system.

  7. Identifying Similar Patterns of Structural Flexibility in Proteins by Disorder Prediction and Dynamic Programming

    Directory of Open Access Journals (Sweden)

    Aidan Petrovich

    2015-06-01

    Full Text Available Computational methods are prevailing in identifying protein intrinsic disorder. The results from predictors are often given as per-residue disorder scores. The scores describe the disorder propensity of amino acids of a protein and can be further represented as a disorder curve. Many proteins share similar patterns in their disorder curves. The similar patterns are often associated with similar functions and evolutionary origins. Therefore, finding and characterizing specific patterns of disorder curves provides a unique and attractive perspective of studying the function of intrinsically disordered proteins. In this study, we developed a new computational tool named IDalign using dynamic programming. This tool is able to identify similar patterns among disorder curves, as well as to present the distribution of intrinsic disorder in query proteins. The disorder-based information generated by IDalign is significantly different from the information retrieved from classical sequence alignments. This tool can also be used to infer functions of disordered regions and disordered proteins. The web server of IDalign is available at (http://labs.cas.usf.edu/bioinfo/service.html.

  8. Identifying Similar Patterns of Structural Flexibility in Proteins by Disorder Prediction and Dynamic Programming.

    Science.gov (United States)

    Petrovich, Aidan; Borne, Adam; Uversky, Vladimir N; Xue, Bin

    2015-06-16

    Computational methods are prevailing in identifying protein intrinsic disorder. The results from predictors are often given as per-residue disorder scores. The scores describe the disorder propensity of amino acids of a protein and can be further represented as a disorder curve. Many proteins share similar patterns in their disorder curves. The similar patterns are often associated with similar functions and evolutionary origins. Therefore, finding and characterizing specific patterns of disorder curves provides a unique and attractive perspective of studying the function of intrinsically disordered proteins. In this study, we developed a new computational tool named IDalign using dynamic programming. This tool is able to identify similar patterns among disorder curves, as well as to present the distribution of intrinsic disorder in query proteins. The disorder-based information generated by IDalign is significantly different from the information retrieved from classical sequence alignments. This tool can also be used to infer functions of disordered regions and disordered proteins. The web server of IDalign is available at (http://labs.cas.usf.edu/bioinfo/service.html).

  9. 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.

  10. Single nucleotide polymorphisms that differentiate two subpopulations of Salmonella enteritidis within phage type

    Science.gov (United States)

    2011-01-01

    Background Salmonella Enteritidis is currently the world's leading cause of salmonellosis, in part because of its ability to contaminate the internal contents of eggs. Previous analyses have shown that it is an exceptionally clonal serotype, which nonetheless generates considerable phenotypic heterogeneity. Due to its clonality, whole genome analysis is required to find genetic determinants that contribute to strain heterogeneity of Salmonella Enteritidis. Comparative whole genome mutational mapping of two PT13a strains that varied in the ability to contaminate eggs and to form biofilm was achieved using a high-density tiling platform with primers designed from a PT4 reference genome. Confirmatory Sanger sequencing was used on each putative SNP identified by mutational mapping to confirm its presence and location as compared to the reference sequence. High coverage pyrosequencing was used as a supporting technology to review results. Results A total of 250 confirmed SNPs were detected that differentiated the PT13a strains. From these 250 SNPS, 247 were in the chromosome and 3 were in the large virulence plasmid. SNPs ranged from single base pair substitutions to a deletion of 215 bp. A total of 15 SNPs (3 in egg-contaminating PT13a 21046 and 12 in biofilm forming PT13a 21027) altered coding sequences of 16 genes. Pyrosequencing of the two PT13a subpopulations detected 8.9% fewer SNPs than were detected by high-density tiling. Deletions and ribosomal gene differences were classes of SNPs not efficiently detected by pyrosequencing. Conclusions These results increase knowledge of evolutionary trends within Salmonella enterica that impact the safety of the food supply. Results may also facilitate designing 2nd generation vaccines, because gene targets were identified that differentiate subpopulations with variant phenotypes. High-throughput genome sequencing platforms should be assessed for the ability to detect classes of SNPs equivalently, because each platform has

  11. Structural identifiability analysis of pharmacokinetic models using DAISY: semi-mechanistic gastric emptying models for 13C-octanoic acid.

    Science.gov (United States)

    Ogungbenro, Kayode; Aarons, Leon

    2011-04-01

    Structural identifiability analysis is necessary for efficient parameter estimation and it is concerned with determination of whether the parameters in a model can be identified from specified experiments with perfect input-output data. Structural identifiability analysis is very important in mathematical modelling of biological and biomedical experiments and should be considered at the design stage of these experiments. There are three possible outcomes from a structural identifiability analysis; globally/uniquely identifiable, locally/non-uniquely identifiable or non-identifiable/unidentifiable. An ideal outcome is a globally/uniquely identifiable model, however a locally/non-uniquely identifiable outcome can help to identify areas of the model or experiment that need improvement. Despite the importance of structural identifiability analysis, it is still not widely used due to the heavy computational burden involved and the lack of software. A new software package, DAISY, that implemented differential algebra for identifiability analysis was recently released. DAISY is freely available, easy to use and does not require any high-level programming skill. The (13)C-octanoic acid breath test is now widely used for assessing the rate of gastric emptying in patients. Unlike scintigraphy, which is the gold standard and is a direct measure of the rate of gastric emptying, the (13)C-octanoic acid breath test is an indirect method for assessing the rate of gastric emptying. However the (13)C-octanoic acid breath test is cheaper, safer and easy to perform. Because the rate of excretion of (13)CO(2) in breath does not only reflect the rate of gastric emptying but other processes involved between the ingestion of (13)C-octanoic acid and elimination of (13)CO(2) in breath, the parameters commonly derived from the excretion data are not direct measures of gastric emptying. The aim of this paper was to propose a new semi-mechanistic model for the analysis of (13)C-octanoic acid

  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. A substrate-bound structure of cyanobacterial biliverdin reductase identifies stacked substrates as critical for activity.

    Science.gov (United States)

    Takao, Haruna; Hirabayashi, Kei; Nishigaya, Yuki; Kouriki, Haruna; Nakaniwa, Tetsuko; Hagiwara, Yoshinori; Harada, Jiro; Sato, Hideaki; Yamazaki, Toshimasa; Sakakibara, Yoichi; Suiko, Masahito; Asada, Yujiro; Takahashi, Yasuhiro; Yamamoto, Ken; Fukuyama, Keiichi; Sugishima, Masakazu; Wada, Kei

    2017-02-07

    Biliverdin reductase catalyses the last step in haem degradation and produces the major lipophilic antioxidant bilirubin via reduction of biliverdin, using NAD(P)H as a cofactor. Despite the importance of biliverdin reductase in maintaining the redox balance, the molecular details of the reaction it catalyses remain unknown. Here we present the crystal structure of biliverdin reductase in complex with biliverdin and NADP+. Unexpectedly, two biliverdin molecules, which we designated the proximal and distal biliverdins, bind with stacked geometry in the active site. The nicotinamide ring of the NADP+ is located close to the reaction site on the proximal biliverdin, supporting that the hydride directly attacks this position of the proximal biliverdin. The results of mutagenesis studies suggest that a conserved Arg185 is essential for the catalysis. The distal biliverdin probably acts as a conduit to deliver the proton from Arg185 to the proximal biliverdin, thus yielding bilirubin.

  14. Scaling collapse and structure functions: identifying self-affinity in finite length time series

    Directory of Open Access Journals (Sweden)

    S. C. Chapman

    2005-01-01

    Full Text Available Empirical determination of the scaling properties and exponents of time series presents a formidable challenge in testing, and developing, a theoretical understanding of turbulence and other out-of-equilibrium phenomena. We discuss the special case of self affine time series in the context of a stochastic process. We highlight two complementary approaches to the differenced variable of the data: i attempting a scaling collapse of the Probability Density Functions which should then be well described by the solution of the corresponding Fokker-Planck equation and ii using structure functions to determine the scaling properties of the higher order moments. We consider a method of conditioning that recovers the underlying self affine scaling in a finite length time series, and illustrate it using a Lévy flight.

  15. Identifying the structure of near-threshold states from the line shape

    Science.gov (United States)

    Chen, Guo-Ying; Huo, Wen-Sheng; Zhao, Qiang

    2015-09-01

    We revisit the compositeness theorem proposed by Weinberg in an effective field theory (EFT) and explore criteria which are sensitive to the structure of S-wave threshold states. On a general basis, we show that the wave function renormalization constant Z, which is the probability of finding an elementary component in the wave function of a threshold state, can be explicitly introduced in the description of the threshold state. As an application of this EFT method, we describe the near-threshold line shape of the D*0D̅0 invariant mass spectrum in B→D*0D̅0K and determine a nonvanishing value of Z. It suggests that the X(3872) as a candidate of the D*0D̅0 molecule may still contain a small cc¯ core. This elementary component, on the one hand, explains its production in the B meson decay via a short-distance mechanism, and on the other hand, is correlated with the D*0D̅0 threshold enhancement observed in the D*0D̅0 invariant mass distributions. Meanwhile, we also show that if Z is non-zero, the near-threshold enhancement of the D*0D̅0 mass spectrum in the B decay will be driven by the short-distance production mechanism. Supported by National Natural Science Foundation of China (11147022, 11035006, 11305137), Chinese Academy of Sciences (KJCX2-EW-N01), Ministry of Science and Technology of China (2009CB825200), DFG and NSFC (11261130311) through funds provided to the Sino-German CRC 110 “Symmetries and the Emergence of Structure in QCD”, and Doctor Foundation of Xinjiang University (BS110104)

  16. Functional and Structural Analysis of Five Mutations Identified in Methylmalonic Aciduria cbIB Type

    Science.gov (United States)

    Jorge-Finnigan, Ana; Aguado, Cristina; Sánchez-Alcudia, Rocio; Abia, David; Richard, Eva; Merinero, Begoña; Gámez, Alejandra; Banerjee, Ruma; Desviat, Lourdes R.; Ugarte, Magdalena; Pérez, Belen

    2010-01-01

    ATP cob(I)alamin adenosyltransferase (ATR, E.C.2.5.1.17) converts reduced cob(I)alamin to the adenosylcobalamin cofactor. Mutations in the MMAB gene encoding ATR are responsible for the cblB type methylmalonic aciduria. Here we report the functional analysis of five cblB mutations to determine the underlying molecular basis of the dysfunction. The transcriptional profile along with minigenes analysis revealed that c.584G>A, c.349-1G>C and c.290G>A affect the splicing process. Wild-type ATR and the p.I96T (c.287T>C) and p.R191W (c.571C>T) mutant proteins were expressed in a prokaryote and a eukaryotic expression systems. The p.I96T protein was enzymatically active with a KM for ATP and KD for cob(I)alamin similar to wild-type enzyme, but exhibited a 40% reduction in specific activity. Both p.I96T and p.R191W mutant proteins are less stable than the wild-type protein, with increased stability when expressed under permissive folding conditions. Analysis of the oligomeric state of both mutants showed a structural defect for p.I96T and also a significant impact on the amount of recovered mutant protein that was more pronounced for p.R191W that, along with the structural analysis, suggest they might be misfolded. These results could serve as a basis for the implementation of pharmacological therapies aimed at increasing the residual activity of this type of mutations. PMID:20556797

  17. 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.

  18. Particle size-density relationships in pyroclastic deposits: using component subpopulations to elucidate depositional conditions

    Science.gov (United States)

    Mackaman-Lofland, C. A.; Brand, B. D.; Taddeucci, J.

    2012-12-01

    Pyroclastic Density Currents (PDCs) are ground-hugging currents of hot gas, ash, and rock that travel at velocities up to 150 m/s down the flanks of volcanoes. PDCs are the most dangerous hazard associated with explosive volcanic eruptions, but because of current opacity and the risk inherent to observing PDCs in real time, their processes are poorly understood. Geologists rely on depositional relationships to lend insight into PDC transport and depositional processes. Outcrop exposure is typically incomplete, however, and the extent to which outcrop-scale depositional characteristics are representative of the parent current is still uncertain. The May 18th, 1980 eruption of Mt. St. Helens (MSH) produced multiple PDCs, burying the area north of the crater under 10s of meters of PDC deposits. Deep drainage erosion over the past 30 years has exposed these deposits in three dimensions, allowing a detailed study of deposit structures to be conducted for a variety of locations and depositional regimes with distance from source. We examine the grain size distribution and density characteristics of the discrete component subpopulations that make up the solids fraction of PDC deposits, focusing on changes associated with lateral facies variation, distance from source, and degree of topographic roughness. We analyze the grain size and density relationships of the component subpopulations using sequential fragmentation / transport theory (SFT), and use crystal morphoscopy to determine how different regional transport systems effect feldspar and hornblende crystal shape following the methods of Taddeucci and Palladino ((2002) Particle size-density relationships in pyroclastic deposits: inferences for emplacement processes. Bull Volcanol 64:273-284). Calculations of representative proximal and distal samples indicate juvenile pumice densities of ~1.3g/mL, accidental lithic densities of ~2.7g/mL, and crystal densities of ~2.6g/mL. We observe a general decrease in grain size and

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

    Science.gov (United States)

    Ghiassian, Sina; Greiner, Russell; Jin, Ping; Brown, Matthew R. G.

    2016-01-01

    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 the (f

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

    Science.gov (United States)

    Ghiassian, Sina; Greiner, Russell; Jin, Ping; Brown, Matthew R G

    2016-01-01

    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 the (f

  1. 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.

  2. Characterization of a migrative subpopulation of adult human nasoseptal chondrocytes with progenitor cell features and their potential for in vivo cartilage regeneration strategies.

    Science.gov (United States)

    Elsaesser, A F; Schwarz, S; Joos, H; Koerber, L; Brenner, R E; Rotter, N

    2016-01-01

    Progenitor cells display interesting features for tissue repair and reconstruction. In the last years, such cells have been identified in different cartilage types. In this study, we isolated a migrative subpopulation of adult human nasoseptal chondrocytes with progenitor cell features by outgrowth from human nasal septum cartilage. These putative progenitor cells were comparatively characterized with mesenchymal stem cells (MSC) and human nasal septum chondrocytes with respect to their cellular characteristics as well as surface marker profile using flow cytometric analyses. Differentiation capacity was evaluated on protein and gene expression levels. The migrative subpopulation differentiated into osteogenic and chondrogenic lineages with distinct differences to chondrocytes and MSC. Cells of the migrative subpopulation showed an intermediate surface marker profile positioned between MSC and chondrocytes. Significant differences were found for CD9, CD29, CD44, CD90, CD105 and CD106. The cells possessed a high migratory ability in a Boyden chamber assay and responded to chemotactic stimulation. To evaluate their potential use in tissue engineering applications, a decellularized septal cartilage matrix was either seeded with cells from the migrative subpopulation or chondrocytes. Matrix production was demonstrated immunohistochemically and verified on gene expression level. Along with secretion of matrix metalloproteinases, cells of the migrative subpopulation migrated faster into the collagen matrix than chondrocytes, while synthesis of cartilage specific matrix was comparable. Cells of the migrative subpopulation, due to their migratory characteristics, are a potential cell source for in vivo regeneration of nasal cartilage. The in vivo mobilization of nasal cartilage progenitor cells is envisioned to be the basis for in situ tissue engineering procedures, aiming at the use of unseeded biomaterials which are able to recruit local progenitor cells for cartilage

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

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    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.

  4. Use of technology assessment databases to identify the issues associated with adoption of structural health monitoring practices.

    Energy Technology Data Exchange (ETDEWEB)

    Roach, Dennis Patrick; Smith, Bryce; Neidigk, Stephen

    2010-09-01

    The goal is to create a systematic method and structure to compile, organize, and summarize SHM related data to identify the level of maturity and rate of evolution and have a quick and ongoing evaluation of the current state of SHM among research institutions and industry. Hundreds of technical publication and conference proceedings were read and analyzed to compile the database. Microsoft Excel was used to create a useable interface that could be filtered to compare any of the entered data fields.

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

    OpenAIRE

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

    2015-01-01

    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 targe...

  6. Using structured and unstructured data to identify patients' need for services that address the social determinants of health.

    Science.gov (United States)

    Vest, Joshua R; Grannis, Shaun J; Haut, Dawn P; Halverson, Paul K; Menachemi, Nir

    2017-11-01

    Increasingly, health care providers are adopting population health management approaches that address the social determinants of health (SDH). However, effectively identifying patients needing services that address a SDH in primary care settings is challenging. The purpose of the current study is to explore how various data sources can identify adult primary care patients that are in need of services that address SDH. A cross-sectional study described patients in need of SDH services offered by a safety-net hospital's federally qualified health center clinics. SDH services of social work, behavioral health, nutrition counseling, respiratory therapy, financial planning, medical-legal partnership assistance, patient navigation, and pharmacist consultation were offered on a co-located basis and were identified using structured billing and scheduling data, and unstructured electronic health record data. We report the prevalence of the eight different SDH service needs and the patient characteristics associated with service need. Moreover, characteristics of patients with SDH services need documented in structured data sources were compared with those documented by unstructured data sources. More than half (53%) of patients needed SDH services. Those in need of such services tended to be female, older, more medically complex, and higher utilizers of services. Structured and unstructured data sources exhibited poor agreement on patient SDH services need. Patients with SDH services need documented by unstructured data tended to be more complex. The need for SDH services among a safety-net population is high. Identifying patients in need of such services requires multiple data sources with structured and unstructured data. Copyright © 2017. Published by Elsevier B.V.

  7. ROC and confusion analysis of structure comparison methods identify the main causes of divergence from manual protein classification

    Directory of Open Access Journals (Sweden)

    Gibrat Jean-Francois

    2006-04-01

    Full Text Available Abstract Background Current classification of protein folds are based, ultimately, on visual inspection of similarities. Previous attempts to use computerized structure comparison methods show only partial agreement with curated databases, but have failed to provide detailed statistical and structural analysis of the causes of these divergences. Results We construct a map of similarities/dissimilarities among manually defined protein folds, using a score cutoff value determined by means of the Receiver Operating Characteristics curve. It identifies folds which appear to overlap or to be "confused" with each other by two distinct similarity measures. It also identifies folds which appear inhomogeneous in that they contain apparently dissimilar domains, as measured by both similarity measures. At a low (1% false positive rate, 25 to 38% of domain pairs in the same SCOP folds do not appear similar. Our results suggest either that some of these folds are defined using criteria other than purely structural consideration or that the similarity measures used do not recognize some relevant aspects of structural similarity in certain cases. Specifically, variations of the "common core" of some folds are severe enough to defeat attempts to automatically detect structural similarity and/or to lead to false detection of similarity between domains in distinct folds. Structures in some folds vary greatly in size because they contain varying numbers of a repeating unit, while similarity scores are quite sensitive to size differences. Structures in different folds may contain similar substructures, which produce false positives. Finally, the common core within a structure may be too small relative to the entire structure, to be recognized as the basis of similarity to another. Conclusion A detailed analysis of the entire available protein fold space by two automated similarity methods reveals the extent and the nature of the divergence between the automatically

  8. Lymphocyte subpopulations during cytomegalovirus disease in renal transplant recipients

    Directory of Open Access Journals (Sweden)

    S.M. Castro

    2003-06-01

    Full Text Available We have determined the number of circulating T, B and natural killer cells in renal transplant recipients in order to detect changes during cytomegalovirus (CMV infections. Serial blood samples were taken from 61 patients on standard triple immunosuppression therapy (cyclosporin A, azathioprine and prednisone. Using two-color flow cytometry analysis, the absolute number of CD3+, CD4+, CD8+, CD19+, CD3+HLA-DR+ and CD16+56+ cells was determined. Forty-eight patients (78.7% developed active CMV infection, and all of them subsequently recovered. Twenty of the infected patients (32.8% presented symptoms compatible with CMV disease during the infectious process. The number of lymphocytes and their main subpopulations were normal before the onset of CMV disease. During the disease there was a decrease followed by a significant increase (P<0.005 in the number of CD3+, CD4+, CD8+ and CD3+HLA-DR+ cells. No significant changes were observed in natural killer cells or B lymphocytes during the disease. We conclude, as observed in all viremic patients recovering from infection, that recovery is associated with an increase in the number of T cell subsets. The monitoring of different lymphocyte subsets along with antigenemia can be extremely useful in the detection of patients at high risk of developing CMV symptoms, allowing the early introduction of antiviral therapy or the reduction of immunosuppression therapy.

  9. B-cell subpopulations in children: National reference values.

    Science.gov (United States)

    Duchamp, Marie; Sterlin, Delphine; Diabate, Aminata; Uring-Lambert, Béatrice; Guérin-El Khourouj, Valérie; Le Mauff, Brigitte; Monnier, Delphine; Malcus, Christophe; Labalette, Myriam; Picard, Capucine

    2014-11-01

    Peripheral B-lymphocytes undergo a series of changes during the first few years of life. Encounters with foreign antigens lead to maturation and differentiation. Several primary antibody deficiencies (PADs) affecting B-cell development are associated with abnormalities in the composition and/or differentiation of B-cell compartments. The most recent international classifications of primary immunodeficiencies (PIDs) and common variable immunodeficiencies (CVID) have highlighted the importance of B-cell immunophenotyping and age-specific reference intervals for diagnostic purposes. We established national reference values for memory B-cell subpopulations, on the basis of CD27 and surface IgD expression in the peripheral blood of 242 healthy children. We report here the absolute counts and percentages of naive, switched and non-switched memory B-cells for seven age groups, from neonates to adults. We found that the naive B-cells percentage declined between the ages of 6 months and 8 years, after which it remained stable at about 70-80%. Memory B-cells are already present at birth and their numbers increase throughout childhood, stabilizing between the ages of 12 and 18 years. The definition of reference intervals for pediatric B-cell levels should facilitate the screening and diagnosis of various B-cell immunodeficiencies. This multicenter study, providing national reference values, should thus facilitate immunological diagnosis in children.

  10. Rapid evolution of distinct Helicobacter pylori subpopulations in the Americas.

    Directory of Open Access Journals (Sweden)

    Kaisa Thorell

    2017-02-01

    Full Text Available For the last 500 years, the Americas have been a melting pot both for genetically diverse humans and for the pathogenic and commensal organisms associated with them. One such organism is the stomach-dwelling bacterium Helicobacter pylori, which is highly prevalent in Latin America where it is a major current public health challenge because of its strong association with gastric cancer. By analyzing the genome sequence of H. pylori isolated in North, Central and South America, we found evidence for admixture between H. pylori of European and African origin throughout the Americas, without substantial input from pre-Columbian (hspAmerind bacteria. In the US, strains of African and European origin have remained genetically distinct, while in Colombia and Nicaragua, bottlenecks and rampant genetic exchange amongst isolates have led to the formation of national gene pools. We found three outer membrane proteins with atypical levels of Asian ancestry in American strains, as well as alleles that were nearly fixed specifically in South American isolates, suggesting a role for the ethnic makeup of hosts in the colonization of incoming strains. Our results show that new H. pylori subpopulations can rapidly arise, spread and adapt during times of demographic flux, and suggest that differences in transmission ecology between high and low prevalence areas may substantially affect the composition of bacterial populations.

  11. Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia

    Science.gov (United States)

    Harper, David G.; Stopa, Edward G.; Kuo-Leblanc, Victoria; McKee, Ann C.; Asayama, Kentaro; Volicer, Ladislav; Kowall, Neil; Satlin, Andrew

    2012-01-01

    The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythmin humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain–behaviour relationships in the human. PMID:18372313

  12. Unequivocal identification of subpopulations in putative multiclonal Trypanosoma cruzi strains by FACs single cell sorting and genotyping.

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    Helder Magno Silva Valadares

    Full Text Available Trypanosoma cruzi, the etiological agent of Chagas disease, is a polymorphic species. Evidence suggests that the majority of the T. cruzi populations isolated from afflicted humans, reservoir animals, or vectors are multiclonal. However, the extent and the complexity of multiclonality remain to be established, since aneuploidy cannot be excluded and current conventional cloning methods cannot identify all the representative clones in an infection. To answer this question, we adapted a methodology originally described for analyzing single spermatozoids, to isolate and study single T. cruzi parasites. Accordingly, the cloning apparatus of a Fluorescence-Activated Cell Sorter (FACS was used to sort single T. cruzi cells directly into 96-wells microplates. Cells were then genotyped using two polymorphic genomic markers and four microsatellite loci. We validated this methodology by testing four T. cruzi populations: one control artificial mixture composed of two monoclonal populations--Silvio X10 cl1 (TcI and Esmeraldo cl3 (TcII--and three naturally occurring strains, one isolated from a vector (A316A R7 and two others derived from the first reported human case of Chagas disease. Using this innovative approach, we were able to successfully describe the whole complexity of these natural strains, revealing their multiclonal status. In addition, our results demonstrate that these T. cruzi populations are formed of more clones than originally expected. The method also permitted estimating of the proportion of each subpopulation of the tested strains. The single-cell genotyping approach allowed analysis of intrapopulation diversity at a level of detail not achieved previously, and may thus improve our comprehension of population structure and dynamics of T. cruzi. Finally, this methodology is capable to settle once and for all controversies on the issue of multiclonality.

  13. Structural variation in the chicken genome identified by paired-end next-generation DNA sequencing of reduced representation libraries

    Directory of Open Access Journals (Sweden)

    Okimoto Ron

    2011-02-01

    Full Text Available Abstract Background Variation within individual genomes ranges from single nucleotide polymorphisms (SNPs to kilobase, and even megabase, sized structural variants (SVs, such as deletions, insertions, inversions, and more complex rearrangements. Although much is known about the extent of SVs in humans and mice, species in which they exert significant effects on phenotypes, very little is known about the extent of SVs in the 2.5-times smaller and less repetitive genome of the chicken. Results We identified hundreds of shared and divergent SVs in four commercial chicken lines relative to the reference chicken genome. The majority of SVs were found in intronic and intergenic regions, and we also found SVs in the coding regions. To identify the SVs, we combined high-throughput short read paired-end sequencing of genomic reduced representation libraries (RRLs of pooled samples from 25 individuals and computational mapping of DNA sequences from a reference genome. Conclusion We provide a first glimpse of the high abundance of small structural genomic variations in the chicken. Extrapolating our results, we estimate that there are thousands of rearrangements in the chicken genome, the majority of which are located in non-coding regions. We observed that structural variation contributes to genetic differentiation among current domesticated chicken breeds and the Red Jungle Fowl. We expect that, because of their high abundance, SVs might explain phenotypic differences and play a role in the evolution of the chicken genome. Finally, our study exemplifies an efficient and cost-effective approach for identifying structural variation in sequenced genomes.

  14. Brain Barriers and a Subpopulation of Astroglial Progenitors of Developing Human Forebrain Are Immunostained for the Glycoprotein YKL-40

    DEFF Research Database (Denmark)

    Bjørnbak, Camilla; Brøchner, Christian B; Larsen, Lars A

    2014-01-01

    and subventricular zones showed specific YKL-40 reactivity confined to pericytes. Furthermore, a population of YKL-40-positive, small, rounded cells was identified in the ventricular and subventricular zones. Real-time quantitative RT-PCR analysis showed strong YKL-40 mRNA expression in the leptomeninges...... in controlling local angiogenesis and access of peripheral cells to the forebrain via secretion from leptomeningeal cells, choroid plexus epithelium and pericytes. Furthermore, we suggest that the small, rounded, YKL-40-positive cells represent a subpopulation of astroglial progenitors, and that YKL-40 could...

  15. Structural genomics analysis of uncharacterized protein families overrepresented in human gut bacteria identifies a novel glycoside hydrolase.

    Science.gov (United States)

    Sheydina, Anna; Eberhardt, Ruth Y; Rigden, Daniel J; Chang, Yuanyuan; Li, Zhanwen; Zmasek, Christian C; Axelrod, Herbert L; Godzik, Adam

    2014-04-17

    Bacteroides spp. form a significant part of our gut microbiome and are well known for optimized metabolism of diverse polysaccharides. Initial analysis of the archetypal Bacteroides thetaiotaomicron genome identified 172 glycosyl hydrolases and a large number of uncharacterized proteins associated with polysaccharide metabolism. BT_1012 from Bacteroides thetaiotaomicron VPI-5482 is a protein of unknown function and a member of a large protein family consisting entirely of uncharacterized proteins. Initial sequence analysis predicted that this protein has two domains, one on the N- and one on the C-terminal. A PSI-BLAST search found over 150 full length and over 90 half size homologs consisting only of the N-terminal domain. The experimentally determined three-dimensional structure of the BT_1012 protein confirms its two-domain architecture and structural analysis of both domains suggests their specific functions. The N-terminal domain is a putative catalytic domain with significant similarity to known glycoside hydrolases, the C-terminal domain has a beta-sandwich fold typically found in C-terminal domains of other glycosyl hydrolases, however these domains are typically involved in substrate binding. We describe the structure of the BT_1012 protein and discuss its sequence-structure relationship and their possible functional implications. Structural and sequence analyses of the BT_1012 protein identifies it as a glycosyl hydrolase, expanding an already impressive catalog of enzymes involved in polysaccharide metabolism in Bacteroides spp. Based on this we have renamed the Pfam families representing the two domains found in the BT_1012 protein, PF13204 and PF12904, as putative glycoside hydrolase and glycoside hydrolase-associated C-terminal domain respectively.

  16. Using Probabilistic Record Linkage of Structured and Unstructured Data to Identify Duplicate Cases in Spontaneous Adverse Event Reporting Systems.

    Science.gov (United States)

    Kreimeyer, Kory; Menschik, David; Winiecki, Scott; Paul, Wendy; Barash, Faith; Woo, Emily Jane; Alimchandani, Meghna; Arya, Deepa; Zinderman, Craig; Forshee, Richard; Botsis, Taxiarchis

    2017-07-01

    Duplicate case reports in spontaneous adverse event reporting systems pose a challenge for medical reviewers to efficiently perform individual and aggregate safety analyses. Duplicate cases can bias data mining by generating spurious signals of disproportional reporting of product-adverse event pairs. We have developed a probabilistic record linkage algorithm for identifying duplicate cases in the US Vaccine Adverse Event Reporting System (VAERS) and the US Food and Drug Administration Adverse Event Reporting System (FAERS). In addition to using structured field data, the algorithm incorporates the non-structured narrative text of adverse event reports by examining clinical and temporal information extracted by the Event-based Text-mining of Health Electronic Records system, a natural language processing tool. The final component of the algorithm is a novel duplicate confidence value that is calculated by a rule-based empirical approach that looks for similarities in a number of criteria between two case reports. For VAERS, the algorithm identified 77% of known duplicate pairs with a precision (or positive predictive value) of 95%. For FAERS, it identified 13% of known duplicate pairs with a precision of 100%. The textual information did not improve the algorithm's automated classification for VAERS or FAERS. The empirical duplicate confidence value increased performance on both VAERS and FAERS, mainly by reducing the occurrence of false-positives. The algorithm was shown to be effective at identifying pre-linked duplicate VAERS reports. The narrative text was not shown to be a key component in the automated detection evaluation; however, it is essential for supporting the semi-automated approach that is likely to be deployed at the Food and Drug Administration, where medical reviewers will perform some manual review of the most highly ranked reports identified by the algorithm.

  17. Extraction of Structural System Matrices from AN Identified State-Space System Using the Combined Measurements of Dva

    Science.gov (United States)

    KO, W. J.; HUNG, C. F.

    2002-01-01

    A time domain method for the extraction of the structural system matrices (mass, damping and stiffness matrices) from an identified state-space system is proposed in this paper using the combined measurements of displacement, velocity and acceleration (DVA) together with the input excitations. The method is based on the invariance of continuous-time Markov parameters. An explicit expression of the relationship between the continuous-time Markov parameters, the structural system matrices, and the influence matrices for output DVA as well as the input force has been derived. The determination of structural system matrices is also valid when only the displacement, velocity or acceleration responses are measured. In this paper, the equivalent state system matrices are obtained by an algorithm, which combines the eigensystem realization algorithm (ERA) and the autoregressive with exogeneous (ARX) model. The ARX model provides the necessary discrete-time Markov parameters from the measured input and output data, and then the equivalent state system matrices are identified from discrete-time Markov parameters by using the ERA. A lumped mass model with three degrees of freedom is employed to illustrate the accuracy and feasibility of the presented method.

  18. 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

    Biofilms are reported to be inherently refractory toward antimicrobial attack and, therefore, cause problems in industrial and medical settings. Pseudomonas aeruginosa biofilms contain subpopulations that exhibit high metabolic activity and subpopulations that exhibit low metabolic activity. We h...

  19. 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

  20. Genome-wide association study for T lymphocyte subpopulations in swine

    Directory of Open Access Journals (Sweden)

    Lu Xin

    2012-09-01

    Full Text Available Abstract Background Lymphocytes act as a major component of the adaptive immune system, taking very crucial responsibility for immunity. Differences in proportions of T-cell subpopulations in peripheral blood among individuals under same conditions provide evidence of genetic control on these traits, but little is known about the genetic mechanism of them, especially in swine. Identification of the genetic control on these variants may help the genetic improvement of immune capacity through selection. Results To identify genomic regions responsible for these immune traits in swine, a genome-wide association study was conducted. A total of 675 pigs of three breeds were involved in the study. At 21 days of age, all individuals were vaccinated with modified live classical swine fever vaccine. Blood samples were collected when the piglets were 20 and 35 days of age, respectively. Seven traits, including the proportions of CD4+, CD8+, CD4+CD8+, CD4+CD8−, CD4−CD8+, CD4−CD8− and the ratio of CD4+ to CD8+ T cells were measured at the two ages. All the samples were genotyped for 62,163 single nucleotide polymorphisms (SNP using the Illumina porcineSNP60k BeadChip. 40833 SNPs were selected after quality control for association tests between SNPs and each immune trait considered based on a single-locus regression model. To tackle the issue of multiple testing in GWAS, 10,000 permutations were performed to determine the chromosome-wise and genome-wise significance levels of association tests. In total, 61 SNPs with chromosome-wise significance level and 3 SNPs with genome-wise significance level were identified. 27 significant SNPs were located within the immune-related QTL regions reported in previous studies. Furthermore, several significant SNPs fell into the regions harboring known immunity-related genes, 14 of them fell into the regions which harbor some known T cell-related genes. Conclusions Our study demonstrated that genome-wide association

  1. 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

  2. Subpopulations of older foster youths with differential risk of diagnosis for alcohol abuse or dependence.

    Science.gov (United States)

    Keller, Thomas E; Blakeslee, Jennifer E; Lemon, Stephenie C; Courtney, Mark E

    2010-11-01

    Distinctive combinations of factors are likely to be associated with serious alcohol problems among adolescents about to emancipate from the foster care system and face the difficult transition to independent adulthood. This study identifies particular subpopulations of older foster youths that differ markedly in the probability of a lifetime diagnosis for alcohol abuse or dependence. Classification and regression tree (CART) analysis was applied to a large, representative sample (N = 732) of individuals, 17 years of age or older, placed in the child welfare system for more than 1 year. CART evaluated two exploratory sets of variables for optimal splits into groups distinguished from each other on the criterion of lifetime alcohol-use disorder diagnosis. Each classification tree yielded four terminal groups with different rates of lifetime alcohol-use disorder diagnosis. Notable groups in the first tree included one characterized by high levels of both delinquency and violence exposure (53% diagnosed) and another that featured lower delinquency but an independent-living placement (21% diagnosed). Notable groups in the second tree included African American adolescents (only 8% diagnosed), White adolescents not close to caregivers (40% diagnosed), and White adolescents closer to caregivers but with a history of psychological abuse (36% diagnosed). Analyses incorporating variables that could be comorbid with or symptomatic of alcohol problems, such as delinquency, yielded classifications potentially useful for assessment and service planning. Analyses without such variables identified other factors, such as quality of caregiving relationships and maltreatment, associated with serious alcohol problems, suggesting opportunities for prevention or intervention.

  3. 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.

  4. IMPACT OF THERAPY WITH BIOLOGICAL AGENTS ON B-LYMPHOCYTE SUBPOPULATIONS IN RHEUMATIC DISEASES: NEW EVIDENCE

    Directory of Open Access Journals (Sweden)

    E. V. Suponitskaya

    2015-01-01

    Full Text Available The paper considers the mechanisms of action of biological agents and their effect on peripheral blood B-lymphocyte subpopulations in patients with systemic lupus erythematosus and rheumatoid arthritis.

  5. Differential impact of tobacco control policies on youth sub-populations

    National Research Council Canada - National Science Library

    Tauras, John A; Huang, Jidong; Chaloupka, Frank J

    2013-01-01

    ...), race/ethnicity, and gender. We examined the relationship between state-level cigarette prices and smoke-free air laws and youth smoking prevalence and intensity for various youth sub-populations in the United States...

  6. Cells release subpopulations of exosomes with distinct molecular and biological properties.

    Science.gov (United States)

    Willms, Eduard; Johansson, Henrik J; Mäger, Imre; Lee, Yi; Blomberg, K Emelie M; Sadik, Mariam; Alaarg, Amr; Smith, C I Edvard; Lehtiö, Janne; El Andaloussi, Samir; Wood, Matthew J A; Vader, Pieter

    2016-03-02

    Cells release nano-sized membrane vesicles that are involved in intercellular communication by transferring biological information between cells. It is generally accepted that cells release at least three types of extracellular vesicles (EVs): apoptotic bodies, microvesicles and exosomes. While a wide range of putative biological functions have been attributed to exosomes, they are assumed to represent a homogenous population of EVs. We hypothesized the existence of subpopulations of exosomes with defined molecular compositions and biological properties. Density gradient centrifugation of isolated exosomes revealed the presence of two distinct subpopulations, differing in biophysical properties and their proteomic and RNA repertoires. Interestingly, the subpopulations mediated differential effects on the gene expression programmes in recipient cells. In conclusion, we demonstrate that cells release distinct exosome subpopulations with unique compositions that elicit differential effects on recipient cells. Further dissection of exosome heterogeneity will advance our understanding of exosomal biology in health and disease and accelerate the development of exosome-based diagnostics and therapeutics.

  7. Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design.

    Science.gov (United States)

    Shechter, Sharon; Thomas, David R; Lundberg, Lindsay; Pinkham, Chelsea; Lin, Shih-Chao; Wagstaff, Kylie M; Debono, Aaron; Kehn-Hall, Kylene; Jans, David A

    2017-12-18

    Therapeutics are currently unavailable for Venezuelan equine encephalitis virus (VEEV), which elicits flu-like symptoms and encephalitis in humans, with an estimated 14% of cases resulting in neurological disease. Here we identify anti-VEEV agents using in silico structure-based-drug-design (SBDD) for the first time, characterising inhibitors that block recognition of VEEV capsid protein (C) by the host importin (IMP) α/β1 nuclear transport proteins. From an initial screen of 1.5 million compounds, followed by in silico refinement and screening for biological activity in vitro, we identified 21 hit compounds which inhibited IMPα/β1:C binding with IC50s as low as 5 µM. Four compounds were found to inhibit nuclear import of C in transfected cells, with one able to reduce VEEV replication at µM concentration, concomitant with reduced C nuclear accumulation in infected cells. Further, this compound was inactive against a mutant VEEV that lacks high affinity IMPα/β1:C interaction, supporting the mode of its antiviral action to be through inhibiting C nuclear localization. This successful application of SBDD paves the way for lead optimization for VEEV antivirals, and is an exciting prospect to identify inhibitors for the many other viral pathogens of significance that require IMPα/β1 in their infectious cycle.

  8. Resolution of Two Sub-Populations of Conformers and Their Individual Dynamics by Time Resolved Ensemble Level FRET Measurements.

    Directory of Open Access Journals (Sweden)

    Gil Rahamim

    Full Text Available Most active biopolymers are dynamic structures; thus, ensembles of such molecules should be characterized by distributions of intra- or intermolecular distances and their fast fluctuations. A method of choice to determine intramolecular distances is based on Förster resonance energy transfer (FRET measurements. Major advances in such measurements were achieved by single molecule FRET measurements. Here, we show that by global analysis of the decay of the emission of both the donor and the acceptor it is also possible to resolve two sub-populations in a mixture of two ensembles of biopolymers by time resolved FRET (trFRET measurements at the ensemble level. We show that two individual intramolecular distance distributions can be determined and characterized in terms of their individual means, full width at half maximum (FWHM, and two corresponding diffusion coefficients which reflect the rates of fast ns fluctuations within each sub-population. An important advantage of the ensemble level trFRET measurements is the ability to use low molecular weight small-sized probes and to determine nanosecond fluctuations of the distance between the probes. The limits of the possible resolution were first tested by simulation and then by preparation of mixtures of two model peptides. The first labeled polypeptide was a relatively rigid Pro7 and the second polypeptide was a flexible molecule consisting of (Gly-Ser7 repeats. The end to end distance distributions and the diffusion coefficients of each peptide were determined. Global analysis of trFRET measurements of a series of mixtures of polypeptides recovered two end-to-end distance distributions and associated intramolecular diffusion coefficients, which were very close to those determined from each of the pure samples. This study is a proof of concept study demonstrating the power of ensemble level trFRET based methods in resolution of subpopulations in ensembles of flexible macromolecules.

  9. Genome-wide association mapping revealed a diverse genetic basis of seed dormancy across subpopulations in rice (Oryza sativa L.).

    Science.gov (United States)

    Magwa, Risper Auma; Zhao, Hu; Xing, Yongzhong

    2016-01-25

    Seed dormancy is an adaptive trait employed by flowering plants to avoid harsh environmental conditions for the continuity of their next generations. In cereal crops, moderate seed dormancy could help prevent pre-harvest sprouting and improve grain yield and quality. We performed a genome wide association study (GWAS) for dormancy, based on seed germination percentage (GP) in freshly harvested seeds (FHS) and after-ripened seeds (ARS) in 350 worldwide accessions that were characterized with strong population structure of indica, japonica and Aus subpopulations. The germination tests revealed that Aus and indica rice had stronger seed dormancy than japonica rice in FHS. Association analysis revealed 16 loci significantly associated with GP in FHS and 38 in ARS. Three out of the 38 loci detected in ARS were also detected in FHS and 13 of the ARS loci were detected near previously mapped dormancy QTL. In FHS, three of the association loci were located within 100 kb around previously cloned GA/IAA inactivation genes such as GA2ox3, EUI1 and GH3-2 and one near dormancy gene, Sdr4. In ARS, an association signal was detected near ABA signaling gene ABI5. No association peaks were commonly detected among the sub-populations in FHS and only one association peak was detected in both indica and japonica populations in ARS. Sdr4 and GA2OX3 haplotype analysis showed that Aus and indica II (IndII) varieties had stronger dormancy alleles whereas indica I (IndI) and japonica had weak or non-dormancy alleles. The association study and haplotype analysis together, indicate an involvement of independent genes and alleles contributing towards regulation and natural variation of seed dormancy among the rice sub-populations.

  10. 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.

  11. Identification of cancer stem cell subpopulations of CD34(+) PLC/PRF/5 that result in three types of human liver carcinomas.

    Science.gov (United States)

    Park, Su Cheol; Nguyen, Ngoc Tue; Eun, Jong Ryeol; Zhang, Yanling; Jung, Yong Jin; Tschudy-Seney, Benjamin; Trotsyuk, Artem; Lam, Alexander; Ramsamooj, Rajendra; Zhang, Yanghong; Theise, Neil D; Zern, Mark A; Duan, Yuyou

    2015-04-15

    CD34(+) stem cells play an important role during liver development and regeneration. Thus, we hypothesized that some human liver carcinomas (HLCs) might be derived from transformed CD34(+) stem cells. Here, we determined that a population of CD34(+) cells isolated from PLC/PRF/5 hepatoma cells (PLC) appears to function as liver cancer stem cells (LCSCs) by forming HLCs in immunodeficient mice with as few as 100 cells. Moreover, the CD34(+) PLC subpopulation cells had an advantage over CD34(-) PLCs at initiating tumors. Three types of HLCs were generated from CD34(+) PLC: hepatocellular carcinomas (HCCs); cholangiocarcinomas (CC); and combined hepatocellular cholangiocarcinomas (CHCs). Tumors formed in mice transplanted with 12 subpopulations and 6 progeny subpopulations of CD34(+) PLC cells. Interestingly, progenies with certain surface antigens (CD133, CD44, CD90, or EPCAM) predominantly yielded HCCs. CD34(+) PLCs that also expressed OV6 and their progeny OV6(+) cells primarily produced CHC and CC. This represents the first experiment to demonstrate that the OV6(+) antigen is associated with human CHC and CC. CD34(+) PLCs that also expressed CD31 and their progeny CD31(+) cells formed CHCs. Gene expression patterns and tumor cell populations from all xenografts exhibited diverse patterns, indicating that tumor-initiating cells (TICs) with distinct antigenic profiles contribute to cancer cell heterogeneity. Therefore, we identified CD34(+) PLC cells functioning as LCSCs generating three types of HLCs. Eighteen subpopulations from one origin had the capacity independently to initiate tumors, thus functioning as TICs. This finding has broad implications for better understanding of the multistep model of tumor initiation and progression. Our finding also indicates that CD34(+) PLCs that also express OV6 or CD31 result in types of HLCs. This is the first report that PLC/PRF/5 subpopulations expressing CD34 in combination with particular antigens defines categories of

  12. Use of First-Principles Theory to Identify materials and nano structures for next-generation solar cells

    Science.gov (United States)

    Zunger, Alex

    2012-02-01

    Three genomic-like material design approaches are explored for finding energy relevant semiconductors:(i) Search of nanostructure combinations leading to intermediate band solar cells: Within the ideology of intermediate band solar cells (IBSC) based on quantum dots, it is presently unknown which combination of dot material + matrix material + substrate satisfies the energetic criteria enabling IBSC. Using the modern theory of nano structures (based on atomistic pseudo potentials in plane waves), we examine various combinations, finding that some of the ``usual suspect'' long believed to be ideal, are, in fact inappropriate. (ii) Finding new inorganic absorbers with first-principles: Standard compilations of inorganic compounds reveal thousands of candidate materials that were unexplored for their potential as PV absorbers, among others, because of the absence of a quantifiable ``Design Principle'' that sorts out various materials. The common Schockley - Queisser criteria gives a universal, gap vs efficiency curve which does not distinguish different types of gaps (direct-allowed vs direct-forbidden vs-indirect) nor does it account for non radiative recombination. A simple treatment, called ``Spectroscopically Limited Maximum efficiency'' (SLME) accounts for such factors and can be calculated for hundreds of compounds (using the GW approach), providing insight into previously unrecognized candidates, as well as to the mechanisms at work causing absorption enhancement.(iii) Inverse Band structure search for direct gap Si-Ge nano structures: Using a genomic approach to pseudo potential configurational search we identify a Si-Ge nano structures that have direct band gaps, solving the long-standing dilemma of crystalline Column IV absorbers. In collaboration with L. Yu, V. Popescu, J.W. Luo and M. Davezac.

  13. Ferritin structure from Mycobacterium tuberculosis: comparative study with homologues identifies extended C-terminus involved in ferroxidase activity.

    Directory of Open Access Journals (Sweden)

    Garima Khare

    Full Text Available Ferritins are recognized as key players in the iron storage and detoxification processes. Iron acquisition in the case of pathogenic bacteria has long been established as an important virulence mechanism. Here, we report a 3.0 Å crystal structure of a ferritin, annotated as Bacterioferritin B (BfrB, from Mycobacterium tuberculosis (Mtb, the causative agent of tuberculosis that continues to be one of the world's deadliest diseases. Similar to the other members of ferritin family, the Mtb BfrB subunit exhibits the characteristic fold of a four-helical bundle that possesses the ferroxidase catalytic centre. We compare the structure of Mtb BfrB with representatives of the ferritin family belonging to the archaea, eubacteria and eukarya. Unlike most other ferritins, Mtb BfrB has an extended C-terminus. To dissect the role of this extended C-terminus, truncated Mtb BfrB was purified and biochemical studies implicate this region in ferroxidase activity and iron release in addition to providing stability to the protein. Functionally important regions in a protein of known 3D-structure can be determined by estimating the degree of conservation of the amino-acid sites with its close homologues. Based on the comparative studies, we identify the slowly evolving conserved sites as well as the rapidly evolving variable sites and analyze their role in relation to structure and function of Mtb BfrB. Further, electrostatic computations demonstrate that although the electrostatic environment of catalytic residues is preserved within the family, extensive variability is exhibited by residues defining the channels and pores, in all likelihood keeping up with the diverse functions executed by these ferritins in varied environments.

  14. Differential impact of tobacco control policies on youth sub-populations.

    Science.gov (United States)

    Tauras, John A; Huang, Jidong; Chaloupka, Frank J

    2013-09-12

    While previous studies have demonstrated the efficacy of tobacco control interventions in reducing tobacco use among youth overall, there have been very few studies that examine the potential differential impact of tobacco control policies on various youth subgroups, defined by socio-economic status (SES), race/ethnicity, and gender. We examined the relationship between state-level cigarette prices and smoke-free air laws and youth smoking prevalence and intensity for various youth sub-populations in the United States. We estimated a 2-part model of cigarette demand using data from the 1991 through 2010 nationally representative surveys of 8th-, 10th-, and 12th-grade students as part of the Monitoring the Future project. We found that real cigarette prices are strong determinants of youth smoking. Blacks, females, Hispanics, and low-SES subpopulations are found to have a larger price response with respect to smoking prevalence than the full sample. Smoke-free air laws are found to have a negative effect on smoking prevalence for the full sample and for the male, white, and high-SES sub-populations. This research concludes that higher cigarette prices will reduce smoking prevalence rates of Blacks, Hispanics, females, and low-SES subpopulations faster than the overall youth population and other youth sub-populations. Moreover, this research concludes that smoke-free air laws will reduce smoking prevalence for the overall youth population with the largest reductions in high SES and male subpopulations.

  15. 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.

  16. Small Molecule Inhibitors of the LEDGF Site of Human Immunodeficiency Virus Integrase Identified by Fragment Screening and Structure Based Design

    Science.gov (United States)

    Peat, Thomas S.; Rhodes, David I.; Vandegraaff, Nick; Le, Giang; Smith, Jessica A.; Clark, Lisa J.; Jones, Eric D.; Coates, Jonathan A. V.; Thienthong, Neeranat; Newman, Janet; Dolezal, Olan; Mulder, Roger; Ryan, John H.; Savage, G. Paul; Francis, Craig L.; Deadman, John J.

    2012-01-01

    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. PMID:22808106

  17. 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.

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

    Science.gov (United States)

    Zheng, Mingyue; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

    2015-01-01

    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. PMID:26047514

  19. Identifying Effective Nurse-Led Care Transition Interventions for Older Adults With Complex Needs Using a Structured Expert Panel.

    Science.gov (United States)

    Jeffs, Lianne; Kuluski, Kerry; Law, Madelyn; Saragosa, Marianne; Espin, Sherry; Ferris, Ella; Merkley, Jane; Dusek, Brenda; Kastner, Monika; Bell, Chaim M

    2017-04-01

    Nursing plays a central role in facilitating care transitions for complex older adults, yet there is no consensus of the components of nurse-led care transitions interventions to facilitate high quality care transitions among complex older adults. A structured expert panel was established with the purpose of identifying effective nurse-led care transition interventions. A modified Delphi consensus technique based on the RAND method was employed. Panelists (n = 23) were asked to individually rate a series of statements derived from a realist synthesis of the literature for relevance, feasibility and likely impact. Statements receiving an aggregate score of ≥75% (7/9) were reviewed and revised at a face-to-face consensus meeting. A second round of rating following the same process as round one was used, followed by a final ranking of the statements. The five highest ranked intervention components and contextual factors were: (a) educating and coaching patients, their family members and caregivers about self-management skills; (b) ensuring patients, their family members and caregivers are aware of follow-up medical appointments and postdischarge care plan; (c) using standardized documentation tools and comprehensive communication strategies during care transitions; (d) optimizing nurses' roles and scopes of practice across the care transitions spectrum; and (e) having strong leadership, strategic alignment and accountability structures in organizations to enable quality care transitions for the complex older person population. Key insights on optimizing the nurses' roles and scope of practice during care transitions included having nurses provide "warm hand-offs" and serve as the "go-to person." The panel also identified current challenges to optimizing the nurses' roles and scope of practice across care transition points. Future research is required to determine effective nurse-led intervention components and in which context do they work or do not. © 2017 Sigma

  20. 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.

  1. 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.

  2. We Happy Few: Using Structured Population Models to Identify the Decisive Events in the Lives of Exceptional Individuals.

    Science.gov (United States)

    Snyder, Robin E; Ellner, Stephen P

    2016-08-01

    In any population, some individuals make it big: they are among the few that produce many offspring, grow to large size, and so on. What distinguishes the lives of these happy few? We present three approaches for identifying what factors distinguish those "lucky" individuals who come to dominate reproduction in a population without fixed differences between individuals (genotype, site quality, etc.): comparing life-history trajectories for lucky and unlucky individuals and calculating the elasticity of the probability of becoming lucky to perturbations in demographic rates at a given size or a given age. As examples we consider published size-structured integral projection models for the tropical tree Dacrydium elatum and the semiarid shrub Artemisia ordosica and an age-size-structured matrix model for the tropical tree Cedrela ordosica. We find that good fortune (e.g., rapid growth) when small and young matters much more than good fortune when older and larger. Becoming lucky is primarily a matter of surviving while others die. For species with more variable growth (such as Cedrela and Ordosica), it is also a matter of growing fast. We focus on reproductive skew, but our methods are broadly applicable and can be used to investigate how individuals come to be exceptional in any aspect.

  3. 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.

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

    Science.gov (United States)

    Zhu, Yun; Fan, Ruzong; Xiong, Momiao

    2017-01-01

    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. PMID:29040274

  5. FEATURES OF IMMUNE RESPONSE AMONG MAJOR LYMPHOCYTE SUBPOPULATIONS FROM PERIPHERAL BLOOD DURING EXACERBATION OF CHRONIC GASTRITIS

    Directory of Open Access Journals (Sweden)

    L. V. Matveeva

    2015-01-01

    Full Text Available The aim of this study was to identify and evaluate the features of immune response for main subpopulations of peripheral blood lymphocytes during exacerbation of chronic gastritis, depending on the severity of gastric mucosal atrophy. A comprehensive survey of 122 patients with acute exacerbation of chronic gastritis was performed. The patients with chronic focal-atrophic and atrophic gastritis in acute stage were characterized by increased numbers of CD3+ lymphocytes, CD4+, CD8+ and CD16+ cell populations, decreased CD19+ lymphocyte counts in peripheral blood. During exacerbation of non-atrophic gastritis, an increase of CD4+ and CD16+ cell counts was associated with a decrease in the CD8+ and CD19+ lymphocytes. A concomitant increase in CD4+ cell numbers, as well as elevated IL-2 and IFNγ levels in peripheral blood of patients may reflect activation of cellular immunity, which could be induced by the dysplasia of gastric mucosa and co-infection with Helicobacter/herpesvirus. Domination of increased IL-2 and IFNγ over IL-4 and IL-10 levels suggests the Th1-profile of cellular immune response. Upon exacerbation of non-atrophic gastritis, the immunoregulatory index exceeded the values of clinically healthy subjects and those of patients with atrophic gastritis. We observed statistically significant differences for CD3+, CD4+, CD8+, CD19+ lymphocytes, immunoregulatory index, and serum levels of IL-2, depending on presence and severity of gastric mucosal atrophy. 

  6. Latent national subpopulations of early education classroom disengagement of children from underresourced families.

    Science.gov (United States)

    McDermott, Paul A; Rovine, Michael J; Watkins, Marley W; Chao, Jessica L; Irwin, Clare W; Reyes, Roland

    2017-12-01

    This research examined the latent developmental patterns for early classroom disengagement among children from some of the most underresourced families in the nation. Based on standardized teacher observations from the Head Start Impact Study, a nationally representative sample of children (N=1377) was assessed for manifestations of reticent/withdrawn and low energy behavior over four years spanning prekindergarten through first grade. For each form of disengagement, latent growth mixture modeling revealed three distinct subpopulations of change patterns featuring a dominant class associated with generally good classroom adjustment, a medial class that varied close to the population average over time, and a more extreme class (about 10% of the population) whose adjustment was relatively marginal and sometimes reached problematic levels. Whereas reticent/withdrawn behavior ordinarily subsided over time, low energy behavior increased. More extreme low energy behaviors tended to dissipate through schooling and extreme reticence/withdrawal became more accentuated, with both types associated with later academic and social problems. Attendant risk and protective factors are identified and mitigating assessment and prevention measures are discussed. Copyright © 2017 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

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

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    Mark P Miller

    Full Text Available BACKGROUND: Identifying causal relationships in phylogeographic and landscape genetic investigations is notoriously difficult, but can be facilitated by use of multispecies comparisons. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  8. NSiteMatch: Prediction of Binding Sites of Nucleotides by Identifying the Structure Similarity of Local Surface Patches

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    Jie Sun

    2017-01-01

    Full Text Available Nucleotides play a central role in life-form metabolism, by interacting with proteins and mediating the function of proteins. It is estimated that nucleotides constitute about 15% of the biologically relevant ligands included in PDB. Prediction of binding sites of nucleotides is useful in understanding the function of proteins and can facilitate the in silico design of drugs. In this study, we propose a nucleotide-binding site predictor, namely, NSiteMatch. The NSiteMatch algorithm integrates three different strategies: geometrical analysis, energy calculation, and template comparison. Unlike a traditional template-based predictor, which identifies global similarity between target structure and template, NSiteMatch concerns the local similarity between a surface patch of the target protein and the binding sites of template. To this end, NSiteMatch identifies more templates than traditional template-based predictors. The NSiteMatch predictor is compared with three representative methods, Findsite, Q-SiteFinder, and MetaPocket. An extensive evaluation demonstrates that NSiteMatch achieves higher success rates than Findsite, Q-SiteFinder, and MetaPocket, in prediction of binding sites of ATP, ADP, and AMP.

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

    Science.gov (United States)

    Naveed, Hammad; Hameed, Umar S; Harrus, Deborah; Bourguet, William; Arold, Stefan T; Gao, Xin

    2015-12-15

    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. 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 11 drugs, with 63% sensitivity and 81% specificity. We then predicted novel targets for these drugs-two that are of high pharmacological interest, the peroxisome proliferator-activated receptor gamma and the oncogene B-cell lymphoma 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. The program, datasets and results are freely available to academic users at http://sfb.kaust.edu.sa/Pages/Software.aspx. © The Author 2015. Published by Oxford University Press.

  10. Crystal structure of an integron gene cassette-associated protein from Vibrio cholerae identifies a cationic drug-binding module.

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    Chandrika N Deshpande

    2011-03-01

    Full Text Available The direct isolation of integron gene cassettes from cultivated and environmental microbial sources allows an assessment of the impact of the integron/gene cassette system on the emergence of new phenotypes, such as drug resistance or virulence. A structural approach is being exploited to investigate the modularity and function of novel integron gene cassettes.We report the 1.8 Å crystal structure of Cass2, an integron-associated protein derived from an environmental V. cholerae. The structure defines a monomeric beta-barrel protein with a fold related to the effector-binding portion of AraC/XylS transcription activators. The closest homologs of Cass2 are multi-drug binding proteins, such as BmrR. Consistent with this, a binding pocket made up of hydrophobic residues and a single glutamate side chain is evident in Cass2, occupied in the crystal form by polyethylene glycol. Fluorescence assays demonstrate that Cass2 is capable of binding cationic drug compounds with submicromolar affinity. The Cass2 module possesses a protein interaction surface proximal to its drug-binding cavity with features homologous to those seen in multi-domain transcriptional regulators.Genetic analysis identifies Cass2 to be representative of a larger family of independent effector-binding proteins associated with lateral gene transfer within Vibrio and closely-related species. We propose that the Cass2 family not only has capacity to form functional transcription regulator complexes, but represents possible evolutionary precursors to multi-domain regulators associated with cationic drug compounds.

  11. Exploiting Structural Analysis, In Silico Screening and Serendipity to Identify Novel Inhibitors of Drug-resistant Falciparum Malaria

    Science.gov (United States)

    Dasgupta, Tina; Chitnumsub, Penchit; Maneeruttanarungroj, Cherdsak; Kamchonwongpaisan, Sumalee; Nichols, Sara E.; Lyons, Theresa M.; Tirado-Rives, Julian; Jorgensen, William L.; Yuthavong, Yongyuth; Anderson, Karen S.

    2009-01-01

    relative free energy of binding and these calculations suggested that the compounds might preferentially interact with the active site over the screened ‘linker’ region. To resolve the two possible modes of binding, co-crystallization studies of the compounds complexed with TS-DHFR enzyme were performed to determine the three-dimensional structures. Surprisingly, the structural analysis revealed that these novel, biguanide compounds, distinct from WR99210, do indeed bind at the active site of DHFR, and additionally revealed the molecular basis by which they overcome drug-resistance. To our knowledge, these are the first co-crystal structures of novel, biguanide, non-WR99210 compounds that are active against folate-resistant malaria parasites in cell culture. These studies reveal how serendipity coupled with computational and structural analysis can identify unique compounds as a promising starting point for rational drug design to combat drug-resistant malaria. PMID:19146480

  12. The CA19-9 and Sialyl-TRA Antigens Define Separate Subpopulations of Pancreatic Cancer Cells.

    Science.gov (United States)

    Barnett, Daniel; Liu, Ying; Partyka, Katie; Huang, Ying; Tang, Huiyuan; Hostetter, Galen; Brand, Randall E; Singhi, Aatur D; Drake, Richard R; Haab, Brian B

    2017-06-22

    Molecular markers to detect subtypes of cancer cells could facilitate more effective treatment. We recently identified a carbohydrate antigen, named sTRA, that is as accurate a serological biomarker of pancreatic cancer as the cancer antigen CA19-9. We hypothesized that the cancer cells producing sTRA are a different subpopulation than those producing CA19-9. The sTRA glycan was significantly elevated in tumor tissue relative to adjacent pancreatic tissue in 3 separate tissue microarrays covering 38 patients. The morphologies of the cancer cells varied in association with glycan expression. Cells with dual staining of both markers tended to be in well-to-moderately differentiated glands with nuclear polarization, but exclusive sTRA staining was present in small clusters of cells with poor differentiation and large vacuoles, or in small and ill-defined glands. Patients with higher dual-staining of CA19-9 and sTRA had statistically longer time-to-progression after surgery. Patients with short time-to-progression (<2 years) had either low levels of the dual-stained cells or high levels of single-stained cells, and such patterns differentiated short from long time-to-progression with 90% (27/30) sensitivity and 80% (12/15) specificity. The sTRA and CA19-9 glycans define separate subpopulations of cancer cells and could together have value for classifying subtypes of pancreatic adenocarcinoma.

  13. Heteroresistance to colistin in Klebsiella pneumoniae is triggered by small colony variants sub-populations within biofilms.

    Science.gov (United States)

    Silva, Ana; Sousa, Ana Margarida; Alves, Diana; Lourenço, Anália; Pereira, Maria Olívia

    2016-07-01

    The emergence of Klebsiella pneumoniae multidrug-resistant strains paves the way to the re-introduction of colistin as a salvage therapy. However, recent planktonic studies have reported several cases of heteroresistance to this antimicrobial agent. The aim of this present work was to gain better understanding about the response of K. pneumoniae biofilms to colistin antibiotherapy and inspect the occurrence of heteroresistance in biofilm-derived cells. Biofilm formation and its susceptibility to colistin were evaluated through the determination of biofilm-cells viability. The profiling of planktonic and biofilm cell populations was conducted to assess the occurrence of heteroresistance. Colony morphology was further characterized in order to inspect the potential role of colistin in K. pneumoniae phenotypic differentiation. Results show that K. pneumoniae was susceptible to colistin in its planktonic form, but biofilms presented enhanced resistance. Population analysis profiles pointed out that K. pneumoniae manifest heteroresistance to colistin only when grown in biofilm arrangements, and it was possible to identify a resistant sub-population presenting a small colony morphology (diameter around 5 mm). To the best of our knowledge, this is the first report linking heteroresistance to biofilm formation and a morphological distinctive sub-population. Moreover, this is the first evidence that biofilm formation can trigger the emergence of heteroresistance in an apparently susceptible strain. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Association of the Porcine Cluster of Differentiation 4 Gene with T Lymphocyte Subpopulations and Its Expression in Immune Tissues

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    Jingen Xu

    2013-04-01

    Full Text Available Cluster of differentiation 4 (CD4 is mainly expressed on CD4+ T cells, which plays an important role in immune response. The aim of this study was to detect the association between polymorphisms of the CD4 gene and T lymphocyte subpopulations in pigs, and to investigate the effects of genetic variation on the CD4 gene expression level in immune tissues. Five missense mutations in the CD4 gene were identified using DNA pooling sequencing assays, and two main haplotypes (CCTCC and AGCTG in strong linkage disequilibrium (with frequencies of 50.26% and 46.34%, respectively were detected in the population of Large White pigs. Our results indicated that the five SNPs and the two haplotypes were significantly associated with the proportions of CD4−CD8−, CD4+CD8+, CD4+CD8−, CD4+ and CD4+/CD8+ in peripheral blood (p0.05. These results indicate that the CD4 gene may influence T lymphocyte subpopulations and can be considered as a candidate gene affecting immunity in pigs.

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

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    Walter Blum

    2017-04-01

    Full Text Available 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.

  16. 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.

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

    Science.gov (United States)

    Soler, Carles; Contell, Jesús; Bori, Lorena; Sancho, María; García-Molina, Almudena; Valverde, Anthony; Segarvall, Jan

    2017-01-01

    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. PMID:27751987

  18. RECOVERY IN VIVO OF NONCULTURABLE SUBPOPULATION OF SALMONELLA ENTERICA

    Directory of Open Access Journals (Sweden)

    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

  19. 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.

  20. 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.

  1. A rapid method for identifying and characterizing structural impacts using distributed sensors: An application for automotive pedestrian protection

    Science.gov (United States)

    Kim, Andrew C.

    This research is motivated by recent activity to improve automotive safety, especially for pedestrians. In many parts of the world today, injuries and fatalities from road accidents are a significant problem. Safety features such as seat restraints and air bags provide considerable levels of protection for car occupants; however, no such protective measures currently exist for pedestrians. Drawing upon the success and effectiveness of occupant air bag systems, current research aims to develop similar devices for pedestrians. These active pedestrian protection systems deploy a safety feature such as an external air bag when a pedestrian is hit by a vehicle. Contact with the front bumper induces a body rotation that may result in a violent head collision. The deployable safety device provides a cushioning surface for the vulnerable pedestrian during impact. The challenge of such a system is an effective sensory unit that can rapidly and correctly discriminate pedestrian impacts from non-pedestrian ones. The fast kinematics of the automobile-pedestrian impact leaves a minimal amount of time for signal processing and computation. This research study focuses on a discrimination scheme that satisfies both the time and accuracy requirements for a proposed sensory system for pedestrian protection. A unique methodology was developed to identify structural impacts using dominant frequency features extracted from sensory data. Contact sensors mounted on the front bumper of an automobile measure the strain response from an impact event. The dominant frequencies obtained from these sensor signals are greatly influenced by the impact object's properties and can be used to discriminate between different objects. Extensive tests were conducted to gather sensor data and validate the proposed methodology and impact discrimination algorithm. Results of the impact tests indicate that the approach is sound, and the sensory system effectively identifies "pedestrian" impacts within a

  2. Coherent modeling and forecasting of mortality patterns for subpopulations using multi-way analysis of compositions: an application to Canadian Provinces and Territories

    DEFF Research Database (Denmark)

    Bergeron Boucher, Marie-Pier; Simonacci, Violetta; Oeppen, James

    2018-01-01

    Mortality levels for subpopulations, such as countries in a region or Provinces within a country, generally change in a similar fashion over time, as a result of common historical experiences in terms of health, culture and economics. Forecasting mortality for such populations should consider...... the correlation between their mortality levels. In this perspective, we suggest using multilinear component techniques to identify a common time trend and then use it to forecast coherently the mortality of subpopulations. Moreover, this multi-way approach is performed on life table deaths by referring...... of the Tucker3 model is implemented for life table deaths arranged in three dimensional arrays indexed by time, age and population. The proposed procedure is used to forecast the mortality of Canadian Provinces in a comparative study. The results show that the proposed model leads to coherent forecasts....

  3. Quantitative analysis of monocyte subpopulations in murine atherosclerotic plaques by multiphoton microscopy.

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    Abigail S Haka

    Full Text Available The progressive accumulation of monocyte-derived cells in the atherosclerotic plaque is a hallmark of atherosclerosis. However, it is now appreciated that monocytes represent a heterogeneous circulating population of cells that differ in functionality. New approaches are needed to investigate the role of monocyte subpopulations in atherosclerosis since a detailed understanding of their differential mobilization, recruitment, survival and emigration during atherogenesis is of particular importance for development of successful therapeutic strategies. We present a novel methodology for the in vivo examination of monocyte subpopulations in mouse models of atherosclerosis. This approach combines cellular labeling by fluorescent beads with multiphoton microscopy to visualize and monitor monocyte subpopulations in living animals. First, we show that multiphoton microscopy is an accurate and timesaving technique to analyze monocyte subpopulation trafficking and localization in plaques in excised tissues. Next, we demonstrate that multiphoton microscopy can be used to monitor monocyte subpopulation trafficking in atherosclerotic plaques in living animals. This novel methodology should have broad applications and facilitate new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.

  4. Quantitative analysis of monocyte subpopulations in murine atherosclerotic plaques by multiphoton microscopy.

    Science.gov (United States)

    Haka, Abigail S; Potteaux, Stephane; Fraser, Haley; Randolph, Gwendalyn J; Maxfield, Frederick R

    2012-01-01

    The progressive accumulation of monocyte-derived cells in the atherosclerotic plaque is a hallmark of atherosclerosis. However, it is now appreciated that monocytes represent a heterogeneous circulating population of cells that differ in functionality. New approaches are needed to investigate the role of monocyte subpopulations in atherosclerosis since a detailed understanding of their differential mobilization, recruitment, survival and emigration during atherogenesis is of particular importance for development of successful therapeutic strategies. We present a novel methodology for the in vivo examination of monocyte subpopulations in mouse models of atherosclerosis. This approach combines cellular labeling by fluorescent beads with multiphoton microscopy to visualize and monitor monocyte subpopulations in living animals. First, we show that multiphoton microscopy is an accurate and timesaving technique to analyze monocyte subpopulation trafficking and localization in plaques in excised tissues. Next, we demonstrate that multiphoton microscopy can be used to monitor monocyte subpopulation trafficking in atherosclerotic plaques in living animals. This novel methodology should have broad applications and facilitate new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.

  5. 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.

  6. Periodic acid-Schiff (PAS) reaction and plastination in whole body slices. A novel technique to identify fascial tissue structures.

    Science.gov (United States)

    Steinke, Hanno; Wiersbicki, Dina; Speckert, Marie-Lynn; Merkwitz, Claudia; Wolfskämpf, Thomas; Wolf, Benjamin

    2017-11-13

    Since collagen rich fascial tissue is often very delicate and difficult to discern on native tissue slices, we have developed a method for staining full-body slices using the periodic acid-Schiff (PAS) reaction with subsequent plastination. Since the PAS reaction primarily stains carbohydrates, we could exploit the circumstance that different collagen types vary in carbohydrate content. Contrary to fasciae, tissues such as muscle, bone, nerves and blood vessels exhibit significantly less staining or remain unstained. We have validated the whole-body slice staining results in microscopic tissue slides which were stained with standard extracellular matrix stains such as Masson-Goldner trichrome stain and van-Gieson stain. Furthermore, we have performed immunofluorescence imaging to confirm the presence of collagen in the stained tissue. We achieved very good staining and plastination results and were able to clearly identify even very thin fascia in transversal body slices. This technique may prove useful in advancing our knowledge on the complex topography of fascial structures. Copyright © 2017 Elsevier GmbH. All rights reserved.

  7. Analytic variability in the enumeration of neutrophil subpopulations in canine blood.

    Science.gov (United States)

    Paltrinieri, Saverio; Talon, Elisa

    2017-12-01

    Conventional differential leukocyte counts do not enumerate hyposegmented neutrophils (Hypo-PMN), ie, immature neutrophils that already lost the band morphology but are not yet completely segmented. They may be early indicators of acute inflammation. The purpose of the study was to evaluate the analytic variability of counts of segmented neutrophils (Seg-PMN), band neutrophils (Band), hyposegmented neutrophils (Hypo-PMN), non-Bands (Hypo-PMN + Seg-PMN), and Young-PMN (Bands + Hypo-PMN) assess if Hypo- or Young-PMN identify inflammation better than Bands. Neutrophil subpopulations were counted by 2 observers on 2 sets of 100 cells in 267 blood smears from dogs with changes potentially consistent with inflammation to calculate the intra- and inter-observer variability. Median intra-observer CVs were < 5.0% for Seg-PMN and non-Bands, and 20.0% and 28.0% for Hypo-PMN and Young-PMN for observer 1 and 2, respectively; median inter-observer CVs for Seg-PMN, non-Bands, Hypo-PMN, and Young-PMN were 4.6%, 5.0%, 60.0%, and 47.1%, respectively. Median CV of Band counts in blood smears with bands was 141%. The analytic variability of Hypo- and Young-PMN is lower than that of Bands. This retrospective study did not allow us to investigate the diagnostic potential or the clinical relevance of these cells. However, the low inter- and intra-observer variabilities with these cell populations suggest that the count of Hypo- or Young-PMN may better identify acute inflammation than the count of Bands. © 2017 American Society for Veterinary Clinical Pathology.

  8. A consideration of the relative contributions of different microbial subpopulations to the soil N cycle

    Directory of Open Access Journals (Sweden)

    Peter eBottomley

    2012-10-01

    Full Text Available We examine and discuss literature targeted at identifying active subpopulations of soil microbial communities with regard to the factors that affect the balance between mineralization and immobilization/assimilation of N. Whereas a large fraction (≥50% of soil microbial biomass can immediately respire exogenous substrates, it remains unclear what percentage of both bacterial and fungal populations are capable of expressing their growth potential. The factors controlling the relative amounts of respiratorily responsive biomass versus growth-active biomass will impact the balance between N mineralization and N immobilization. Stable isotope probing of de novo DNA synthesis, and pyrosequence analyses of rRNA:rDNA ratios in soils have identified both numerically dominant and rare microbial taxa showing greatest growth potential. The relative growth responses of numerically dominant or rare members of a soil community could influence the amount of N immobilized into biomass during a growth event. Recent studies have used selective antibiotics targeted at protein synthesis to measure the relative contributions of fungi and bacteria to ammonification and NH4+ consumption, and of NH3 oxidizing archaea (AOA and bacteria (AOB to NH3 oxidation. Evidence was obtained for bacteria to dominate NH4+ assimilation and for fungi to be involved in both consumption of dissolved organic nitrogen (DON and its ammonification. Soil conditions, phase of cropping system, NH4+ availability, and soil pH influence the relative contributions of AOA and AOB to soil nitrification. A recent discovery that AOA can ammonify organic N sources and oxidize it to NO2- serves to illustrate roles for AOA in both the production and consumption of NH3/NH4+. Clearly, much remains to be learned about the factors influencing the relative contributions of bacteria, archaea and fungi to processing organic and inorganic N, and their impact on the balance between mineralization and

  9. Selection of a breast cancer subpopulation-specific antibody using phage display on tissue sections

    DEFF Research Database (Denmark)

    Larsen, Simon Asbjørn; Meldgaard, Theresa; Fridriksdottir, Agla J

    2015-01-01

    on cryostat sections of human breast cancer tissue. This method allows for selection of recombinant antibodies binding to antigens specifically expressed in a small part of the tissue section. In this case, a CD271(+) subpopulation of breast cancer cells was targeted, and these may be potential breast cancer...... it is possible to better target cellular heterogeneity in proteomic studies. The identification of novel biomarkers is relevant for our understanding and intervention in human diseases. The selection of the breast cancer-specific antibody fragment LH 7 may reveal novel subpopulation-specific biomarkers, which......Breast cancer tumors are composed of heterogeneous cell populations. These populations display a high variance in morphology, growth and metastatic propensity. They respond differently to therapeutic interventions, and some may be more prone to cause recurrence. Studying individual subpopulations...

  10. 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

    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......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...... small subpopulations of breast cancer cells. Selections were performed against a subpopulation of breast cancer cells expressing CD271(+), as these previously have been indicated to be potential breast cancer stem cells. The selected antibody fragments were screened by phage ELISA on both breast cancer...

  11. The contribution of specific cell subpopulations to submandibular salivary gland branching morphogenesis.

    Science.gov (United States)

    Kwon, Hae Ryong; Larsen, Melinda

    2015-06-01

    Branching morphogenesis is the developmental program responsible for generating a large surface to volume ratio in many secretory and absorptive organs. To accomplish branching morphogenesis, spatiotemporal regulation of specific cell subpopulations is required. Here, we review recent studies that define the contributions of distinct cell subpopulations to specific cellular processes during branching morphogenesis in the mammalian submandibular salivary gland, including the initiation of the gland, the coordination of cleft formation, and the contribution of stem/progenitor cells to morphogenesis. In conclusion, we provide an overview of technological advances that have opened opportunities to further probe the contributions of specific cell subpopulations and to define the integration of events required for branching morphogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes.

    Science.gov (United States)

    Schulte, Ina; Batty, Elizabeth M; Pole, Jessica C M; Blood, Katherine A; Mo, Steven; Cooke, Susanna L; Ng, Charlotte; Howe, Kevin L; Chin, Suet-Feung; Brenton, James D; Caldas, Carlos; Howarth, Karen D; Edwards, Paul A W

    2012-12-22

    It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements. We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing-55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer-in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator. This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important

  13. Differential Impact of Tobacco Control Policies on Youth Sub-Populations

    Directory of Open Access Journals (Sweden)

    John A. Tauras

    2013-09-01

    Full Text Available Background: While previous studies have demonstrated the efficacy of tobacco control interventions in reducing tobacco use among youth overall, there have been very few studies that examine the potential differential impact of tobacco control policies on various youth subgroups, defined by socio-economic status (SES, race/ethnicity, and gender. Objective: We examined the relationship between state-level cigarette prices and smoke-free air laws and youth smoking prevalence and intensity for various youth sub-populations in the United States. Methods: We estimated a 2-part model of cigarette demand using data from the 1991 through 2010 nationally representative surveys of 8th-, 10th-, and 12th-grade students as part of the Monitoring the Future project. Findings: We found that real cigarette prices are strong determinants of youth smoking. Blacks, females, Hispanics, and low-SES subpopulations are found to have a larger price response with respect to smoking prevalence than the full sample. Smoke-free air laws are found to have a negative effect on smoking prevalence for the full sample and for the male, white, and high-SES sub-populations. Conclusions: This research concludes that higher cigarette prices will reduce smoking prevalence rates of Blacks, Hispanics, females, and low-SES subpopulations faster than the overall youth population and other youth sub-populations. Moreover, this research concludes that smoke-free air laws will reduce smoking prevalence for the overall youth population with the largest reductions in high SES and male subpopulations.

  14. 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

    to 108 CFU ml−1, and 103 to 104 CFU ml−1 survived 72-h treatment with 100 μg of norfloxacin ml−1, indicating a persister subpopulation. This survival was not caused by antibiotic resistance as regrown persisters were as sensitive to norfloxacin as the parental strain. Higher numbers of persisters (105...... persisters could be activated by the addition of fermentable carbohydrates and subsequently killed by gentamicin; however, a stable surviving subpopulation of 103 CFU ml−1 remained. Nitrofurantoin that has a growth-independent mode of action was effective against both growing and dormant cells, suggesting...

  15. Reactive microgliosis engages distinct responses by microglial subpopulations after minor central nervous system injury

    DEFF Research Database (Denmark)

    Wirenfeldt, Martin; Babcock, Alicia Anne; Ladeby, Rune

    2005-01-01

    that was induced to express CD34. The proportion of immigrant GFP(+) microglia (CD11b(+)CD45(dim)) increased signficantly by 3 and 5 days postlesion and reached a maximum of 13% by 7 days. These cells expressed lower CD11b levels than resident microglia, forming a distinct subpopulation on CD11b/CD45 profiles....... The proportion of CD34(+)CD11b(+) microglia was significantly increased at 3 days postlesion but had normalized by 5 and 7 days, when the microglial reaction is known to be at its maximum. Our results show that distinct subpopulations of microglia respond to minor CNS injury. The heterogeneity in microglial...

  16. 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...... in vitro growth of two sets of small cell lung cancer (SCLC) subpopulations (54A, 54B and NYH, NYH2). The tumour cell lines differed in cellular DNA content enabling flow cytometric DNA analysis (FCM) to be used to monitor changes in the fractional composition of the mixed cell populations. The progeny...

  17. Population structure and genetic differentiation associated with breeding history and selection in tomato (Solanum lycopersicum L.).

    Science.gov (United States)

    Sim, S-C; Robbins, M D; Van Deynze, A; Michel, A P; Francis, D M

    2011-06-01

    Tomato (Solanum lycopersicum L.) has undergone intensive selection during and following domestication. We investigated population structure and genetic differentiation within a collection of 70 tomato lines representing contemporary (processing and fresh-market) varieties, vintage varieties and landraces. The model-based Bayesian clustering software, STRUCTURE, was used to detect subpopulations. Six independent analyses were conducted using all marker data (173 markers) and five subsets of markers based on marker type (single-nucleotide polymorphisms, simple sequence repeats and insertion/deletions) and location (exon and intron sequences) within genes. All of these analyses consistently separated four groups predefined by market niche and age into distinct subpopulations. Furthermore, we detected at least two subpopulations within the processing varieties. These subpopulations correspond to historical patterns of breeding conducted for specific production environments. We found no subpopulation within fresh-market varieties, vintage varieties and landraces when using all marker data. High levels of admixture were shown in several varieties representing a transition in the demarcation between processing and fresh-market breeding. The genetic clustering detected by using the STRUCTURE software was confirmed by two statistics, pairwise F(st) (θ) and Nei's standard genetic distance. We also identified a total of 19 loci under positive selection between processing, fresh-market and vintage germplasm by using an F(st)-outlier method based on the deviation from the expected distribution of F(st) and heterozygosity. The markers and genome locations we identified are consistent with known patterns of selection and linkage to traits that differentiate the market classes. These results demonstrate how human selection through breeding has shaped genetic variation within cultivated tomato.

  18. 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

    Conclusions: These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc 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.

  19. B-cell subpopulations from normal human secondary lymphoid tissues with specific gene expression profiles and phenotypes

    DEFF Research Database (Denmark)

    Johnsen, Hans Erik; Schmitz, Alexander; Perez Andres, Martin

    included homogenization, isolation of mononuclear cells, MFC and FACS sorting using multicolour fluorescence single tube panels.of antibodies against surface molecules as CD10/20/27/38/45, supplemented with tissue related antibodies. Isolated B-cell subpopulations were evaluated by morphological inspection......In order to improve insights into the B-cell biology and thereby B-cell myelomagenesis we have established a MSCNET standard for multiparametric flow cytometry (MFC) and cell sorting (FACS) for subsequent genetic analysis. The material analysed was fresh tonsils, blood and bone marrow. The method...... and single gene expression analysis (qRT-PCR) for transcription factors as well as global gene expression profiling (GEP; GeneChip Human Exon 1.0 ST Array). For example for tonsils, based on the immunophenotypic presentation (including CD3/44/CXCR4 in the panel), B-cell subsets were identified and sorted...

  20. 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

    2017-06-01

    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 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.

  1. 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 <99 °F (adjusted OR = 4.9, 95% CI 3.3, 7.2). The 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.

  2. Structure-from-Motion as a method to quantify erosion volumes and to identify sediment sources in eroding rills

    Science.gov (United States)

    Brings, Christine; André Remke, Alexander; Gronz, Oliver; Becker, Kerstin; Seeger, Manuel; Ries, Johannes B.

    2014-05-01

    One particular problem in the study of rill erosion is the lack of information about sediment sources. So far, the sediment sources can only be identified by observation during the event or the experiment. Furthermore, only large and clear visible changes are considered and observations do not allow the quantification of erosion rates. A solution to this problem can be provided by 3D-modeling using the Structure from Motion (SfM)technique. Digital elevation models (DEM) from terrestrial and aircraft based images have been produced for many years; however, traditional photogrammetric analysis techniques require considerable expertise both for imaging and for data processing. The recent development of SfM providing for geoscientific applications the potential and greatly facilitated conditions for creating accurate 3D models from terrestrial and aerial photographs that were recorded by standard, non-metric cameras. Before and after the rill erosion experiments, coherent and largely overlapping terrestrial photos have been acquired. Afterwards, VisualSfM constructs 3D models by searching unique features in single images, searching for common features in image pairs and by triangulation of camera and feature positions using these pairs. The results are point clouds with x-, y- and z-coordinates, which are the basis for the preparation of the 3D-digital elevation models or volumetric surface models. The before and after models are all in their own, arbitrary coordinate systems and therefore they need to be superimposed and scaled. From the point clouds, surface models are created and via difference calculations of the before and after models, sediment sources can be detected, and erosion volumes can be quantified. Until now, the volume deviations between the 3D models and reference volumes do not exceed 10%. The noise of the 3D models in the worst dimension (z-axis) does not exceed the pixel spacing times 4-5. The results show that VisualSfM is a good, easy to apply and

  3. [Peripheral blood neutrophil subpopulations and capacities of NBT test in the diagnosis of neonatal diseases].

    Science.gov (United States)

    Gerasimov, I G

    2011-04-01

    By analyzing the data available in the literature, the author shows new capacities of the nitroblue tetrazolium (NBT) test in the diagnosis of neonatal diseases and conditions. The findings versus the, data obtained in adult patients are characterized. The NBT test has been used to determine changes in neutrophil subpopulations. The kinetic parameters of the process are analyzed.

  4. Evaluation of a multicolor, single-tube technique to enumerate lymphocyte subpopulations.

    Science.gov (United States)

    Colombo, F; Cattaneo, A; Lopa, R; Portararo, P; Rebulla, P; Porretti, L

    2008-07-01

    To evaluate the fully automated FACSCanto software, we compared lymphocyte subpopulation counts obtained using three-color FACSCalibur-CELLQuest and six-color FACSCanto-FACSCanto software techniques. High correlations were observed between data obtained with these techniques. Our study indicated that FACSCanto clinical software is accurate and sensitive in single-platform lymphocyte immunophenotyping.

  5. 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...

  6. 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...

  7. Changes in circulating lymphocyte subpopulations in pigs receiving therapeutic doses of ceftiofur and tulathromycin

    Directory of Open Access Journals (Sweden)

    Czyżewska-Dors Ewelina

    2016-12-01

    Full Text Available Introduction: The aim of the study was to evaluate the effect of administration of therapeutic doses of ceftiofur and tulathromycin on the circulating lymphocyte subpopulations in healthy pigs. Material and Methods: The study was conducted on thirty healthy 7- to 10-week-old pigs, assigned to three groups: the TUL group, injected with tulathromycin (n = 10; the CEF group, injected with ceftiofur (n = 10; and the C group, the control with no antibiotic administration (n = 10. Blood samples were collected before, during, and after treatment with antimicrobials. Lymphocyte subpopulations circulating in the blood were determined by immunostaining and flow cytometry analyses. Results: Following administration of a therapeutic dose of tulathromycin, there were no changes in the lymphocyte subpopulations circulating in blood. In contrast, administration of ceftiofur at the recommended dose decreased the absolute number of CD3+, CD21+, CD4+CD8-, CD4-CD8+, and double positive CD4CD8 cells. Conclusion: Results from the study indicate that ceftiofur possesses the ability to modulate the immune system in healthy pigs by decreasing lymphocyte subpopulations circulating in blood.

  8. Analysis by mass spectrometry of POMC-derived peptides in amphibian melanotrope subpopulations

    NARCIS (Netherlands)

    Vázquez-Martínez, R.M.; Malagón, M.M.; Strien, F.J.C. van; Jespersen, S.; Greef, J. van der; Roubos, E.W.; Gracia-Navarro, F.

    1999-01-01

    We have previously shown that the melanotrope population of the pituitary intermediate lobe of Rana ridibunda is composed of two subpopulations, of low (LD) and high density (HD), that show distinct ultrastructural features and display different synthetic and secretory rates. To investigate whether

  9. 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

  10. Intratumoral Heterogeneity as a Therapy Resistance Mechanism: Role of Melanoma Subpopulations

    Science.gov (United States)

    Somasundaram, Rajasekharan; Villanueva, Jessie; Herlyn, Meenhard

    2013-01-01

    Malignant melanoma is an aggressive form of skin cancer whose incidence continues to increase worldwide. Increased exposure to sun, ultraviolet radiation and the use of tanning beds can increase the risk of melanoma. Early detection of melanomas is the key to successful treatment mainly through surgical excision of the primary tumor lesion. But in advanced stage melanomas, once the disease has spread beyond the primary site to distant organs, the tumors are difficult to treat and quickly develop resistance to most available forms of therapy. The advent of molecular and cellular techniques has led to a better characterization of tumor cells revealing the presence of heterogeneous melanoma subpopulations. The discovery of gene mutations and alterations of cell-signaling pathways in melanomas has led to the development of new targeted drugs that show dramatic response rates in patients. Single agent therapies generally target one subpopulation of tumor cells while leaving others unharmed. The surviving subpopulations will have the ability to repopulate the original tumors that can continue to progress. Thus, a rational approach to target multiple subpopulations of tumor cells with a combination of drugs instead of single agent therapy will be necessary for long-lasting inhibition of melanoma lesions. In this context, the recent development of immune checkpoint reagents provides an additional armor that can be used in combination with targeted drugs to expand the presence of melanoma reactive T-cells in circulation to prevent tumor recurrence. PMID:22959031

  11. Differences in cancer incidence among predominantly Muslim and Buddhist subpopulations in Songkhla.

    Science.gov (United States)

    Sriplung, Hutcha; Bilheem, Surichai; Kuntipundee, Tirada; Geater, Sarayut Lucian

    2014-01-01

    The population of Songkhla, a province in Southern Thailand, can be divided into a predominantly Muslim subpopulation (PMSP, approximately 70% Muslim) and a predominantly Buddhist subpopulation (PBSP, around 14% Muslim). This study was conducted to 1) describe the incidence of various cancers in both PMSP and PBSP, and 2) compare the incidence of various cancers between the two subpopulations. Cancer cases diagnosed between 1990 and 2010 were drawn from the database of Songkhla Cancer Registry. Population denominators were estimated from the 3 population censuses surveyed by the National Statistical Office of Thailand in 1990, 2000, and 2010. The age-standardized incidence rates (ASR) of the 5 commonest male cancers among both subpopulations were calculated. In females, a lower incidence of cancers of the cervix and breast in PMSP compared to PBSP, with odds ratios of 0.54 (95% CI: 0.45-0.64) and 0.51 (95% CI: 0.43-0.60) respectively, was observed. In males, the incidence of cancers of the lung, liver, colon-rectum, and some other cancers were significantly different between the two populations in the past, but only prostate cancer showed a lower incidence among males in PMSP in recent years. Independent of sex and year of diagnosis, the incidence of lung, liver, NHL, and colorectal cancers was lower in MPSP compared to BPSP, with odds ratios of 0.75 (95% CI: 0.65-0.85), 0.74 (95% CI: 0.62-0.88), 0.74 (95% CI: 0.60-0.91), and 0.67 (95% CI: 0.56-0.78) respectively. The differences in incidence of some cancers and religion- related culture between the two subpopulations need 2 sets of cancer-control plans and goals to fit the unique population context in deep Southern Thailand. This plan can be used in the 3 southernmost provinces of Thailand where the percentage of Muslims is over 85%.

  12. 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...

  13. Distinguishing subpopulations of marijuana users with latent profile analysis.

    Science.gov (United States)

    Pearson, Matthew R; Bravo, Adrian J; Conner, Bradley T

    2017-03-01

    Although marijuana is the most commonly used illicit drug in the United States, little is known about the effects of typical marijuana use patterns and whether there are distinct subgroups of marijuana users. The present study used latent profile analysis to determine the number of distinct subgroups of marijuana users in a large sample of college students (n=2129 past month marijuana users across 11 universities). We also examined how these distinct groups differ on several putative risk/protective factors (e.g., personality traits, perceptions of marijuana, and motives for using marijuana). Using the Lo-Mendell-Rubin Likelihood Ratio Test, we identified four latent classes with the largest class consisting of infrequent marijuana users, and three other classes demonstrating increasingly frequent use and more negative consequences with the most severe class being the smallest class. We found the largest between-class differences (i.e., distinctions across classes) to be on identification with being a marijuana user and use of protective behavioral strategies (PBS), such that the heavier user classes showed higher identification with marijuana users and lower use of PBS. Our findings demonstrate that college student marijuana users are a heterogeneous group with different profiles of risk/protective factors and that those who use marijuana a few times per month are different from those who are near-daily or daily users. Our findings also serve as a call to action for the field to consider examining identification with being a marijuana user and the use of PBS in future marijuana studies. Copyright © 2016. Published by Elsevier B.V.

  14. Platelet activation patterns in platelet size sub-populations: differential responses to aspirin in vitro.

    Science.gov (United States)

    Mangalpally, Kiran Kumar R; Siqueiros-Garcia, Alan; Vaduganathan, Muthiah; Dong, Jing-Fei; Kleiman, Neal S; Guthikonda, Sasidhar

    2010-10-01

    Circulating platelets are heterogeneous in size and structure. Whether this translates into differences in platelet function and efficacy of antiplatelet therapy is unclear. Hence, we decided to investigate the activation patterns among different platelet populations differentiated by size, and to compare the inhibitory effects of aspirin in these populations. Circulating platelets from 9 healthy volunteers were separated by size and stratified into the largest and smallest quintiles. Platelets were stimulated with 75 μM arachidonic acid (AA), 10 μM ADP or 25 μM TRAP. Alpha-granule protein secretion and expression (P-selectin, VWF, fibrinogen), surface-protein activation (activated integrin αIIbβ3) were assessed. Platelet thromboxane B(2) (TxB(2)) synthesis following AA stimulation was measured in vitro before and after incubation with 265 μM aspirin. Reticulated (juvenile) platelets were assessed using thiazole orange staining. A greater number of large platelets in the largest quintile were reticulated compared with the smallest quintile (6.1 ± 2.8% vs. 1.2 ± 1.5% respectively, p aspirin (1029 ± 190 pg/mL vs. 851 ± 159 pg/mL, respectively, p = 0.03). After stimulation with each agonist, a greater proportion of large platelets bound fibrinogen, VWF, P-selectin and activated integrin αIIbβ3 than small platelets both in the presence and in the absence of in vitro aspirin. In an in vitro setting, large platelets appear to be more active than small platelets and continue to be more active even after in vitro aspirin. Platelets exhibit heterogeneity in size and structure. Whether this translates into platelet function and efficacy of antiplatelet therapy is unclear. We evaluated platelet functional properties and the effects of aspirin on separated platelet subpopulations in an in vitro setting. Platelets were sorted into the largest and smallest size quintiles using flow cytometry forward scatter. Alpha-granule protein release, dense granule content

  15. Identifying the Atomic-Level Effects of Metal Composition on the Structure and Catalytic Activity of Peptide-Templated Materials.

    Science.gov (United States)

    Merrill, Nicholas A; McKee, Erik M; Merino, Kyle C; Drummy, Lawrence F; Lee, Sungsik; Reinhart, Benjamin; Ren, Yang; Frenkel, Anatoly I; Naik, Rajesh R; Bedford, Nicholas M; Knecht, Marc R

    2015-12-22

    Bioinspired approaches for the formation of metallic nanomaterials have been extensively employed for a diverse range of applications including diagnostics and catalysis. These materials can often be used under sustainable conditions; however, it is challenging to control the material size, morphology, and composition simultaneously. Here we have employed the R5 peptide, which forms a 3D scaffold to direct the size and linear shape of bimetallic PdAu nanomaterials for catalysis. The materials were prepared at varying Pd:Au ratios to probe optimal compositions to achieve maximal catalytic efficiency. These materials were extensively characterized at the atomic level using transmission electron microscopy, extended X-ray absorption fine structure spectroscopy, and atomic pair distribution function analysis derived from high-energy X-ray diffraction patterns to provide highly resolved structural information. The results confirmed PdAu alloy formation, but also demonstrated that significant surface structural disorder was present. The catalytic activity of the materials was studied for olefin hydrogenation, which demonstrated enhanced reactivity from the bimetallic structures. These results present a pathway to the bioinspired production of multimetallic materials with enhanced properties, which can be assessed via a suite of characterization methods to fully ascertain structure/function relationships.

  16. 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...

  17. 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.

  18. Genetic diversity and population structure analysis of spinach by single-nucleotide polymorphisms identified through genotyping-by-sequencing

    Science.gov (United States)

    Spinach (Spinacia oleracea L., 2n=2x=12) is an economically important vegetable crop worldwide and one of the healthiest vegetables due to its high concentrations of nutrients and mineral compounds. The objective of this research is to conduct genetic diversity and population structure analysis of w...

  19. 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…

  20. Structural variation in the chicken genome identified by paired-end next-generation DNA sequencing of reduced representation libraries

    NARCIS (Netherlands)

    Kerstens, H.H.D.; Crooijmans, R.P.M.A.; Dibbits, B.W.; Vereijken, A.; Okimoto, R.; Groenen, M.A.M.

    2011-01-01

    Background Variation within individual genomes ranges from single nucleotide polymorphisms (SNPs) to kilobase, and even megabase, sized structural variants (SVs), such as deletions, insertions, inversions, and more complex rearrangements. Although much is known about the extent of SVs in humans and

  1. 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

  2. The genetic position of the autochthonous subpopulation of Northern Navarre (Spain) in relation to other basque subpopulations. A study based on GM and KM immunoglobulin allotypes.

    Science.gov (United States)

    Calderón, R; Perez-Miranda, A; Peña, J A; Vidales, C; Aresti, U; Dugoujon, J M

    2000-08-01

    GM and KM immunoglobulin (Ig) allotypes were tested in 118 autochthonous Basques from northern Navarre. The results are compared to those obtained for the same genetic markers in 6 other Basque subpopulations, 3 from Spain (Guipúzcoa, Vizcaya, and Alava) and 3 from France: Macaye, Saint-Jean Pied de Port, and Mauleon. The northern Navarrese appear genetically closer to the Alava and Saint-Jean Pied de Port subpopulations. The Basques present 3 GM haplotypes that are uncommon in Caucasian populations, suggesting that they have not been completely isolated either from Asian or African populations. The GM*1,17 23' 10,11,13,15,16 north Asian haplotype was probably the first to be introduced into the Basque area. The GM*1,17 23' 5* haplotype, considered an African genetic marker although also detected in Central Asia, would have reached the Iberian Peninsula through consecutive historic migrations from North Africa. The rare haplotype GM*1,17 23 21,28 results probably from a genetic recombination or crossing-over between the 2 common haplotypes GM*1, 17 23' 21,28 and GM*3 23 5*. It is also found with a low frequency in other neighboring regions and countries; but the possibility of its having been introduced through the main passage connecting western France and Spain during the Roman Empire and Middle Ages cannot be ruled out.

  3. 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.

  4. Genetic diversity and population structure analysis of spinach by single-nucleotide polymorphisms identified through genotyping-by-sequencing.

    Directory of Open Access Journals (Sweden)

    Ainong Shi

    Full Text Available Spinach (Spinacia oleracea L., 2n = 2x = 12 is an economically important vegetable crop worldwide and one of the healthiest vegetables due to its high concentrations of nutrients and minerals. The objective of this research was to conduct genetic diversity and population structure analysis of a collection of world-wide spinach genotypes using single nucleotide polymorphisms (SNPs markers. Genotyping by sequencing (GBS was used to discover SNPs in spinach genotypes. Three sets of spinach genotypes were used: 1 268 USDA GRIN spinach germplasm accessions originally collected from 30 countries; 2 45 commercial spinach F1 hybrids from three countries; and 3 30 US Arkansas spinach cultivars/breeding lines. The results from this study indicated that there was genetic diversity among the 343 spinach genotypes tested. Furthermore, the genetic background in improved commercial F1 hybrids and in Arkansas cultivars/lines had a different structured populations from the USDA germplasm. In addition, the genetic diversity and population structures were associated with geographic origin and germplasm from the US Arkansas breeding program had a unique genetic background. These data could provide genetic diversity information and the molecular markers for selecting parents in spinach breeding programs.

  5. Transcriptome analysis of the Brassica napus-Leptosphaeria maculans pathosystem identifies receptor, signaling and structural genes underlying plant resistance.

    Science.gov (United States)

    Becker, Michael G; Zhang, Xuehua; Walker, Philip L; Wan, Joey C; Millar, Jenna L; Khan, Deirdre; Granger, Matthew J; Cavers, Jacob D; Chan, Ainsley C; Fernando, Dilantha W G; Belmonte, Mark F

    2017-05-01

    The hemibiotrophic fungal pathogen Leptosphaeria maculans is the causal agent of blackleg disease in Brassica napus (canola, oilseed rape) and causes significant loss of yield worldwide. While genetic resistance has been used to mitigate the disease by means of traditional breeding strategies, there is little knowledge about the genes that contribute to blackleg resistance. RNA sequencing and a streamlined bioinformatics pipeline identified unique genes and plant defense pathways specific to plant resistance in the B. napus-L. maculans LepR1-AvrLepR1 interaction over time. We complemented our temporal analyses by monitoring gene activity directly at the infection site using laser microdissection coupled to quantitative PCR. Finally, we characterized genes involved in plant resistance to blackleg in the Arabidopsis-L. maculans model pathosystem. Data reveal an accelerated activation of the plant transcriptome in resistant host cotyledons associated with transcripts coding for extracellular receptors and phytohormone signaling molecules. Functional characterization provides direct support for transcriptome data and positively identifies resistance regulators in the Brassicaceae. Spatial gradients of gene activity were identified in response to L. maculans proximal to the site of infection. This dataset provides unprecedented spatial and temporal resolution of the genes required for blackleg resistance and serves as a valuable resource for those interested in host-pathogen interactions. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  6. 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...

  7. The Prevalence of Taurodontism in a North Anatolian Dental Patient Subpopulation

    OpenAIRE

    Çakıcı, Fatih; Benkli, Yasin; Çakıcı, Elif

    2015-01-01

    Objective: The aim of this study was to determine the prevalence of taurodontism in a north Anatolian dental patient subpopulation, considering factors such as dental localization.Methods:We designed a descriptive study evaluated of panoramic radiography of 1044 patients who presented to our Endodontic Services of Dentistry Faculty, Ordu University, in the city of Ordu in the north of Turkey. All the data (age and sex) were obtained from Turcasoft software (Samsun, Turkey). Patients who were ...

  8. Concentration of Potentially Preventable Spending Among High-Cost Medicare Subpopulations: An Observational Study.

    Science.gov (United States)

    Figueroa, Jose F; Joynt Maddox, Karen E; Beaulieu, Nancy; Wild, Robert C; Jha, Ashish K

    2017-10-17

    Little is known about whether potentially preventable spending is concentrated among a subset of high-cost Medicare beneficiaries. To determine the proportion of total spending that is potentially preventable across distinct subpopulations of high-cost Medicare beneficiaries. Beneficiaries in the highest 10% of total standardized individual spending were defined as "high-cost" patients, using a 20% sample of Medicare fee-for-service claims from 2012. The following 6 subpopulations were defined using a claims-based algorithm: nonelderly disabled, frail elderly, major complex chronic, minor complex chronic, simple chronic, and relatively healthy. Potentially preventable spending was calculated by summing costs for avoidable emergency department visits using the Billings algorithm plus inpatient and associated 30-day postacute costs for ambulatory care-sensitive conditions (ACSCs). The amount and proportion of potentially preventable spending were then compared across the high-cost subpopulations and by individual ACSCs. Medicare. 6 112 450 Medicare beneficiaries. Proportion of spending deemed potentially preventable. In 2012, 4.8% of Medicare spending was potentially preventable, of which 73.8% was incurred by high-cost patients. Despite making up only 4% of the Medicare population, high-cost frail elderly persons accounted for 43.9% of total potentially preventable spending ($6593 per person). High-cost nonelderly disabled persons accounted for 14.8% of potentially preventable spending ($3421 per person) and the major complex chronic group for 11.2% ($3327 per person). Frail elderly persons accounted for most spending related to admissions for urinary tract infections, dehydration, heart failure, and bacterial pneumonia. Potential misclassification in the identification of preventable spending and lack of detailed clinical data in administrative claims. Potentially preventable spending varied across Medicare subpopulations, with the majority concentrated among

  9. 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...

  10. Identifying relevant biomarkers of brain injury from structural MRI: Validation using automated approaches in children with unilateral cerebral palsy.

    Science.gov (United States)

    Pagnozzi, Alex M; Dowson, Nicholas; Doecke, James; Fiori, Simona; Bradley, Andrew P; Boyd, Roslyn N; Rose, Stephen

    2017-01-01

    Previous studies have proposed that the early elucidation of brain injury from structural Magnetic Resonance Images (sMRI) is critical for the clinical assessment of children with cerebral palsy (CP). Although distinct aetiologies, including cortical maldevelopments, white and grey matter lesions and ventricular enlargement, have been categorised, these injuries are commonly only assessed in a qualitative fashion. As a result, sMRI remains relatively underexploited for clinical assessments, despite its widespread use. In this study, several automated and validated techniques to automatically quantify these three classes of injury were generated in a large cohort of children (n = 139) aged 5-17, including 95 children diagnosed with unilateral CP. Using a feature selection approach on a training data set (n = 97) to find severity of injury biomarkers predictive of clinical function (motor, cognitive, communicative and visual function), cortical shape and regional lesion burden were most often chosen associated with clinical function. Validating the best models on the unseen test data (n = 42), correlation values ranged between 0.545 and 0.795 (p<0.008), indicating significant associations with clinical function. The measured prevalence of injury, including ventricular enlargement (70%), white and grey matter lesions (55%) and cortical malformations (30%), were similar to the prevalence observed in other cohorts of children with unilateral CP. These findings support the early characterisation of injury from sMRI into previously defined aetiologies as part of standard clinical assessment. Furthermore, the strong and significant association between quantifications of injury observed on structural MRI and multiple clinical scores accord with empirically established structure-function relationships.

  11. 3-Substituted Indole Inhibitors Against Francisella tularensis FabI Identified by Structure-Based Virtual Screening

    Science.gov (United States)

    2013-07-01

    and excreted in the urine , making it ineffective as an oral antibiotic.38 While several species-specific FabI inhibitors have been identified,39 broad...imidazole. The protein was further purified using a Superdex G-75 column (GE Healthcare) equilibrated with 30 mM PIPES pH 8.0, 150 mM NaCl, and 1 mM EDTA...carrier protein reductase (ENR) (EC 1.3.1.9), serves to catalyze the final reaction in the chain elongation cycle (eq 1).19,20However, at least three

  12. A CD44high/EGFRlow subpopulation within head and neck cancer cell lines shows an epithelial-mesenchymal transition phenotype and resistance to treatment.

    Directory of Open Access Journals (Sweden)

    Linnea La Fleur

    Full Text Available Mortality in head and neck squamous cell carcinoma (HNSCC is high due to emergence of therapy resistance which results in local and regional recurrences that may have their origin in resistant cancer stem cells (CSCs or cells with an epithelial-mesenchymal transition (EMT phenotype. In the present study, we investigate the possibility of using the cell surface expression of CD44 and epidermal growth factor receptor (EGFR, both of which have been used as stem cell markers, to identify subpopulations within HNSCC cell lines that differ with respect to phenotype and treatment sensitivity. Three subpopulations, consisting of CD44(high/EGFR(low, CD44(high/EGFR(high and CD44(low cells, respectively, were collected by fluorescence-activated cell sorting. The CD44(high/EGFR(low population showed a spindle-shaped EMT-like morphology, while the CD44(low population was dominated by cobblestone-shaped cells. The CD44(high/EGFR(low population was enriched with cells in G0/G1 and showed a relatively low proliferation rate and a high plating efficiency. Using a real time PCR array, 27 genes, of which 14 were related to an EMT phenotype and two with stemness, were found to be differentially expressed in CD44(high/EGFR(low cells in comparison to CD44(low cells. Moreover, CD44(high/EGFR(low cells showed a low sensitivity to radiation, cisplatin, cetuximab and gefitinib, and a high sensitivity to dasatinib relative to its CD44(high/EGFR(high and CD44(low counterparts. In conclusion, our results show that the combination of CD44 (high and EGFR (low cell surface expression can be used to identify a treatment resistant subpopulation with an EMT phenotype in HNSCC cell lines.

  13. Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts.

    Science.gov (United States)

    Wang, Weikang; Quan, Yi; Fu, Qibin; Liu, Yu; Liang, Ying; Wu, Jingwen; Yang, Gen; Luo, Chunxiong; Ouyang, Qi; Wang, Yugang

    2014-01-01

    Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC) model and the stochastic model. To clarify the controversy, we measured probabilities of different division types and transitions of cells via in situ immunofluorescence. Based on the experiment data, we constructed a model that combines the CSC with the stochastic concepts, showing the existence of both distinctive CSC subpopulations and the stochastic transitions from NSCCs to CSCs. The results showed that the dynamic variations between CSCs and non-stem cancer cells (NSCCs) can be simulated with the model. Further studies also showed that the model can be used to describe the dynamics of the two subpopulations after radiation treatment. More importantly, analysis demonstrated that the experimental detectable equilibrium CSC proportion can be achieved only when the stochastic transitions from NSCCs to CSCs occur, indicating that tumor heterogeneity may exist in a model coordinating with both the CSC and the stochastic concepts. The mathematic model based on experimental parameters may contribute to a better understanding of the tumor heterogeneity, and provide references on the dynamics of CSC subpopulation during radiotherapy.

  14. Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts.

    Directory of Open Access Journals (Sweden)

    Weikang Wang

    Full Text Available Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC model and the stochastic model. To clarify the controversy, we measured probabilities of different division types and transitions of cells via in situ immunofluorescence. Based on the experiment data, we constructed a model that combines the CSC with the stochastic concepts, showing the existence of both distinctive CSC subpopulations and the stochastic transitions from NSCCs to CSCs. The results showed that the dynamic variations between CSCs and non-stem cancer cells (NSCCs can be simulated with the model. Further studies also showed that the model can be used to describe the dynamics of the two subpopulations after radiation treatment. More importantly, analysis demonstrated that the experimental detectable equilibrium CSC proportion can be achieved only when the stochastic transitions from NSCCs to CSCs occur, indicating that tumor heterogeneity may exist in a model coordinating with both the CSC and the stochastic concepts. The mathematic model based on experimental parameters may contribute to a better understanding of the tumor heterogeneity, and provide references on the dynamics of CSC subpopulation during radiotherapy.

  15. Functional heterogeneity with respect to oestrogen treatment in prolactin cell subpopulations separated by Percoll gradient centrifugation.

    Science.gov (United States)

    Velkeniers, B; Kazemzadeh, M; Vanhaelst, L; Hooghe-Peters, E L

    1994-05-01

    The effects of oestradiol on prolactin gene expression were studied by quantitative in situ hybridization histochemistry in different prolactin pituitary cell (sub)populations, which had been obtained by separation on a discontinuous Percoll gradient. When cells were incubated in vitro in the presence of oestradiol (10(-8) M) for a period of 4, 24, 48 and 72 h, there was an increase in the amount of prolactin mRNA, from 24 h on, only in high-density prolactin cells and lactotrophs of the total cell suspension. In contrast, the amount of prolactin mRNA in lactotrophs of low density did not change upon treatment with oestradiol. Pharmacological treatment with 50 micrograms oestradiol/day (s.c.) of random cycling female rats in vivo for 14 days increased the total number of prolactin gene-expressing cells and more lactotrophs were recovered at high density after Percoll gradient centrifugation. These results suggest a preferential stimulatory effect of oestradiol on prolactin gene transcription on a subpopulation of lactotrophs. Changes observed in prolactin cell layers after oestradiol treatment in vivo may represent a preferential effect in situ on a particular mammotroph cell subpopulation.

  16. Identifying the genetic diversity, genetic structure and a core collection of Ziziphus jujuba Mill. var. jujuba accessions using microsatellite markers

    Science.gov (United States)

    Xu, Chaoqun; Gao, Jiao; Du, Zengfeng; Li, Dengke; Wang, Zhe; Li, Yingyue; Pang, Xiaoming

    2016-01-01

    Ziziphus is a genus of spiny shrubs and small trees in the Rhamnaceae family. This group has a controversial taxonomy, with more than 200 species described, including Chinese jujube (Ziziphus jujuba Mill. var. jujuba) and Indian jujube (Z. mauritiana), as well as several other important cultivated fruit crops. Using 24 SSR markers distributed across the Chinese jujube genome, 962 jujube accessions from the two largest germplasm repositories were genotyped with the aim of analyzing the genetic diversity and structure and constructing a core collection that retain high genetic diversity. A molecular profile comparison revealed 622 unique genotypes, among which 123 genotypes were genetically identical to at least one other accessions. STRUCTURE analysis and multivariate analyses (Cluster and PCoA) roughly divided the accessions into three major groups, with some admixture among groups. A simulated annealing algorithm and a heuristic algorithm were chosen to construct the core collection. A final core of 150 accessions was selected, comprising 15.6% of the analyzed accessions and retaining more than 99.5% of the total alleles detected. We found no significant differences in allele frequency distributions or in genetic diversity parameters between the chosen core accessions and the 622 genetically unique accessions. This work contributes to the understanding of Chinese jujube diversification and the protection of important germplasm resources. PMID:27531220

  17. 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

    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.

  18. Identifying the component structure of job satisfaction by principal components analysis among extension officers in North West Province, South Africa

    Directory of Open Access Journals (Sweden)

    Lenah Karabo Mabe

    2010-10-01

    Full Text Available The component structure of a 34-item scale measuring different aspects of job satisfaction was investigated among extension officers in North West Province, South Africa. A simple random sampling technique was used to select 40 extension officers from which data were collected. A structured questionnaire consisting of 34 job satisfaction and 10 personal characteristic items was administered to the extension officers. Items on job satisfaction were measured at interval level and analyzedwith Principal ComponentAnalysis. Most of the respondents (82.5% weremales, between 40 to 45 years, 85% were married and 87.5% had a diploma as their educational qualification. Furthermore, 54% of the households size between 4 to 6 persons, whereas 75% were Christians. The majority of the extension officers lived in their job area (82.5, while 80% covered at least 3 communities and 3 farmer groups. In terms of number of farmers covered, only 40% of the extension officers covered more than 500 farmers and 45% travelled more than 40 km to reach their farmers. From the job satisfaction items 9 components were extracted to show areas for job satisfaction among extension officers. These were in-service training, research policies, communicating recommended practices, financial support for self and family, quality of technical help, opportunity to advance education, management and control of operations, rewarding system and sanctions. The results have several implications for motivating extension officers for high job performance especially with large number of clients and small number of extension agents.

  19. Ligand- and structure-based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents.

    Science.gov (United States)

    Balakumar, Chandrasekaran; Ramesh, Muthusamy; Tham, Chuin Lean; Khathi, Samukelisiwe Pretty; Kozielski, Frank; Srinivasulu, Cherukupalli; Hampannavar, Girish A; Sayyad, Nisar; Soliman, Mahmoud E; Karpoormath, Rajshekhar

    2017-11-29

    Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis through the generation of monoastral MT arrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligand binding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays.

  20. THE NATURE OF THE MAIN STRUCTURAL DAMAGE IN BOEING 737-400 AS IDENTIFIED DURING OVERHAUL TYPE C

    Directory of Open Access Journals (Sweden)

    Piotr GOLDA

    2016-03-01

    Full Text Available In its preliminary part, the article characterises Boeings 737-400 as due to undergo further tests as well as the basic materials used in their construction. It also defines to what extend these materials are prone to damage in the course of their regular use over the planes’ working lives. The object of the analysis is the most prevalent structural damage to the fuselage of the planes discovered during overhaul type C and the definition of the best preventive service. Further on the article categorises the discovered problems and provides their genesis. The main part of the article is devoted to the definition of the sources and reasons for the damage. Consequently, the article forms guidelines how to prevent the occurrence of such and similar damage to the uselage.

  1. Combining a Ru(II) "Building Block" and Rapid Screening Approach to Identify DNA Structure-Selective "Light Switch" Compounds.

    Science.gov (United States)

    Wachter, Erin; Moyá, Diego; Glazer, Edith C

    2017-02-13

    A chemically reactive Ru(II) "building block", able to undergo condensation reactions with substituted diamines, was utilized to create a small library of luminescent "light switch" dipyrido-[3,2-a:2',3'-c] phenazine (dppz) complexes. The impact of substituent identity, position, and the number of substituents on the light switch effect was investigated. An unbiased, parallel screening approach was used to evaluate the selectivity of the compounds for a variety of different biomolecules, including protein, nucleosides, single stranded DNA, duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two approaches allowed for the identification of hit molecules that showed different selectivities for biologically relevant DNA structures, particularly triplex and quadruplex DNA.

  2. Crystal Structure of 12-Lipoxygenase Catalytic-Domain-Inhibitor Complex Identifies a Substrate-Binding Channel for Catalysis

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shu; Mueser, Timothy C.; Marnett, Lawrence J.; Funk, Jr., Max O. (Toledo); (Vanderbilt)

    2014-10-02

    Lipoxygenases are critical enzymes in the biosynthesis of families of bioactive lipids including compounds with important roles in the initiation and resolution of inflammation and in associated diseases such as diabetes, cardiovascular disease, and cancer. Crystals diffracting to high resolution (1.9 {angstrom}) were obtained for a complex between the catalytic domain of leukocyte 12-lipoxygenase and the isoform-specific inhibitor, 4-(2-oxapentadeca-4-yne)phenylpropanoic acid (OPP). In the three-dimensional structure of the complex, the inhibitor occupied a new U-shaped channel open at one end to the surface of the protein and extending past the redox-active iron site that is essential for catalysis. In models, the channel accommodated arachidonic acid, defining the binding site for the substrate of the catalyzed reaction. There was a void adjacent to the OPP binding site connecting to the surface of the enzyme and providing a plausible access channel for the other substrate, oxygen.

  3. 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...

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Agustina Malizia

    Full Text Available 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.

  6. 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

  7. 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

  8. Genetic diversity, population structure and marker trait associations for seed quality traits in cotton (Gossypium hirsutum).

    Science.gov (United States)

    Badigannavar, Ashok; Myers, Gerald O

    2015-03-01

    Cottonseed contains 16% seed oil and 23% seed protein by weight. High levels of palmitic acid provides a degree of stability to the oil, while the presence of bound gossypol in proteins considerably changes their properties, including their biological value. This study uses genetic principles to identify genomic regions associated with seed oil, protein and fibre content in upland cotton cultivars. Cotton association mapping panel representing the US germplasm were genotyped using amplified fragment length polymorphism markers, yielding 234 polymorphic DNA fragments. Phenotypic analysis showed high genetic variability for the seed traits, seed oil range from 6.47-25.16%, protein from 1.85-28.45% and fibre content from 15.88-37.12%. There were negative correlations between seed oil and protein content.With reference to genetic diversity, the average estimate of FST was 8.852 indicating a low level of genetic differentiation among subpopulations. The AMOVA test revealed that variation was 94% within and 6% among subpopulations. Bayesian population structure identified five subpopulations and was in agreement with their geographical distribution. Among the mixed models analysed, mixed linear model (MLM) identified 21 quantitative trait loci for lint percentage and seed quality traits, such as seed protein and oil. Establishing genetic diversity, population structure and marker trait associations for the seed quality traits could be valuable in understanding the genetic relationships and their utilization in breeding programmes.

  9. A 'fragile cell' sub-population revealed during cytometric assessment of Saccharomyces cerevisiae viability in lipid-limited alcoholic fermentation.

    Science.gov (United States)

    Delobel, P; Pradal, M; Blondin, B; Tesniere, C

    2012-11-01

    To show that in anaerobic fermentation with limiting lipid nutrients, cell preparation impacts the viability assessment of yeast cells, and to identify the factors involved. Saccharomyces cerevisiae viability was determined using propidium iodide staining and the flow cytometry. Analyses identified intact cells, dead cells and, under certain conditions, the presence of a third subpopulation of apparently damaged cells. This intermediate population could account for up to 40% of the entire cell population. We describe, analyse and discuss the effects of different solutions for cell resuspension on the respective proportion of these three populations, in particular that of the intermediate population. We show that this intermediate cell population forms in the absence of Ca(2+)/Mg(2+). Cell preparation significantly impacts population viability assessment by FCM. The intermediate population, revealed under certain conditions, could be renamed as 'fragile cells'. For these cells, Ca(2+) and Mg(2+) reduce cell membrane permeability to PI. This is the first study that analyses and discusses the factors influencing the formation of an intermediate population when studying viability in yeast alcoholic fermentation. With a wider application in biological research, this study provides important support to the relatively new questioning of propidium iodide staining as a universal cell death indicator. © 2012 The Authors. Letters in Applied Microbiology © 2012 The Society for Applied Microbiology.

  10. Identifying sub-categories of social fears using an alternative factor analytic structure of the Social Phobia and Anxiety Inventory.

    Science.gov (United States)

    Panayiotou, Georgia; Michaelides, Michalis P; Theodorou, Marios; Neophytou, Klavdia

    2017-05-01

    This study evaluates an alternative factor structure of the Social Phobia and Anxiety Inventory (Turner et al., 1989), a widely used measure of social anxiety. Existing models ignore variance due to the different social contexts where social fears are expressed. Taking a different approach to scoring than previous studies, this investigation proposes a new model, which, in addition to 4-5 symptom dimensions, is able to capture the situations (strangers, authority figures, members of the opposite sex and people in general) that are of concern to the examinee. To test this model, all 96 items of the Social Phobia scale, rather than the average of the sub-items of its 23 questions were subjected to confirmatory factor analysis. The model shows good fit and is superior to models ignoring the "situation" factors, which show good predictive validity in respect to real life demographics. Utilization of all single questions of the SPAI can capture a wider range of social fears related to social anxiety than using the average of the items, which has implications for the understanding and clinical assessment of social anxiety. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  11. Structure of the biliverdin radical intermediate in phycocyanobilin:ferredoxin oxidoreductase identified by high-field EPR and DFT.

    Science.gov (United States)

    Stoll, Stefan; Gunn, Alexander; Brynda, Marcin; Sughrue, Wesley; Kohler, Amanda C; Ozarowski, Andrew; Fisher, Andrew J; Lagarias, J Clark; Britt, R David

    2009-02-11

    The cyanobacterial enzyme phycocyanobilin:ferredoxin oxidoreductase (PcyA) catalyzes the two-step four-electron reduction of biliverdin IXalpha to phycocyanobilin, the precursor of biliprotein chromophores found in phycobilisomes. It is known that catalysis proceeds via paramagnetic radical intermediates, but the structure of these intermediates and the transfer pathways for the four protons involved are not known. In this study, high-field electron paramagnetic resonance (EPR) spectroscopy of frozen solutions and single crystals of the one-electron reduced protein-substrate complex of two PcyA mutants D105N from the cyanobacteria Synechocystis sp. PCC6803 and Nostoc sp. PCC7120 are examined. Detailed analysis of Synechocystis D105N mutant spectra at 130 and 406 GHz reveals a biliverdin radical with a very narrow g tensor with principal values 2.00359(5), 2.00341(5), and 2.00218(5). Using density-functional theory (DFT) computations to explore the possible protonation states of the biliverdin radical, it is shown that this g tensor is consistent with a biliverdin radical where the carbonyl oxygen atoms on both the A and the D pyrrole rings are protonated. This experimentally confirms the reaction mechanism recently proposed (Tu, et al. Biochemistry 2007, 46, 1484).

  12. The structure of the biliverdin radical intermediate in phycocyanobilin:ferredoxin oxidoreductase identified by high-field EPR and DFT

    Science.gov (United States)

    Stoll, Stefan; Gunn, Alexander; Brynda, Marcin; Sughrue, Wesley; Kohler, Amanda C.; Ozarowski, Andrew; Fisher, Andrew J.; Lagarias, J. Clark; Britt, R. David

    2009-01-01

    The cyanobacterial enzyme phycocyanobilin:ferredoxin oxidoreductase (PcyA) catalyzes the two-step four-electron reduction of biliverdin IXα to phycocyanobilin, the precursor of biliprotein chromophores found in phycobilisomes. It is known that catalysis proceeds via paramagnetic radical intermediates, but the structure of these intermediates and the transfer pathways for the four protons involved are not known. In this study, high-field electron paramagnetic resonance (EPR) spectroscopy of frozen solutions and single crystals of the one-electron reduced protein-substrate complex of two PcyA mutants D105N from the cyanobacteria Synechocystis sp. PCC6803 and Nostoc sp. PCC7120 are examined. Detailed analysis of Synechocystis D105N mutant spectra at 130 GHz and 406 GHz reveals a biliverdin radical with a very narrow g tensor with principal values 2.00359(5), 2.00341(5) and 2.00218(5). Using density-functional theory (DFT) computations to explore the possible protonation states of the biliverdin radical, it is shown that this g tensor is consistent with a biliverdin radical where the carbonyl oxygen atoms on both the A and the D pyrrole rings are protonated. This experimentally confirms the reaction mechanism recently proposed (Tu et al, Biochemistry 2007, 46, 1484). PMID:19159240

  13. Using Structural Equation Modeling to Identify Predictors of Sexual Behaviors among Hispanic Men who have Sex with Men

    Science.gov (United States)

    De Santis, Joseph P; Arcia, Adriana; Vermeesch, Amber; Gattamorta, Karina A.

    2013-01-01

    Background Hispanic men who have sex with men (MSM) are at risk for HIV and other sexually transmitted infections related to high risk sexual behaviors. Little attention has been paid to the identification of predictors of sexual behaviors among this population. Objective The aim of this study was to test a model that predicts the sexual behaviors of Hispanic MSM that is based on an epidemiological framework. Methods Structural equation modeling was used to test relationships between demographic and study variables of alcohol abuse, body image, depressive symptoms, eating attitudes and behaviors, and self-esteem as predictors of sexual behaviors using a sample of 100 Hispanic MSM. Results A number of participants were at risk for alcohol abuse, body image disturbance, depression, eating disorders, and low self-esteem. Physical and social factors were not predictive of sexual behaviors. A model that included the latent variables of mental health and appearance concern adequately fit the data (X2 (10, N = 100) = 14.498, CFI = 0.966, RMSEA = 0.067, SRMR = 0.043), demonstrating that mental health is a significant predictor of sexual behaviors in this sample. Discussion The results of this study supported a model predicting sexual behaviors of Hispanic MSM. This study highlights the importance of understanding the influence of psychological/mental health on the sexual behaviors of Hispanic MSM. Interventions to decrease high risk sexual behaviors among this population must consider the impact of psychological/mental health on sexual behaviors. PMID:21501734

  14. Identifying structural characteristics of humic acid to static and dynamic fluorescence quenching of phenanthrene, 9-phenanthrol, and naphthalene.

    Science.gov (United States)

    Wang, Lin; Li, Hao; Yang, Yu; Zhang, Di; Wu, Min; Pan, Bo; Xing, Baoshan

    2017-10-01

    Fluorescence quenching is a sensitive and fast method to quantify the interactions between a fluorescent organic contaminant and a quencher, such as dissolved organic matter (DOM). Dynamic fluorescence quenching is resulted from molecular collision, not the real binding, and thus it complicates the binding data interpretation. On the other hand, static fluorescence quenching occurs for fluorescent contaminants of ground states, which decreases the concentration of freely dissolved contaminants. However, how a particular structure in DOM contributes to the static and dynamic fluorescence quenching of a fluorescent contaminant is still unclear, which has greatly hindered the application of fluorescence quenching technique. A humic acid (HA) extracted from sediment was chemically modified, i.e., bleaching, acid hydrolysis, and decarboxylation. HAs before and after these modifications were used in fluorescence quenching experiments for phenanthrene (PHE), 9-phenanthrol (PTR) and naphthalene (NAP). Different quenching mechanisms were observed for these chemicals depending on HA properties. For PHE and NAP, aromatic components showed static quenching, while carboxyl groups primarily showed dynamic quenching. Aromatic components and carbohydrates in HAs primarily bound (static quenching) rather than collided (dynamic quenching) with PTR. Carboxyl groups showed interactions with PTR through dynamic quenching only when carboxyl groups were on the benzene ring. Based on the results, we emphasized that dynamic quenching should be carefully excluded in fluorescence quenching studies. This line of study is important to establish a general relationship between DOM properties and static/dynamic quenching contributions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. 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)

  16. A novel algorithm identifies stress-induced alterations in mitochondrial connectivity and inner membrane structure from confocal images.

    Directory of Open Access Journals (Sweden)

    Mathieu Ouellet

    2017-06-01

    Full Text Available Mitochondria exist as a highly interconnected network that is exquisitely sensitive to variations in nutrient availability, as well as a large array of cellular stresses. Changes in length and connectivity of this network, as well as alterations in the mitochondrial inner membrane (cristae, regulate cell fate by controlling metabolism, proliferation, differentiation, and cell death. Given the key roles of mitochondrial dynamics, the process by which mitochondria constantly fuse and fragment, the measure of mitochondrial length and connectivity provides crucial information on the health and activity of various cell populations. However, despite the importance of accurately measuring mitochondrial networks, the tools required to rapidly and accurately provide this information are lacking. Here, we developed a novel probabilistic approach to automatically measure mitochondrial length distribution and connectivity from confocal images. This method accurately identified mitochondrial changes caused by starvation or the inhibition of mitochondrial function. In addition, we successfully used the algorithm to measure changes in mitochondrial inner membrane/matrix occurring in response to Complex III inhibitors. As cristae rearrangements play a critical role in metabolic regulation and cell survival, this provides a rapid method to screen for proteins or compounds affecting this process. The algorithm will thus provide a robust tool to dissect the molecular mechanisms underlying the key roles of mitochondria in the regulation of cell fate.

  17. 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

  18. Distinguishing Galactomyces citri-aurantii from G. geotrichum and characterizing population structure of the two postharvest sour rot pathogens of fruit crops in California.

    Science.gov (United States)

    McKay, A H; Förster, H; Adaskaveg, J E

    2012-05-01

    A growth assay in lemon juice and polymerase chain reaction amplifications using newly designed species-specific primers from endopolygalacturonase and β-tubulin genes rapidly differentiated isolates of the morphologically similar fruit sour rot pathogens Galactomyces citriaurantii and G. geotrichum. Isolates of both species were collected from agricultural soils and decaying fruit at locations within and outside California, including worldwide locations, and were used in population genetic studies based on amplified fragment length polymorphic (AFLP) DNA markers. For all four geographically defined subpopulations (three counties of California and locations outside California) among 97 isolates of G. citri-aurantii and for the two subpopulations (origin within or outside California) among 35 isolates of G. geotrichum, the proportion of polymorphic loci and haplotypic diversity was high. In total, 82 unique haplotypes were identified for G. citri-aurantii for the four subpopulations and, of these, 80 haplotypes were unique among subpopulations. For G. geotrichum, 25 unique haplotypes were identified among the two subpopulations and no haplotype was shared. Indices of genetic differences (F(ST)) between subpopulations within each species were all low (e.g., 0.038 for G. geotrichum and 0.085 to 0.226 for G. citriaurantii), indicating a low level of genetic differentiation. Following clone correction, mating type segregation ratios for G. citri-aurantii did not significantly (P > 0.1) deviate from a 1:1 ratio for all four subpopulations or the entire population. Tests of the index of association (I(A)) and parsimony tree-length permutation tests (PTLPT) supported a random mating structure for clone-corrected data for the Kern, Tulare, and Ventura County subpopulations and the null hypothesis of random mating could not be rejected. Additionally, PTLPT also supported random mating for the "outside of California" population. For G. geotrichum, random mating was only

  19. Subpopulation-Specific Metabolic Pathway Usage in Mixed Cultures as Revealed by Reporter Protein-Based 13C Analysis▿

    OpenAIRE

    Rühl, Martin; Hardt, Wolf-Dietrich; Sauer, Uwe

    2011-01-01

    Most large-scale biological processes, like global element cycling or decomposition of organic matter, are mediated by microbial consortia. Commonly, the different species in such consortia exhibit mutual metabolic dependencies that include the exchange of nutrients. Despite the global importance, surprisingly little is known about the metabolic interplay between species in particular subpopulations. To gain insight into the intracellular fluxes of subpopulations and their interplay within su...

  20. Artificial neural networks for the definition of kinetic subpopulations in electroejaculated and epididymal spermatozoa in the domestic cat.

    Science.gov (United States)

    Contri, Alberto; Zambelli, Daniele; Faustini, Massimo; Cunto, Marco; Gloria, Alessia; Carluccio, Augusto

    2012-09-01

    This study was designed for the identification of different sperm kinetic subpopulations in feline semen using artificial neural networks (ANNs) and for the evaluation of the effect of ejaculation on motility patterns of these subpopulations. Seven tomcats presented for routine orchiectomy were electroejaculated, and after 5 days, orchiectomized and epididymal tail sperms were collected. Sperm motility characteristics were evaluated using a computer-assisted sperm analyzer that provided individual kinetic characteristics of each spermatozoon. A total of 23 400 spermatozoa for electroejaculated and 9200 for epididymal tail samples were evaluated using a multivariate approach, comprising principal component analysis and ANN classification. The multivariate approach allowed the identification and characterization of three different and well-defined sperm subpopulations. There were significant differences before (epididymal tail spermatozoa) and after (electroejaculated sperm) ejaculation in sperm kinetic subpopulation characteristics. In both epididymal and ejaculated samples, the majority of subpopulation was characterized by high velocity and progressiveness; however, the electroejaculated samples showed significantly higher values, suggesting that the microenvironment of the epididymal tail could affect the sperm motility or, alternatively, seminal plasma could increase the kinetic characteristics of the spermatozoa, indicating that only after ejaculation, the spermatozoa express their motility potential. Nevertheless, further studies are required to clarify the functional significance of each kinetic subpopulation.

  1. Three-dimensional database mining identifies a unique chemotype that unites structurally diverse botulinum neurotoxin serotype A inhibitors in a three-zone pharmacophore.

    Science.gov (United States)

    Hermone, Ann R; Burnett, James C; Nuss, Jonathan E; Tressler, Lyal E; Nguyen, Tam L; Solaja, Bogdan A; Vennerstrom, Jonathan L; Schmidt, James J; Wipf, Peter; Bavari, Sina; Gussio, Rick

    2008-12-01

    A search query consisting of two aromatic centers and two cationic centers was defined based on previously identified small molecule inhibitors of the botulinum neurotoxin serotype A light chain (BoNT/A LC) and used to mine the National Cancer Institute Open Repository. Ten small molecule hits were identified, and upon testing, three demonstrated inhibitory activity. Of these, one was structurally unique, possessing a rigid diazachrysene scaffold. The steric limitations of the diazachrysene imposed a separation between the overlaps of previously identified inhibitors, revealing an extended binding mode. As a result, the pharmacophore for BoNT/A LC inhibition has been modified to encompass three zones. To demonstrate the utility of this model, a novel three-zone inhibitor was mined and its activity was confirmed.

  2. 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

  3. Crystal structure of human Charcot-Leyden crystal protein, an eosinophil lysophospholipase, identifies it as a new member of the carbohydrate-binding family of galectins.

    Science.gov (United States)

    Leonidas, D D; Elbert, B L; Zhou, Z; Leffler, H; Ackerman, S J; Acharya, K R

    1995-12-15

    The Charcot-Leyden crystal (CLC) protein is a major autocrystallizing constituent of human eosinophils and basophils, comprising approximately 10% of the total cellular protein in these granulocytes. Identification of the distinctive hexagonal bipyramidal crystals of CLC protein in body fluids and secretions has long been considered a hallmark of eosinophil-associated allergic inflammation. Although CLC protein possesses lysophospholipase activity, its role(s) in eosinophil or basophil function or associated inflammatory responses has remained speculative. The crystal structure of the CLC protein has been determined at 1.8 A resolution using X-ray crystallography. The overall structural fold of CLC protein is highly similar to that of galectins -1 and -2, members of an animal lectin family formerly classified as S-type or S-Lac (soluble lactose-binding) lectins. This is the first structure of an eosinophil protein to be determined and the highest resolution structure so far determined for any member of the galectin family. The CLC protein structure possesses a carbohydrate-recognition domain comprising most, but not all, of the carbohydrate-binding residues that are conserved among the galectins. The protein exhibits specific (albeit weak) carbohydrate-binding activity for simple saccharides including N-acetyl-D-glucosamine and lactose. Despite CLC protein having no significant sequence or structural similarities to other lysophospholipase catalytic triad has also been identified within the CLC structure, making it a unique dual-function polypeptide. These structural findings suggest a potential intracellular and/or extracellular role(s) for the galectin-associated activities of CLC protein in eosinophil and basophil function in allergic diseases and inflammation.

  4. Association between Influenza A Virus Infection and Pigs Subpopulations in Endemically Infected Breeding Herds.

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    Andres Diaz

    Full Text Available Influenza A viruses (IAVs are distributed worldwide in birds, pigs and humans, and cause important endemic disease affecting hosts in all countries. Although pigs play a key role in the ecology of IAVs, the epidemiology of IAVs within swine herds is poorly understood. In this longitudinal study we describe the prevalence of IAVs infection in three subpopulations of pigs in 5 breeding herds in the Midwestern USA. Each herd was sampled monthly for a year and, at each visit, 30 individual nasal swabs were collected from the three subpopulations, namely, a replacement females, resident on-farm for less than 4 weeks (new gilts, b replacement females, resident on-farm for more than 4 weeks (gilts, and c neonatal pigs less than 21 days of age (piglets. Real time reverse transcriptase polymerase chain reaction (RRT-PCR was used to detect IAVs, and the association between IAVs infection and pig subpopulation was measured using a mixed logistic regression model. Nasal swabs (n = 4,190 were collected from 141 groups of pigs. At least, one IAV-positive nasal swab was found in 19.9% (n = 28 of the sampled groups, and 7.7% (n = 324 of all nasal swabs tested positive. After adjusting by annual quarter and sampling event, the odds of testing IAV positive were 7.9 (95% CI 1.4, 43.9 and 4.4 (95% CI 1.1, 17.1 times higher in groups of new gilts and piglets compared to groups of gilts, respectively. Results indicate that new gilts and piglets had higher odds of testing IAV positive than gilts in swine breeding herds and that season influences IAV infection in pigs. Based on these findings, we recommend that IAV control strategies be aimed at preventing infection before gilts are introduced into the farm, and in pigs prior to weaning.

  5. 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.

  6. Disparities in colorectal cancer incidence among Latino subpopulations in California defined by country of origin.

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    Stern, Mariana C; Zhang, Juanjuan; Lee, Eunjung; Deapen, Dennis; Liu, Lihua

    2016-02-01

    In California, colorectal cancer (CRC) is the second most common cancer in Latinos. Using data from the California Cancer Registry, we investigated demographic and clinical characteristics of 36,133 Latinos with CRC living in California during 1995-2011 taking into account subpopulations defined by country of origin. Cases were defined as Latino according to the North American Association of Central Cancer Registries Hispanic Identification Algorithm, which was also used to group cases by country of origin: Mexico (9,678, 27 %), Central or South America (2,636, 7 %), Cuban (558, 2 %), Puerto Rico (295, 1 %), and other or unknown origin (22,966, 64 %; Other/NOS). 174,710 non-Hispanic white (NHW) CRC cases were included for comparison purposes. Annual age-adjusted incidence rates (AAIR) and proportional incidence ratios (PIRs) were calculated. Differences were observed for age at diagnosis, sex distribution, socioeconomic status (SES), nativity (US born vs. foreign born), stage, and tumor localization across Latino subpopulations and compared to NHW. Mexican Latinos had the lowest AAIR and Cuban Latinos had the highest. PIRs adjusted for age, SES, and nativity showed an excess of CRC males and female cases from Cuba, female cases from Puerto Rico and reduced number of female cases from Mexico. Differences in cancer incidence patterns and tumor characteristics were observed among Latino subpopulations in California. These disparities may reflect differences in cancer determinants among Latinos; therefore, given that country of origin information is unavailable for a large proportion of these patients, greater efforts to collect these data are warranted.

  7. Morphological Evidence for a Subpopulation Selection Effect by Estrogen and Antiestrogen Treatments in the Heterogeneous MCF-7 Cell Line

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    Jacqueline Palmari

    2000-01-01

    Full Text Available Recently, we developed a method to quantitatively study tumour cell heterogeneity in terms of both nuclear size and estrogen receptor (ER content by image cytometry. The method, previously used to analyse the proliferation of the breast cancer cell line MCF‐7, was applied here to analyse the growth of this cell line under estradiol (E2, hydroxytamoxifen (OH‐TAM, and both E2 and OH‐TAM treatments. The method extracts characteristic parameters of single nuclei and features that measure the global and local organisation of the cells in their growing phase. Modifications of the heterogeneity of the cell line are emphasised through phenotypic changes and modifications of the spatial organisation of the cells. The hormone (E2 generates a very fast growth of cells with small nuclei that became ER negative in the long term. The antihormone (OH‐TAM produces a gradual selection of ER negative or poorly positive cells with large nuclei. These modifications are reversed when E2 and OH‐TAM are simultaneously used. Moreover, estradiol induces a permissive context of proliferation, whereas hydroxytamoxifen acts only on some subpopulations. The combination of cell count, cytomorphology, and cell organisation revealed the magnitude of the potential of structuration of hormones or antihormones on in vitro growing cells.

  8. Differential responses to x-irradiation of subpopulations of two heterogeneous human carcinomas in vitro

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    Leith, J.T.; Dexter, D.L.; DeWyngaert, J.K.; Zeman, E.M.; Chu, M.Y.; Calabresi, P.; Glicksman, A.S.

    1982-07-01

    The responses of two heterogeneous human cancer cell lines and their derivative clones to graded single doses of X-rays were examined in vitro. One system consisted of the human colon carcinoma line DLD-1 and two subpopulations (clones A and D). The second system consisted of the human lung carcinoma line (LX1) and four subpopulations (LX1-1, LX1-2, LX1-3, and LX1-9). These subpopulations have previously been shown to be markedly heterogeneous in terms of such characteristics as karyotype, morphology, drug sensitivity, tumorigenicity, and expression of membrane glycoproteins (such as carcinoembryonic antigen and tumor colonic mucoprotein antigen). Exponentially growing cultures were irradiated with graded single doses of 100-kVp X-rays. Survival was assessed using colony formation as the end point, and responses from multiple experiments were fitted to the single-hit, multitarget equation of cell survival. Values for the mean lethal dose (D0, grays), quasithreshold dose (Dq, grays), and extrapolation number (n) were obtained. For the human colon adenocarcinoma system, these values for the three tumor lines were: DLD-1, 0.95, 2.34, and 11.7; clone A, 1.06, 2.23 and 8.20; and clone D, 1.08, 1.89, and 5.80. For the human lung carcinoma system, these values for the five sublines were: LX1, 1.14, 0.19, and 1.20; LX1-1, 0.96, 2.06, and 8.54; LX1-2, 0.98, 0.88, and 2.48; LX1-3, 0.68, 2.05, and 20.3; and LX1-9, 1.12, 0.00, and 1.00. These two human tumor systems therefore exhibit variability in their intrinsic sensitivity to X-irradiation. The data indicate that failure of some human carcinomas to respond to physical treatment modalities can be due to preexisting resistant subpopulations.

  9. The predictable narwhal: satellite tracking shows behavioural similarities between isolated subpopulations

    DEFF Research Database (Denmark)

    Heide-Jørgensen, M. P.; Nielsen, N.H.; Hansen, R. G.

    2015-01-01

    Comparison of behavioural similarities between subpopulations of species that have been isolated for a long time is important for understanding the general ecology of species that are under pressure from large-scale changes in habitats. Narwhals (Monodon monoceros) east and west of Greenland...... are examples of separated populations that, in different ocean parts, will be coping with similar anthropogenic and climate-driven habitat alterations. To study this, 28 narwhals from the Scoresby Sound fjord system were tracked by satellite in 2010-2013. The average duration of contact with the whales was 124...

  10. 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

    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......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...

  11. A CD44v+ subpopulation of breast cancer stem-like cells with enhanced lung metastasis capacity.

    Science.gov (United States)

    Hu, Jing; Li, Gang; Zhang, Peiyuan; Zhuang, Xueqian; Hu, Guohong

    2017-03-16

    Cancer stem-like cells (CSCs) are a subpopulation of cancer cells responsible for tumor growth, and recent evidence suggests that CSCs also contribute to cancer metastasis. However, the heterogeneity of CSCs in metastasis capacities is still unclear in breast cancer. Here we show that among the CD24-/CD44+ breast CSCs, a subset expressing the variant isoform of CD44 (CD44v) displays significantly higher capacity of lung metastasis than that expressing the standard CD44 isoform CD44s. Increasing or reducing the CD44v/CD44s ratio of breast cancer cells by regulating the expression of epithelial splicing regulatory protein 1 (ESRP1) leads to promotion or suppression of lung metastasis without influencing cancer cell stemness. Directly suppressing CD44v expression significantly alleviates the metastasis burden in lungs. Mechanically, CD44v, but not CD44s, responds to osteopontin (OPN) in the lung environment to enhance cancer cell invasiveness and promote lung metastasis. In clinical samples expression of ESRP1 and CD44v, rather than CD44s or total CD44, positively correlates with distant metastasis. Overall, our data identify a subset of metastatic breast CSCs characterized by CD44v expression, and suggest that CD44v and ESRP1 might be better prognosis markers and therapeutic targets for breast cancer metastasis.

  12. Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy.

    Science.gov (United States)

    Wu, Feng-Hua; Mu, Lei; Li, Xiao-Lan; Hu, Yi-Bing; Liu, Hui; Han, Lin-Tao; Gong, Jian-Ping

    2017-10-03

    The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo . Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo . Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro . Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence.

  13. 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

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    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

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

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    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.

  15. 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.

  16. Lymphocytes Subpopulation in Peripheral Blood and Spleen of Village Chickens Recognized by Monoclonal Antibodies (SUBPOPULASI LIMFOSIT PADA DARAH TEPI DAN LIMPA AYAM KAMPUNG YANG DIKENALI OLEH ANTIBODI MONOCLONAL

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    Nyoman Mantik Astawa

    2016-07-01

    Full Text Available Lymphocytes play important role in host defence system against pathogenic agents both in mammalianand avian species. Monoclonal antibodies (mAbs have been widely used to identify lymphocytessubpopulation in a host based on their surface cluster differentiation (CD markers. Currently, mAbsagainst lymphocytes surface markers of village chickens have been produced by fusion of myeloma withlymphocytes derived from spleen of mice immune to chicken lymphocytes. In two fusion experiments, 623clones of hybridomas were produced and four (BG4, CB1, DB2 and BB2 of which secreted mAbs againstchickens lymphocyte surface molecules. Two mAbs (BG4 and DB2 recognized protein of 32 kDa, one mAb(CB1 recognized protein of 64 kDa, and one mAb was unable to recognize any protein of chicken lymphocytesurface molecule. Three mAbs recognized lymphocyte subpopulation in spleen and peripheral blood ofvillage chickens. In peripheral blood, mAbs BG4, CB1 and DB2 recognized lymphocytes subpopulationwith the percentages of 11.2%, 21.4% and 7.4% respectively. In spleen those three mAbs recognizedlymphocytes subpopulations at the percentages of 38.2%, 51.54% and 31.5% respectively. Based on thoseresult, it is very likely that mAbs BG4 and DB2 recognized CD4 molecule and mAb CB1 recognized CD8molecule of village chickens lymphocytes.

  17. 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

    2014-01-01

    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 has 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 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. PMID:25464947

  18. A fluorescent protein scaffold for presenting structurally constrained peptides provides an effective screening system to identify high affinity target-binding peptides.

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    Tetsuya Kadonosono

    Full Text Available Peptides that have high affinity for target molecules on the surface of cancer cells are crucial for the development of targeted cancer therapies. However, unstructured peptides often fail to bind their target molecules with high affinity. To efficiently identify high-affinity target-binding peptides, we have constructed a fluorescent protein scaffold, designated gFPS, in which structurally constrained peptides are integrated at residues K131-L137 of superfolder green fluorescent protein. Molecular dynamics simulation supported the suitability of this site for presentation of exogenous peptides with a constrained structure. gFPS can present 4 to 12 exogenous amino acids without a loss of fluorescence. When gFPSs presenting human epidermal growth factor receptor type 2 (HER2-targeting peptides were added to the culture medium of HER2-expressing cells, we could easily identify the peptides with high HER2-affinity and -specificity based on gFPS fluorescence. In addition, gFPS could be expressed on the yeast cell surface and applied for a high-throughput screening. These results demonstrate that gFPS has the potential to serve as a powerful tool to improve screening of structurally constrained peptides that have a high target affinity, and suggest that it could expedite the one-step identification of clinically applicable cancer cell-binding peptides.

  19. A fluorescent protein scaffold for presenting structurally constrained peptides provides an effective screening system to identify high affinity target-binding peptides.

    Science.gov (United States)

    Kadonosono, Tetsuya; Yabe, Etsuri; Furuta, Tadaomi; Yamano, Akihiro; Tsubaki, Takuya; Sekine, Takuya; Kuchimaru, Takahiro; Sakurai, Minoru; Kizaka-Kondoh, Shinae

    2014-01-01

    Peptides that have high affinity for target molecules on the surface of cancer cells are crucial for the development of targeted cancer therapies. However, unstructured peptides often fail to bind their target molecules with high affinity. To efficiently identify high-affinity target-binding peptides, we have constructed a fluorescent protein scaffold, designated gFPS, in which structurally constrained peptides are integrated at residues K131-L137 of superfolder green fluorescent protein. Molecular dynamics simulation supported the suitability of this site for presentation of exogenous peptides with a constrained structure. gFPS can present 4 to 12 exogenous amino acids without a loss of fluorescence. When gFPSs presenting human epidermal growth factor receptor type 2 (HER2)-targeting peptides were added to the culture medium of HER2-expressing cells, we could easily identify the peptides with high HER2-affinity and -specificity based on gFPS fluorescence. In addition, gFPS could be expressed on the yeast cell surface and applied for a high-throughput screening. These results demonstrate that gFPS has the potential to serve as a powerful tool to improve screening of structurally constrained peptides that have a high target affinity, and suggest that it could expedite the one-step identification of clinically applicable cancer cell-binding peptides.

  20. Novel circular single-stranded DNA viruses identified in marine invertebrates reveal high sequence diversity and consistent predicted intrinsic disorder patterns within putative structural proteins.

    Science.gov (United States)

    Rosario, Karyna; Schenck, Ryan O; Harbeitner, Rachel C; Lawler, Stephanie N; Breitbart, Mya

    2015-01-01

    Viral metagenomics has recently revealed the ubiquitous and diverse nature of single-stranded DNA (ssDNA) viruses that encode a conserved replication initiator protein (Rep) in the marine environment. Although eukaryotic circular Rep-encoding ssDNA (CRESS-DNA) viruses were originally thought to only infect plants and vertebrates, recent studies have identified these viruses in a number of invertebrates. To further explore CRESS-DNA viruses in the marine environment, this study surveyed CRESS-DNA viruses in various marine invertebrate species. A total of 27 novel CRESS-DNA genomes, with Reps that share less than 60.1% identity with previously reported viruses, were recovered from 21 invertebrate species, mainly crustaceans. Phylogenetic analysis based on the Rep revealed a novel clade of CRESS-DNA viruses that included approximately one third of the marine invertebrate associated viruses identified here and whose members may represent a novel family. Investigation of putative capsid proteins (Cap) encoded within the eukaryotic CRESS-DNA viral genomes from this study and those in GenBank demonstrated conserved patterns of predicted intrinsically disordered regions (IDRs), which can be used to complement similarity-based searches to identify divergent structural proteins within novel genomes. Overall, this study expands our knowledge of CRESS-DNA viruses associated with invertebrates and explores a new tool to evaluate divergent structural proteins encoded by these viruses.

  1. Markers of Increased Cardiovascular Risk in Postmenopausal Women: Focus on Oxidized-LDL and HDL Subpopulations

    Science.gov (United States)

    Mascarenhas-Melo, Filipa; Sereno, José; Teixeira-Lemos, Edite; Rocha-Pereira, Petronila; Teixeira, Frederico; Reis, Flávio

    2013-01-01

    Objective. To evaluate the effect of gender and menopause in cardiovascular risk (CVR) in a healthy population based on both classical and nontraditional markers. Methods. 56 men and 68 women (48 pre- and 20 postmenopause) were enrolled in the study. The following markers were analyzed: blood pressure (BP), body mass index (BMI), waist circumference (WC), glucose, total cholesterol (total-c), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-c), oxidized-LDL (Ox-LDL), HDL-c and subpopulations, paraoxonase-1 activity, hsCRP, uric acid, tumor necrosis factor alpha (TNF-α), adiponectin, vascular endothelial growth factor (VEGF), and intercellular adhesion molecular 1 (ICAM1). Results. Relative to the women, men present significantly increased BMI, WC, BP, glucose, total-c, TGs, LDL-c, Ox-LDL, uric acid, and TNF-α and reduced adiponectin and total and large HDL-c. The protective profile of women is lost after menopause with a significantly increased BMI, WC, BP, glucose, LDL-c, Ox-LDL, hsCRP, and VEGF and decreased total and large HDL-c. Significant correlations were found in women population and in postmenopausal women between Ox-LDL and total, large, and small HDL-c and between TNF-α and total, large, and small HDL-c, LDL-c, and Ox-LDL. Conclusions. Men present higher CVR than women who lost protection after menopause, evidenced by nontraditional markers, including Ox-LDL and HDL subpopulations. PMID:24167352

  2. Markers of Increased Cardiovascular Risk in Postmenopausal Women: Focus on Oxidized-LDL and HDL Subpopulations

    Directory of Open Access Journals (Sweden)

    Filipa Mascarenhas-Melo

    2013-01-01

    Full Text Available Objective. To evaluate the effect of gender and menopause in cardiovascular risk (CVR in a healthy population based on both classical and nontraditional markers. Methods. 56 men and 68 women (48 pre- and 20 postmenopause were enrolled in the study. The following markers were analyzed: blood pressure (BP, body mass index (BMI, waist circumference (WC, glucose, total cholesterol (total-c, triglycerides (TGs, low-density lipoprotein cholesterol (LDL-c, oxidized-LDL (Ox-LDL, HDL-c and subpopulations, paraoxonase-1 activity, hsCRP, uric acid, tumor necrosis factor alpha (TNF-α, adiponectin, vascular endothelial growth factor (VEGF, and intercellular adhesion molecular 1 (ICAM1. Results. Relative to the women, men present significantly increased BMI, WC, BP, glucose, total-c, TGs, LDL-c, Ox-LDL, uric acid, and TNF-α and reduced adiponectin and total and large HDL-c. The protective profile of women is lost after menopause with a significantly increased BMI, WC, BP, glucose, LDL-c, Ox-LDL, hsCRP, and VEGF and decreased total and large HDL-c. Significant correlations were found in women population and in postmenopausal women between Ox-LDL and total, large, and small HDL-c and between TNF-α and total, large, and small HDL-c, LDL-c, and Ox-LDL. Conclusions. Men present higher CVR than women who lost protection after menopause, evidenced by nontraditional markers, including Ox-LDL and HDL subpopulations.

  3. Circadian variations of cortisol, melatonin and lymphocyte subpopulations in geriatric age.

    Science.gov (United States)

    Mazzoccoli, G; Vendemiale, G; La Viola, M; De Cata, A; Carughi, S; Greco, A; Balzanelli, M; Tarquini, R

    2010-01-01

    A number of age-related changes in the 24-hour hormonal and non-hormonal rhythms have been found in older human beings. Lymphocyte subpopulations present circadian variation of some of their subsets and this variation may influence magnitude and expression of the immune responses. Numerous interactions exist among the nervous, endocrine and immune systems, mediated by neurotransmitters, hormones and cytokines. The aim of this study is to evaluate circadian variations of some endocrine and immune factors in older adults. Cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from ten healthy young and middle-aged subjects and from ten healthy elderly subjects. There was a statistically significant difference between the groups in the observed values of CD20 (higher in young and middle-aged subjects) and CD25 and DR+ T cells (higher in elderly subjects). In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the factors studied. In the group of elderly subjects a number of rhythms were absent or altered. The results of the current study show that aging is associated with enhanced responsiveness of T cell compartment and alterations of circadian rhythmicity.

  4. A comparison between protein profiles of B cell subpopulations and mantle cell lymphoma cells

    Directory of Open Access Journals (Sweden)

    Lehtiö Janne

    2009-11-01

    Full Text Available Abstract Background B-cell lymphomas are thought to reflect different stages of B-cell maturation. Based on cytogenetics and molecular markers, mantle cell lymphoma (MCL is presumed to derive predominantly from naïve, pre-germinal centre (pre-GC B lymphocytes. The aim of this study was to develop a method to investigate the similarity between MCL cells and different B-cell compartments on a protein expression level. Methods Subpopulations of B cells representing the germinal centre (GC, the pre-GC mantle zone and the post-GC marginal zone were isolated from tonsils using automated magnetic cell sorting (AutoMACS of cells based on their expression of CD27 and IgD. Protein profiling of the B cell subsets, of cell lines representing different lymphomas and of primary MCL samples was performed using top-down proteomics profiling by surface-enhanced laser detection/ionization time-of-flight mass spectrometry (SELDI-TOF-MS. Results Quantitative MS data of significant protein peaks (p-value Conclusion AutoMACS sorting generates sufficient purity to enable a comparison between protein profiles of B cell subpopulations and malignant B lymphocytes applying SELDI-TOF-MS. Further validation with an increased number of patient samples and identification of differentially expressed proteins would enable a search for possible treatment targets that are expressed during the early development of MCL.

  5. A Cone-Beam Computed Tomographic Study on Mandibular First Molars in a Chinese Subpopulation

    Science.gov (United States)

    Ma, Yue; Han, Ting; Chen, Xinyu; Wan, Fang; Lu, Yating; Yan, Songhe; Wang, Yan

    2015-01-01

    The purpose of this study was to conduct a cone-beam computed tomographic (CBCT) investigation on the root and canal configuration of the mandibular first molars, especially the morphology of the disto-lingual (DL) root, in a Chinese subpopulation. A total of 910 CBCT images of the mandibular first molars were collected from 455 patients who underwent CBCT examinations as a preoperative assessment for implants or orthodontic treatment. The following information was analyzed and evaluated: tooth position, gender, root and root canal number per tooth, root canal type of the mesial root(s) and distal root(s), angle of the DL root canal curvature, distance between two distal canal orifices in the teeth with DL root, and angle of disto-buccal canal orifice–disto-lingual canal orifice–mesio-lingual canal orifice (DB-DL-ML). Most of the mandibular first molars (64.9%, n = 591) had two roots with three root canals, and most of the mesial root canals (87.7%, n = 798) were type VI. The prevalence of the DL root was 22.1% (n = 201). The right side had a higher prevalence of DL root than the left side (pcanal were greater in the bucco-lingual (BL) orientation (30.10°±14.02°) than in the mesio-distal (MD) orientation (14.03°± 8.56°) (pcanal morphology of the mandibular first molars in a Chinese subpopulation. PMID:26241480

  6. Separation of haemocyte subpopulations in shrimp Fenneropenaeus chinensis by immunomagnetic bead using monoclonal antibody against granulocytes.

    Science.gov (United States)

    Xing, Jing; Chang, Yanhong; Tang, Xiaoqian; Sheng, Xiuzhen; Zhan, Wenbin

    2017-01-01

    In our previous work, two monoclonal antibodies (Mabs) against granulocytes of shrimp (Fenneropenaeus chinensis) had been produced, in this paper, haemocyte subpopulations were analyzed by flow cytometry (FCM) using the Mabs. Then immunomagnetic bead (IMB) method was applied for separation hyalinocytes and granulocytes using the Mabs. The separated hyalinocytes and granulocytes were analyzed by FCM, indirect immunofluorescence assay, Giemsa staining and transmission electron microscopy, respectively. The results showed the proportion of hyalinocytes in haemolymph of F. chinensis was 15.14 ± 1.22%, and that of granulocytes was 75.43 ± 2.31%. After two times separation by IMB, the purity rate of hyalinocytes and granulocytes was 96.27 ± 1.06% and 98.13 ± 0.86%, respectively. The hyalinocytes possessed 0.60-0.85 in nucleus/cytoplasm (N/C) ratio and had few granule in cytoplasm, whereas the separated granulocytes with N/C ratio of 0.12-0.36 and high electronic density of double membrane granules. The results reported the separation of haemocyte subpopulations using Mabs in shrimp for the first time, and the hyalinocytes and granulocytes isolated by IMB could be used for their differential protein analysis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Effects of ovarian structures identified at Ovsynch™ enrolment, disease history and lactation variables on odds of pregnancy to a fixed-time artificial insemination after Ovsynch™.

    Science.gov (United States)

    Ingenhoff, L; Hall, E; Ranjbar Ni, S; House, J K

    2017-04-01

    To determine the effects of ovarian structures present at Ovsynch™ enrolment, disease history, lactation variables and times bred on pregnancy per fixed-time artificial insemination (FTAI) following fixed-time insemination after Ovsynch and to determine the relationship between the size of ovarian follicular structures and concurrent presence of a corpus luteum (CL). The study was conducted in a 3000-cow Holstein dairy herd. Over a 6-month period, 886 non-pregnant cows were examined by transrectal ultrasound and enrolled into 1132 Ovsynch events. Enrolled cows were synchronised using an Ovsynch-56 protocol. At enrolment, both ovaries were scanned by transrectal ultrasound to identify and record the presence and size of ovarian structures. Cows that did not return to oestrus were pregnancy tested 32-38 days post-insemination. Univariable and multivariable generalised linear mixed models (GLMMs) were used to determine the effect of each variable on pregnancy per FTAI. A univariable GLMM was also used to analyse the relationship between size of the dominant follicular structure and concurrent presence of a CL. CL size (P = 0.039) and presence of a luteal cyst (P = 0.002) at Ovsynch enrolment significantly increased the odds of pregnancy. Occurrence of lameness (P = 0.035) or mastitis (P = 0.008) between calving and enrolment significantly decreased the odds of pregnancy. Neither the presence nor size of a follicular structure significantly affected the odds of pregnancy, although cows with larger follicular structures were less likely to have a concurrent CL (P < 0.001). Presence of luteal tissue at Ovsynch enrolment and recent disease events affected pregnancy per FTAI in cows inseminated after Ovsynch. © 2017 Australian Veterinary Association.

  8. 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.

  9. A site of varicella-zoster virus vulnerability identified by structural studies of neutralizing antibodies bound to the glycoprotein complex gHgL.

    Science.gov (United States)

    Xing, Yi; Oliver, Stefan L; Nguyen, TuongVi; Ciferri, Claudio; Nandi, Avishek; Hickman, Julie; Giovani, Cinzia; Yang, Edward; Palladino, Giuseppe; Grose, Charles; Uematsu, Yasushi; Lilja, Anders E; Arvin, Ann M; Carfí, Andrea

    2015-05-12

    Varicella-zoster virus (VZV), of the family Alphaherpesvirinae, causes varicella in children and young adults, potentially leading to herpes zoster later in life on reactivation from latency. The conserved herpesvirus glycoprotein gB and the heterodimer gHgL mediate virion envelope fusion with cell membranes during virus entry. Naturally occurring neutralizing antibodies against herpesviruses target these entry proteins. To determine the molecular basis for VZV neutralization, crystal structures of gHgL were determined in complex with fragments of antigen binding (Fabs) from two human monoclonal antibodies, IgG-94 and IgG-RC, isolated from seropositive subjects. These structures reveal that the antibodies target the same site, composed of residues from both gH and gL, distinct from two other neutralizing epitopes identified by negative-stain electron microscopy and mutational analysis. Inhibition of gB/gHgL-mediated membrane fusion and structural comparisons with herpesvirus homologs suggest that the IgG-RC/94 epitope is in proximity to the site on VZV gHgL that activates gB. Immunization studies proved that the anti-gHgL IgG-RC/94 epitope is a critical target for antibodies that neutralize VZV. Thus, the gHgL/Fab structures delineate a site of herpesvirus vulnerability targeted by natural immunity.

  10. 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.

  11. Lessons From the Polio Endgame: Overcoming the Failure to Vaccinate and the Role of Subpopulations in Maintaining Transmission.

    Science.gov (United States)

    Thompson, Kimberly M; Duintjer Tebbens, Radboud J

    2017-07-01

    Recent detections of circulating serotype 2 vaccine-derived poliovirus in northern Nigeria (Borno and Sokoto states) and Pakistan (Balochistan Province) and serotype 1 wild poliovirus in Pakistan, Afghanistan, and Nigeria (Borno) represent public health emergencies that require aggressive response. We demonstrate the importance of undervaccinated subpopulations, using an existing dynamic poliovirus transmission and oral poliovirus vaccine evolution model. We review the lessons learned during the polio endgame about the role of subpopulations in sustaining transmission, and we explore the implications of subpopulations for other vaccine-preventable disease eradication efforts. Relatively isolated subpopulations benefit little from high surrounding population immunity to transmission and will sustain transmission as long as they do not attain high vaccination coverage. Failing to reach such subpopulations with high coverage represents the root cause of polio eradication delays. Achieving and maintaining eradication requires addressing the weakest links, which includes immunizing populations in insecure areas and/or with disrupted or poor-performing health systems and managing the risks of individuals with primary immunodeficiencies who can excrete vaccine-derived poliovirus long-term. Eradication efforts for vaccine-preventable diseases need to create performance expectations for countries to immunize all people living within their borders and maintain high coverage with appropriate interventions.Keywords. Polio; eradication; transmission; heterogeneity.

  12. Environmental stress induced by the tumor bed effect leads to subpopulation exclusion within heterogeneous neoplasms: modeling studies

    Energy Technology Data Exchange (ETDEWEB)

    Michelson, S.; Leith, J.T.

    1988-09-01

    Three nested mathematical models were used to describe the compositional stability of subpopulations within artificial heterogeneous neoplasms in a stressed environment. The first models a microecology in which each subpopulation grows independently and no competition for resources occurs. In the second model, subpopulations compete for common resources, while in the third, the subpopulations compete for resources, and an additional dynamic term describes the emergence of the second population from the first. Environmental stress is a consequence of ionizing radiation damage to the normal tissue in which the tumor grows (the tumor bed effect, TBE). Compositional data observed as a function of time from experimental assays of artificial heterogeneous colon adenocarcinoma xenografts were used for this theoretical analysis. The results show that in the stressed environment, tumor subpopulations do compete for common resources, and that the weight of competition (i.e., the rate at which competition can retard total growth) is significantly enhanced. In contrast to unperturbed artificial heterogeneous tumors which exhibit stable composition as a function of time, TBE stress leads to selection of the majority neoplastic population.

  13. Differential down-regulation of HLA-DR on monocyte subpopulations during systemic inflammation

    Science.gov (United States)

    2010-01-01

    Introduction Decreased expression of human leukocyte antigen class II (HLA-DR) on monocytes is a hallmark of altered immune status in patients with a systemic inflammatory response syndrome (SIRS). So far, the analyses were mainly performed without taking into account monocytes subpopulations. Methods We studied this modification on CD14HIGH and CD14LOW monocytes of 20 SIRS patients undergoing abdominal aortic surgery (AAS), 20 patients undergoing carotid artery surgery (CAS), and 9 healthy controls, and we investigated mediators and intracellular molecules that may be involved in this process. Results HLA-DR on CD14HIGH monocytes started to decrease during surgery, after blood reperfusion, and was further reduced post-surgery. In contrast, HLA-DR expression on CD14LOW cells only decreased after surgery, and to a lesser extent than on CD14HIGH monocytes. Negative correlations were found between the reduction of HLA-DR expression and the change in cortisol levels for both subpopulations, whereas a negative correlation between interleukin-10 (IL-10) levels and HLA-DR modulation was only observed for CD14HIGH cells. In accordance with these ex vivo results, HLA-DR on CD14HIGH and CD14LOW monocytes of healthy donors was reduced following incubation with hydrocortisone, whereas IL-10 only acted on CD14HIGH subpopulation. Furthermore, flow cytometry revealed that the expression of IL-10 receptor was higher on CD14HIGH versus CD14LOW monocytes. In addition, hydrocortisone, and to a lesser extent IL-10, reversed the up-regulation of HLA-DR induced by bacterial products. Finally, membrane-associated RING-CH-1 protein (MARCH1) mRNA, a negative regulator of MHC class II, was up-regulated in monocytes of AAS patients on Day 1 post-surgery, and in those of healthy subjects exposed to hydrocortisone. Conclusions This study reveals that HLA-DR expression is modulated differently on CD14HIGH (classical) versus CD14LOW (inflammatory) monocytes after systemic inflammation. PMID

  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. Interaction between three subpopulations of Ehrlich carcinoma in mixed solid tumours in nude mice: evidence of contact domination

    DEFF Research Database (Denmark)

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

    1994-01-01

    Clonal interaction between three subpopulations of Ehrlich carcinoma were studied during growth as mixed solid tumours and as ascites tumours in immune-incompetent nude NMRI mice. The tumour cell lines differed in DNA content as determined by DNA flow cytometry (FCM). Tumour growth was evaluated...... by tumour growth curves including calculation of tumour volume doubling times, tumour weight on day 14, cell cycle times (per cent labelled mitoses) and cell cycle distributions (FCM). Two subpopulations (E1.15 and E1.95) showed nearly identical growth characteristics during both solid and ascites tumour...... growth. The third subpopulation (E1.80) grew more slowly. FCM on fine-needle tumour aspirates was used to determine the relative proportions of the cell populations in mixed solid tumours in which E1.95 showed a growth-dominating effect on E1.15. No such effect was demonstrated during single-cell tumour...

  16. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential.

    Science.gov (United States)

    Coteron, Jose M; Marco, María; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M; Angulo-Barturen, Iñigo; Ferrer, Santiago B; Jiménez-Díaz, María Belén; Gamo, Francisco-Javier; Goldsmith, Elizabeth J; Charman, William N; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N; Rathod, Pradipsinh K; Charman, Susan A; Phillips, Margaret A

    2011-08-11

    Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.

  17. Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

    Energy Technology Data Exchange (ETDEWEB)

    Coteron, Jose M.; Marco, Maria; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L.; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M.; Angulo-Barturen, Inigo; Ferrer, Santiago B.; Jimenez-Diaz, Maria Belen; Gamo, Francisco-Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A. (UWASH); (MMV, Switzerland); (GSK); (Monash); (UW); (UTSMC)

    2012-02-27

    Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.

  18. Phagocytic activity of monocytes, their subpopulations and granulocytes during post-transplant adverse events after hematopoietic stem cell transplantation.

    Science.gov (United States)

    Döring, Michaela; Cabanillas Stanchi, Karin Melanie; Erbacher, Annika; Haufe, Susanne; Schwarze, Carl Philipp; Handgretinger, Rupert; Hofbeck, Michael; Kerst, Gunter

    2015-05-01

    Phagocytosis of granulocytes and monocytes presents a major mechanism that contributes to the clearance of pathogens and cell debris. We analyzed the phagocytic activity of the peripheral blood cell monocytes, three monocyte subpopulations and granulocytes before and up to one year after hematopoietic stem cell transplantation, as well as during transplant-related adverse events. 25 pediatric patients and young adults (median age of 11.0 years) with hemato-oncological malignancies and non malignancies were enrolled in the prospective study. Ingestion of fluorescence-labeled Escherichia coli bacteria was used to assess the phagocytic activity of monocytes and their subpopulations and granulocytes by means of flow cytometry in the patient group as well as in a control group (n=36). During sepsis, a significant increase of phagocytic activity of monocytes (P=0.0003) and a significant decrease of the phagocytic activity of granulocytes (P=0.0003) and the CD14+ CD16++ monocyte subpopulation (P=0.0020) occurred. At the onset of a veno-occlusive disease, a significant increase of phagocytic activity in the CD14++ CD16+ monocyte subpopulation (P=0.001) and a significant decrease in the phagocytic activity of the CD14++ CD16- monocyte subpopulation (P=0.0048) were observed. In conclusion, the phagocytic activity of monocytes, their subpopulations and granulocytes might be a useful and easy determinable parameter that enables identification of post-transplant complications after hematopoietic stem cell transplantation. The alterations of phagocytic activity contribute to the altered immune response that accompanies adverse events after hematopoietic stem cell transplantation. Copyright © 2014 Elsevier GmbH. All rights reserved.

  19. Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure.

    Science.gov (United States)

    Guler, Gulfem Dilek; Tindell, Charles Albert; Pitti, Robert; Wilson, Catherine; Nichols, Katrina; KaiWai Cheung, Tommy; Kim, Hyo-Jin; Wongchenko, Matthew; Yan, Yibing; Haley, Benjamin; Cuellar, Trinna; Webster, Joshua; Alag, Navneet; Hegde, Ganapati; Jackson, Erica; Nance, Tracy Leah; Giresi, Paul Garrett; Chen, Kuan-Bei; Liu, Jinfeng; Jhunjhunwala, Suchit; Settleman, Jeff; Stephan, Jean-Philippe; Arnott, David; Classon, Marie

    2017-08-14

    Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell subpopulation that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1). Disruption of the repressive chromatin over LINE-1 elements in DTPs results in DTP ablation, which is partially rescued by reducing LINE-1 expression or function. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. DENTAL INFECTIONS AND THE ATHEROSCLEROSIS RISK IN A SUBPOPULATION OF SOUTH ROMANIA

    Directory of Open Access Journals (Sweden)

    Alexandru Andrei ILIESCU

    2015-06-01

    Full Text Available Periodontal disease and chronic apical periodontitis are considered risk factors for cardiovascular diseases. This cross-sectional study, performed in a subpopulation living in the South area of Romania, investigated the association between the afore-mentioned oral lesions and atherosclerosis. The research was focused on common carotid artery intima-media wall thickness IMT and dislipidemia, in a batch of 30 hypertensive subjects, age 41-50. Over 40% of the patients diagnosed with periodontal disease and/or chronic apical periodontitis developed subclinical atherosclerosis. Associated dyslipidemia to an increased IMT over 0.9 mm in subjects affected by periodontal disease or combined lesions with chronic apical periodontitis might be considered a strong predictor of future cardiovascular events.

  1. 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.

  2. 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.

  3. A Cone-Beam Computed Tomographic Study on Mandibular First Molars in a Chinese Subpopulation.

    Directory of Open Access Journals (Sweden)

    Xin Zhang

    Full Text Available The purpose of this study was to conduct a cone-beam computed tomographic (CBCT investigation on the root and canal configuration of the mandibular first molars, especially the morphology of the disto-lingual (DL root, in a Chinese subpopulation. A total of 910 CBCT images of the mandibular first molars were collected from 455 patients who underwent CBCT examinations as a preoperative assessment for implants or orthodontic treatment. The following information was analyzed and evaluated: tooth position, gender, root and root canal number per tooth, root canal type of the mesial root(s and distal root(s, angle of the DL root canal curvature, distance between two distal canal orifices in the teeth with DL root, and angle of disto-buccal canal orifice-disto-lingual canal orifice-mesio-lingual canal orifice (DB-DL-ML. Most of the mandibular first molars (64.9%, n = 591 had two roots with three root canals, and most of the mesial root canals (87.7%, n = 798 were type VI. The prevalence of the DL root was 22.1% (n = 201. The right side had a higher prevalence of DL root than the left side (p<0.05. Additionally, the curvature of the DL root canal were greater in the bucco-lingual (BL orientation (30.10°±14.02° than in the mesio-distal (MD orientation (14.03°± 8.56° (p<0.05. Overall there was a high prevalence of DL root in the mandibular first molars, and most of the DL roots were curved in different degrees. This study provided detailed information about the root canal morphology of the mandibular first molars in a Chinese subpopulation.

  4. Effects of vitamin A deficiency and Newcastle disease virus infection on lymphocyte subpopulations in chicken blood.

    Science.gov (United States)

    Rombout, J H; van Rens, B T; Sijtsma, S R; van der Weide, M C; West, C E

    1992-02-15

    The effect of vitamin A deficiency and Newcastle disease virus (NDV)-infection on peripheral blood lymphocytes (PBL) was studied by differential cell counting and flow cytometry. Day-old chickens were fed purified diets containing either marginal or adequate levels of vitamin A and at 26 days of age half of the chickens in each group were infected with NDV. The absolute numbers of PBL and their subpopulations were studied until 10 days after infection. Vitamin A deficiency resulted in significantly lower numbers of PBL throughout the experiment. NDV-infection produced lymphopenia during the first 3 days, followed by a strong increase in PBL numbers after 6 days. Both changes in PBL were less pronounced in vitamin A-deficient birds. For flow cytometric analysis monoclonal antibodies reacting specifically with B-cells or a subpopulation of T-cells were used. Vitamin A-induced lymphopenia could be attributed to a decreased number of PBL, negative for both antibodies, and to the absence of an increase in B-cells which normally occurs at this age. The negative cells are suggested to represent, at least partially, cytotoxic T-cells, which may explain the impaired cytotoxic T-cell-activity found in earlier studies. NDV-induced lymphopenia and subsequent increase of PBL could be attributed to all cell types investigated. However, in vitamin A-deficient birds negative cells did not show these reactions. Therefore, it can be concluded that vitamin A deficiency has a detrimental effect on PBL, negative for both antibodies used, and on the normal growth of the number of B-cells at this age.

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

    Science.gov (United States)

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

    2016-01-26

    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

  6. Cancer stem cells: a minor cancer subpopulation that redefines global cancer features

    Directory of Open Access Journals (Sweden)

    Heiko eEnderling

    2013-04-01

    Full Text Available In recent years cancer stem cells (CSCs have been hypothesized to comprise only a minor subpopulation in solid tumors that drives tumor initiation, development and metastasis; the so-called cancer stem cell hypothesis. While a seemingly trivial statement about numbers, much is put at stake. If true, the conclusions of many studies of cancer cell populations could be challenged, as the bulk assay methods upon which they depend have, by and large, taken for granted the notion that a ‘typical’ cell of the population possesses the attributes of a cell capable of perpetuating the cancer, i.e., a CSC. In support of the CSC hypothesis, populations enriched for so-called ‘tumor-initiating’ cells have demonstrated a corresponding increase in tumorigenicity as measured by dilution assay, although estimates have varied widely as to what the fractional contribution of tumor-initiating cells is in any given population. Some have taken this variability to suggest the CSC fraction may be nearly 100% after all, countering the CSC hypothesis, and that there are simply assay-dependent error rates in our ability to ‘reconfirm’ CSC status at the cell level. To explore this controversy more quantitatively, we developed a simple theoretical model of cancer stem cell-driven tumor growth dynamics. Assuming CSC and non-stem cancer cell subpopulations coexist to some degree, we evaluated the impact of an environmentally-dependent cancer stem cell symmetric division probability and a non-stem cancer cell proliferation capacity on tumor progression and morphology. Our model predicts, as expected, that the frequency of CSC divisions that are symmetric highly influences the frequency of CSCs in the population, but goes on to predict the two frequencies can be widely divergent, and that spatial constraints will tend to increase the CSC fraction over time.

  7. Unravelling the differential functions and regulation of striatal neuron sub-populations in motor control, reward and motivational processes

    Directory of Open Access Journals (Sweden)

    Sabrina eEna

    2011-07-01

    Full Text Available The striatum, the major input structure of the basal ganglia, is critically involved in motor control and learning of habits and skills, and is also involved in motivational and reward processes. The dorsal striatum, caudate-putamen, is primarily implicated in motor functions whereas the ventral striatum, the nucleus accumbens, is essential for motivation and drug reinforcement. Severe basal ganglia dysfunction occurs in movement disorders as Parkinson’s and Huntington’s disease, and in psychiatric disorders such as schizophrenia and drug addiction. The striatum is essentially composed of GABAergic medium-sized spiny neurons (MSNs that are output neurons giving rise to the so-called direct and indirect pathways and are targets of the cerebral cortex and mesencephalic dopaminergic neurons. Although the involvement of striatal sub-areas in motor control and motivation has been thoroughly characterized, major issues remained concerning the specific and respective functions of the two MSNs sub-populations, D2R-striatopallidal (dopamine D2 receptor-positive and D1R-striatonigral (dopamine D1 receptor-positive neurons, as well as their specific regulation. Here, we review recent advances that gave new insight in the understanding of the differential roles of striatopallidal and striatonigral neurons in the basal ganglia circuit. We discuss innovative techniques developed in the last decade which allowed a much precise evaluation of molecular pathways implicated in motivational processes and functional roles of striatopallidal and striatonigral neurons in motor control and in the establishment of reward-associated behaviour.

  8. Lymphocyte subpopulations in high endothelial venules and lymphatic capillaries of bronchus-associated lymphoid tissue (BALT) in the rat.

    Science.gov (United States)

    Otsuki, Y; Ito, Y; Magari, S

    1989-02-01

    The subpopulations of lymphocytes and non-lymphoid cells in high endothelial venules (HEV) and in lymphatic capillaries surrounding lymphoid follicles in bronchus-associated lymphoid tissue (BALT) were examined by electron microscopy after preembedding the tissue and staining with an immunoperoxidase technique. The results were compared with those obtained in gut-associated lymphoid tissue (GALT) reported previously. Monoclonal mouse-anti-rat T cell, IgG, IgM, IgA, and Ia antisera were used. Plasma cells that were reactive to anti-IgG, anti-IgM, and anti-IgA were detected as cells in which the 3',3'-diaminobenzidine tetrahydroxychloride reaction product was localized in rough endoplasmic reticulum and perinuclear spaces but not on plasma membranes. These plasma cells did not occur in either lymphatic capillaries or HEV in BALT as they did in GALT. Cells with surface Ig (sIg cells), T-cell antigen (T cells), and Ia antigen (Ia cells) were present in BALT. T cells were located predominantly in the follicular area opposite the bronchial epithelium; IgM- and IgG-reactive cells were found in the follicular area adjacent to the bronchial epithelium; and IgA-positive cells were found in the lateral part of the area where the T cells were localized (T-cell area). Ia cells were abundant throughout BALT and in moderate numbers in the epithelium. A striking observation was the presence of "nurse-cell"-like structures in the periphery of BALT. The percentages of T, sIgG, sIgM, and sIgA cells in the HEV were 54.7%, 2.4%, 28.9%, and 27.3%, respectively, and in the lymphatic capillaries, 41.2%, 3.8%, 38.2%, and 21.2%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Tendon progenitor cells in injured tendons have strong chondrogenic potential: the CD105-negative subpopulation induces chondrogenic degeneration.

    Science.gov (United States)

    Asai, Shuji; Otsuru, Satoru; Candela, Maria Elena; Cantley, Leslie; Uchibe, Kenta; Hofmann, Ted J; Zhang, Kairui; Wapner, Keith L; Soslowsky, Louis J; Horwitz, Edwin M; Enomoto-Iwamoto, Motomi

    2014-12-01

    To study the cellular mechanism of the tendon repair process, we used a mouse Achilles tendon injury model to focus on the cells recruited to the injured site. The cells isolated from injured tendon 1 week after the surgery and uninjured tendons contained the connective tissue progenitor populations as determined by colony-forming capacity, cell surface markers, and multipotency. When the injured tendon-derived progenitor cells (inTPCs) were transplanted into injured Achilles tendons, they were not only integrated in the regenerating area expressing tenogenic phenotype but also trans-differentiated into chondrogenic cells in the degenerative lesion that underwent ectopic endochondral ossification. Surprisingly, the micromass culture of the inTPCs rapidly underwent chondrogenic differentiation even in the absence of exogenous bone morphogenetic proteins or TGFβs. The cells isolated from human ruptured tendon tissues also showed connective tissue progenitor properties and exhibited stronger chondrogenic ability than bone marrow stromal cells. The mouse inTPCs contained two subpopulations one positive and one negative for CD105, a coreceptor of the TGFβ superfamily. The CD105-negative cells showed superior chondrogenic potential in vitro and induced larger chondroid degenerative lesions in mice as compared to the CD105-positive cells. These findings indicate that tendon progenitor cells are recruited to the injured site of tendons and have a strong chondrogenic potential and that the CD105-negative population of these cells would be the cause for chondroid degeneration in injured tendons. The newly identified cells recruited to the injured tendon may provide novel targets to develop therapeutic strategies to facilitate tendon repair. © 2014 AlphaMed Press.

  10. CD133+ subpopulation of the HT1080 human fibrosarcoma cell line exhibits cancer stem-like characteristics.

    Science.gov (United States)

    Feng, Bao-Hua; Liu, Ai-Guo; Gu, Wen-Guang; Deng, Liang; Cheng, Xian-Gyang; Tong, Tie-Jun; Zhang, Hong-Zhi

    2013-08-01

    The cancer stem cell (CSC) theory holds that a minority population within tumors possesses stem cell properties of self-renewal and multilineage differentiation capacity and provides the initiating cells from which tumors are derived and sustained. However, verifying the existence of these CSCs has been a significant challenge. The CD133 antigen is a pentaspan membrane glycoprotein proposed to be a CSC marker for cancer-initiating subpopulations in the brain, colon and various other tissues. Here, CD133+ cells were obtained and characterized from the HT1080 cell line to determine the utility of this marker for isolating CSCs from human fibrosarcoma cells. In this study, CD133+ cells were separated from HT1080 cells using magnetic beads and characterized for their proliferation rate and resistance to chemotherapeutic drugs, cisplatin and doxorubicin, by MTS assay. Relative expression of tumor-associated genes Sox2, Oct3/4, Nanog, c-Myc, Bmi-1 and ABCG2 was measured by real-time polymerase chain reaction (PCR). Clonal sphere formation and the ability of CD133+ cells to initiate tumors in BALB/c nude mice was also evaluated. We found that CD133+ cells showed a high proliferation rate, increased resistance to chemotherapy drugs and overexpression of tumor-associated genes compared with these features in CD133- cells. Additionally, CD133+ cells were able to form spherical clusters in serum-free medium with high clonogenic efficiency, indicating a significantly greater tumor-initiating potential when compared with CD133- cells. These findings indicate that CD133+ cells identified within the HT1080 human fibrosarcoma cell line possess many CSC properties and may facilitate the development of improved therapies for fibrosarcoma.

  11. Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.

    Science.gov (United States)

    Helal, Christopher J; Arnold, Eric P; Boyden, Tracey L; Chang, Cheng; Chappie, Thomas A; Fennell, Kimberly F; Forman, Michael D; Hajos, Mihaly; Harms, John F; Hoffman, William E; Humphrey, John M; Kang, Zhijun; Kleiman, Robin J; Kormos, Bethany L; Lee, Che-Wah; Lu, Jiemin; Maklad, Noha; McDowell, Laura; Mente, Scot; O'Connor, Rebecca E; Pandit, Jayvardhan; Piotrowski, Mary; Schmidt, Anne W; Schmidt, Christopher J; Ueno, Hirokazu; Verhoest, Patrick R; Yang, Edward X

    2017-07-13

    Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.

  12. GWAS-identified risk variants for major depressive disorder: Preliminary support for an association with late-life depressive symptoms and brain structural alterations.

    Science.gov (United States)

    Ryan, Joanne; Artero, Sylvaine; Carrière, Isabelle; Maller, Jerome J; Meslin, Chantal; Ritchie, Karen; Ancelin, Marie-Laure

    2016-01-01

    A number of genome-wide association studies (GWAS) have investigated risk factors for major depressive disorder (MDD), however there has been little attempt to replicate these findings in population-based studies of depressive symptoms. Variants within three genes, BICC1, PCLO and GRM7 were selected for replication in our study based on the following criteria: they were identified in a prior MDD GWAS study; a subsequent study found evidence that they influenced depression risk; and there is a solid biological basis for a role in depression. We firstly investigated whether these variants were associated with depressive symptoms in our population-based cohort of 929 elderly (238 with clinical depressive symptoms and 691 controls), and secondly to investigate associations with structural brain alterations. A number of nominally significant associations were identified, but none reached Bonferroni-corrected significance levels. Common SNPs in BICC1 and PCLO were associated with a 50% and 30% decreased risk of depression, respectively. PCLO rs2522833 was also associated with the volume of grey matter (p=1.6×10(-3)), and to a lesser extent with hippocampal volume and white matter lesions. Among depressed individuals rs9870680 (GRM7) was associated with the volume of grey and white matter (p=10(-4) and 8.3×10(-3), respectively). Our results provide some support for the involvement of BICC1 and PCLO in late-life depressive disorders and preliminary evidence that these genetic variants may also influence brain structural volumes. However effect sizes remain modest and associations did not reach corrected significance levels. Further large imaging studies are needed to confirm our findings. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  13. 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.

  14. 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.

  15. 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.

    Directory of Open Access Journals (Sweden)

    Sandra Witz

    Full Text Available 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.

  16. Development of a quasi-continuous laser Doppler measurement method to identify structural dynamics parameters; Entwicklung einer quasi-kontinuierlichen Laser Doppler Messmethode zur Identifikation strukturdynamischer Parameter

    Energy Technology Data Exchange (ETDEWEB)

    Brehmer, A.

    2003-07-01

    Vibration tests are performed since a long time to identify the structural parameters of aerospace structures. Usually the responses are measured by means of acceleration transducers. But meanwhile optical measurement methods are possible as well. New possibilities of experimental modal analysis arise due to the non-contacting recording of dynamic responses. In the present work the method of a continuously scanning laser Doppler Vibrometer is addressed and new measurement methods are developed. It is shown how structures can be scanned using one or two dimensional scan paths. For that purpose scan algorithms are used with constant and time varying scan frequencies and amplitudes. Moreover an adapting algorithm is developed to improve the scan procedure by adapting the scan path to the selected mode shape. The developed methods are demonstrated on an undamaged and a delaminated aluminum sandwich plate. Comparative measurements using accelerometers and digital shearography serve to evaluate the methods in practical environment. Based on the results specific properties and potential application areas of the different scan methods are derived and discussed. (orig.) [German] Versuche zur strukturdynamischen Identifikation werden bereits seit langem routinemaessig an verschiedenen Strukturen der Luft- und Raumfahrt durchgefuehrt. Dabei werden die Strukturschwingungen im Wesentlichen mit Beschleunigungsaufnehmern erfasst. Sie lassen sich seit einiger Zeit aber auch mit optischen Messmethoden aufnehmen. Aufgrund der beruehrungslosen Messung der Strukturschwingungen eroeffnen sich neue Moeglichkeiten der experimentellen Modalanalyse. In der vorliegenden Arbeit wird die Messmethode eines kontinuierlich scannenden Laser Doppler Vibrometers aufgegriffen, dargestellt und darauf aufbauend neue Messmethoden entwickelt. Es wird gezeigt, wie Strukturen ein- und zweidimensional abgescannt werden koennen. Dabei werden Scanalgorithmen mit konstanten und zeitlich veraenderlichen

  17. Trait Self-Control, Identified-Introjected Religiosity and Health-Related-Feelings in Healthy Muslims: A Structural Equation Model Analysis

    Science.gov (United States)

    Briki, Walid; Chaouachi, Anis; Patrick, Thomas; Chamari, Karim

    2015-01-01

    Aim The present study attempted to test McCullough and Willoughby’s hypothesis that self-control mediates the relationships between religiosity and psychosocial outcomes. Specifically, this study examined whether trait self-control (TSC) mediates the relationship of identified-introjected religiosity with positive and negative health-related-feelings (HRF) in healthy Muslims. Methods Two hundred eleven French-speaking participants (116 females, 95 males; Mage = 28.15, SDage = 6.90) answered questionnaires. One hundred ninety participants were retained for the analyses because they reported to be healthy (105 females, 85 males; Mage = 27.72, SDage = 6.80). To examine the relationships between religiosity, TSC and HRF, two competing mediation models were tested using structural equation model analysis: While a starting model used TSC as mediator of the religiosity-HRF relationship, an alternative model used religiosity as mediator of the TSC-HRF relationship. Results The findings revealed that TSC mediated the relationship between identified religiosity and positive HRF, and that identified religiosity mediated the relationship between TSC and positive and negative HRF, thereby validating both models. Moreover, the comparison of both models showed that the starting model explained 13.211% of the variance (goodness of fit = 1.000), whereas the alternative model explained 6.877% of the variance (goodness of fit = 0.987). Conclusion These results show that the starting model is the most effective model to account for the relationships between religiosity, TSC, and HRF. Therefore, this study provides initial insights into how religiosity influences psychological health through TSC. Important practical implications for the religious education are suggested. PMID:25962179

  18. Laboratory parameters provided by Advia 2120 analyser identify structural haemoglobinopathy carriers and discriminate between Hb S trait and Hb C trait.

    Science.gov (United States)

    Velasco-Rodríguez, Diego; Alonso-Domínguez, Juan-Manuel; González-Fernández, Fernando-Ataúlfo; Muriel, Alfonso; Abalo, Lorena; Sopeña, María; Villarrubia, Jesús; Ropero, Paloma; Plaza, María Paz; Tenorio, María; Jiménez-Martín, Ana; Moreno, Gemma; Martínez-Nieto, Jorge; de la Fuente-Gonzalo, Félix; Fernández-Escribano, Marina; López-Jiménez, Francisco Javier; Cava, Fernando

    2016-10-01

    Haemoglobinopathies have spread owing to human migration, and the number of people needing diagnosis and management of these conditions is increasing. Clinicians need to accurately identify carriers and provide adequate genetic counselling in order to prevent the occurrence of homozygous or compound heterozygous offspring. To identify red blood cell (RBC) laboratory parameters that discriminate between structural haemoglobinopathy carriers and healthy subjects, and to compare RBC laboratory indices between HbAS and HbAC individuals. Samples of 500 variant Hb carriers (355 HbAS, 104 HbAC, 19 HbAD, 7 HbAE, 7 HbAO-Arab, 4 α-chain variants and 4 Hb Lepore) and 251 normal controls were run on an Advia 2120 analyser (Siemens). Classic haematological parameters and RBC populations were assessed in all subjects. A multivariable binary logistic regression model was created to predict the probability of a subject carrying any structural haemoglobinopathy. HbAS (n=355, 71%) and HbAC (n=104, 20.8%) subjects were compared. A clinical prediction rule was developed by assigning one point to each of the most efficient variables: mean corpuscular volume (MCV) 13.4%, percentage of microcytic RBCs (%MICRO) >0.7% and the ratio of microcytic RBCs to hypochromic RBCs >0.8. A score of 0, 1, 2, 3 or 4, resulted in a probability of 9.6%, 36.3%, 66.7%, 85.2% or 98.3%, respectively. Among the most frequent variant Hb, HbAC subjects had lower values of parameters related to cell size (MCV, %MICRO) and higher values of parameters related to haemoglobin concentration (MCHC, %HYPER) than HbAS subjects. Coexistence of α-thalassaemia in both HbAS and HbAC individuals resulted in decreased Hb, MCV, MCH and MCHC. Structural haemoglobinopathy should be investigated in subjects belonging to ethnic groups with high prevalence of variant Hb and with a score of 3 or 4. Erythrocytes of HbAC subjects are smaller and denser than those of HbAS subjects. Published by the BMJ Publishing Group Limited. For

  19. Genetic analysis of scattered populations of the Indian eri silkworm, Samia cynthia ricini Donovan: differentiation of subpopulations

    Directory of Open Access Journals (Sweden)

    Appukuttannair R. Pradeep

    2011-01-01

    Full Text Available Deforestation and exploitation has led to the fragmentation of habitats and scattering of populations of the economically important eri silkworm, Samia cynthia ricini, in north-east India. Genetic analysis of 15 eri populations, using ISSR markers, showed 98% inter-population, and 23% to 58% intra-population polymorphism. Nei's genetic distance between populations increased significantly with altitude (R² = 0.71 and geographic distance (R² = 0.78. On the dendrogram, the lower and upper Assam populations were clustered separately, with intermediate grouping of those from Barpathar and Chuchuyimlang, consistent with geographical distribution. The Nei's gene diversity index was 0.350 in total populations and 0.121 in subpopulations. The genetic differentiation estimate (Gst was 0.276 among scattered populations. Neutrality tests showed deviation of 118 loci from Hardy-Weinberg equilibrium. The number of loci that deviated from neutrality increased with altitude (R² = 0.63. Test of linkage disequilibrium showed greater contribution of variance among eri subpopulations to total variance. D'2IS exceeded D'2ST, showed significant contribution of random genetic drift to the increase in variance of disequilibrium in subpopulations. In the Lakhimpur population, the peripheral part was separated from the core by a genetic distance of 0.260. Patchy habitats promoted low genetic variability, high linkage disequilibrium and colonization by new subpopulations. Increased gene flow and habitat-area expansion are required to maintain higher genetic variability and conservation of the original S. c. ricini gene pool.

  20. Determining the Anchor Composition for a Mixed-Format Test: Evaluation of Subpopulation Invariance of Linking Functions

    Science.gov (United States)

    Kim, Sooyeon; Walker, Michael

    2012-01-01

    This study examined the appropriateness of the anchor composition in a mixed-format test, which includes both multiple-choice (MC) and constructed-response (CR) items, using subpopulation invariance indices. Linking functions were derived in the nonequivalent groups with anchor test (NEAT) design using two types of anchor sets: (a) MC only and (b)…

  1. 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.

  2. Subpopulation-based correspondence modelling for improved respiratory motion estimation in the presence of inter-fraction motion variations

    Science.gov (United States)

    Wilms, Matthias; Werner, René; Yamamoto, Tokihiro; Handels, Heinz; Ehrhardt, Jan

    2017-07-01

    Correspondence modelling between low-dimensional breathing signals and internal organ motion is a prerequisite for application of advanced techniques in radiotherapy of moving targets. Patient-specific correspondence models can, for example, be built prior to treatment based on a planning 4D CT and simultaneously acquired breathing signals. Reliability of pre-treatment-built models depends, however, on the degree of patient-specific inter-fraction motion variations. This study investigates whether motion estimation accuracy in the presence of inter-fraction motion variations can be improved using correspondence models that incorporate motion information from different patients. The underlying assumption is that inter-patient motion variations resemble patient-specific inter-fraction motion variations for subpopulations of patients with similar breathing characteristics. The hypothesis is tested by integrating a sparse manifold clustering approach into a regression-based correspondence modelling framework that allows for automated identification of patient subpopulations. The evaluation is based on a total of 73 lung 4D CT data sets, including two cohorts of patients with repeat 4D CT scans (cohort 1: 14 patients; cohort 2: ten patients). The results are consistent for both cohorts: The subpopulation-based modelling approach outperforms general population modelling (models built on all data sets available) as well as pre-treatment-built models trained on only the patient-specific motion information. The results thereby support the hypothesis and illustrate the potential of subpopulation-based correspondence modelling.

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

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    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

  4. 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

  5. Testing for Local Adaptation to Spawning Habitat in Sympatric Subpopulations of Pike by Reciprocal Translocation of Embryos.

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    Hanna Berggren

    Full Text Available We tested for local adaption in early life-history traits by performing a reciprocal translocation experiment with approximately 2,500 embryos of pike (Esox lucius divided in paired split-family batches. The experiment indicated local adaptation in one of the two subpopulations manifested as enhanced hatching success of eggs in the native habitat, both when compared to siblings transferred to a non-native habitat, and when compared to immigrant genotypes from the other subpopulation. Gene-by-environment effects on viability of eggs and larvae were evident in both subpopulations, showing that there existed genetic variation allowing for evolutionary responses to divergent selection, and indicating a capacity for plastic responses to environmental change. Next, we tested for differences in female life-history traits. Results uncovered that females from one population invested more resources into reproduction and also produced more (but smaller eggs in relation to their body size compared to females from the other population. We suggest that these females have adjusted their reproductive strategies as a counter-adaptation because a high amount of sedimentation on the eggs in that subpopulations spawning habitat might benefit smaller eggs. Collectively, our findings point to adaptive divergence among sympatric subpopulations that are physically separated only for a short period during reproduction and early development-which is rare. These results illustrate how combinations of translocation experiments and field studies of life-history traits might infer about local adaptation and evolutionary divergence among populations. Local adaptations in subdivided populations are important to consider in management and conservation of biodiversity, because they may otherwise be negatively affected by harvesting, supplementation, and reintroduction efforts targeted at endangered populations.

  6. Physical discrimination between human T-lymphocyte subpopulations by means of light scattering, revealing two populations of T8-positive cells

    NARCIS (Netherlands)

    Terstappen, Leonardus Wendelinus Mathias Marie; de Grooth, B.G.; Nolten, G.M.J.; ten Napel, C.H.H.; van Berkel, W.; Greve, Jan

    1986-01-01

    Light-scattering properties of human T-lymphocyte subpopulations selected by immunofluorescence were studied. Based on differences in orthogonal light scattering, two subpopulations of T8-positive cells can be distinguished. The first population (T8a) has the same orthogonal light-scattering

  7. Immune evasion by Yersinia enterocolitica: differential targeting of dendritic cell subpopulations in vivo.

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    Stella E Autenrieth

    Full Text Available CD4(+ T cells are essential for the control of Yersinia enterocolitica (Ye infection in mice. Ye can inhibit dendritic cell (DC antigen uptake and degradation, maturation and subsequently T-cell activation in vitro. Here we investigated the effects of Ye infection on splenic DCs and T-cell proliferation in an experimental mouse infection model. We found that OVA-specific CD4(+ T cells had a reduced potential to proliferate when stimulated with OVA after infection with Ye compared to control mice. Additionally, proliferation of OVA-specific CD4(+ T cells was markedly reduced when cultured with splenic CD8α(+ DCs from Ye infected mice in the presence of OVA. In contrast, T-cell proliferation was not impaired in cultures with CD4(+ or CD4(-CD8α(- DCs isolated from Ye infected mice. However, OVA uptake and degradation as well as cytokine production were impaired in CD8α(+ DCs, but not in CD4(+ and CD4(-CD8α(- DCs after Ye infection. Pathogenicity factors (Yops from Ye were most frequently injected into CD8α(+ DCs, resulting in less MHC class II and CD86 expression than on non-injected CD8α(+ DCs. Three days post infection with Ye the number of splenic CD8α(+ and CD4(+ DCs was reduced by 50% and 90%, respectively. The decreased number of DC subsets, which was dependent on TLR4 and TRIF signaling, was the result of a faster proliferation and suppressed de novo DC generation. Together, we show that Ye infection negatively regulates the stimulatory capacity of some but not all splenic DC subpopulations in vivo. This leads to differential antigen uptake and degradation, cytokine production, cell loss, and cell death rates in various DC subpopulations. The data suggest that these effects might be caused directly by injection of Yops into DCs and indirectly by affecting the homeostasis of CD4(+ and CD8α(+ DCs. These events may contribute to reduced T-cell proliferation and immune evasion of Ye.

  8. Alterations with age in peripheral blood lymphocyte subpopulations and cytokine synthesis in beagles

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    Ohtsuka H

    2012-08-01

    Full Text Available Megumi Fujiwara,1,2 Tomohiro Yonezawa,3 Toshiro Arai,1 Ichiro Yamamoto,1 Hiromichi Ohtsuka21Laboratory of Veterinary Biochemistry, Nippon Veterinary and Life Science University, Tokyo, Japan; 2Laboratory of Large Animal Internal Medicine, 3Laboratory of Veterinary Physiology, Kitasato University, Towada, JapanPurpose: The immune system is considered to be affected by aging, which is linked to various immune pathogeneses. The purpose of this study was to determine age-associated changes in immune function of healthy dogs (beagles, specifically those of naive and memory T lymphocytes, based on cytokine synthesis.Patients and methods: Blood samples were obtained from 44 healthy beagles that were divided into three age-groups: young (<4 years, middle-aged (4–8 years, and older dogs (>8 years. Subpopulations of T lymphocytes were determined by flow cytometry. Transcriptional (mRNA levels of cytokines were determined for primary-cultured leukocytes using quantitative real-time polymerase chain reaction.Results: There were negative correlations between dogs’ages and the number of peripheral blood mononuclear cells, T cells, and B cells. In particular, the number of naive CD4+ CD45RA+ T cells and CD8+ CD45RA+ T cells significantly decreased with age. The mRNA levels for interleukin (IL-2, IL-2Rα, and interferon-gamma were significantly higher in young or middle-aged dogs (P < 0.05, whereas IL-4 mRNA expression was not significantly different over the different age-groups. IL-2Rγ mRNA expression tended to decrease with age.Conclusion: Decreases of naive CD4+ and naive CD8+ T cells may be related to age-related immunosenescence in dogs. With regard to cytokine production, leukocyte IL-4 and IL-10 mRNA levels did not change with age, whereas IL-2, IL-2Rα, and IL-2Rγ mRNA levels decreased with age. These altered cytokine mRNA expression patterns may contribute to decreased naive T-cell function(s with aging.Keywords: aging, leukocyte subpopulation

  9. 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/m2, 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/mm3), 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.

  10. Changes in natural killer cell subpopulations over a winter training season in elite swimmers.

    Science.gov (United States)

    Rama, Luís; Teixeira, Ana Maria; Matos, Alice; Borges, Grasiely; Henriques, Ana; Gleeson, Michael; Pedreiro, Susana; Filaire, Edith; Alves, Francisco; Paiva, Artur

    2013-04-01

    Immune changes and increased susceptibility to infection are often reported in elite athletes. Infectious episodes can often impair training and performance with consequences for health and sporting success. This study monitored the occurrence of episodes of upper respiratory symptoms (URS) and the variation in circulating NK cells, CD56(bright) and CD56(dim) NK cells subpopulations, over a winter swimming season. Nineteen national elite swimmers and 11 non-athlete controls participated in this study. URS episodes were monitored using daily log books. Blood samples were taken at rest at four time points during the season: before the start of the season (t1--middle September), after 7 weeks of an initial period of gradually increasing training load (t2--early November), after 6 weeks of an intense training cycle (t3--late February) and 48 h after the main competition (t4--early April) and from the controls at three similar time points (t1--early November; t2--late February; t3--early April). In the swimmers, the occurrence of URS clustered around the periods of elevated training load (67 %). No URS were reported at equivalent time points in the non-athletes. Athletes showed a decrease in the percentage (t2 = 21 %; t3 = 27 %; t4 = 17 %) and absolute counts of circulating NK cells (t2 = 35 %; t3 = 22 %; t4 = 22 %), coinciding with the periods of increased training load, never recovering to the initial values observed at the start of the season. The reduction in the CD56(dim) and an increase in the CD56(bright) NK cell subpopulations were significant at t2 and t3 (p < 0.05). Concomitant with the fall in values of NK cells, in athletes that shown more than three URS episodes, a moderate correlation (r = 0.493; p = 0.036) was found between CD56(bright)/CD56(dim) ratio and the number of URS episodes after the more demanding training phase (t3). At t3, a lower value of CD56 cell counts was found in the group who reported three or more URS episodes (t = 2.239; p = 0.032). A

  11. Delineation of genetic relatedness and population structure of oral and enteric Campylobacter concisus strains by analysis of housekeeping genes.

    Science.gov (United States)

    Mahendran, Vikneswari; Octavia, Sophie; Demirbas, Omer Faruk; Sabrina, Sheryl; Ma, Rena; Lan, Ruiting; Riordan, Stephen M; Grimm, Michael C; Zhang, Li

    2015-08-01

    Campylobacter concisus is an oral bacterium that has been shown to be associated with inflammatory bowel disease (IBD). In this study we examined clusters of oral C. concisus strains isolated from patients with IBD and healthy controls by analysing six housekeeping genes. In addition, we investigated the population structure of C. concisus strains. Whether oral and enteric strains form distinct clusters based on the sequences of these housekeeping genes was also investigated. The oral C. concisus strains were found to contain two genomospecies, which belong to the two genomospecies previously found in enteric C. concisus strains. C. concisus clusters formed based on the sequences of a single aspA gene were the same as that formed by using previously reported MLST schemes. The analysis of combined oral and enteric C. concisus strains found that enteric C. concisus strains did not form distinct clusters. Genetic structure analysis identified five subpopulations of C. concisus and showed that genetic recombination between C. concisus strains was common. However, genetic recombination was significantly less in oral strains isolated from patients with IBD than from healthy individuals. Previously reported oral and enteric intestinal epithelial invasive C. concisus strains were in cluster II and subpopulation III. Furthermore, this study shows that there are no distinct enteric C. concisus strain clusters or subpopulations.

  12. Structure-activity relationship study of indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1).

    Science.gov (United States)

    Mahmoud, Mariam M; Ali, Hamed I; Ahn, Kwang H; Damaraju, Aparna; Samala, Sushma; Pulipati, Venkata K; Kolluru, Srikanth; Kendall, Debra A; Lu, Dai

    2013-10-24

    The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CB1. To better understand the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor. We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator's high binding affinity for the allosteric site but not for generating allostery on the orthosteric site. However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand. A robust CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide (11j) was identified. It showed an equilibrium dissociation constant (KB) of 167.3 nM with a markedly high binding cooperativity factor (α = 16.55) and potent antagonism of agonist-induced GTPγS binding.

  13. Analysis of the nonstructural and structural polyprotein regions, and complete genome sequences of Israel acute paralysis viruses identified from honeybees (Apis mellifera) in Korea.

    Science.gov (United States)

    Reddy, Kondreddy Eswar; Noh, Jin Hyeong; Kim, Young-Ha; Yoo, Mi Sun; Doan, Huong Thi Thanh; Ramya, Mummadireddy; Jung, Suk-Chan; Quyen, Dong Van; Kang, Seung-Won

    2013-09-01

    Phylogenetic trees were constructed for 24 partial nucleotide sequences of the nonstructural polyprotein (ORF1) and structural polyprotein regions (ORF2) of Korean IAPV genotypes, as well as eight previously reported IAPV sequences from various countries. Most of the Korean genotypes formed a distinct cluster, separate from other country genotypes. To investigate this phenomenon in more detail, three complete IAPV genome sequences were identified from different regions in Korea, i.e., Korea1, Korea2, and Korea3. These sequences were aligned with eight previously reported complete genome sequences and various genome regions were compared. The Korean IAPVs were very similar to those from China and Israel, but highly diverged from USA and Australian genotypes. Interestingly, they showed greater variability than the USA and Australian genotypes in ORF1, but highly similar to the Australian genotype in the ORF2 region. Thus, genetic recombination may account for the spatial distance between the Korean IAPV genotypes and those from other countries. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Heterogeneous Structure of Stem Cells Dynamics: Statistical Models and Quantitative Predictions

    Science.gov (United States)

    Bogdan, Paul; Deasy, Bridget M.; Gharaibeh, Burhan; Roehrs, Timo; Marculescu, Radu

    2014-01-01

    Understanding stem cell (SC) population dynamics is essential for developing models that can be used in basic science and medicine, to aid in predicting cells fate. These models can be used as tools e.g. in studying patho-physiological events at the cellular and tissue level, predicting (mal)functions along the developmental course, and personalized regenerative medicine. Using time-lapsed imaging and statistical tools, we show that the dynamics of SC populations involve a heterogeneous structure consisting of multiple sub-population behaviors. Using non-Gaussian statistical approaches, we identify the co-existence of fast and slow dividing subpopulations, and quiescent cells, in stem cells from three species. The mathematical analysis also shows that, instead of developing independently, SCs exhibit a time-dependent fractal behavior as they interact with each other through molecular and tactile signals. These findings suggest that more sophisticated models of SC dynamics should view SC populations as a collective and avoid the simplifying homogeneity assumption by accounting for the presence of more than one dividing sub-population, and their multi-fractal characteristics. PMID:24769917

  15. 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?

  16. Changes in Leukocyte Subpopulations with Decline in Glomerular Filtration Rate in Patients with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Manouchehr Nakhjavani

    2015-10-01

    Full Text Available Recent studies suggested the role of white blood cells (WBCs in the pathogenesis and complications of type 2 diabetes. Increased WBC counts predict mortality in patients with chronic kidney disease (CKD. In this study alterations in WBC subpopulations in diabetic patients with non-dialysis dependent CKD are investigated. This was a cross-sectional study  on 376 participants, including   272 diabetic  patients  and  104  healthy  controls.  Total  and  differential  WBC  counts  were  compared  among diabetics with CKD, diabetics without CKD and controls. Among patients with type 2 diabetes, there was no significant difference in total WBC count between those with and without CKD. Diabetic patients with CKD had higher neutrophil, monocyte and eosinophil and lower lymphocyte count compared with both diabetic patients without CKD and healthy controls. Except for monocytes, a significant association was observed between GFR and differential WBC counts, which persisted after adjustment for conventional diabetes riskfactors (R2=0.272, P P

  17. Epidemiological differences of lower urinary tract symptoms among female subpopulations and group level interventions

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    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.

  18. Characteristics of the rat cardiac sphingolipid pool in two mitochondrial subpopulations.

    Science.gov (United States)

    Monette, Jeffrey S; Gómez, Luis A; Moreau, Régis F; Bemer, Brett A; Taylor, Alan W; Hagen, Tory M

    2010-07-23

    Mitochondrial sphingolipids play a diverse role in normal cardiac function and diseases, yet a precise quantification of cardiac mitochondrial sphingolipids has never been performed. Therefore, rat heart interfibrillary mitochondria (IFM) and subsarcolemmal mitochondria (SSM) were isolated, lipids extracted, and sphingolipids quantified by LC-tandem mass spectrometry. Results showed that sphingomyelin (approximately 10,000 pmol/mg protein) was the predominant sphingolipid regardless of mitochondrial subpopulation, and measurable amounts of ceramide (approximately 70 pmol/mg protein) sphingosine, and sphinganine were also found in IFM and SSM. Both mitochondrial populations contained similar quantities of sphingolipids except for ceramide which was much higher in SSM. Analysis of sphingolipid isoforms revealed ten different sphingomyelins and six ceramides that differed from 16- to 24-carbon units in their acyl side chains. Sub-fractionation experiments further showed that sphingolipids are a constituent part of the inner mitochondrial membrane. Furthermore, inner membrane ceramide levels were 32% lower versus whole mitochondria (45 pmol/mg protein). Three ceramide isotypes (C20-, C22-, and C24-ceramide) accounted for the lower amounts. The concentrations of the ceramides present in the inner membranes of SSM and IFM differed greatly. Overall, mitochondrial sphingolipid content reflected levels seen in cardiac tissue, but the specific ceramide distribution distinguished IFM and SSM from each other. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  19. 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.

  20. Hypotonic resistance of boar spermatozoa: sperm subpopulations and relationship with epididymal maturation and fertility.

    Science.gov (United States)

    Druart, Xavier; Gatti, Jean-Luc; Huet, Sylvie; Dacheux, Jean-Louis; Humblot, Patrice

    2009-02-01

    Hypotonic resistance of boar spermatozoa was investigated by measuring the ratio of live/dead spermatozoa (SYBR-14/propidium iodide) by flow cytometry after hypotonic stress. The survival rate of ejaculated spermatozoa incubated in hypotonic solutions ranging from 3 to 330 mmol/kg followed a sigmoid curve that fitted a simple logistic model. The critical osmolality value (Osm(crit)) at which 50% of spermatozoa died was determined with this model. Hypotonic resistance of spermatozoa increased with temperature between 15 and 39 degrees C and decreased after hydrogen superoxide treatment, but was not modified during 8 days of preservation in Beltsville thawing solution. Hypotonic resistance markedly decreased during epididymal maturation and after ejaculation as Osm(crit) at 15 degrees C was 54.7+/-3.2, 68.5+/-10.6, 116.7+/-2.1 and 194.3+/-3.7 mmol/kg for the caput, corpus, cauda and ejaculated spermatozoa respectively. Hypo-osmotic stress of 100 mmol/kg revealed a sperm subpopulation exhibiting increased hypotonic resistance compared with the whole ejaculate (Osm(crit)=67.8+/-2.1 mmol/kg). Consistent differences were observed between lean and standard breeds (Pietrain versus Large White) and between boars within the same breed. According to data collected by artificial insemination centers during a large-scale field trial, hypotonic resistance of ejaculates was found to be positively correlated with in vivo fertility.

  1. Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray.

    Science.gov (United States)

    Samineni, Vijay K; Grajales-Reyes, Jose G; Copits, Bryan A; O'Brien, Daniel E; Trigg, Sarah L; Gomez, Adrian M; Bruchas, Michael R; Gereau, Robert W

    2017-01-01

    The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception.

  2. Technical brief: Optimized pipeline for isolation of high-quality RNA from corneal cell subpopulations.

    Science.gov (United States)

    Bath, Chris; Fink, Trine; Vorum, Henrik; Hjortdal, Jesper; Zachar, Vladimir

    2014-01-01

    Attempts to determine the transcriptional profile of discrete subsets of limbal epithelial cells in situ using laser capture microdissection (LCM) face two major challenges. First, the transcriptional profile of cells within a tissue may rapidly change as the tissue is excised and exposed to cold ischemia. Second, there is a risk of degradation of the RNA as the cellular compartment is separated from the remaining tissue. An optimized protocol for LCM of corneal epithelium is presented to address these issues. Experiments using porcine eye globes were carried out to determine both optimal procedures and settings for tissue harvest, transport, storage, histology, LCM, and RNA isolation. The optimized protocol was validated using human corneal epithelium. To facilitate preservation of the gene expression profile, we have developed a mechanical tool for dissection of cornea that, in combination with flash freezing, enables tissue to be stored within 5 min of enucleation of the eye. Furthermore, we describe how RNA from limbal crypt cells may be obtained using a procedure involving cryosectioning, histological staining, and LCM. In this paper, we describe an optimized method for isolating high-quality RNA from cellular subpopulations confined to the limbal crypts of the cornea. The procedure yields RNA in amounts and quality suitable for downstream gene expression analyses, such as microarrays or next generation sequencing.

  3. 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

  4. Genetic diversity and population structure of Miscanthus sinensis germplasm in China.

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    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.

  5. A comparison of 3-T magnetic resonance imaging and computed tomography arthrography to identify structural cartilage defects of the fetlock joint in the horse.

    Science.gov (United States)

    Hontoir, Fanny; Nisolle, Jean-François; Meurisse, Hubert; Simon, Vincent; Tallier, Max; Vanderstricht, Renaud; Antoine, Nadine; Piret, Joëlle; Clegg, Peter; Vandeweerd, Jean-Michel

    2014-01-01

    Articular cartilage defects are prevalent in metacarpo/metatarsophalangeal (MCP/MTP) joints of horses. The aim of this study was to determine and compare the sensitivity and specificity of 3-Tesla magnetic resonance imaging (3-T MRI) and computed tomography arthrography (CTA) to identify structural cartilage defects in the equine MCP/MTP joint. Forty distal cadaver limbs were imaged by CTA (after injection of contrast medium) and by 3-T MRI using specific sequences, namely, dual-echo in the steady-state (DESS), and sampling perfection with application-optimised contrast using different flip-angle evolutions (SPACE). Gross anatomy was used as the gold standard to evaluate sensitivity and specificity of both imaging techniques. CTA sensitivity and specificity were 0.82 and 0.96, respectively, and were significantly higher than those of MRI (0.41 and 0.93, respectively) in detecting overall cartilage defects (no defect vs. defect). The intra and inter-rater agreements were 0.96 and 0.92, respectively, and 0.82 and 0.88, respectively, for CT and MRI. The positive predictive value for MRI was low (0.57). CTA was considered a valuable tool for assessing cartilage defects in the MCP/MTP joint due to its short acquisition time, its specificity and sensitivity, and it was also more accurate than MRI. However, MRI permits assessment of soft tissues and subchondral bone and is a useful technique for joint evaluation, although clinicians should be aware of the limitations of this diagnostic technique, including reduced accuracy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Voluntary Medical Male Circumcision for HIV Prevention: New Mathematical Models for Strategic Demand Creation Prioritizing Subpopulations by Age and Geography.

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    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

  7. 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

  8. Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons.

    Science.gov (United States)

    Burke, Luke K; Doslikova, Barbora; D'Agostino, Giuseppe; Greenwald-Yarnell, Megan; Georgescu, Teodora; Chianese, Raffaella; Martinez de Morentin, Pablo B; Ogunnowo-Bada, Emmanuel; Cansell, Celine; Valencia-Torres, Lourdes; Garfield, Alastair S; Apergis-Schoute, John; Lam, Daniel D; Speakman, John R; Rubinstein, Marcelo; Low, Malcolm J; Rochford, Justin J; Myers, Martin G; Evans, Mark L; Heisler, Lora K

    2016-03-01

    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.

  9. In vitro lymphocyte-differentiating effects of thymulin (Zn-FTS) on lymphocyte subpopulations of severely malnourished children.

    Science.gov (United States)

    Parent, G; Chevalier, P; Zalles, L; Sevilla, R; Bustos, M; Dhenin, J M; Jambon, B

    1994-08-01

    This work investigates how thymic dysfunction contributes to the depression of cell-mediated immunity in protein-energy malnutrition (PEM). In Bolivian children hospitalized for severe PEM, the size of the thymus was measured by echography, and the lymphocyte subpopulations were detected by using monoclonal antibodies. These data were compared with those obtained from healthy control subjects. Regardless of the clinical form of PEM, our results show a high degree of T lymphocyte immaturity in severely malnourished children, which correlates with a severe involution of the thymus. Before in vitro incubation with thymulin, this significant increase in the percentage of circulating immature T lymphocytes was concomitant with a decrease in mature T lymphocytes and a slight increase in cytotoxic T subpopulations. After in vitro incubation with thymulin, immature T lymphocytes decreased and mature T lymphocytes increased.

  10. Comparison of algorithms to infer genetic population structure from unlinked molecular markers.

    Science.gov (United States)

    Peña-Malavera, Andrea; Bruno, Cecilia; Fernandez, Elmer; Balzarini, Monica

    2014-08-01

    Identifying population genetic structure (PGS) is crucial for breeding and conservation. Several clustering algorithms are available to identify the underlying PGS to be used with genetic data of maize genotypes. In this work, six methods to identify PGS from unlinked molecular marker data were compared using simulated and experimental data consisting of multilocus-biallelic genotypes. Datasets were delineated under different biological scenarios characterized by three levels of genetic divergence among populations (low, medium, and high FST) and two numbers of sub-populations (K=3 and K=5). The relative performance of hierarchical and non-hierarchical clustering, as well as model-based clustering (STRUCTURE) and clustering from neural networks (SOM-RP-Q). We use the clustering error rate of genotypes into discrete sub-populations as comparison criterion. In scenarios with great level of divergence among genotype groups all methods performed well. With moderate level of genetic divergence (FST=0.2), the algorithms SOM-RP-Q and STRUCTURE performed better than hierarchical and non-hierarchical clustering. In all simulated scenarios with low genetic divergence and in the experimental SNP maize panel (largely unlinked), SOM-RP-Q achieved the lowest clustering error rate. The SOM algorithm used here is more effective than other evaluated methods for sparse unlinked genetic data.

  11. Passive smoking alters circulating naïve/memory lymphocyte T-cell subpopulations in children.

    Science.gov (United States)

    Vardavas, Constantine I; Plada, Maria; Tzatzarakis, Manolis; Marcos, Ascension; Warnberg, Julia; Gomez-Martinez, Sonia; Breidenassel, Christina; Gonzalez-Gross, Marcela; Tsatsakis, Aristeidis M; Saris, Wim H; Moreno, Luis A; Kafatos, Anthony G

    2010-12-01

    While it has been indicated that exposure to second-hand smoke (SHS) can cause a local in vivo response, limited evidence exists on its possible systemic effects from population-based levels of exposure. We investigated into a possible systemic response in the immune parameters and lymphocyte subsets, i.e. B cell (CD19+), T cell (CD4+CD45RO+, CD4+CD45RA+, CD3+CD45RO+, CD3+CD45RA+) and natural killer (CD3+CD16CD56+) lymphocyte subsets relative to exposure to SHS. Blood was drawn from healthy, verified non-smoker, adolescent subjects (n = 68, mean age 14.2) and analysed for cotinine, antioxidants and lymphocyte immunophenotyping. SHS exposure was assessed using serum cotinine. Biomarker quantified exposure to SHS was correlated with a linear dose-response reduction in the percentages of memory CD4+CD45RO+ (p = 0.005) and CD3+CD45RO+ T-cell subsets (p = 0.005 and p = 0.003, respectively) and a linear increase in the percentage of naïve CD4+CD45RA+ and CD3+CD45RA+ T-cell subsets (p = 0.006 and p = 0.003, respectively). Additionally, higher exposure to SHS was associated with a higher CD4+CD45RA+ count (532 vs. 409 cells/ml, p = 0.017). Moreover, after controlling for age, gender, body mass index and plasma antioxidants, SHS exposure was found to be associated with the percentage of circulating naïve and memory CD4+ and CD3+ T-cell subpopulations, as revealed through a linear regression analysis. These findings indicate a systemic immunological response in healthy adolescents exposed to population-based levels of SHS exposure and imply an additional biological pathway for the interaction between exposure to SHS and its adverse effects on human health. © 2010 John Wiley & Sons A/S.

  12. Radiographic investigation of in vivo endodontically treated maxillary premolars in a Saudi Arabian sub-population

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    Saad Al-Nazhan

    2012-01-01

    Full Text Available Aim: To determine the prevalence of the number of root canals in permanent maxillary first and second premolars of a Saudi Arabian sub-population. Results will be compared to previous Asian studies. Materials and Methods: A total of 894 periapical radiographs of endodontically treated maxillary first and second premolars of 628 Saudi patients (268 males and 360 females were viewed. The teeth were segregated into maxillary first premolars (463 and maxillary second premolars (431. The diagnostic, working length, master cone and final films with different angles were mounted, projected and, with the utilization of written clinical records, evaluated. Teeth with multiple canal systems were categorized according to whether the canals exited the root by common or separate apical foramen. Data was analyzed statistically using Chi-square test and professional t-test, by comparing pairs of groups with the significant level established at 5% (P < 0.05. Results: More than 90% of first maxillary premolar and more than 50% of the second maxillary premolar was found to have two canals. There was no significant difference between male (92% and female (95% in the distribution of the two root canals of the first maxillary premolar (t-test = 1.21, P value = 0.228, however, there was significant difference between the distributions of male (69.4% and female (52.2% of the two root canals within the second maxillary premolar (t-test = 3.75, P value = 0.000. Few teeth showed three canals. Conclusion: The number of root canals of the maxillary first premolar in Saudi population shows a higher incidence of two canals (93.6% than previously reported. In addition, the figure is higher than most of the Asian countries.

  13. Fine scale gene flow and individual movements among subpopulations of Centrolene prosoblepon (Anura: Centrolenidae).

    Science.gov (United States)

    Robertson, Jeanne M; Lips, Karen R; Heist, Edward J

    2008-03-01

    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 < 0.001). Using mtDNA ND1 gene sequences, we quantified gene flow within and among headwater streams at two spatial scales: among headwater streams within two adjacent watersheds (2.5 km2) and among streams within a longitudinal gradient covering 5.0 km2. We found high gene flow among headwater streams (phi(ST) = 0.007, p = 0.325) but gene flow was more limited across greater distances (phi(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.

  14. A subpopulation of smooth muscle cells, derived from melanocyte-competent precursors, prevents patent ductus arteriosus.

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    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.

  15. 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

  16. 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.

  17. Both superficial and deep zone articular chondrocyte subpopulations exhibit the Crabtree effect but have different basal oxygen consumption rates.

    Science.gov (United States)

    Heywood, Hannah K; Knight, Martin M; Lee, David A

    2010-06-01

    In the absence of in vivo measurements, the oxygen concentration within articular cartilage is calculated from the balance between cellular oxygen consumption and mass transfer. Current estimates of the oxygen tension within articular cartilage are based on oxygen consumption data from full-depth tissue samples. However, superficial and deep cell subpopulations of articular cartilage express intrinsic metabolic differences. We test the hypothesis that the subpopulations differ with respect to their intrinsic oxygen consumption rate. Chondrocytes from the full cartilage thickness demonstrate enhanced oxygen consumption when deprived of glucose, consistent with the Crabtree phenomena. Chondrocyte subpopulations differ in the prevailing availability of oxygen and glucose, which decrease with distance from the cartilage-synovial fluid interface. Thus, we tested the hypothesis that the oxygen consumption of each subpopulation is modulated by nutrient availability, by examining the expression of the Crabtree effect. The deep cells had a greater oxygen consumption than the superficial cells (V(max) of 6.6 compared to 3.2 fmol/cell/h), consistent with our observations of mitochondrial volume (mean values 52.0 vs. 36.4 microm(3)/cell). Both populations expressed the Crabtree phenomena, with oxygen consumption increasing approximately 2.5-fold in response to glycolytic inhibition by glucose deprivation or 2-deoxyglucose. Over 90% of this increase was oligomycin-sensitive and thus accounted for by oxidative phosphorylation. The data contributes towards our understanding of chondrocyte energy metabolism and provides information valuable for the accurate calculation of the oxygen concentration that the cells experience in vivo. The work has further application to the optimisation of bioreactor design and engineered tissues. (c) 2010 Wiley-Liss, Inc.

  18. Radiologic assessment of quality of root canal fillings and periapical status in an Austrian subpopulation ? An observational study

    OpenAIRE

    Andrej M Kielbassa; Wilhelm Frank; Theresa Madaus

    2017-01-01

    Background/Objective Progress in endodontic techniques and methodological advances have altered root canal therapy over the last decades. These techniques and methods need periodical documentation. This observational study determined the current prevalence of endodontic treatments, and investigated the relationship of various factors with the periapical status in a Lower Austrian subpopulation. Methodology One thousand orthopantomograms of first-time university adult patients radiographed at ...

  19. 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.

  20. Not all sperm are equal: functional mitochondria characterize a subpopulation of human sperm with better fertilization potential.

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    Ana Paula Sousa

    Full Text Available Human sperm samples are very heterogeneous and include a low amount of truly functional gametes. Distinct strategies have been developed to characterize and isolate this specific subpopulation. In this study we have used fluorescence microscopy and fluorescence-activated cell sorting to determine if mitochondrial function, as assessed using mitochondrial-sensitive probes, could be employed as a criterion to obtain more functional sperm from a given ejaculate. We first determined that mitochondrial activity correlated with the quality of distinct human samples, from healthy donors to patients with decreased semen quality. Furthermore, using fluorescence-activated cell sorting to separate sperm with active and inactive mitochondria we found that this was also true within samples. Indeed, sperm with active mitochondria defined a more functional subpopulation, which contained more capacitated and acrosome intact cells, sperm with lower chromatin damage, and, crucially, sperm more able to decondense and participate in early development using both chemical induction and injection into mature bovine oocytes. Furthermore, cell sorting using mitochondrial activity produced a more functional sperm subpopulation than classic swim-up, both in terms of improvement in a variety of functional sperm parameters and in statistical significance. In conclusion, whatever the true biological role of sperm mitochondria in fertilization, mitochondrial activity is a clear hallmark of human sperm functionality.

  1. Subpopulations of lymphoid and non-lymphoid cells in bronchus-associated lymphoid tissue (BALT) of the mouse.

    Science.gov (United States)

    Breel, M; Van der Ende, M; Sminia, T; Kraal, G

    1988-01-01

    Lymphoid and non-lymphoid subpopulations were investigated in the lung of the mouse with immunocyto-, immunohisto- and enzyme-histochemical methods. Special attention was paid to the cell populations in bronchus-associated lymphoid tissue (BALT), which is positioned between a bronchus and an artery. In BALT, discrete T- and B-cell areas can be found. The majority of the T cells belong to the L3T4+ (T-helper) subpopulation. In the T-cell area interdigitating cells can be recognized by anti-class II antibodies as well as by specific monoclonal antibodies, NLDC-145 and MIDC-8. Macrophage subpopulations can be discriminated by location, enzyme reactivity and various macrophage-specific monoclonal antibody markers. On the outer rim of BALT macrophages are recognized by the MOMA-1 and ERTR9 antibody. Macrophages dispersed in BALT can only be discriminated with the MOMA-2 antibody. The macrophage markers F4/80 and Mac-1 show no reactivity in BALT. In lung, tissue macrophages around bronchi and blood vessels are predominantly recognized by the MOMA-1 and MOMA-2 antibody, and a minor population by the ERTR9 antibody. Alveolar macrophages show heterogeneity with the MOMA-1, MOMA-2 and NLDC-145 antibody. The relationship between alveolar macrophages and antigen-presenting cells is discussed here. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3259206

  2. Embryogenic cells in Dactylis glomerata L. (Poaceae) explants identified by cell tracking and by SERK expression

    NARCIS (Netherlands)

    Somleva, M.N.; Schmidt, E.D.L.; Vries, de S.C.

    2000-01-01

    Single mesophyll cells in leaf explants of Dactylis glomerata L. (Dactylis) that were competent to form somatic embryos directly or through callus were identified by semi-automatic cell tracking. These competent cells were a subpopulation of small, isodiametric, cytoplasm-rich cells located close to

  3. Identifying source populations and genetic structure for savannah elephants in human-dominated landscapes and protected areas in the Kenya-Tanzania borderlands

    National Research Council Canada - National Science Library

    Ahlering, Marissa A; Eggert, Lori S; Western, David; Estes, Anna; Munishi, Linus; Fleischer, Robert; Roberts, Melissa; Maldonado, Jesus E

    2012-01-01

    We investigated the genetic metapopulation structure of elephants across the trans Rift Valley region of Kenya and Tanzania, one of the remaining strongholds for savannah elephants (Loxodonata africana...

  4. Establishing a food list for a Total Diet Study: how does food consumption of specific subpopulations need to be considered?

    Science.gov (United States)

    Akhandaf, Y; De Henauw, S; Dofkova, M; Ruprich, J; Papadopoulos, A; Sirot, V; Kennedy, M C; Pinchen, H; Blume, K; Lindtner, O; Brantsaeter, A L; Meltzer, H M; Sioen, I

    2015-01-01

    A Total Diet Study (TDS) consists of selecting, collecting and analysing commonly consumed foods to obtain concentration data of different chemical compounds in foods as eaten. A TDS food list summarises the most consumed foods and represents the dietary habits of the general population of the country under study. The work reported here investigated whether TDS food lists that were initially designed for the whole population of the country under study also sufficiently cover the dietary pattern of specific subpopulations that are extra vulnerable for certain contaminants. The work was performed using data of three European countries: the Czech Republic, France and the UK. Each national food consumption database was combined with the corresponding national TDS food list (containing 336, 212 and 119 food items for the Czech Republic, France and the UK, respectively). The data were aggregated on the highest level of hierarchy of FoodEx-1, a pan-European food classification system, including 20 main FoodEx-1 groups. For the group 'milk and dairy products', the coverage of the consumption by the food list was investigated for more refined subgroups. For each food group or subgroup and country, the average percentage of coverage of the diet by the national TDS food list was calculated for different subpopulations, including children versus adults, women versus men, vegetarians versus non-vegetarians, and women of child-bearing age versus older women. The average diet of the different subpopulations was sufficiently covered by the food list of the Czech Republic and France. For the UK the average coverage was low due to a different food-coding approach and because food lists were not derived directly from national food consumption data. At the level of the 20 main food groups, differences between the subpopulations with respect to the average coverage of consumption by the TDS food list were minimal. The differences were more pronounced when looking in detail at the

  5. Subpopulations of Staphylococcus aureus clonal complex 121 are associated with distinct clinical entities.

    Directory of Open Access Journals (Sweden)

    Kevin Kurt

    Full Text Available We investigated the population structure of Staphylococcus aureus clonal complex CC121 by mutation discovery at 115 genetic housekeeping loci from each of 154 isolates, sampled on five continents between 1953 and 2009. In addition, we pyro-sequenced the genomes from ten representative isolates. The genome-wide SNPs that were ascertained revealed the evolutionary history of CC121, indicating at least six major clades (A to F within the clonal complex and dating its most recent common ancestor to the pre-antibiotic era. The toxin gene complement of CC121 isolates was correlated with their SNP-based phylogeny. Moreover, we found a highly significant association of clinical phenotypes with phylogenetic affiliations, which is unusual for S. aureus. All isolates evidently sampled from superficial infections (including staphylococcal scalded skin syndrome, bullous impetigo, exfoliative dermatitis, conjunctivitis clustered in clade F, which included the European epidemic fusidic-acid resistant impetigo clone (EEFIC. In comparison, isolates from deep-seated infections (abscess, furuncle, pyomyositis, necrotizing pneumonia were disseminated in several clades, but not in clade F. Our results demonstrate that phylogenetic lineages with distinct clinical properties exist within an S. aureus clonal complex, and that SNPs serve as powerful discriminatory markers, able to identify these lineages. All CC121 genomes harboured a 41-kilobase prophage that was dissimilar to S. aureus phages sequenced previously. Community-associated MRSA and MSSA from Cambodia were extremely closely related, suggesting this MRSA arose in the region.

  6. 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.

  7. Development of a versatile Cas9-driven subpopulation-selection toolbox inLactococcus lactis.

    Science.gov (United States)

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

    2018-02-16

    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 was constructed, encoding the Streptocccus pyogenes Cas9 under control of a constitutive promoter, and allowing plug and play introduction of sgRNA sequences to target specific genetic loci. Introduction of a pepN -targeting derivative of pLABTarget into L. lactis 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 containing sgRNAs designed to target mobile genetic elements, allowed the effective curing of plasmids, prophages and integrative conjugative elements (ICE). 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 be readily expanded to other Gram-positive bacteria. Significance statement Mobile genetic elements in Lactococcus lactis and other lactic acid bacteria 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 towards mobile genetic elements enabled their effective curing, which is of particular interest in the context of potentially

  8. Dynamics of peripheral blood lymphocyte subpopulations in the acute and subacute phase of Legionnaires' disease.

    Directory of Open Access Journals (Sweden)

    Cornelis P C de Jager

    Full Text Available STUDY OBJECTIVE: Absolute lymphocytopenia is recognised as an important hallmark of the immune response to severe infection and observed in patients with Legionnaires' disease. To explore the immune response, we studied the dynamics of peripheral blood lymphocyte subpopulations in the acute and subacute phase of LD. METHODS AND RESULTS: EDTA-anticoagulated blood was obtained from eight patients on the day the diagnosis was made through detection of L. pneumophila serogroup 1 antigen in urine. A second blood sample was obtained in the subacute phase. Multiparametric flow cytometry was used to calculate lymphocyte counts and values for B-cells, T-cells, NK cells, CD4+ and CD8+ T-cells. Expression of activation markers was analysed. The values obtained in the subacute phase were compared with an age and gender matched control group. Absolute lymphocyte count (×10⁹/l, median and range significantly increased from 0.8 (0.4-1.6 in the acute phase to 1.4 (0.8-3.4 in the subacute phase. B-cell count showed no significant change, while T-cell count (×10⁶/l, median and range significantly increased in the subacute phase (495 (182-1024 versus 979 (507-2708, p = 0.012 as a result of significant increases in both CD4+ and CD8+ T-cell counts (374 (146-629 versus 763 (400-1507, p = 0.012 and 119 (29-328 versus 224 (107-862, p = 0.012. In the subacute phase of LD, significant increases were observed in absolute counts of activated CD4+ T-cells, naïve CD4+ T-cells and memory CD4+ T-cells. In the CD8+ T-cell compartment, activated CD8+ T-cells, naïve CD8+ T-cell and memory CD8+ T-cells were significantly increased (p<0.05. CONCLUSION: The acute phase of LD is characterized by absolute lymphocytopenia, which recovers in the subacute phase with an increase in absolute T-cells and re-emergence of activated CD4+ and CD8+ T cells. These observations are in line with the suggested role for T-cell activation in the immune response to LD.

  9. 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...

  10. Identifying Source Populations and Genetic Structure for Savannah Elephants in Human-Dominated Landscapes and Protected Areas in the Kenya-Tanzania Borderlands: e52288

    National Research Council Canada - National Science Library

    Marissa A Ahlering; Lori S Eggert; David Western; Anna Estes; Linus Munishi; Robert Fleischer; Melissa Roberts; Jesus E Maldonado

    2012-01-01

      We investigated the genetic metapopulation structure of elephants across the trans Rift Valley region of Kenya and Tanzania, one of the remaining strongholds for savannah elephants (Loxodonata africana...

  11. Predicting germination response to temperature. II. Three-dimensional regression, statistical gridding and iterative-probit optimization using measured and interpolated-subpopulation data.

    Science.gov (United States)

    Hardegree, Stuart P; Winstral, Adam H

    2006-08-01

    Most current thermal-germination models are parameterized with subpopulation-specific rate data, interpolated from cumulative-germination-response curves. The purpose of this study was to evaluate the relative accuracy of three-dimensional models for predicting cumulative germination response to temperature. Three-dimensional models are relatively more efficient to implement than two-dimensional models and can be parameterized directly with measured data. Seeds of four rangeland grass species were germinated over the constant-temperature range of 3 to 38 degrees C and monitored for subpopulation variability in germination-rate response. Models for estimating subpopulation germination rate were generated as a function of temperature using three-dimensional regression, statistical gridding and iterative-probit optimization using both measured and interpolated-subpopulation data as model inputs. Statistical gridding is more accurate than three-dimensional regression and iterative-probit optimization for modelling germination rate and germination time as a function of temperature and subpopulation. Optimization of the iterative-probit model lowers base-temperature estimates, relative to two-dimensional cardinal-temperature models, and results in an inability to resolve optimal-temperature coefficients as a function of subpopulation. Residual model error for the three-dimensional model was extremely high when parameterized with measured-subpopulation data. Use of measured data for model evaluation provided a more realistic estimate of predictive error than did evaluation of the larger set of interpolated-subpopulation data. Statistical-gridding techniques may provide a relatively efficient method for estimating germination response in situations where the primary objective is to estimate germination time. This methodology allows for direct use of germination data for model parameterization and automates the significant computational requirements of a two

  12. Lectins identify distinct populations of coelomocytes in Strongylocentrotus purpuratus.

    Directory of Open Access Journals (Sweden)

    Wen-Yun Liao

    Full Text Available Coelomocytes represent the immune cells of echinoderms, but detailed knowledge about their roles during immune responses is very limited. One major challenge for studying coelomocyte biology is the lack of reagents to identify and purify distinct populations defined by objective molecular markers rather than by morphology-based classifications that are subjective at times. Glycosylation patterns are known to differ significantly between cell types in vertebrates, and furthermore they can vary depending on the developmental stage and activation states within a given lineage. Thus fluorescently labeled lectins that recognize distinct glycan structures on cell surface proteins are routinely used to identify discrete cell populations in the vertebrate immune system. Here we now employed a panel of fifteen fluorescently-labeled lectins to determine differences in the glycosylation features on the surface of Strongylocentrotus purpuratus coelomocytes by fluorescence microscopy and flow cytometry. Eight of the lectins (succinylated wheat germ agglutinin, Len culinaris lectin, Pisum sativum agglutinin, Saphora japonica agglutinin, Solanum tuberosum lectin, Lycopersicon esculentum lectin, Datura stramonium lectin, Vicia villosa lectin showed distinct binding patterns to fixed and live cells of three major coelomocyte classes: phagocytic cells, red spherule cells, and vibratile cells. Importantly, almost all lectins bound only to a subgroup of cells within each cell type. Lastly, we established fluorescently-labeled lectin-based fluorescence activated cell sorting as a strategy to purify distinct S. purpuratus coelomocyte (sub-populations based on molecular markers. We anticipate that this will become a routine approach in future studies focused on dissecting the roles of different coelomocytes in echinoderm immunity.

  13. Phenotypic, genomic and functional characterization reveals no differences between CD138++ and CD138low subpopulations in multiple myeloma cell lines.

    Science.gov (United States)

    Paíno, Teresa; Sarasquete, María E; Paiva, Bruno; Krzeminski, Patryk; San-Segundo, Laura; Corchete, Luis A; Redondo, Alba; Garayoa, Mercedes; García-Sanz, Ramón; Gutiérrez, Norma C; Ocio, Enrique M; San-Miguel, Jesús F

    2014-01-01

    Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations--CD138++ (95-99%) and CD138low (1-5%)--in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.

  14. Differences in the prevalence rates and correlates of alcohol use and binge alcohol use among five Asian American subpopulations.

    Science.gov (United States)

    Lee, Hae Kook; Han, Beth; Gfroerer, Joseph C

    2013-03-01

    This study (1) estimated the prevalence of alcohol and binge alcohol use among adult Asian Americans by sub-ethnicity; (2) examined alcohol drinking patterns among these subpopulations; and (3) investigated sub-ethnic differences in characteristics associated with alcohol and binge alcohol use. Data from 8900 Asian Americans aged 18 or older who participated in the 2002-2008 National Surveys on Drug Use and Health (NSDUHs) were analyzed. Descriptive analyses and multivariate logistic regression modeling were applied. Korean Americans (51.8%) and Japanese Americans (49.7%) reported higher rates of past-month alcohol use than Chinese Americans (42.0%), Filipino Americans (37.9%), and Asian Indian Americans (34.0%). Korean Americans (24.6%) reported the highest rate of past-month binge alcohol use, followed by Filipino Americans (14.5%), Japanese Americans (14.2%), Asian Indian Americans (10.1%), and Chinese Americans (8.1%). Among these examined Asian Americans, foreign-born Chinese, Filipino, and Asian Indian Americans were less likely to have past-month alcohol use than their corresponding U.S. born counterparts; and only foreign-born Asian Indian Americans were less likely to have past-month binge alcohol use than their U.S. born counterparts. Males were 3-5 times more likely to have binge alcohol use than females among examined Asian American subpopulations except for Korean Americans. Korean Americans were more likely to have binge alcohol use than the other examined sub-ethnic Asian Americans. Adult Asian Americans are heterogeneous in sociodemographic characteristics and alcohol and binge alcohol use. These differences suggest the need for sub-ethnically specific prevention and treatment programs for alcohol use problems among Asian American subpopulations. Published by Elsevier Ltd.

  15. 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