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Sample records for typing identifies distinct

  1. DNA affinity labeling of adenovirus type 2 upstream promoter sequence-binding factors identifies two distinct proteins

    SciTech Connect

    Safer, B.; Cohen, R.B.; Garfinkel, S.; Thompson, J.A.

    1988-01-01

    A rapid affinity labeling procedure with enhanced specificity was developed to identify DNA-binding proteins. /sup 32/P was first introduced at unique phosphodiester bonds within the DNA recognition sequence. UV light-dependent cross-linking of pyrimidines to amino acid residues in direct contact at the binding site, followed by micrococcal nuclease digestion, resulted in the transfer of /sup 32/P to only those specific protein(s) which recognized the binding sequence. This method was applied to the detection and characterization of proteins that bound to the upstream promoter sequence (-50 to -66) of the human adenovirus type 2 major late promoter. We detected two distinct proteins with molecular weights of 45,000 and 116,000 that interacted with this promoter element. The two proteins differed significantly in their chromatographic and cross-linking behaviors.

  2. High-throughput bacterial SNP typing identifies distinct clusters of Salmonella Typhi causing typhoid in Nepalese children

    PubMed Central

    2010-01-01

    Background Salmonella Typhi (S. Typhi) causes typhoid fever, which remains an important public health issue in many developing countries. Kathmandu, the capital of Nepal, is an area of high incidence and the pediatric population appears to be at high risk of exposure and infection. Methods We recently defined the population structure of S. Typhi, using new sequencing technologies to identify nearly 2,000 single nucleotide polymorphisms (SNPs) that can be used as unequivocal phylogenetic markers. Here we have used the GoldenGate (Illumina) platform to simultaneously type 1,500 of these SNPs in 62 S. Typhi isolates causing severe typhoid in children admitted to Patan Hospital in Kathmandu. Results Eight distinct S. Typhi haplotypes were identified during the 20-month study period, with 68% of isolates belonging to a subclone of the previously defined H58 S. Typhi. This subclone was closely associated with resistance to nalidixic acid, with all isolates from this group demonstrating a resistant phenotype and harbouring the same resistance-associated SNP in GyrA (Phe83). A secondary clone, comprising 19% of isolates, was observed only during the second half of the study. Conclusions Our data demonstrate the utility of SNP typing for monitoring bacterial populations over a defined period in a single endemic setting. We provide evidence for genotype introduction and define a nalidixic acid resistant subclone of S. Typhi, which appears to be the dominant cause of severe pediatric typhoid in Kathmandu during the study period. PMID:20509974

  3. Molecular epidemiology of Legionella pneumophila serogroup 1 isolates identify a prevalent sequence type, ST505, and a distinct clonal group of clinical isolates in Toyama Prefecture, Japan.

    PubMed

    Kanatani, Jun-Ichi; Isobe, Junko; Kimata, Keiko; Shima, Tomoko; Shimizu, Miwako; Kura, Fumiaki; Sata, Tetsutaro; Watahiki, Masanori

    2013-08-01

    We performed comparative analyses of Legionella pneumophila serogroup (SG) 1 isolates obtained during 2005-2012 in Toyama Prefecture, Japan, by sequence-based typing (SBT) and pulsed-field gel electrophoresis (PFGE). Seventy-three isolates of L. pneumophila SG 1, including 17 isolates from patients, 51 from public baths, 4 from cooling towers, and 1 from a shower, were analyzed. The isolates were classified into 43 sequence types (STs) by SBT and 52 types by PFGE. Fourteen STs were unique to Toyama Prefecture, as determined from the SBT database of European Working Group for Legionella Infections (EWGLI), as of October 31, 2012. ST505 strain was identified in 4 isolates from patients and 5 isolates from public baths, and these isolates belonged to 2 PFGE types. These, however, were similar because of the difference with only two restriction fragments, indicating that ST505 strain was prevalent among L. pneumophila SG 1 isolates in this area. ST505 strains isolated from patients and public baths were distributed along the river in a western part of Toyama Prefecture. SBT and PFGE profiles of 3 clinical isolates were identical with those of 3 environmental isolates from the suspected origins of the infection in each case, respectively. This finding suggested that SBT and PFGE were useful for epidemiological study. Furthermore, by SBT analysis, we identified a clonal group formed only by 7 clinical isolates that are not associated with bathwater, suggesting that they were derived from unrecognized sources. PMID:23269379

  4. Gingival Tissue Transcriptomes Identify Distinct Periodontitis Phenotypes

    PubMed Central

    Kebschull, M.; Demmer, R.T.; Grün, B.; Guarnieri, P.; Pavlidis, P.; Papapanou, P.N.

    2014-01-01

    The currently recognized principal forms of periodontitis—chronic and aggressive—lack an unequivocal, pathobiology-based foundation. We explored whether gingival tissue transcriptomes can serve as the basis for an alternative classification of periodontitis. We used cross-sectional whole-genome gene expression data from 241 gingival tissue biopsies obtained from sites with periodontal pathology in 120 systemically healthy nonsmokers with periodontitis, with available data on clinical periodontal status, subgingival microbial profiles, and serum IgG antibodies to periodontal microbiota. Adjusted model-based clustering of transcriptomic data using finite mixtures generated two distinct clusters of patients that did not align with the current classification of chronic and aggressive periodontitis. Differential expression profiles primarily related to cell proliferation in cluster 1 and to lymphocyte activation and unfolded protein responses in cluster 2. Patients in the two clusters did not differ with respect to age but presented with distinct phenotypes (statistically significantly different whole-mouth clinical measures of extent/severity, subgingival microbial burden by several species, and selected serum antibody responses). Patients in cluster 2 showed more extensive/severe disease and were more often male. The findings suggest that distinct gene expression signatures in pathologic gingival tissues translate into phenotypic differences and can provide a basis for a novel classification. PMID:24646639

  5. Distinctively elderly mobility: types and determinants.

    PubMed

    Meyer, J W; Speare, A

    1985-01-01

    "Distinctive types of mobility are identified for the [U.S.] elderly, many of whom also move for traditional reasons. Using a longitudinal data set from adult residents in Rhode Island, univariate, chi square, and logit analyses indicate associations between sociodemographic characteristics of the elderly and their mobility behavior. Mobility for assistance reasons is associated with older age, unmarried status, higher previous mobility, and renter status. Mobility in preparation for aging (e.g., to an elderly complex) is more likely for unmarried, previously mobile residents. Out-of-state mobility to amenity destinations is not limited to the elderly, but younger, married, more affluent elderly were more likely to make such moves." PMID:12280179

  6. Distinct types of eigenvector localization in networks.

    PubMed

    Pastor-Satorras, Romualdo; Castellano, Claudio

    2016-01-01

    The spectral properties of the adjacency matrix provide a trove of information about the structure and function of complex networks. In particular, the largest eigenvalue and its associated principal eigenvector are crucial in the understanding of nodes' centrality and the unfolding of dynamical processes. Here we show that two distinct types of localization of the principal eigenvector may occur in heterogeneous networks. For synthetic networks with degree distribution P(q) ~ q(-γ), localization occurs on the largest hub if γ > 5/2; for γ < 5/2 a new type of localization arises on a mesoscopic subgraph associated with the shell with the largest index in the K-core decomposition. Similar evidence for the existence of distinct localization modes is found in the analysis of real-world networks. Our results open a new perspective on dynamical processes on networks and on a recently proposed alternative measure of node centrality based on the non-backtracking matrix. PMID:26754565

  7. Distinct types of eigenvector localization in networks

    PubMed Central

    Pastor-Satorras, Romualdo; Castellano, Claudio

    2016-01-01

    The spectral properties of the adjacency matrix provide a trove of information about the structure and function of complex networks. In particular, the largest eigenvalue and its associated principal eigenvector are crucial in the understanding of nodes’ centrality and the unfolding of dynamical processes. Here we show that two distinct types of localization of the principal eigenvector may occur in heterogeneous networks. For synthetic networks with degree distribution P(q) ~ q−γ, localization occurs on the largest hub if γ > 5/2; for γ < 5/2 a new type of localization arises on a mesoscopic subgraph associated with the shell with the largest index in the K-core decomposition. Similar evidence for the existence of distinct localization modes is found in the analysis of real-world networks. Our results open a new perspective on dynamical processes on networks and on a recently proposed alternative measure of node centrality based on the non-backtracking matrix. PMID:26754565

  8. Distinct types of eigenvector localization in networks

    NASA Astrophysics Data System (ADS)

    Pastor-Satorras, Romualdo; Castellano, Claudio

    2016-01-01

    The spectral properties of the adjacency matrix provide a trove of information about the structure and function of complex networks. In particular, the largest eigenvalue and its associated principal eigenvector are crucial in the understanding of nodes’ centrality and the unfolding of dynamical processes. Here we show that two distinct types of localization of the principal eigenvector may occur in heterogeneous networks. For synthetic networks with degree distribution P(q) ~ q-γ, localization occurs on the largest hub if γ > 5/2 for γ < 5/2 a new type of localization arises on a mesoscopic subgraph associated with the shell with the largest index in the K-core decomposition. Similar evidence for the existence of distinct localization modes is found in the analysis of real-world networks. Our results open a new perspective on dynamical processes on networks and on a recently proposed alternative measure of node centrality based on the non-backtracking matrix.

  9. Neural Precursor Lineages Specify Distinct Neocortical Pyramidal Neuron Types

    PubMed Central

    Tyler, William A.; Medalla, Maria; Guillamon-Vivancos, Teresa

    2015-01-01

    Several neural precursor populations contemporaneously generate neurons in the developing neocortex. Specifically, radial glial stem cells of the dorsal telencephalon divide asymmetrically to produce excitatory neurons, but also indirectly to produce neurons via three types of intermediate progenitor cells. Why so many precursor types are needed to produce neurons has not been established; whether different intermediate progenitor cells merely expand the output of radial glia or instead generate distinct types of neurons is unknown. Here we use a novel genetic fate mapping technique to simultaneously track multiple precursor streams in the developing mouse brain and show that layer 2 and 3 pyramidal neurons exhibit distinctive electrophysiological and structural properties depending upon their precursor cell type of origin. These data indicate that individual precursor subclasses synchronously produce functionally different neurons, even within the same lamina, and identify a primary mechanism leading to cortical neuronal diversity. PMID:25878286

  10. Propionibacterium acnes Types I and II Represent Phylogenetically Distinct Groups

    PubMed Central

    McDowell, Andrew; Valanne, Susanna; Ramage, Gordon; Tunney, Michael M.; Glenn, Josephine V.; McLorinan, Gregory C.; Bhatia, Ajay; Maisonneuve, Jean-Francois; Lodes, Michael; Persing, David H.; Patrick, Sheila

    2005-01-01

    Although two phenotypes of the opportunistic pathogen Propionibacterium acnes (types I and II) have been described, epidemiological investigations of their roles in different infections have not been widely reported. Using immunofluorescence microscopy with monoclonal antibodies (MAbs) QUBPa1 and QUBPa2, specific for types I and II, respectively, we investigated the prevalences of the two types among 132 P. acnes isolates. Analysis of isolates from failed prosthetic hip implants (n = 40) revealed approximately equal numbers of type I and II organisms. Isolates from failed prosthetic hip-associated bone (n = 6) and tissue (n = 38) samples, as well as isolates from acne (n = 22), dental infections (n = 8), and skin removed during surgical incision (n = 18) were predominately of type I. A total of 11 (8%) isolates showed atypical MAb labeling and could not be conclusively identified. Phylogenetic analysis of P. acnes by nucleotide sequencing revealed the 16S rRNA gene to be highly conserved between types I and II. In contrast, sequence analysis of recA and a putative hemolysin gene (tly) revealed significantly greater type-specific polymorphisms that corresponded to phylogenetically distinct cluster groups. All 11 isolates with atypical MAb labeling were identified as type I by sequencing. Within the recA and tly phylogenetic trees, nine of these isolates formed a cluster distinct from other type I organisms, suggesting a further phylogenetic subdivision within type I. Our study therefore demonstrates that the phenotypic differences between P. acnes types I and II reflect deeper differences in their phylogeny. Furthermore, nucleotide sequencing provides an accurate method for identifying the type status of P. acnes isolates. PMID:15634990

  11. Individual Distinctiveness in Call Types of Wild Western Female Gorillas

    PubMed Central

    Salmi, Roberta; Hammerschmidt, Kurt; Doran-Sheehy, Diane M.

    2014-01-01

    Individually distinct vocalizations play an important role in animal communication, allowing call recipients to respond differentially based on caller identity. However, which of the many calls in a species' repertoire should have more acoustic variability and be more recognizable is less apparent. One proposed hypothesis is that calls used over long distances should be more distinct because visual cues are not available to identify the caller. An alternative hypothesis proposes that close calls should be more recognizable because of their importance in social interactions. To examine which hypothesis garners more support, the acoustic variation and individual distinctiveness of eight call types of six wild western gorilla (Gorilla gorilla) females were investigated. Acoustic recordings of gorilla calls were collected at the Mondika Research Center (Republic of Congo). Acoustic variability was high in all gorilla calls. Similar high inter-individual variation and potential for identity coding (PIC) was found for all call types. Discriminant function analyses confirmed that all call types were individually distinct (although for call types with lowest sample size - hum, grumble and scream - this result cannot be generalized), suggesting that neither the distance at which communication occurs nor the call social function alone can explain the evolution of identity signaling in western gorilla communication. PMID:25029238

  12. Categorically distinct types of receptive fields in early visual cortex.

    PubMed

    Talebi, Vargha; Baker, Curtis L

    2016-05-01

    In the visual cortex, distinct types of neurons have been identified based on cellular morphology, response to injected current, or expression of specific markers, but neurophysiological studies have revealed visual receptive field (RF) properties that appear to be on a continuum, with only two generally recognized classes: simple and complex. Most previous studies have characterized visual responses of neurons using stereotyped stimuli such as bars, gratings, or white noise and simple system identification approaches (e.g., reverse correlation). Here we estimate visual RF models of cortical neurons using visually rich natural image stimuli and regularized regression system identification methods and characterize their spatial tuning, temporal dynamics, spatiotemporal behavior, and spiking properties. We quantitatively demonstrate the existence of three functionally distinct categories of simple cells, distinguished by their degree of orientation selectivity (isotropic or oriented) and the nature of their output nonlinearity (expansive or compressive). In addition, these three types have differing average values of several other properties. Cells with nonoriented RFs tend to have smaller RFs, shorter response durations, no direction selectivity, and high reliability. Orientation-selective neurons with an expansive output nonlinearity have Gabor-like RFs, lower spontaneous activity and responsivity, and spiking responses with higher sparseness. Oriented RFs with a compressive nonlinearity are spatially nondescript and tend to show longer response latency. Our findings indicate multiple physiologically defined types of RFs beyond the simple/complex dichotomy, suggesting that cortical neurons may have more specialized functional roles rather than lying on a multidimensional continuum. PMID:26936978

  13. Discovering Distinct Functional Modules of Specific Cancer Types Using Protein-Protein Interaction Networks

    PubMed Central

    Shen, Ru; Wang, Xiaosheng; Guda, Chittibabu

    2015-01-01

    Background. The molecular profiles exhibited in different cancer types are very different; hence, discovering distinct functional modules associated with specific cancer types is very important to understand the distinct functions associated with them. Protein-protein interaction networks carry vital information about molecular interactions in cellular systems, and identification of functional modules (subgraphs) in these networks is one of the most important applications of biological network analysis. Results. In this study, we developed a new graph theory based method to identify distinct functional modules from nine different cancer protein-protein interaction networks. The method is composed of three major steps: (i) extracting modules from protein-protein interaction networks using network clustering algorithms; (ii) identifying distinct subgraphs from the derived modules; and (iii) identifying distinct subgraph patterns from distinct subgraphs. The subgraph patterns were evaluated using experimentally determined cancer-specific protein-protein interaction data from the Ingenuity knowledgebase, to identify distinct functional modules that are specific to each cancer type. Conclusion. We identified cancer-type specific subgraph patterns that may represent the functional modules involved in the molecular pathogenesis of different cancer types. Our method can serve as an effective tool to discover cancer-type specific functional modules from large protein-protein interaction networks. PMID:26495282

  14. Comparison of melanoblast expression patterns identifies distinct classes of genes

    PubMed Central

    Loftus, Stacie K.; Baxter, Laura L.; Buac, Kristina; Watkins-Chow, Dawn E.; Larson, Denise M.; Pavan, William J.

    2010-01-01

    Summary A full understanding of transcriptional regulation requires integration of information obtained from multiple experimental datasets. These include datasets annotating gene expression within the context of an entire organism under normal and genetically perturbed conditions. Here we describe an expression dataset annotating pigment cell-expressed genes of the developing melanocyte and RPE lineages. Expression images are annotated and available at http://research.nhgri.nih.gov/manuscripts/Loftus/March2009/. Data is also summarized in a standardized manner using a universal melanoblast scoring scale that accounts for the embryonic location of cells and regional cell density. This approach allowed us to classify 14 pigment genes into 4 groupings classified by cell lineage expression, temporal-spatial context, and differential alteration in response to altered MITF and SOX10 status. Significant differences in regional populations were also observed across inbred strain backgrounds highlighting the value of this approach to identify modifier allele influences on melanoblast number and distributions. This analysis revealed novel features of in vivo expression patterns that are not measurable by in vitro-based assays, providing data that in combination with genomic analyses will allow modeling of pigment cell gene expression in development and disease. PMID:19493314

  15. Biochemical analysis of TssK, a core component of the bacterial Type VI secretion system, reveals distinct oligomeric states of TssK and identifies a TssK–TssFG subcomplex

    PubMed Central

    English, Grant; Byron, Olwyn; Cianfanelli, Francesca R.; Prescott, Alan R.; Coulthurst, Sarah J.

    2014-01-01

    Gram-negative bacteria use the Type VI secretion system (T6SS) to inject toxic proteins into rival bacteria or eukaryotic cells. However, the mechanism of the T6SS is incompletely understood. In the present study, we investigated a conserved component of the T6SS, TssK, using the antibacterial T6SS of Serratia marcescens as a model system. TssK was confirmed to be essential for effector secretion by the T6SS. The native protein, although not an integral membrane protein, appeared to localize to the inner membrane, consistent with its presence within a membrane-anchored assembly. Recombinant TssK purified from S. marcescens was found to exist in several stable oligomeric forms, namely trimer, hexamer and higher-order species. Native-level purification of TssK identified TssF and TssG as interacting proteins. TssF and TssG, conserved T6SS components of unknown function, were required for T6SS activity, but not for correct localization of TssK. A complex containing TssK, TssF and TssG was subsequently purified in vitro, confirming that these three proteins form a new subcomplex within the T6SS. Our findings provide new insight into the T6SS assembly, allowing us to propose a model whereby TssK recruits TssFG into the membrane-associated T6SS complex and different oligomeric states of TssK may contribute to the dynamic mechanism of the system. PMID:24779861

  16. Biochemical analysis of TssK, a core component of the bacterial Type VI secretion system, reveals distinct oligomeric states of TssK and identifies a TssK-TssFG subcomplex.

    PubMed

    English, Grant; Byron, Olwyn; Cianfanelli, Francesca R; Prescott, Alan R; Coulthurst, Sarah J

    2014-07-15

    Gram-negative bacteria use the Type VI secretion system (T6SS) to inject toxic proteins into rival bacteria or eukaryotic cells. However, the mechanism of the T6SS is incompletely understood. In the present study, we investigated a conserved component of the T6SS, TssK, using the antibacterial T6SS of Serratia marcescens as a model system. TssK was confirmed to be essential for effector secretion by the T6SS. The native protein, although not an integral membrane protein, appeared to localize to the inner membrane, consistent with its presence within a membrane-anchored assembly. Recombinant TssK purified from S. marcescens was found to exist in several stable oligomeric forms, namely trimer, hexamer and higher-order species. Native-level purification of TssK identified TssF and TssG as interacting proteins. TssF and TssG, conserved T6SS components of unknown function, were required for T6SS activity, but not for correct localization of TssK. A complex containing TssK, TssF and TssG was subsequently purified in vitro, confirming that these three proteins form a new subcomplex within the T6SS. Our findings provide new insight into the T6SS assembly, allowing us to propose a model whereby TssK recruits TssFG into the membrane-associated T6SS complex and different oligomeric states of TssK may contribute to the dynamic mechanism of the system. PMID:24779861

  17. Cell-Surface Protein Profiling Identifies Distinctive Markers of Progenitor Cells in Human Skeletal Muscle.

    PubMed

    Uezumi, Akiyoshi; Nakatani, Masashi; Ikemoto-Uezumi, Madoka; Yamamoto, Naoki; Morita, Mitsuhiro; Yamaguchi, Asami; Yamada, Harumoto; Kasai, Takehiro; Masuda, Satoru; Narita, Asako; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi; Fukada, So-Ichiro; Nishino, Ichizo; Tsuchida, Kunihiro

    2016-08-01

    Skeletal muscle contains two distinct stem/progenitor populations. One is the satellite cell, which acts as a muscle stem cell, and the other is the mesenchymal progenitor, which contributes to muscle pathogeneses such as fat infiltration and fibrosis. Detailed and accurate characterization of these progenitors in humans remains elusive. Here, we performed comprehensive cell-surface protein profiling of the two progenitor populations residing in human skeletal muscle and identified three previously unrecognized markers: CD82 and CD318 for satellite cells and CD201 for mesenchymal progenitors. These markers distinguish myogenic and mesenchymal progenitors, and enable efficient isolation of the two types of progenitors. Functional study revealed that CD82 ensures expansion and preservation of myogenic progenitors by suppressing excessive differentiation, and CD201 signaling favors adipogenesis of mesenchymal progenitors. Thus, cell-surface proteins identified here are not only useful markers but also functionally important molecules, and provide valuable insight into human muscle biology and diseases. PMID:27509136

  18. Ferroan anorthosite - A widespread and distinctive lunar rock type

    NASA Technical Reports Server (NTRS)

    Dowty, E.; Prinz, M.; Keil, K.

    1974-01-01

    Eight of eleven Apollo 16 rake-sample anorthosites are very similar to each other, to hand-specimen Apollo 16 anorthosites, and to Apollo 15 anorthosites. They have feldspar An-96.6, both high- and low-Ca pyroxene with a restricted range of (low-magnesium) composition, minor olivine, traces of ilmenite and chromite, and originally coarse-grained, but now cataclastic texture. Such ferroan anorthosite is evidently a coherent, distinctive and widespread lunar rock type of cumulate origin which may not necessarily be very closely related genetically to other highland rock types.

  19. Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing.

    PubMed

    Drissen, Roy; Buza-Vidas, Natalija; Woll, Petter; Thongjuea, Supat; Gambardella, Adriana; Giustacchini, Alice; Mancini, Elena; Zriwil, Alya; Lutteropp, Michael; Grover, Amit; Mead, Adam; Sitnicka, Ewa; Jacobsen, Sten Eirik W; Nerlov, Claus

    2016-06-01

    According to current models of hematopoiesis, lymphoid-primed multi-potent progenitors (LMPPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)Flt3(hi)) and common myeloid progenitors (CMPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)CD41(hi)) establish an early branch point for separate lineage-commitment pathways from hematopoietic stem cells, with the notable exception that both pathways are proposed to generate all myeloid innate immune cell types through the same myeloid-restricted pre-granulocyte-macrophage progenitor (pre-GM) (Lin(-)Sca-1(-)c-Kit(+)CD41(-)FcγRII/III(-)CD150(-)CD105(-)). By single-cell transcriptome profiling of pre-GMs, we identified distinct myeloid differentiation pathways: a pathway expressing the gene encoding the transcription factor GATA-1 generated mast cells, eosinophils, megakaryocytes and erythroid cells, and a pathway lacking expression of that gene generated monocytes, neutrophils and lymphocytes. These results identify an early hematopoietic-lineage bifurcation that separates the myeloid lineages before their segregation from other hematopoietic-lineage potential. PMID:27043410

  20. Identifying marker typing incompatibilities in linkage analysis

    SciTech Connect

    Stringham, H.M.; Boehnke, M.

    1996-10-01

    A common problem encountered in linkage analyses is that execution of the computer program is halted because of genotypes in the data that are inconsistent with Mendelian inheritance. Such inconsistencies may arise because of pedigree errors or errors in typing. In some cases, the source of the inconsistencies is easily identified by examining the pedigree. In others, the error is not obvious, and substantial time and effort are required to identify the responsible genotypes. We have developed two methods for automatically identifying those individuals whose genotypes are most likely the cause of the inconsistencies. First, we calculate the posterior probability of genotyping error for each member of the pedigree, given the marker data on all pedigree members and allowing anyone in the pedigree to have an error. Second, we identify those individuals whose genotypes could be solely responsible for the inconsistency in the pedigree. We illustrate these methods with two examples: one a pedigree error, the second a genotyping error. These methods have been implemented as a module of the pedigree analysis program package MENDEL. 9 refs., 2 figs., 2 tabs.

  1. Nocturnal Sleep Dynamics Identify Narcolepsy Type 1

    PubMed Central

    Pizza, Fabio; Vandi, Stefano; Iloti, Martina; Franceschini, Christian; Liguori, Rocco; Mignot, Emmanuel; Plazzi, Giuseppe

    2015-01-01

    Study Objectives: To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Design: Cross-sectional. Setting: Sleep laboratory. Patients: One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and “subjective” hypersomnolence (sHS, n = 52). Interventions: None. Methods: Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Results: Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P < 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P < 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P < 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P < 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P < 0.0001) and at MSLT (0.956 ± 0.015, P < 0.0001). Conclusions: Sleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies hypocretin-deficient narcolepsy type 1 among central disorders of hypersomnolence. Citation: Pizza F, Vandi S

  2. A Distinct Type of Pilus from the Human Microbiome.

    PubMed

    Xu, Qingping; Shoji, Mikio; Shibata, Satoshi; Naito, Mariko; Sato, Keiko; Elsliger, Marc-André; Grant, Joanna C; Axelrod, Herbert L; Chiu, Hsiu-Ju; Farr, Carol L; Jaroszewski, Lukasz; Knuth, Mark W; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Curtis, Michael A; Nakayama, Koji; Wilson, Ian A

    2016-04-21

    Pili are proteinaceous polymers of linked pilins that protrude from the cell surface of many bacteria and often mediate adherence and virulence. We investigated a set of 20 Bacteroidia pilins from the human microbiome whose structures and mechanism of assembly were unknown. Crystal structures and biochemical data revealed a diverse protein superfamily with a common Greek-key β sandwich fold with two transthyretin-like repeats that polymerize into a pilus through a strand-exchange mechanism. The assembly mechanism of the central, structural pilins involves proteinase-assisted removal of their N-terminal β strand, creating an extended hydrophobic groove that binds the C-terminal donor strands of the incoming pilin. Accessory pilins at the tip and base have unique structural features specific to their location, allowing initiation or termination of the assembly. The Bacteroidia pilus, therefore, has a biogenesis mechanism that is distinct from other known pili and likely represents a different type of bacterial pilus. PMID:27062925

  3. Fluids, fault zone permeability and two distinct types of pseudotachylyte

    NASA Astrophysics Data System (ADS)

    Bjornerud, M.

    2010-12-01

    The comparative rarity of pseudotachylyte in ancient fault zones is surprising in light of estimates that ca. 90% of the energy budget of an earthquake is expended in frictional heating. One explanation is that frictional melting (pseudotachylyte generation) is suppressed after the initial rupture on a fault zone because fluids infiltrate the zone and thermal pressurization of these fluids inhibits melting in subsequent seismic events. While this seems plausible for many of the iconic occurrences of pseudotachylyte in otherwise undamaged crystalline rocks, some pseudotachylytes clearly formed in host rocks in which permeability was apparently high and fluids were present at the time of frictional melting. In these fault zones, cataclasites and pseudotachylyte commonly have mutually cross cutting relationships, and both types of fault rock have been complexly intruded into the surrounding damage zone. In contrast, cataclasites associated with pseudotachylyte in pristine crystalline rocks occur in smaller volumes and have simpler geometries, typically limited to the margins of fault veins or in dilational jogs. These observations suggest that there may be two distinct physical circumstances under which frictional melting may occur and thus two distinct genetic types of pseudotachylyte. Classic “dry” pseudotachylytes (e.g., Holsnøy, Bergen Arcs, Norway; Gole Larghe Fault, Italy) probably represent the initial seismic rupture of intact, low-permeability rock at high effective stress in the absence of fluids. When fluids are present, however (e.g., central Otago, New Zealand; Nojima fault, Japan), the potential for frictional melting depends on the relative rates at which heat and fluids can escape from a fault zone. Geophysical models of dynamic weakening mechanisms during earthquakes (Rempel and Rice, JGR, 2006) show that thermal pressurization occurs when the hydraulic diffusivity is effectively less than thermal diffusivity, while melting occurs when thermal

  4. Identifying Clinically Distinct Subgroups of Self-Injurers among Young Adults: A Latent Class Analysis

    ERIC Educational Resources Information Center

    Klonsky, E. David; Olino, Thomas M.

    2008-01-01

    High rates of nonsuicidal self-injury (NSSI; 14%-17%) in adolescents and young adults suggest that some self-injurers may exhibit more or different psychiatric problems than others. In the present study, the authors utilized a latent class analysis to identify clinically distinct subgroups of self-injurers. Participants were 205 young adults with…

  5. Subtypes of Cocaine Abusers: Support for a Type A-Type B Distinction.

    ERIC Educational Resources Information Center

    Ball, Samuel A.; And Others

    1995-01-01

    Systematically assessed replicability and generalizability of a multidimensional alcoholism typological system in 399 inpatient, outpatient, and non-treatment-seeking cocaine abusers. Two different procedures supported the construct, concurrent, and predictive validity of the Type A-Type B distinction in cocaine abusers. Multidimensional…

  6. Distinct Types of Feeding Related Neurons in Mouse Hypothalamus

    PubMed Central

    Tang, Yan; Benusiglio, Diego; Grinevich, Valery; Lin, Longnian

    2016-01-01

    The last two decades of research provided evidence for a substantial heterogeneity among feeding-related neurons (FRNs) in the hypothalamus. However, it remains unclear how FRNs differ in their firing patterns during food intake. Here, we investigated the relationship between the activity of neurons in mouse hypothalamus and their feeding behavior. Using tetrode-based in vivo recording technique, we identified various firing patterns of hypothalamic FRNs, which, after the initiation of food intake, can be sorted into four types: sharp increase (type I), slow increase (type II), sharp decrease (type III), and sustained decrease (type IV) of firing rates. The feeding-related firing response of FRNs was rigidly related to the duration of food intake and, to a less extent, associated with the type of food. The majority of these FRNs responded to glucose and leptin and exhibited electrophysiological characteristics of putative GABAergic neurons. In conclusion, our study demonstrated the diversity of neurons in the complex hypothalamic network coordinating food intake. PMID:27242460

  7. Two Distinct Types of Hypercontractile Esophagus: Classic and Spastic Jackhammer.

    PubMed

    Hong, Yun Soo; Min, Yang Won; Rhee, Poong-Lyul

    2016-09-15

    Hypercontractile esophagus (nicknamed jackhammer esophagus) is a recently defined disease within the esophageal motility disorders classification. Responses to treatments for jackhammer esophagus have been inconsistent in previous trials, possibly due to its heterogeneous manifestation. Thus, we reviewed 10 patients diagnosed with jackhammer esophagus and compared their clinical and manometric features at baseline. Additionally, manometric and symptomatic responses after treatment with known smooth muscle relaxants, including anticholinergic drugs (cimetropium bromide and scopolamine butylbromide) and a phosphodiesterase-5 inhibitor (sildenafil) were compared. We observed two distinct subgroups in the findings: one with hypercontractility and normal distal latencies ("classic jackhammer esophagus," n=7) and the other with hypercontractility and short distal latencies ("spastic jackhammer esophagus," n=3). The two types also differed in their responses to medications in that symptoms improved upon treatment with an anticholinergic agent in classic jackhammer esophagus patients, while spastic jackhammer esophagus was unresponsive to both the anticholinergic drugs and the phosphodiesterase-5 inhibitor. In conclusion, hypercontractile esophagus may be a heterogeneous disease with different underlying pathophysiologies. We introduced two novel terms, "classic jackhammer esophagus" and "spastic jackhammer esophagus," to distinguish the two types. PMID:27458179

  8. Two Distinct Types of Hypercontractile Esophagus: Classic and Spastic Jackhammer

    PubMed Central

    Hong, Yun Soo; Min, Yang Won; Rhee, Poong-Lyul

    2016-01-01

    Hypercontractile esophagus (nicknamed jackhammer esophagus) is a recently defined disease within the esophageal motility disorders classification. Responses to treatments for jackhammer esophagus have been inconsistent in previous trials, possibly due to its heterogeneous manifestation. Thus, we reviewed 10 patients diagnosed with jackhammer esophagus and compared their clinical and manometric features at baseline. Additionally, manometric and symptomatic responses after treatment with known smooth muscle relaxants, including anticholinergic drugs (cimetropium bromide and scopolamine butylbromide) and a phosphodiesterase-5 inhibitor (sildenafil) were compared. We observed two distinct subgroups in the findings: one with hypercontractility and normal distal latencies (“classic jackhammer esophagus,” n=7) and the other with hypercontractility and short distal latencies (“spastic jackhammer esophagus,” n=3). The two types also differed in their responses to medications in that symptoms improved upon treatment with an anticholinergic agent in classic jackhammer esophagus patients, while spastic jackhammer esophagus was unresponsive to both the anticholinergic drugs and the phosphodiesterase-5 inhibitor. In conclusion, hypercontractile esophagus may be a heterogeneous disease with different underlying pathophysiologies. We introduced two novel terms, “classic jackhammer esophagus” and “spastic jackhammer esophagus,” to distinguish the two types. PMID:27458179

  9. Laminar Specificity of Functional Input to Distinct Types of Inhibitory Cortical Neurons

    PubMed Central

    Xu, Xiangmin; Callaway, Edward M.

    2009-01-01

    Despite the presence of numerous inhibitory cell types, laminar excitatory input has only been characterized for limited identified types, and it is unknown whether there are differences between cell types in their laminar sources of inhibitory input. In the present study, we characterized sources of local input to nine distinct types of layer 2/3 inhibitory neurons in living slices of mouse somatosensory cortex. Whole-cell recordings from identified cell types, facilitated by use of transgenic mice expressing green fluorescent protein in limited inhibitory neuron populations, were combined with laser scanning photostimulation. We found that each inhibitory cell type received distinct excitatory and inhibitory laminar input patterns. Excitatory inputs could be grouped into three categories. All inhibitory cell types received strong excitation from layer 2/3, and for calretinin (CR)-positive Martinotti cells and burst-spiking interneurons, this was their dominant source of excitatory input. Three other cell types, including fast-spiking basket cells, CR-negative Martinotti cells, and bipolar interneurons, also received strong excitatory input from layer 4. The remaining four inhibitory cell types, including chandelier cells, neurogliaform cells, irregular spiking basket cells, and regular spiking presumptive basket cells, received strong excitatory input from layer 5A and not layer 4. Laminar sources of inhibitory input varied between cell types and could not be predicted from the sources of excitatory input. Thus, there are cell-type specific differences in laminar sources of both excitation and inhibition, and complementary input patterns from layer 4 versus layer 5A suggest cell type differences in their relationships to lemniscal versus paralemniscal pathways. PMID:19129386

  10. Coronal type II bursts and interplanetary type II bursts: Distinct shock drivers

    NASA Astrophysics Data System (ADS)

    Suryanarayana, G. S.

    2012-02-01

    We study solar radio type II bursts combining with Wind/WAVES type II bursts and coronal mass ejections (CMEs). The aim of the present work is to investigate the effectiveness of shocks to cause type II bursts in the solar corona and the interplanetary space. We consider the following findings. The distribution of the cessation heights of type II emission is confined to a rather narrow range of height than the distribution of the heights of start frequencies. This is suggestive of the presence of a gradient for the Alfvén speed from the heliocentric height of ˜1.4 solar radii. The range of the kinetic energy of CMEs associated with coronal type II emission taken together with the suggested computation method and the Alfvén speed gradient, indicates the limit to the height up to which type II emission could be expected. This height is ˜2 solar radii from the center of the Sun. Further, the large time gap between the cessation time and heights of coronal type II emission and the commencement time and heights of most of the IP type II bursts do not account for the difference between the two heights and the average shock speed. Also, there is clear difference in the magnitude of the kinetic energies and the distinct characteristics of the CMEs associated with coronal and IP type II bursts. Hence, we suggest that in most instances the coronal type II bursts and IP type II bursts occur due to distinct shocks. We also address the question of the origin of type II bursts and discuss the possible explanation of observed results.

  11. Distinct Host Tropism Protein Signatures to Identify Possible Zoonotic Influenza A Viruses

    PubMed Central

    Eng, Christine L. P.; Tong, Joo Chuan; Tan, Tin Wee

    2016-01-01

    Zoonotic influenza A viruses constantly pose a health threat to humans as novel strains occasionally emerge from the avian population to cause human infections. Many past epidemic as well as pandemic strains have originated from avian species. While most viruses are restricted to their primary hosts, zoonotic strains can sometimes arise from mutations or reassortment, leading them to acquire the capability to escape host species barrier and successfully infect a new host. Phylogenetic analyses and genetic markers are useful in tracing the origins of zoonotic infections, but there are still no effective means to identify high risk strains prior to an outbreak. Here we show that distinct host tropism protein signatures can be used to identify possible zoonotic strains in avian species which have the potential to cause human infections. We have discovered that influenza A viruses can now be classified into avian, human, or zoonotic strains based on their host tropism protein signatures. Analysis of all influenza A viruses with complete proteome using the host tropism prediction system, based on machine learning classifications of avian and human viral proteins has uncovered distinct signatures of zoonotic strains as mosaics of avian and human viral proteins. This is in contrast with typical avian or human strains where they show mostly avian or human viral proteins in their signatures respectively. Moreover, we have found that zoonotic strains from the same influenza outbreaks carry similar host tropism protein signatures characteristic of a common ancestry. Our results demonstrate that the distinct host tropism protein signature in zoonotic strains may prove useful in influenza surveillance to rapidly identify potential high risk strains circulating in avian species, which may grant us the foresight in anticipating an impending influenza outbreak. PMID:26915079

  12. Distinct Host Tropism Protein Signatures to Identify Possible Zoonotic Influenza A Viruses.

    PubMed

    Eng, Christine L P; Tong, Joo Chuan; Tan, Tin Wee

    2016-01-01

    Zoonotic influenza A viruses constantly pose a health threat to humans as novel strains occasionally emerge from the avian population to cause human infections. Many past epidemic as well as pandemic strains have originated from avian species. While most viruses are restricted to their primary hosts, zoonotic strains can sometimes arise from mutations or reassortment, leading them to acquire the capability to escape host species barrier and successfully infect a new host. Phylogenetic analyses and genetic markers are useful in tracing the origins of zoonotic infections, but there are still no effective means to identify high risk strains prior to an outbreak. Here we show that distinct host tropism protein signatures can be used to identify possible zoonotic strains in avian species which have the potential to cause human infections. We have discovered that influenza A viruses can now be classified into avian, human, or zoonotic strains based on their host tropism protein signatures. Analysis of all influenza A viruses with complete proteome using the host tropism prediction system, based on machine learning classifications of avian and human viral proteins has uncovered distinct signatures of zoonotic strains as mosaics of avian and human viral proteins. This is in contrast with typical avian or human strains where they show mostly avian or human viral proteins in their signatures respectively. Moreover, we have found that zoonotic strains from the same influenza outbreaks carry similar host tropism protein signatures characteristic of a common ancestry. Our results demonstrate that the distinct host tropism protein signature in zoonotic strains may prove useful in influenza surveillance to rapidly identify potential high risk strains circulating in avian species, which may grant us the foresight in anticipating an impending influenza outbreak. PMID:26915079

  13. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs.

    PubMed

    Clark, Matt Q; McCumsey, Stephanie J; Lopez-Darwin, Sereno; Heckscher, Ellie S; Doe, Chris Q

    2016-01-01

    Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons) are used in all these behaviors, but the identity (or even existence) of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines-chosen for sparse neuronal expression-to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°). A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program. PMID:27172197

  14. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs

    PubMed Central

    Clark, Matt Q.; McCumsey, Stephanie J.; Lopez-Darwin, Sereno; Heckscher, Ellie S.; Doe, Chris Q.

    2016-01-01

    Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons) are used in all these behaviors, but the identity (or even existence) of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines—chosen for sparse neuronal expression—to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°). A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program. PMID:27172197

  15. DNA Methylome of Familial Breast Cancer Identifies Distinct Profiles Defined by Mutation Status

    PubMed Central

    Flanagan, James M.; Cocciardi, Sibylle; Waddell, Nic; Johnstone, Cameron N.; Marsh, Anna; Henderson, Stephen; Simpson, Peter; da Silva, Leonard; Khanna, Kumkum; Lakhani, Sunil; Boshoff, Chris; Chenevix-Trench, Georgia

    2010-01-01

    It is now understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA-methylation profiling on familial breast cancers (n = 33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2, and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2-amplified, and normal-like). We used methylated DNA immunoprecipitation (MeDIP) on Affymetrix promoter chips to interrogate methylation profiles across 25,500 distinct transcripts. Using a support vector machine classification algorithm, we demonstrated that genome-wide methylation profiles predicted tumor mutation status with estimated error rates of 19% (BRCA1), 31% (BRCA2), and 36% (BRCAx) but did not accurately predict the intrinsic subtypes defined by gene expression. Furthermore, using unsupervised hierarchical clustering, we identified a distinct subgroup of BRCAx tumors defined by methylation profiles. We validated these findings in the 33 tumors in the test set, as well as in an independent validation set of 47 formalin-fixed, paraffin-embedded familial breast tumors, by pyrosequencing and Epityper. Finally, gene-expression profiling and SNP CGH array previously performed on the same samples allowed full integration of methylation, gene-expression, and copy-number data sets, revealing frequent hypermethylation of genes that also displayed loss of heterozygosity, as well as of genes that show copy-number gains, providing a potential mechanism for expression dosage compensation. Together, these data show that methylation profiles for familial breast cancers are defined by the mutation status and are distinct from the intrinsic subtypes. PMID:20206335

  16. Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes

    PubMed Central

    James, Sally; Fox, James; Afsari, Farinaz; Lee, Jennifer; Clough, Sally; Knight, Charlotte; Ashmore, James; Ashton, Peter; Preham, Olivier; Hoogduijn, Martin; Ponzoni, Raquel De Almeida Rocha; Hancock, Y.; Coles, Mark; Genever, Paul

    2015-01-01

    Summary Bone marrow stromal cells (BMSCs, also called bone-marrow-derived mesenchymal stromal cells) provide hematopoietic support and immunoregulation and contain a stem cell fraction capable of skeletogenic differentiation. We used immortalized human BMSC clonal lines for multi-level analysis of functional markers for BMSC subsets. All clones expressed typical BMSC cell-surface antigens; however, clones with trilineage differentiation capacity exhibited enhanced vascular interaction gene sets, whereas non-differentiating clones were uniquely CD317 positive with significantly enriched immunomodulatory transcriptional networks and high IL-7 production. IL-7 lineage tracing and CD317 immunolocalization confirmed the existence of a rare non-differentiating BMSC subtype, distinct from Cxcl12-DsRed+ perivascular stromal cells in vivo. Colony-forming CD317+ IL-7hi cells, identified at ∼1%–3% frequency in heterogeneous human BMSC fractions, were found to have the same biomolecular profile as non-differentiating BMSC clones using Raman spectroscopy. Distinct functional identities can be assigned to BMSC subpopulations, which are likely to have specific roles in immune control, lymphopoiesis, and bone homeostasis. PMID:26070611

  17. Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles.

    PubMed

    Nandi, Tannistha; Holden, Matthew T G; Holden, Mathew T G; Didelot, Xavier; Mehershahi, Kurosh; Boddey, Justin A; Beacham, Ifor; Peak, Ian; Harting, John; Baybayan, Primo; Guo, Yan; Wang, Susana; How, Lee Chee; Sim, Bernice; Essex-Lopresti, Angela; Sarkar-Tyson, Mitali; Nelson, Michelle; Smither, Sophie; Ong, Catherine; Aw, Lay Tin; Hoon, Chua Hui; Michell, Stephen; Studholme, David J; Titball, Richard; Chen, Swaine L; Parkhill, Julian; Tan, Patrick

    2015-01-01

    Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity. PMID:25236617

  18. Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles

    PubMed Central

    Nandi, Tannistha; Holden, Matthew T.G.; Didelot, Xavier; Mehershahi, Kurosh; Boddey, Justin A.; Beacham, Ifor; Peak, Ian; Harting, John; Baybayan, Primo; Guo, Yan; Wang, Susana; How, Lee Chee; Sim, Bernice; Essex-Lopresti, Angela; Sarkar-Tyson, Mitali; Nelson, Michelle; Smither, Sophie; Ong, Catherine; Aw, Lay Tin; Hoon, Chua Hui; Michell, Stephen; Studholme, David J.; Titball, Richard; Chen, Swaine L.; Parkhill, Julian

    2015-01-01

    Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity. PMID:25236617

  19. Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells

    PubMed Central

    Lobato-Márquez, Damián; Moreno-Córdoba, Inmaculada; Figueroa, Virginia; Díaz-Orejas, Ramón; García-del Portillo, Francisco

    2015-01-01

    Toxin-antitoxin (TA) modules contribute to the generation of non-growing cells in response to stress. These modules abound in bacterial pathogens although the bases for this profusion remain largely unknown. Using the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as a model, here we show that a selected group of TA modules impact bacterial fitness inside eukaryotic cells. We characterized in this pathogen twenty-seven TA modules, including type I and type II TA modules encoding antisense RNA and proteinaceous antitoxins, respectively. Proteomic and gene expression analyses revealed that the pathogen produces numerous toxins of TA modules inside eukaryotic cells. Among these, the toxins HokST, LdrAST, and TisBST, encoded by type I TA modules and T4ST and VapC2ST, encoded by type II TA modules, promote bacterial survival inside fibroblasts. In contrast, only VapC2ST shows that positive effect in bacterial fitness when the pathogen infects epithelial cells. These results illustrate how S. Typhimurium uses distinct type I and type II TA modules to regulate its intracellular lifestyle in varied host cell types. This function specialization might explain why the number of TA modules increased in intracellular bacterial pathogens. PMID:25792384

  20. Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

    PubMed Central

    Kool, Marcel; Koster, Jan; Bunt, Jens; Hasselt, Nancy E.; Lakeman, Arjan; van Sluis, Peter; Troost, Dirk; Meeteren, Netteke Schouten-van; Caron, Huib N.; Cloos, Jacqueline; Mršić, Alan; Ylstra, Bauke; Grajkowska, Wieslawa; Hartmann, Wolfgang; Pietsch, Torsten; Ellison, David; Clifford, Steven C.; Versteeg, Rogier

    2008-01-01

    Background Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in β-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of

  1. Online Discourse on Fibromyalgia: Text-Mining to Identify Clinical Distinction and Patient Concerns

    PubMed Central

    Park, Jungsik; Ryu, Young Uk

    2014-01-01

    Background The purpose of this study was to evaluate the possibility of using text-mining to identify clinical distinctions and patient concerns in online memoires posted by patients with fibromyalgia (FM). Material/Methods A total of 399 memoirs were collected from an FM group website. The unstructured data of memoirs associated with FM were collected through a crawling process and converted into structured data with a concordance, parts of speech tagging, and word frequency. We also conducted a lexical analysis and phrase pattern identification. After examining the data, a set of FM-related keywords were obtained and phrase net relationships were set through a web-based visualization tool. Results The clinical distinction of FM was verified. Pain is the biggest issue to the FM patients. The pains were affecting body parts including ‘muscles,’ ‘leg,’ ‘neck,’ ‘back,’ ‘joints,’ and ‘shoulders’ with accompanying symptoms such as ‘spasms,’ ‘stiffness,’ and ‘aching,’ and were described as ‘sever,’ ‘chronic,’ and ‘constant.’ This study also demonstrated that it was possible to understand the interests and concerns of FM patients through text-mining. FM patients wanted to escape from the pain and symptoms, so they were interested in medical treatment and help. Also, they seemed to have interest in their work and occupation, and hope to continue to live life through the relationships with the people around them. Conclusions This research shows the potential for extracting keywords to confirm the clinical distinction of a certain disease, and text-mining can help objectively understand the concerns of patients by generalizing their large number of subjective illness experiences. However, it is believed that there are limitations to the processes and methods for organizing and classifying large amounts of text, so these limits have to be considered when analyzing the results. The development of research methodology to overcome

  2. Identifying Distinct Healthcare Pathways During Episodes of Chronic Obstructive Pulmonary Disease Exacerbations

    PubMed Central

    Kuwornu, John P.; Lix, Lisa M.; Quail, Jacqueline M.; Forget, Evelyn; Muthukumarana, Saman; Wang, Xiaoyun E.; Osman, Meric; Teare, Gary F.

    2016-01-01

    Abstract Healthcare pathways are important to measure because they are expected to affect outcomes. However, they are challenging to define because patients exhibit heterogeneity in their use of healthcare services. The objective of this study was to identify and describe healthcare pathways during episodes of chronic obstructive pulmonary disease (COPD) exacerbations. Linked administrative databases from Saskatchewan, Canada were used to identify a cohort of newly diagnosed COPD patients and their episodes of healthcare use for disease exacerbations. Latent class analysis (LCA) was used to classify the cohort into homogeneous pathways using indicators of respiratory-related hospitalizations, emergency department (ED) visits, general and specialist physician visits, and outpatient prescription drug dispensations. Multinomial logistic regression models tested patients’ demographic and disease characteristics associated with pathway group membership. The most frequent healthcare contact sequences in each pathway were described. Tests of mean costs across groups were conducted using a model-based approach with χ2 statistics. LCA identified 3 distinct pathways for patients with hospital- (n = 963) and ED-initiated (n = 364) episodes. For the former, pathway group 1 members followed complex pathways in which multiple healthcare services were repeatedly used and incurred substantially higher costs than patients in the other pathway groups. For patients with an ED-initiated episode, pathway group 1 members also had higher costs than other groups. Pathway groups differed with respect to patient demographic and disease characteristics. A minority of patients were discharged from ED or hospital, but did not have any follow-up care during the remainder of their episode. Patients who followed complex pathways could benefit from case management interventions to streamline their journeys through the healthcare system. The minority of patients whose pathways were not

  3. Adenovirus vectors targeting distinct cell types in the retina.

    PubMed

    Sweigard, J Harry; Cashman, Siobhan M; Kumar-Singh, Rajendra

    2010-04-01

    Purpose. Gene therapy for a number of retinal diseases necessitates efficient transduction of photoreceptor cells. Whereas adenovirus (Ad) serotype 5 (Ad5) does not transduce photoreceptors efficiently, previous studies have demonstrated improved photoreceptor transduction by Ad5 pseudotyped with Ad35 (Ad5/F35) or Ad37 (Ad5/F37) fiber or by the deletion of the RGD domain in the Ad5 penton base (Ad5DeltaRGD). However, each of these constructs contained a different transgene cassette, preventing the evaluation of the relative performance of these vectors, an important consideration before the use of these vectors in the clinic. The aim of this study was to evaluate these vectors in the retina and to attempt photoreceptor-specific transgene expression. Methods. Three Ad5-based vectors containing the same expression cassette were generated and injected into the subretinal space of adult mice. Eyes were analyzed for green fluorescence protein expression in flat-mounts, cross-sections, quantitative RT-PCR, and a modified stereological technique. A 257-bp fragment derived from the mouse opsin promoter was analyzed in the context of photoreceptor-specific transgene expression. Results. Each virus tested efficiently transduced the retinal pigment epithelium. The authors found no evidence that Ad5/F35 or Ad5/F37 transduced photoreceptors. Instead, they found that Ad5/F37 transduced Müller cells. Robust photoreceptor transduction by Ad5DeltaRGD was detected. Photoreceptor-specific transgene expression from the 257-bp mouse opsin promoter in the context of Ad5DeltaRGD vectors was found. Conclusions. Adenovirus vectors may be designed with tropism to distinct cell populations. Robust photoreceptor-specific transgene expression can be achieved in the context of Ad5DeltaRGD vectors. PMID:19892875

  4. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

    PubMed

    Sifrim, Alejandro; Hitz, Marc-Phillip; Wilsdon, Anna; Breckpot, Jeroen; Turki, Saeed H Al; Thienpont, Bernard; McRae, Jeremy; Fitzgerald, Tomas W; Singh, Tarjinder; Swaminathan, Ganesh Jawahar; Prigmore, Elena; Rajan, Diana; Abdul-Khaliq, Hashim; Banka, Siddharth; Bauer, Ulrike M M; Bentham, Jamie; Berger, Felix; Bhattacharya, Shoumo; Bu'Lock, Frances; Canham, Natalie; Colgiu, Irina-Gabriela; Cosgrove, Catherine; Cox, Helen; Daehnert, Ingo; Daly, Allan; Danesh, John; Fryer, Alan; Gewillig, Marc; Hobson, Emma; Hoff, Kirstin; Homfray, Tessa; Kahlert, Anne-Karin; Ketley, Ami; Kramer, Hans-Heiner; Lachlan, Katherine; Lampe, Anne Katrin; Louw, Jacoba J; Manickara, Ashok Kumar; Manase, Dorin; McCarthy, Karen P; Metcalfe, Kay; Moore, Carmel; Newbury-Ecob, Ruth; Omer, Seham Osman; Ouwehand, Willem H; Park, Soo-Mi; Parker, Michael J; Pickardt, Thomas; Pollard, Martin O; Robert, Leema; Roberts, David J; Sambrook, Jennifer; Setchfield, Kerry; Stiller, Brigitte; Thornborough, Chris; Toka, Okan; Watkins, Hugh; Williams, Denise; Wright, Michael; Mital, Seema; Daubeney, Piers E F; Keavney, Bernard; Goodship, Judith; Abu-Sulaiman, Riyadh Mahdi; Klaassen, Sabine; Wright, Caroline F; Firth, Helen V; Barrett, Jeffrey C; Devriendt, Koenraad; FitzPatrick, David R; Brook, J David; Hurles, Matthew E

    2016-09-01

    Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD. PMID:27479907

  5. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes.

    PubMed

    Ai, Rizi; Hammaker, Deepa; Boyle, David L; Morgan, Rachel; Walsh, Alice M; Fan, Shicai; Firestein, Gary S; Wang, Wei

    2016-01-01

    Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients. PMID:27282753

  6. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes

    PubMed Central

    Ai, Rizi; Hammaker, Deepa; Boyle, David L.; Morgan, Rachel; Walsh, Alice M.; Fan, Shicai; Firestein, Gary S.; Wang, Wei

    2016-01-01

    Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients. PMID:27282753

  7. Clustering analysis to identify distinct spectral components of encephalogram burst suppression in critically ill patients.

    PubMed

    Zhou, David W; Westover, M Brandon; McClain, Lauren M; Nagaraj, Sunil B; Bajwa, Ednan K; Quraishi, Sadeq A; Akeju, Oluwaseun; Cobb, J Perren; Purdon, Patrick L

    2015-01-01

    Millions of patients are admitted each year to intensive care units (ICUs) in the United States. A significant fraction of ICU survivors develop life-long cognitive impairment, incurring tremendous financial and societal costs. Delirium, a state of impaired awareness, attention and cognition that frequently develops during ICU care, is a major risk factor for post-ICU cognitive impairment. Recent studies suggest that patients experiencing electroencephalogram (EEG) burst suppression have higher rates of mortality and are more likely to develop delirium than patients who do not experience burst suppression. Burst suppression is typically associated with coma and deep levels of anesthesia or hypothermia, and is defined clinically as an alternating pattern of high-amplitude "burst" periods interrupted by sustained low-amplitude "suppression" periods. Here we describe a clustering method to analyze EEG spectra during burst and suppression periods. We used this method to identify a set of distinct spectral patterns in the EEG during burst and suppression periods in critically ill patients. These patterns correlate with level of patient sedation, quantified in terms of sedative infusion rates and clinical sedation scores. This analysis suggests that EEG burst suppression in critically ill patients may not be a single state, but instead may reflect a plurality of states whose specific dynamics relate to a patient's underlying brain function. PMID:26737967

  8. Clustering analysis to identify distinct spectral components of encephalogram burst suppression in critically ill patients

    PubMed Central

    Zhou, David W.; Westover, M. Brandon; McClain, Lauren M.; Nagaraj, Sunil B.; Bajwa, Ednan K.; Quraishi, Sadeq A.; Akeju, Oluwaseun; Cobb, J. Perren; Purdon, Patrick L.

    2016-01-01

    Millions of patients are admitted each year to intensive care units (ICUs) in the United States. A significant fraction of ICU survivors develop life-long cognitive impairment, incurring tremendous financial and societal costs. Delirium, a state of impaired awareness, attention and cognition that frequently develops during ICU care, is a major risk factor for post-ICU cognitive impairment. Recent studies suggest that patients experiencing electroencephalogram (EEG) burst suppression have higher rates of mortality and are more likely to develop delirium than patients who do not experience burst suppression. Burst suppression is typically associated with coma and deep levels of anesthesia or hypothermia, and is defined clinically as an alternating pattern of high-amplitude “burst” periods interrupted by sustained low-amplitude “suppression” periods. Here we describe a clustering method to analyze EEG spectra during burst and suppression periods. We used this method to identify a set of distinct spectral patterns in the EEG during burst and suppression periods in critically ill patients. These patterns correlate with level of patient sedation, quantified in terms of sedative infusion rates and clinical sedation scores. This analysis suggests that EEG burst suppression in critically ill patients may not be a single state, but instead may reflect a plurality of states whose specific dynamics relate to a patient’s underlying brain function. PMID:26737967

  9. Two distinct subpopulations of neurons in the thalamic intergeniculate leaflet identified by subthreshold currents.

    PubMed

    Chrobok, Lukasz; Palus, Katarzyna; Lewandowski, Marian Henryk

    2016-08-01

    The intergeniculate leaflet (IGL) is a flat retinorecipient thalamic structure implicated in orchestrating circadian rhythm, historically considered to be a subdivision of the neighboring ventrolateral geniculate nucleus (VLG). IGL consists of two main neuronal subpopulations: enkephalinergic and neuropeptide Y (NPY)-synthesizing cells. These cell types have different functions, connectivity and firing pattern in vivo, which suggest that they have different membrane currents to support their functional differences. We therefore performed patch-clamp experiments combined with immunohistochemical staining to clarify possible differences in the subthreshold currents of IGL neurons. Our results suggest that IGL neurons can be divided into two subpopulations based on two ionic currents. A T-type calcium current (IT) was identified in neurons that do not synthesise NPY, whereas all NPY-positive neurons were found to express a marked A-type potassium current (IA). Due to the fact that the clear electrophysiological discriminants between IGL and VLG are lacking, we decided to compare the amplitudes of the identified currents between those two structures. Our data suggest that VLG neurons can be characterized by a high amplitude IT and a low IA. Finally, we compared both currents with WAG/Rij rats, a well-established model of absence epilepsy, with co-occurring retinal pathologies, sleep-onset disturbances, and seizures exhibiting circadian rhythmicity. Data presented in this study uncovered pathologies in the IT exhibiting neurons of the IGL and VLG. In conclusion, the data presented here suggest that different subthreshold current expression supports the functional differences of thalamic nuclei. Those differences are promising for possible pharmacological manipulations of specified cell types in pathophysiologies including absence epilepsy. PMID:27208616

  10. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts

    PubMed Central

    Karimi, Mohsen; Papaemmanuil, Elli; Ambaglio, Ilaria; Jädersten, Martin; Jansson, Monika; Elena, Chiara; Gallì, Anna; Walldin, Gunilla; Della Porta, Matteo G.; Raaschou-Jensen, Klas; Travaglino, Erica; Kallenbach, Klaus; Pietra, Daniela; Ljungström, Viktor; Conte, Simona; Boveri, Emanuela; Invernizzi, Rosangela; Rosenquist, Richard; Campbell, Peter J.; Cazzola, Mario; Hellström Lindberg, Eva

    2015-01-01

    Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome. PMID:25957392

  11. Biological Analysis of Human Immunodeficiency Virus Type 1 R5 Envelopes Amplified from Brain and Lymph Node Tissues of AIDS Patients with Neuropathology Reveals Two Distinct Tropism Phenotypes and Identifies Envelopes in the Brain That Confer an Enhanced Tropism and Fusigenicity for Macrophages

    PubMed Central

    Peters, Paul J.; Bhattacharya, Jayanta; Hibbitts, Samantha; Dittmar, Matthias T.; Simmons, Graham; Bell, Jeanne; Simmonds, Peter; Clapham, Paul R.

    2004-01-01

    Complete envelope genes were amplified from autopsy brain tissue of five individuals who had died of AIDS and had neurological complications. Lymph node samples were included for two of the patients. Nineteen different envelope clones from the five patients had distinct V1V2 sequences. Thirteen of the envelopes were functional and conferred fusigenicity and infectivity for CD4+ CCR5+ cells. Infectivity and cell-cell fusion assays showed that most envelopes used both CCR5 and CCR3. One brain-derived envelope used a broad range of coreceptors, while three other brain envelopes from one individual were restricted to CCR5. However, there was no correlation between tissue of origin and coreceptor use. Envelopes showed two very distinct phenotypes depending on their capacity to infect macrophages and to exploit low levels of CD4 and/or CCR5 for infection. Envelopes that were highly fusigenic and tropic for macrophages were identified in brain tissue from four of the five patients. The enhanced macrophage tropism correlated with reduced sensitivity to inhibition by Q4120, a CD4-specific antibody, but not with sensitivity to the CCR5 inhibitor, TAK779. The highly macrophage-tropic envelopes were able to infect cells expressing low levels of CD4 and/or CCR5. Comparison with several well-characterized macrophage-tropic envelopes showed that the four identified patient envelopes were at the top limit of macrophage tropism. In contrast, all four lymph node-derived envelopes exhibited a non-macrophage-tropic phenotype and required high levels of CD4 for infection. Our data support the presence of envelopes that are highly fusigenic and tropic for macrophages in the brains of patients with neurological complications. These envelopes are able to infect cells that express low levels of CD4 and/or CCR5 and may have adapted for replication in brain macrophages and microglia, which are known to express limited amounts of CD4. PMID:15194768

  12. Tryptophan Scanning Mutagenesis Identifies the Molecular Determinants of Distinct Barttin Functions.

    PubMed

    Wojciechowski, Daniel; Fischer, Martin; Fahlke, Christoph

    2015-07-24

    CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function. Barttin consists of two transmembrane helices followed by a long intracellular carboxyl terminus, and earlier work demonstrated that the transmembrane core of barttin suffices for most effects on the α-subunit. We individually substituted every amino acid of the predicted transmembrane core (amino acids 9-26 and 35-55) with tryptophan, co-expressed mutant barttin with hClC-Ka or V166E rClC-K1, and characterized CLC-K/barttin channels by patch clamp techniques, biochemistry, and confocal microscopy. The majority of mutations left the chaperone function of barttin, i.e. the effects on endoplasmic reticulum exit and surface membrane insertion, unaffected. In contrast, tryptophan insertion at multiple positions resulted in impaired activity of hClC-Ka/barttin and changes in gating of V166E rClC-K1/barttin. These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit. Whereas tight interaction is necessary for functional modification, even impaired association of barttin and CLC-K suffices for normal intracellular trafficking. Our findings allow definition of a likely interaction surface and clarify the mechanisms underlying CLC-K channel modification by barttin. PMID:26063802

  13. Automated retinal fovea type distinction in spectral-domain optical coherence tomography of retinal vein occlusion

    NASA Astrophysics Data System (ADS)

    Wu, Jing; Waldstein, Sebastian M.; Gerendas, Bianca S.; Langs, Georg; Simader, Christian; Schmidt-Erfurth, Ursula

    2015-03-01

    to differentiate between the remaining two fovea types. Validation employs ground truth fovea types identified by clinical experts at the Vienna Reading Center (VRC). The results presented here are intended to show the feasibility of this method for the accurate and reproducible distinction of retinal fovea types from multiple vendor 3D SD-OCT scans of patients suffering from RVO, and for use in fovea position detection systems as a landmark for intra- and cross-vendor 3D OCT registration.

  14. Hedgehog signaling to distinct cell types differentially regulates coronary artery and vein development.

    PubMed

    Lavine, Kory J; Long, Fanxin; Choi, Kyunghee; Smith, Craig; Ornitz, David M

    2008-09-01

    Vascular development begins with formation of a primary capillary plexus that is later remodeled to give rise to the definitive vasculature. Although the mechanism by which arterial and venous fates are acquired is well understood, little is known about when during vascular development arterial and venous vessels emerge and how their growth is regulated. Previously, we have demonstrated that a hedgehog (HH)/vascular endothelial growth factor (VEGF) and angiopoeitin 2 (ANG2) signaling pathway is essential for the development of the coronary vasculature. Here, we use conditional gene targeting to identify the cell types that receive HH signaling and mediate coronary vascular development. We show that HH signaling to the cardiomyoblast is required for the development of coronary veins, while HH signaling to the perivascular cell (PVC) is necessary for coronary arterial growth. Moreover, the cardiomyoblast and PVC appear to be the exclusive cell types that receive HH signals, as ablation of HH signaling in both cell types leads to an arrest in coronary development. Finally, we present evidence suggesting that coronary arteries and veins may be derived from distinct lineages. PMID:18725519

  15. Identified motor terminals in Drosophila larvae show distinct differences in morphology and physiology

    NASA Technical Reports Server (NTRS)

    Lnenicka, G. A.; Keshishian, H.

    2000-01-01

    In Drosophila, the type I motor terminals innervating the larval ventral longitudinal muscle fibers 6 and 7 have been the most popular preparation for combining synaptic studies with genetics. We have further characterized the normal morphological and physiological properties of these motor terminals and the influence of muscle size on terminal morphology. Using dye-injection and physiological techniques, we show that the two axons supplying these terminals have different innervation patterns: axon 1 innervates only muscle fibers 6 and 7, whereas axon 2 innervates all of the ventral longitudinal muscle fibers. This difference in innervation pattern allows the two axons to be reliably identified. The terminals formed by axons 1 and 2 on muscle fibers 6 and 7 have the same number of branches; however, axon 2 terminals are approximately 30% longer than axon 1 terminals, resulting in a corresponding greater number of boutons for axon 2. The axon 1 boutons are approximately 30% wider than the axon 2 boutons. The excitatory postsynaptic potential (EPSP) produced by axon 1 is generally smaller than that produced by axon 2, although the size distributions show considerable overlap. Consistent with vertebrate studies, there is a correlation between muscle fiber size and terminal size. For a single axon, terminal area and length, the number of terminal branches, and the number of boutons are all correlated with muscle fiber size, but bouton size is not. During prolonged repetitive stimulation, axon 2 motor terminals show synaptic depression, whereas axon 1 EPSPs facilitate. The response to repetitive stimulation appears to be similar at all motor terminals of an axon. Copyright 2000 John Wiley & Sons, Inc.

  16. Distinct sites on tenascin-C mediate repellent or adhesive interactions with different neuronal cell types.

    PubMed

    Husmann, K; Carbonetto, S; Schachner, M

    1995-11-01

    In this study we have determined the binding specificities of four different neuronal cell types to tenascin-C (TN-C) and laminin using a cell adhesion assay. TN-C was repulsive for small cerebellar neurons and PC12 phaeochromocytoma cells, since after short-term adhesion to the substrate-bound molecule with a maximum of cell binding at 45 min, the cells detached from the substrate and after 22 h only about 25% of the originally adherent cells were still bound. For N2A neuroblastoma cells and retinal cells TN-C was an adhesive substrate, since the number of adherent cells did not decrease after the initial attachment period. All four cell types adhered well to laminin at all time points studied. For short-term adhesion of small cerebellar neurons and PC12 cells two binding sites were identified on TN-C, one being localized within the epidermal growth factor-like repeats three to five and the second within fibronectin type III-like repeats three and four. One binding site for N2A and retinal cells was localized within fibronectin type III-like repeat seven. Binding of small cerebellar neurons to TN-C was dependent on Ca2+, but not on Mg2+ and was inhibitable by polyclonal antibodies to beta 1 integrin. Short-term adhesion of small cerebellar neurons was also inhibitable with a mixture of recombinant fragments of TN-C encompassing the whole molecule, although the specific inhibitory activity of this mixture was ten-fold lower on a molar basis when compared to the native molecule. Our observations indicate that different neuronal cell types use distinct binding sites on TN-C for repellent or adhesive interactions and that beta 1 integrin is involved in the recognition event leading to repulsion of small cerebellar neurons. PMID:8821032

  17. VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System.

    PubMed

    Cianfanelli, Francesca R; Alcoforado Diniz, Juliana; Guo, Manman; De Cesare, Virginia; Trost, Matthias; Coulthurst, Sarah J

    2016-06-01

    The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently ('specialised') or non-covalently ('cargo' effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a 'core' T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the machinery with

  18. VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System

    PubMed Central

    Cianfanelli, Francesca R.; Alcoforado Diniz, Juliana; Guo, Manman; De Cesare, Virginia; Trost, Matthias; Coulthurst, Sarah J.

    2016-01-01

    The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently (‘specialised’) or non-covalently (‘cargo’ effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a ‘core’ T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the

  19. Cocaine withdrawal symptoms identify "Type B" cocaine-dependent patients.

    PubMed

    Ahmadi, Jamshid; Kampman, Kyle; Dackis, Charles; Sparkman, Thorne; Pettinati, Helen

    2008-01-01

    Recent studies of substance dependence typologies briefly show that multivariate systems originally developed for identifying subtypes of alcoholics, such as Babor's Type A and B system, may also be valid in abusers of other substances, such as cocaine. Type B patients are characterized by an earlier onset of addiction and more severe symptoms of their addiction, psychopathology, and impulsivity. The Type B classification has also been associated with deficits in serotonergic function. We have found that patients who exhibit more severe cocaine withdrawal symptoms, as measured by scores on the Cocaine Selective Severity Assessment (CSSA), have poor treatment outcome and share many characteristics with "Type B" patients. In this paper, we review baseline characteristics of cocaine-dependent patients from several recently completed outpatient cocaine dependence treatment trials to assess the association of cocaine withdrawal symptom severity and the Type B profile. Identifying subtypes of cocaine-dependent patients may improve our ability to treat cocaine dependence by targeting treatments for specific subtypes of patients. We examined the ability of the CSSA scores to capture Type B characteristics in cocaine dependence by analyzing a series of cocaine medication trials that included 255 cocaine-dependent subjects. High CSSA scores at baseline were associated with a history of violent behavior, a family history of substance abuse, antisocial personality disorder, higher addiction severity, and co-morbid psychiatric diseases. Patients with high CSSA scores are also more likely to meet criteria for Type B (Type II) cocaine dependence. Identifying Type B cocaine-dependent patients may help to develop targeted psychosocial or pharmacological treatments for these difficult-to-treat patients. PMID:18214724

  20. Two distinct human parainfluenza virus type 1 genotypes detected during the 1991 Milwaukee epidemic.

    PubMed Central

    Henrickson, K J; Savatski, L L

    1996-01-01

    The extent of genetic and antigenic variation found in a population of human parainfluenza virus type 1 (HPIV-1) during a single local epidemic was investigated. Fifteen HPIV-1 strains isolated from children in 1991 were analyzed. Nucleotide sequence variation in the hemagglutinin-neuraminidase protein (HN) gene demonstrated two distinct genotypes (genotypes C and D). Unique patterns were identified involving 62 nucleotide and 10 amino acid positions. These patterns represented 40% of all mutations within the HN gene. The remaining mutations were randomly distributed, and 74% involved only one (55%) or two isolates. Genotypes were statistically different from each other at both the nucleotide (P = 0.001) and amino acid (P = 0.001) levels and demonstrated unique potential N-linked glycosylation patterns. Thirty-eight monoclonal antibodies (MAbs) made to four different viral proteins (22 HN, 2 fusion [F], 1 phosphoprotein, and 13 nucleoprotein) (originating from two different genotypes [genotypes A and D]) were compared for their ability to bind to the clinical isolates in enzyme-linked immunosorbent assays (ELISAs) and hemagglutinin-inhibition (HI) assays. Twenty-one MAbs bound well to all clinical isolates in ELISAs and HI assays. The remaining 17 MAbs showed variation in all four structural proteins. Three HN MAbs demonstrated genotype C- and D-specific antigenic and neutralization differences. Evolutionary analysis using parsimony methods confirmed the differences between the two genotypes. No differences in either clinical presentation or disease severity between the two genotypes were found. Geographically localized HPIV-1 epidemics can be caused by at least two distinct genotypes with minor but specific antigenic changes. The clinical and immunologic roles of HPIV-1 genotypes have not been determined. PMID:8904440

  1. Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations.

    PubMed

    Louissaint, Abner; Schafernak, Kristian T; Geyer, Julia T; Kovach, Alexandra E; Ghandi, Mahmoud; Gratzinger, Dita; Roth, Christine G; Paxton, Christian N; Kim, Sunhee; Namgyal, Chungdak; Morin, Ryan; Morgan, Elizabeth A; Neuberg, Donna S; South, Sarah T; Harris, Marian H; Hasserjian, Robert P; Hochberg, Ephraim P; Garraway, Levi A; Harris, Nancy Lee; Weinstock, David M

    2016-08-25

    Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers. PMID:27325104

  2. Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations

    PubMed Central

    Schafernak, Kristian T.; Geyer, Julia T.; Kovach, Alexandra E.; Ghandi, Mahmoud; Gratzinger, Dita; Roth, Christine G.; Paxton, Christian N.; Kim, Sunhee; Namgyal, Chungdak; Morin, Ryan; Morgan, Elizabeth A.; Neuberg, Donna S.; South, Sarah T.; Harris, Marian H.; Hasserjian, Robert P.; Hochberg, Ephraim P.; Garraway, Levi A.; Harris, Nancy Lee; Weinstock, David M.

    2016-01-01

    Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers. PMID:27325104

  3. Achondrogenesis type I: delineation of further heterogeneity and identification of two distinct subgroups.

    PubMed

    Borochowitz, Z; Lachman, R; Adomian, G E; Spear, G; Jones, K; Rimoin, D L

    1988-01-01

    Achondrogenesis has traditionally been divided into type I (Parenti-Fraccaro) and type II (Langer-Saldino). We studied the clinical, radiologic, and morphologic features of 17 cases previously diagnosed as achondrogenesis type I to define whether there is even further heterogeneity. On radiographic analysis, two distinct groups of patients were defined based on the presence or absence of rib fractures and ossification of the vertebral pedicles, ischium, and fibula. Two distinct chondroosseous morphologic patterns were observed that directly correlated with the radiographic grouping. One group had round vacuolated chondrocytes with inclusion bodies; the other had collagenous rings around the chondrocytes. We conclude that achondrogenesis type I (Parenti-Fraccaro) consists of two distinct disorders: type IA, which corresponds to the cases originally published by Houston et al. and Harris et al., and type IB, which corresponds to the case originally published by Fraccaro. Analysis of Parenti's case suggests the diagnosis of achondrogenesis type II. All three types of achondrogenesis appear to be inherited as autosomal recessive traits. PMID:3275766

  4. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

    PubMed Central

    Silva-Santos, Sara; van Woerden, Geeske M.; Bruinsma, Caroline F.; Mientjes, Edwin; Jolfaei, Mehrnoush Aghadavoud; Distel, Ben; Kushner, Steven A.; Elgersma, Ype

    2015-01-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design. PMID:25866966

  5. Distinct Roles of Type I and Type III Interferons in Intestinal Immunity to Homologous and Heterologous Rotavirus Infections

    PubMed Central

    Balan, Murugabaskar; Tseng, Hsiang-Chi; McElrath, Constance; Smirnov, Sergey V.; Peng, Jianya; Yasukawa, Linda L.; Durbin, Russell K.; Durbin, Joan E.; Greenberg, Harry B.; Kotenko, Sergei V.

    2016-01-01

    Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Collectively, our findings revealed a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets

  6. A novel split kinesin assay identifies motor proteins that interact with distinct vesicle populations

    PubMed Central

    Jenkins, Brian; Decker, Helena; Bentley, Marvin; Luisi, Julie

    2012-01-01

    Identifying the kinesin motors that interact with different vesicle populations is a longstanding and challenging problem with implications for many aspects of cell biology. Here we introduce a new live-cell assay to assess kinesin–vesicle interactions and use it to identify kinesins that bind to vesicles undergoing dendrite-selective transport in cultured hippocampal neurons. We prepared a library of “split kinesins,” comprising an axon-selective kinesin motor domain and a series of kinesin tail domains that can attach to their native vesicles; when the split kinesins were assembled by chemical dimerization, bound vesicles were misdirected into the axon. This method provided highly specific results, showing that three Kinesin-3 family members—KIF1A, KIF13A, and KIF13B—interacted with dendritic vesicle populations. This experimental paradigm allows a systematic approach to evaluate motor–vesicle interactions in living cells. PMID:22908316

  7. Identifying the distinct phases of THz waves from K-valley electrons in graphite

    SciTech Connect

    Irfan, Muhammad; Yim, Jong-Hyuk Jho, Young-Dahl; Kim, Changyoung

    2013-12-04

    The polarity change of THz electromagnetic waves radiated from single-crystalline graphite and polycrystalline graphite films has been studied to identify the main generation mechanism in conventional reflective THz time-domain spectroscopy scheme. The excitation wavelength variation around the K-valley produces no significant changes in THz field strength. We further found that THz waves become fully dispersed without polarity change in lateral detection geometry.

  8. Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution

    PubMed Central

    Kumar, Narender; Mariappan, Vanitha; Baddam, Ramani; Lankapalli, Aditya K.; Shaik, Sabiha; Goh, Khean-Lee; Loke, Mun Fai; Perkins, Tim; Benghezal, Mohammed; Hasnain, Seyed E.; Vadivelu, Jamuna; Marshall, Barry J.; Ahmed, Niyaz

    2015-01-01

    The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host–pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner. PMID:25452339

  9. Using networks to identify fine structural differences between functionally distinct protein states.

    PubMed

    Swint-Kruse, Liskin

    2004-08-31

    The vast increase in available data from the "-omics" revolution has enabled the fields of structural proteomics and structure prediction to make great progress in assigning realistic three-dimensional structures to each protein molecule. The challenge now lies in determining the fine structural details that endow unique functions to sequences that assume a common fold. Similar problems are encountered in understanding how distinct conformations contribute to different phases of a single protein's dynamic function. However, efforts are hampered by the complexity of these large, three-dimensional molecules. To overcome this limitation, structural data have been recast as two-dimensional networks. This analysis greatly reduces visual complexity but retains information about individual residues. Such diagrams are very useful for comparing multiple structures, including (1) homologous proteins, (2) time points throughout a dynamics simulation, and (3) functionally different conformations of a given protein. Enhanced structural examination results in new functional hypotheses to test experimentally. Here, network representations were key to discerning a difference between unliganded and inducer-bound lactose repressor protein (LacI), which were previously presumed to be identical structures. Further, the interface of unliganded LacI was surprisingly similar to that of the K84L variant and various structures generated by molecular dynamics simulations. Apo-LacI appears to be poised to adopt the conformation of either the DNA- or inducer-bound structures, and the K84L mutation appears to freeze the structure partway through the conformational transition. Additional examination of the effector binding pocket results in specific hypotheses about how inducer, anti-inducer, and neutral sugars exert their effects on repressor function. PMID:15323549

  10. Distinct and Conserved Prominin-1/CD133–Positive Retinal Cell Populations Identified across Species

    PubMed Central

    Jászai, József; Fargeas, Christine A.; Graupner, Sylvi; Tanaka, Elly M.; Brand, Michael; Huttner, Wieland B.; Corbeil, Denis

    2011-01-01

    Besides being a marker of various somatic stem cells in mammals, prominin-1 (CD133) plays a role in maintaining the photoreceptor integrity since mutations in the PROM1 gene are linked with retinal degeneration. In spite of that, little information is available regarding its distribution in eyes of non-mammalian vertebrates endowed with high regenerative abilities. To address this subject, prominin-1 cognates were isolated from axolotl, zebrafish and chicken, and their retinal compartmentalization was investigated and compared to that of their mammalian orthologue. Interestingly, prominin-1 transcripts—except for the axolotl—were not strictly restricted to the outer nuclear layer (i.e., photoreceptor cells), but they also marked distinct subdivisions of the inner nuclear layer (INL). In zebrafish, where the prominin-1 gene is duplicated (i.e., prominin-1a and prominin-1b), a differential expression was noted for both paralogues within the INL being localized either to its vitreal or scleral subdivision, respectively. Interestingly, expression of prominin-1a within the former domain coincided with Pax-6–positive cells that are known to act as progenitors upon injury-induced retino-neurogenesis. A similar, but minute population of prominin-1–positive cells located at the vitreal side of the INL was also detected in developing and adult mice. In chicken, however, prominin-1–positive cells appeared to be aligned along the scleral side of the INL reminiscent of zebrafish prominin-1b. Taken together our data indicate that in addition to conserved expression of prominin-1 in photoreceptors, significant prominin-1–expressing non-photoreceptor retinal cell populations are present in the vertebrate eye that might represent potential sources of stem/progenitor cells for regenerative therapies. PMID:21407811

  11. Resolving Tumor Heterogeneity: Genes Involved in Chordoma Cell Development Identified by Low-Template Analysis of Morphologically Distinct Cells

    PubMed Central

    Wagner, Karin; Meditz, Katharina; Kolb, Dagmar; Feichtinger, Julia; Thallinger, Gerhard G.; Quehenberger, Franz; Liegl-Atzwanger, Bernadette; Rinner, Beate

    2014-01-01

    The classical sacrococcygeal chordoma tumor presents with a typical morphology of lobulated myxoid tumor tissue with cords, strands and nests of tumor cells. The population of cells consists of small non-vacuolated cells, intermediate cells with a wide range of vacuolization and large heavily vacuolated (physaliferous) cells. To date analysis was only performed on bulk tumor mass because of its rare incidence, lack of suited model systems and technical limitations thereby neglecting its heterogeneous composition. We intended to clarify whether the observed cell types are derived from genetically distinct clones or represent different phenotypes. Furthermore, we aimed at elucidating the differences between small non-vacuolated and large physaliferous cells on the genomic and transcriptomic level. Phenotype-specific analyses of small non-vacuolated and large physaliferous cells in two independent chordoma cell lines yielded four candidate genes involved in chordoma cell development. UCHL3, coding for an ubiquitin hydrolase, was found to be over-expressed in the large physaliferous cell phenotype of MUG-Chor1 (18.7-fold) and U-CH1 (3.7-fold) cells. The mannosyltransferase ALG11 (695-fold) and the phosphatase subunit PPP2CB (18.6-fold) were found to be up-regulated in large physaliferous MUG-Chor1 cells showing a similar trend in U-CH1 cells. TMEM144, an orphan 10-transmembrane family receptor, yielded contradictory data as cDNA microarray analysis showed up- but RT-qPCR data down-regulation in large physaliferous MUG-Chor1 cells. Isolation of few but morphologically identical cells allowed us to overcome the limitations of bulk analysis in chordoma research. We identified the different chordoma cell phenotypes to be part of a developmental process and discovered new genes linked to chordoma cell development representing potential targets for further research in chordoma tumor biology. PMID:24503940

  12. Functional Analysis of Dishevelled-3 Phosphorylation Identifies Distinct Mechanisms Driven by Casein Kinase 1ϵ and Frizzled5*

    PubMed Central

    Bernatík, Ondřej; Šedová, Kateřina; Schille, Carolin; Ganji, Ranjani Sri; Červenka, Igor; Trantírek, Lukáš; Schambony, Alexandra; Zdráhal, Zbyněk; Bryja, Vítězslav

    2014-01-01

    Dishevelled-3 (Dvl3), a key component of the Wnt signaling pathways, acts downstream of Frizzled (Fzd) receptors and gets heavily phosphorylated in response to pathway activation by Wnt ligands. Casein kinase 1ϵ (CK1ϵ) was identified as the major kinase responsible for Wnt-induced Dvl3 phosphorylation. Currently it is not clear which Dvl residues are phosphorylated and what is the consequence of individual phosphorylation events. In the present study we employed mass spectrometry to analyze in a comprehensive way the phosphorylation of human Dvl3 induced by CK1ϵ. Our analysis revealed >50 phosphorylation sites on Dvl3; only a minority of these sites was found dynamically induced after co-expression of CK1ϵ, and surprisingly, phosphorylation of one cluster of modified residues was down-regulated. Dynamically phosphorylated sites were analyzed functionally. Mutations within PDZ domain (S280A and S311A) reduced the ability of Dvl3 to activate TCF/LEF (T-cell factor/lymphoid enhancer factor)-driven transcription and induce secondary axis in Xenopus embryos. In contrast, mutations of clustered Ser/Thr in the Dvl3 C terminus prevented ability of CK1ϵ to induce electrophoretic mobility shift of Dvl3 and its even subcellular localization. Surprisingly, mobility shift and subcellular localization changes induced by Fzd5, a Wnt receptor, were in all these mutants indistinguishable from wild type Dvl3. In summary, our data on the molecular level (i) support previous the assumption that CK1ϵ acts via phosphorylation of distinct residues as the activator as well as the shut-off signal of Wnt/β-catenin signaling and (ii) suggest that CK1ϵ acts on Dvl via different mechanism than Fzd5. PMID:24993822

  13. Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1.

    PubMed Central

    Doranz, B J; Lu, Z H; Rucker, J; Zhang, T Y; Sharron, M; Cen, Y H; Wang, Z X; Guo, H H; Du, J G; Accavitti, M A; Doms, R W; Peiper, S C

    1997-01-01

    The chemokine receptor CCR5 is the major fusion coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). To define the structures of CCR5 that can support envelope (Env)-mediated membrane fusion, we analyzed the activity of homologs, chimeras, and mutants of human CCR5 in a sensitive gene reporter cell-cell fusion assay. Simian, but not murine, homologs of CCR5 were fully active as HIV-1 fusion coreceptors. Chimeras between CCR5 and divergent chemokine receptors demonstrated the existence of two distinct regions of CCR5 that could be utilized for Env-mediated fusion, the amino-terminal domain and the extracellular loops. Dual-tropic Env proteins were particularly sensitive to alterations in the CCR5 amino-terminal domain, suggesting that this domain may play a pivotal role in the evolution of coreceptor usage in vivo. We identified individual residues in both functional regions, Asp-11, Lys-197, and Asp-276, that contribute to coreceptor function. Deletion of a highly conserved cytoplasmic motif rendered CCR5 incapable of signaling but did not abrogate its ability to function as a coreceptor, implying the independence of fusion and G-protein-mediated chemokine receptor signaling. Finally, we developed a novel monoclonal antibody to CCR5 to assist in future studies of CCR5 expression. PMID:9261347

  14. Maternal Glutaric Acidemia, Type I Identified by Newborn Screening*

    PubMed Central

    Crombez, Eric A.; Cederbaum, Stephen D.; Spector, Elaine; Chan, Erica; Salazar, Denise; Neidich, Julie; Goodman, Stephen

    2008-01-01

    We report two women with glutaric acidemia type I in whom the diagnosis was unsuspected until a low carnitine level was found in their newborn children. Both mothers had low carnitine in plasma. In the first, organic acid analysis was only done after fibroblast studies revealed normal carnitine uptake. Having learned from the first family, organic acid analysis was done immediately in the mother of family 2. In both, the plasma acylcarnitine profile was normal but both excreted the metabolites typical of their disorder. One of the women was a compound heterozygote for distinct mutations in the glutaric acid dehydrogenase gene, whereas the second was either homozygous or hemizygous for a mutation in Exon 6 of the gene. PMID:18304851

  15. A Bacterial Pathogen uses Distinct Type III Secretion Systems to Alternate between Host Kingdom

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gram-negative bacterial pathogens of eukaryotes often secrete proteins directly into host cells via a needle-like protein channel called a ‘type III secretion system’ (T3SS). Bacteria that are adapted to either animal or plant hosts use phylogenetically distinct T3SSs for secreting proteins. Here, ...

  16. A bacterial pathogen uses distinct type III secretion systems to alternate between host kingdoms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant and animal-pathogenic bacteria utilize phylogenetically distinct type III secretion systems (T3SS) that produce needle-like injectisomes or pili for the delivery of effector proteins into host cells. Pantoea stewartii subsp. stewartii (Pnss), the causative agent of Stewart’s bacterial wilt and...

  17. 'Gene shaving' as a method for identifying distinct sets of genes with similar expression patterns

    PubMed Central

    Hastie, Trevor; Tibshirani, Robert; Eisen, Michael B; Alizadeh, Ash; Levy, Ronald; Staudt, Louis; Chan, Wing C; Botstein, David; Brown, Patrick

    2000-01-01

    Background: Large gene expression studies, such as those conducted using DNA arrays, often provide millions of different pieces of data. To address the problem of analyzing such data, we describe a statistical method, which we have called 'gene shaving'. The method identifies subsets of genes with coherent expression patterns and large variation across conditions. Gene shaving differs from hierarchical clustering and other widely used methods for analyzing gene expression studies in that genes may belong to more than one cluster, and the clustering may be supervised by an outcome measure. The technique can be 'unsupervised', that is, the genes and samples are treated as unlabeled, or partially or fully supervised by using known properties of the genes or samples to assist in finding meaningful groupings. Results: We illustrate the use of the gene shaving method to analyze gene expression measurements made on samples from patients with diffuse large B-cell lymphoma. The method identifies a small cluster of genes whose expression is highly predictive of survival. Conclusions: The gene shaving method is a potentially useful tool for exploration of gene expression data and identification of interesting clusters of genes worth further investigation. PMID:11178228

  18. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

    PubMed Central

    Moffitt, Richard A.; Marayati, Raoud; Flate, Elizabeth L.; Volmar, Keith E.; Loeza, S. Gabriela Herrera; Hoadley, Katherine A.; Rashid, Naim U.; Williams, Lindsay A.; Eaton, Samuel C.; Chung, Alexander H.; Smyla, Jadwiga K.; Anderson, Judy M.; Kim, Hong Jin; Bentrem, David J.; Talamonti, Mark S.; Iacobuzio-Donahue, Christine A.; Hollingsworth, Michael A.; Yeh, Jen Jen

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical. PMID:26343385

  19. Array CGH analysis identifies two distinct subgroups of primary angiosarcoma of bone.

    PubMed

    Verbeke, Sofie L J; de Jong, Danielle; Bertoni, Franco; Sciot, Raf; Antonescu, Cristina R; Szuhai, Karoly; Bovée, Judith V M G

    2015-02-01

    Molecular genetic studies on vascular tumors are rare. Recently, possible involvement of MYC and KDR has been documented in a subset of angiosarcomas of soft tissue. We performed a cytogenetic analysis of primary angiosarcomas of bone (n = 13) and soft tissue (n = 5) using high density array-comparative genomic hybridization (array-CGH). Regions of interest were validated by fluorescence in situ hybridization (FISH). Antibodies for candidate genes (SKI, MYC, KDR, and MAPK9) were selected and immunohistochemistry was performed. Six angiosarcomas of bone and four angiosarcomas of soft tissue showed chromosomal losses, gains, and high level amplifications. Cluster analysis identified two groups: a group with a complex genetic profile and a group with only few genetic aberrations. Five regions of interest were selected, which were located at chromosome bands 1p36.23, 2q32-34, 5q35, 8q24, and 17q21.32-24.2. Interphase FISH confirmed the high-level amplifications. Immunohistochemical analysis showed high expression of MYC (16/60), MAPK9 (63/69), and SKI (52/62). There were no differences between the two groups with regards to location, immunohistochemical expression nor survival. In summary, we identified two subgroups of angiosarcoma: those with few or no gross aberrations and those which show numerous genetic aberrations consisting of chromosomal losses, gains and high level amplifications or complex aberrations. The most common finding was amplification of 2q and 17q in both angiosarcoma of bone and soft tissue, suggesting overlap in tumorigenesis irrespective of their location. We show MYC amplification in primary angiosarcoma indicating this is not entirely specific for radiation-induced angiosarcoma. PMID:25231439

  20. Genetically distinct pathways guide effector export through the type VI secretion system

    PubMed Central

    Whitney, John C.; Beck, Christina M.; Goo, Young Ah; Russell, Alistair B.; Harding, Brittany; De Leon, Justin A.; Cunningham, David A.; Tran, Bao Q.; Low, David A.; Goodlett, David R.; Hayes, Christopher S.; Mougous, Joseph D.

    2014-01-01

    Summary Bacterial secretion systems often employ molecular chaperones to recognize and facilitate export of their substrates. Recent work demonstrated that a secreted component of the type VI secretion system (T6SS), hemolysin co-regulated protein (Hcp), binds directly to effectors, enhancing their stability in the bacterial cytoplasm. Herein, we describe a quantitative cellular proteomics screen for T6S substrates that exploits this chaperone-like quality of Hcp. Application of this approach to the Hcp secretion island I-encoded T6SS (H1-T6SS) of Pseudomonas aeruginosa led to the identification of a novel effector protein, termed Tse4 (type VI secretion exported 4), subsequently shown to act as a potent intra-specific H1-T6SS-delivered antibacterial toxin. Interestingly, our screen failed to identify two predicted H1-T6SS effectors, Tse5 and Tse6, which differ from Hcp-stabilized substrates by the presence of toxin-associated PAAR-repeat motifs and genetic linkage to members of the valine-glycine repeat protein G (vgrG) genes. Genetic studies further distinguished these two groups of effectors: Hcp-stabilized effectors were found to display redundancy in interbacterial competition with respect to the requirement for the two H1-T6SS-exported VgrG proteins, whereas Tse5 and Tse6 delivery strictly required a cognate VgrG. Together, we propose that interaction with either VgrG or Hcp defines distinct pathways for T6S effector export. PMID:24589350

  1. Over 400 previously undocumented Svalbard surge-type glaciers identified

    NASA Astrophysics Data System (ADS)

    Farnsworth, Wesley R.; Ingólfsson, Ólafur; Retelle, Michael; Schomacker, Anders

    2016-07-01

    Identifying glaciers that exhibit surge-type behavior is important when using evidence of ice front fluctuations as a proxy for reconstructing past climate oscillations. This study identifies previously undocumented surge-type glaciers in Svalbard, based on the presence of crevasse squeeze ridges in glacier forelands. Crevasse squeeze ridges are landforms suggested to be unique to surging glacier land systems. Estimates vary greatly as to the actual percentage of surge-type glaciers in Svalbard, and consequently their distribution pattern is poorly understood. A detailed survey of recent (2008-2012), high-resolution aerial imagery from TopoSvalbard, provided by the Norwegian Polar Institute, allowed for a survey of all the glacier forelands in Svalbard. Before our study, 277 individual glaciers in Svalbard have been documented to exhibit surge behavior. By using crevasse squeeze ridges as indicators of surge behavior, we have identified 431 additional glaciers that have surged. We suggest that this is a modest value as the unique surge landforms were not visible in approximately one-third of the forelands with documented surge histories. Limits to the crevasse squeeze ridge technique are presented and potential controlling factors for crevasse squeeze ridge formation/preservation are discussed.

  2. HydroCalc Proteome: a tool to identify distinct characteristics of effector proteins.

    PubMed

    da Silva, G J; da Silva, R G T M; Silva, V A; C Caritá, E; Fachin, A L; Marins, M

    2016-01-01

    Bacterial pathogenicity is associated with secretion of effector proteins into intra- and extracellular spaces. These proteins interfere with cellular processes such as inhibition of phagosome-lysosome fusion, induction of apoptosis and autophagy, activation and suppression of kinases, regulation of receptor activity, and modulation of transcription factors. Knowledge regarding the characteristics of these proteins would assist in pathogenicity studies, and help to identify possible and novel targets for antibacterial drugs. Amino acid hydropathy is a property that can affect behavior patterns in effector proteins. The HydroCalc Proteome tool analyzes total hydropathy, average hydropathy, C-terminal hydropathy, C-terminal load, and basic polar amino acids at the C-terminus. These five properties could contribute to the identification of proteins with an effector potential. HydroCalc Proteome is a web tool that provides a simple interface for the analysis of hydropathy properties in proteins. This tool permits the analysis of a single protein or even the complete proteome, which cannot be achieved by using other hydropathy tools. The tool displays the result of five properties related to effector proteins in a single table. The HydroCalc Proteome (www.gmb.bio.br/hydrocalc) is a powerful tool for protein analysis, and can contribute to the study of effector proteins. PMID:27525880

  3. Identifying aquifer type in fractured rock aquifers using harmonic analysis.

    PubMed

    Rahi, Khayyun A; Halihan, Todd

    2013-01-01

    Determining aquifer type, unconfined, semi-confined, or confined, by drilling or performing pumping tests has inherent problems (i.e., cost and complex field issues) while sometimes yielding inconclusive results. An improved method to cost-effectively determine aquifer type would be beneficial for hydraulic mapping of complex aquifer systems like fractured rock aquifers. Earth tides are known to influence water levels in wells penetrating confined aquifers or unconfined thick, low-porosity aquifers. Water-level fluctuations in wells tapping confined and unconfined aquifers are also influenced by changes in barometric pressure. Harmonic analyses of water-level fluctuations of a thick (~1000 m) carbonate aquifer located in south-central Oklahoma (Arbuckle-Simpson aquifer) were utilized in nine wells to identify aquifer type by evaluating the influence of earth tides and barometric-pressure variations using signal identification. On the basis of the results, portions of the aquifer responded hydraulically as each type of aquifer even though there was no significant variation in lithostratigraphy. The aquifer type was depth dependent with confined conditions becoming more prevalent with depth. The results demonstrate that harmonic analysis is an accurate and low-cost method to determine aquifer type. PMID:22463080

  4. Stetson Revisited: Identifying High-Velocity Early-Type Stars

    NASA Astrophysics Data System (ADS)

    Kinman, T. D.

    1999-02-01

    Our current knowledge of the local blue horizontal branch (BHB) and other high-velocity early-type stars largely depends upon Stetson's survey (in the 1980s) that was based on the SAO catalog. He selected the stars by their reduced proper motion as a function of spectral type. We argue that it is worth repeating Stetson's work using a more recent proper motion source such as the PPM catalog (published 1991) which (inter alia) contains many more stars with spectral types than the SAO. A photometric program is described (using the 0.9-m telescope at full moon) to observe the candidate stars (mostly with V<=10 mag.) and so identify the interesting stars (BHB, RR Lyrae, SW Phoenicis variables, Blue stragglers) that may be expected among them. The new data would materially improve our knowledge of the local space densities of these stars (Kinman 1998).

  5. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases

    PubMed Central

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent. PMID:27200087

  6. Nucleotide sequence variation of the envelope protein gene identifies two distinct genotypes of yellow fever virus.

    PubMed Central

    Chang, G J; Cropp, B C; Kinney, R M; Trent, D W; Gubler, D J

    1995-01-01

    The evolution of yellow fever virus over 67 years was investigated by comparing the nucleotide sequences of the envelope (E) protein genes of 20 viruses isolated in Africa, the Caribbean, and South America. Uniformly weighted parsimony algorithm analysis defined two major evolutionary yellow fever virus lineages designated E genotypes I and II. E genotype I contained viruses isolated from East and Central Africa. E genotype II viruses were divided into two sublineages: IIA viruses from West Africa and IIB viruses from America, except for a 1979 virus isolated from Trinidad (TRINID79A). Unique signature patterns were identified at 111 nucleotide and 12 amino acid positions within the yellow fever virus E gene by signature pattern analysis. Yellow fever viruses from East and Central Africa contained unique signatures at 60 nucleotide and five amino acid positions, those from West Africa contained unique signatures at 25 nucleotide and two amino acid positions, and viruses from America contained such signatures at 30 nucleotide and five amino acid positions in the E gene. The dissemination of yellow fever viruses from Africa to the Americas is supported by the close genetic relatedness of genotype IIA and IIB viruses and genetic evidence of a possible second introduction of yellow fever virus from West Africa, as illustrated by the TRINID79A virus isolate. The E protein genes of American IIB yellow fever viruses had higher frequencies of amino acid substitutions than did genes of yellow fever viruses of genotypes I and IIA on the basis of comparisons with a consensus amino acid sequence for the yellow fever E gene. The great variation in the E proteins of American yellow fever virus probably results from positive selection imposed by virus interaction with different species of mosquitoes or nonhuman primates in the Americas. PMID:7637022

  7. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases.

    PubMed

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent. PMID:27200087

  8. Analysis of the nucleoprotein gene identifies three distinct lineages of viral haemorrhagic septicemia virus (VHSV) within the European marine environment

    USGS Publications Warehouse

    Snow, M.; Cunningham, C.O.; Melvin, W.T.; Kurath, G.

    1999-01-01

    A ribonuclease (RNase) protection assay (RPA) has been used to detect nucleotide sequence variation within the nucleoprotein gene of 39 viral haemorrhagic septicaemia virus (VHSV) isolates of European marine origin. The classification of VHSV isolates based on RPA cleavage patterns permitted the identification of ten distinct groups of viruses based on differences at the molecular level. The nucleotide sequence of representatives of each of these groupings was determined and subjected to phylogenetic analysis. This revealed grouping of the European marine isolates of VHSV into three genotypes circulating within distinct geographic areas. A fourth genotype was identified comprising isolates originating from North America. Phylogenetic analyses indicated that VHSV isolates recovered from wild caught fish around the British Isles were genetically related to isolates responsible for losses in farmed turbot. Furthermore, a relationship between naturally occurring marine isolates and VHSV isolates causing mortality among rainbow trout in continental Europe was demonstrated. Analysis of the nucleoprotein gene identifies distinct lineages of viral haemorrhagic septicaemia virus within the European marine environment. Virus Res. 63, 35-44. Available from: 

  9. Sequence Analysis of 96 Genomic Regions Identifies Distinct Evolutionary Lineages within CC156, the Largest Streptococcus pneumoniae Clonal Complex in the MLST Database

    PubMed Central

    Moschioni, Monica; Lo Sapio, Morena; Crisafulli, Giovanni; Torricelli, Giulia; Guidotti, Silvia; Muzzi, Alessandro; Barocchi, Michèle A.; Donati, Claudio

    2013-01-01

    Multi-Locus Sequence Typing (MLST) of Streptococcus pneumoniae is based on the sequence of seven housekeeping gene fragments. The analysis of MLST allelic profiles by eBURST allows the grouping of genetically related strains into Clonal Complexes (CCs) including those genotypes with a common descent from a predicted ancestor. However, the increasing use of MLST to characterize S. pneumoniae strains has led to the identification of a large number of new Sequence Types (STs) causing the merger of formerly distinct lineages into larger CCs. An example of this is the CC156, displaying a high level of complexity and including strains with allelic profiles differing in all seven of the MLST loci, capsular type and the presence of the Pilus Islet-1 (PI-1). Detailed analysis of the CC156 indicates that the identification of new STs, such as ST4945, induced the merging of formerly distinct clonal complexes. In order to discriminate the strain diversity within CC156, a recently developed typing schema, 96-MLST, was used to analyse 66 strains representative of 41 different STs. Analysis of allelic profiles by hierarchical clustering and a minimum spanning tree identified ten genetically distinct evolutionary lineages. Similar results were obtained by phylogenetic analysis on the concatenated sequences with different methods. The identified lineages are homogenous in capsular type and PI-1 presence. ST4945 strains were unequivocally assigned to one of the lineages. In conclusion, the identification of new STs through an exhaustive analysis of pneumococcal strains from various laboratories has highlighted that potentially unrelated subgroups can be grouped into a single CC by eBURST. The analysis of additional loci, such as those included in the 96-MLST schema, will be necessary to accurately discriminate the clonal evolution of the pneumococcal population. PMID:23593373

  10. Identifying Essential Cell Types and Circuits in Autism Spectrum Disorders

    PubMed Central

    Maloney, Susan E.; Rieger, Michael A.; Dougherty, Joseph D.

    2014-01-01

    Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits –information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets. PMID:24290383

  11. Candidate PET Radioligand Development for Neurofibrillary Tangles: Two Distinct Radioligand Binding Sites Identified in Postmortem Alzheimer's Disease Brain.

    PubMed

    Cai, Lisheng; Qu, Baoxi; Hurtle, Bryan T; Dadiboyena, Sureshbabu; Diaz-Arrastia, Ramon; Pike, Victor W

    2016-07-20

    [(18)F]THK-523 and [(18)F]807 are promising radioligands for imaging neurofibrillary tangles (NFTs) with positron emission tomography (PET) in neurodegenerative diseases, such as Alzheimer's disease (AD) and traumatic brain injury. Although [(18)F]THK-523 and [(18)F]T807 are considered high-affinity selective radioligands for NFTs, uncertainty has existed as to whether PET radioligands for imaging NFTs bind to the same molecular site because in vitro assays for ligands binding to NFTs have been lacking. We labeled THK-523 and T807 with tritium to serve as reference radioligands for in vitro binding assays with AD brain homogenates for newly synthesized ligands. With these radioligands, we identified two distinct binding sites for small molecules, one site with high affinity for THK-523 and the other with high affinity for T807. Moreover, binding assays with [(3)H]PIB confirmed that the two newly identified binding sites are also distinct from the thioflavin-T binding site where all current clinically useful PET radioligands for imaging β-amyloid plaque bind with high affinity. The two newly identified binding sites are considered to reside on NFTs rather than on β-amyloid plaques. Furthermore, we applied all three binding assays to a set of newly prepared compounds, based on chain modifications to THK-523. Some compounds with high affinity and selectivity for the THK-523 binding site emerged from this set, including one with amenability to labeling with fluorine-18, namely, ligand 10b. PMID:27171905

  12. An holistic view on aquifer vulnerability based on a distinction of different types of vulnerability

    NASA Astrophysics Data System (ADS)

    De Luca, Domenico Antonio; Lasagna, Manuela; Franchino, Elisa

    2016-04-01

    AN HOLISTIC VIEW ON AQUIFER VULNERABILITY BASED ON A DISTINCTION OF DIFFERENT TYPES OF VULNERABILITY D.A. De Luca1 , M. Lasagna1, E. Franchino1 1Department of Earth Sciences, University of Turin The concept of vulnerability is certainly useful in the field of groundwater protection. Nevertheless, within the scientific community, the definition of groundwater vulnerability is still debatable and not clear and conclusive. This is probably due to the fact that researchers often have very different experiences and education. A positive effect of it is a constant exchange of ideas, but there are also negative consequences and difficulties in deepening the issue. The different approaches are very important but they are usable only if the concept of vulnerability is standardized: thus, for the sake of clarity, a number of definitions should be laid down, based on the different types of vulnerability. These definitions can then provide the necessary holistic view for the aquifer vulnerability assessment. Nowadays vulnerability methods focus on the degree of vulnerability and the parameters needed for its evaluation, often neglecting to clarify what is the type of vulnerability the proposed methods are referred. The type of vulnerability, indeed, is both logically and hierarchically superior to the degree of vulnerability. More specifically the type of vulnerability represents the evaluation of the hydrogeological conditions considered in the vulnerability assessment and able to influence the way in which the contamination can take place. Currently the only distinction, based on of the type of vulnerability, is referred to intrinsic and specific vulnerability. Intrinsic vulnerability assesses the susceptibility of the receptor based on the natural properties of the land and subsurface; specific vulnerability also includes properties of the analyzed contaminant. This distinction is useful but not exhaustive. In addition to this, e.g., a distinction of vertical vulnerability

  13. Identifying patients at risk of type 2 diabetes.

    PubMed

    Savill, Peter

    2012-01-01

    At present there are nearly 3 million people with diabetes in the UK. It is predicted that this number will almost double by 2025. Nine out of ten of these individuals will have type 2 diabetes. It is estimated that one in seven adults have impaired glucose regulation and up to 12% of these will develop type 2 diabetes each year. The impact of obesity on the development of type 2 diabetes cannot be overemphasised, with a 1 kg/m2 increase in BMI raising the risk of impaired fasting glycaemia by 9.5% and of developing new-onset type 2 diabetes by 8.4%. A 1 cm increase in waist circumference increases the risks by 3.2% and 3.5% respectively. NICE advises using a validated risk assessment tool to identify patients at risk of diabetes. Risk factors used by such tools include: age; ethnicity; weight; first-degree relative with type 2 diabetes; low birthweight and sedentary lifestyle. Certain comorbidities increase the risk of type 2 diabetes, these include: cardiovascular and cerebrovascular disease; polycystic ovary syndrome; a history of gestational diabetes; and mental health problems. The initial screening blood test could be a fasting plasma glucose, HbA1c, or an oral glucose tolerance test, according to WHO criteria. NICE recommends that high-risk patients should be offered a programme encouraging them to undertake a minimum of 150 minutes of moderate intensity physical activity a week, gradually lose weight to reach and maintain a BMI within the healthy range, increase consumption of whole grains, vegetables, and other foods that are high in dietary fibre, reduce the total amount of fat in their diet and eat less saturated fat. PMID:22988703

  14. ON IDENTIFYING THE PROGENITORS OF Type Ia SUPERNOVAE

    SciTech Connect

    Livio, Mario; Pringle, J. E.

    2011-10-10

    We propose two new means of identifying the main class of progenitors of Type Ia supernovae-single or double degenerate: (1) if the range of supernova properties is significantly determined by the range of viewing angles of non-spherically symmetric explosions, then the nature of the correlation between polarization and another property (for example, the velocity gradient) can be used to determine the geometry of the asymmetry and hence the nature of the progenitor, and (2) in the double- but not in the single-degenerate case, the range in the observed properties (e.g., velocity gradients) is likely to increase with the amount of carbon seen in the ejecta.

  15. Identifying Distinct Geographic Health Service Environments in British Columbia, Canada: Cluster Analysis of Population-Based Administrative Data.

    PubMed

    Lavergne, M Ruth

    2016-08-01

    Definitions of "urban" and "rural" developed for general purposes may not reflect the organization and delivery of healthcare. This research used cluster analysis to group Local Health Areas based on the distribution of healthcare spending across service categories. Though total spending was similar, the metropolitan areas of Vancouver and Victoria were identified as distinct from non-metropolitan and remote communities, based on the distribution of healthcare spending alone. Non-metropolitan communities with large community hospitals and greater physician supply were further distinguished from those with fewer healthcare resources. This approach may be useful to other researchers and service planners. PMID:27585025

  16. Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

    PubMed Central

    Smyth, Deborah J; Plagnol, Vincent; Walker, Neil M; Cooper, Jason D; Downes, Kate; Yang, Jennie HM; Howson, Joanna MM; Stevens, Helen; McManus, Ross; Wijmenga, Cisca; Heap, Graham A.; Dubois, Patrick C.; Clayton, David G.; Hunt, Karen A; van Heel, David A; Todd, John A

    2009-01-01

    BACKGROUND The inflammatory disorders type 1 diabetes (T1D) and celiac disease co-segregate in populations, suggesting a common genetic origin. Both are associated with the HLA class II genes on chromosome 6p21, and the present paper tested whether non-HLA loci are shared. METHODS We evaluated eight celiac disease risk loci in T1D by genotyping and statistical analyses of 8,064 T1D cases, 9,339 controls and 2,519 families. We also investigated 18 T1D loci in 2,560 celiac disease cases and 9,339 controls. RESULTS Three celiac disease loci, listed as chromosome/candidate gene: 1q31/RGS1, 2q12/IL18RAP and 6q25/TAGAP, were associated with T1D (P < 10−4). The 3p21/CCR5 32 base pair insertion/deletion variant was newly identified as a T1D locus (P = 1.81 × 10−8), and was also associated with celiac disease, as were 18p11/PTPN2 and 2q33/CTLA4, bringing the total loci shared to seven, including 12q24/SH2B3. The 2q12/IL18RAP and 6q25/TAGAP allele associations were in the opposite direction in T1D as compared to celiac disease. Distinct effects included 11p15/INS, 10p15/IL2RA and 1q13/PTPN22 in T1D and 3q25/IL12A and 3q28/LPP in celiac disease. CONCLUSIONS Genetic susceptibility to T1D and celiac disease shares common alleles. These data suggest that common biological mechanisms, such as autoimmunity related tissue damage and intolerance to dietary antigens may be a feature of T1D. PMID:19073967

  17. Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma.

    PubMed

    Lober, Robert M; Cho, Yoon-Jae; Tang, Yujie; Barnes, Patrick D; Edwards, Michael S; Vogel, Hannes; Fisher, Paul G; Monje, Michelle; Yeom, Kristen W

    2014-03-01

    While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-naïve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 × 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG. PMID:24522717

  18. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    PubMed

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form. PMID:22288561

  19. The effect of temperature stress on coral- Symbiodinium associations containing distinct symbiont types

    NASA Astrophysics Data System (ADS)

    Fisher, P. L.; Malme, M. K.; Dove, S.

    2012-06-01

    Several studies have demonstrated that the temperature tolerance of scleractinian reef-building corals is controlled, in part, by hosting physiologically distinct symbiotic algae. We investigated the thermal tolerance of coral-algal associations within seven common species of reef-building corals hosting distinct Symbiodinium sub-clades collected from Heron Island during experimentally induced bleaching conditions. During experimental heating, photosynthetic fitness was assessed by the dark-adapted yield of PSII ( F v/ F m), and excitation pressure across PSII ( Q m) of each coral-algal association using pulse amplitude modulation fluorometry. The onset of bleaching was determined by the measurement of Symbiodinium cell density. Using the ribosomal internal transcribed spacer 2 (ITS-2) region, we showed that Symbiodinium type-coral host associations were temporally and spatially conserved in a high proportion of the colonies sampled within each species. Generally, the species Acropora millepora, Platygyra daedalea, Acropora aspera and Acropora formosa contained Symbiodinium ITS-2 type C3, whereas the species Montipora digitata, Porites cylindrica and Porites lutea contained Symbiodinium type C15. Bleaching susceptibility showed some association with Symbiodinium type, but further research is required to confirm this. Corals hosting C3 Symbiodinium displayed higher reductions in F v/ F m during heating compared to their C15 counterparts, irrespective of host species. However, a corresponding reduction in Symbiodinium density was not observed. Nonetheless, A. aspera and A. formosa showed significant reductions in Symbiodinium density relative to controls. This correlated with large increases in Q m and decreases in F v/ F m in heated explants. Our results suggest a range of bleaching susceptibilities for the coral species investigated, with A. aspera and A. formosa showing the greatest susceptibility to bleaching and M. digitata showing the lowest bleaching

  20. Layer-Specific Input to Distinct Cell Types in Layer 6 of Monkey Primary Visual Cortex

    PubMed Central

    Briggs, Farran; Callaway, Edward M.

    2007-01-01

    Layer 6 of monkey V1 contains a physiologically and anatomically diverse population of excitatory pyramidal neurons. Distinctive arborization patterns of axons and dendrites within the functionally specialized cortical layers define eight types of layer 6 pyramidal neurons and suggest unique information processing roles for each cell type. To address how input sources contribute to cellular function, we examined the laminar sources of functional excitatory input onto individual layer 6 pyramidal neurons using scanning laser photostimulation. We find that excitatory input sources correlate with cell type. Class I neurons with axonal arbors selectively targeting magnocellular (M) recipient layer 4Cα receive input from M-dominated layer 4B, whereas class I neurons whose axonal arbors target parvocellular (P) recipient layer 4Cβ receive input from P-dominated layer 2/3. Surprisingly, these neuronal types do not differ significantly in the inputs they receive directly from layers 4Cα or 4Cβ. Class II cells, which lack dense axonal arbors within layer 4C, receive excitatory input from layers targeted by their local axons. Specifically, type IIA cells project axons to and receive input from the deep but not superficial layers. Type IIB neurons project to and receive input from the deepest and most superficial, but not middle layers. Type IIC neurons arborize throughout the cortical layers and tend to receive inputs from all cortical layers. These observations have implications for the functional roles of different layer 6 cell types in visual information processing. PMID:11331389

  1. Animal Models of GWAS-Identified Type 2 Diabetes Genes

    PubMed Central

    da Silva Xavier, Gabriela; Bellomo, Elisa A.; McGinty, James A.; French, Paul M.; Rutter, Guy A.

    2013-01-01

    More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics. PMID:23710470

  2. Identifying different types of stochastic processes with the same spectra

    NASA Astrophysics Data System (ADS)

    Kim, Jong U.; Kish, Laszlo B.; Schmera, Gabor

    2005-05-01

    We propose a new way of pattern recognition which can distinguish different stochastic processes even if they have the same power density spectrum. Known crosscorrelation techniques recognize only the same realizations of a stochastic process in the two signal channels. However, crosscorrelation techniques do not work for recognizing independent realizations of the same stochastic process because their crosscorrelation function and cross spectrum are zero. A method able to do that would have the potential to revolutionize identification and pattern recognition, techniques, including sensing and security applications. The new method we are proposing is able to identify independent realizations of the same process, and at the same time, does not give false alarm for different processes which are very similar in nature. We demonstrate the method by using different realizations of two different types of random telegram signals, which are indistinguishable with respect to power density spectra (PDS). We call this method bispectrum correlation coefficient (BCC) technique.

  3. Histopathology of duodenal mucosal lesions in pediatric patients with inflammatory bowel disease: statistical analysis to identify distinctive features.

    PubMed

    Hardee, Steven; Alper, Arik; Pashankar, Dinesh S; Morotti, Raffaella A

    2014-01-01

    Histopathologic lesions of the upper gastrointestinal tract (UGT) are common in inflammatory bowel disease (IBD) patients. Pediatric patients have a higher incidence of IBD-associated gastritis and duodenitis than do adults. This study aimed to identify histopathologic features of duodenal lesions in the pediatric population that are characteristic of IBD, compared to duodenal pathology of different etiopathogenesis. We performed a retrospective analysis of UGT biopsies from pediatric patients with a histopathologic diagnosis of duodenitis (0-18 years of age) over a 7-year period. We identified 40 cases of duodenitis associated with Crohn's disease (CD) and 10 cases associated with ulcerative colitis (UC) and compared the histopathologic characteristics of the duodenitis with age-matched controls consisting of 40 cases duodenitis associated with celiac disease and 40 non-Helicobacter pylori-associated (NOS) etiology duodenitis cases. The histologic features that were evaluated included presence of granulomas, duodenal cryptitis, erosion, lamina propria eosinophils, villous blunting, increased intraepithelial lymphocytes (IELs), and crypt hyperplasia, among others. Additionally, we evaluated the presence of associated gastritis in all of these groups. Statistical analysis to identify significant differences was performed using Kruskal-Wallis testing. Cryptitis was the most distinctive feature of IBD-associated duodenitis. Granulomas were exceptionally rare. The severity of villous blunting and presence of IELs was significantly different in the IBD versus the celiac group. There is a significant overlap with duodenal lesions of different etiopathogenesis, including villous blunting and eosinophilia. With the exclusion of granulomas, cryptitis seems the most distinctive feature of the duodenal lesions associated with IBD. PMID:25207874

  4. Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study

    PubMed Central

    2014-01-01

    Introduction The aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile dermatomyositis (JDM). Methods Serum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist). Results Anti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P = 0.03) oral ulceration (P = 0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P = 0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P = 0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease. Conclusions Anti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed. PMID:24989778

  5. Anti-angiogenic peptides identified in thrombospondin type I domains

    SciTech Connect

    Karagiannis, Emmanouil D. . E-mail: ekaragi1@jhmi.edu; Popel, Aleksander S.

    2007-07-20

    Thrombospondin 1, the prototypical protein of the thrombospondin protein family, is a potent endogenous inhibitor of angiogenesis. Although the effects of the thrombospondin 1 on neovascularization have been well studied, little is known about the anti-angiogenic potency of other proteins or peptide fragments derived from the proteins in this family. Here we identify a set of 18 novel, anti-angiogenic 17- to 20-amino acid peptides that are derived from proteins containing type I thrombospondin motifs. We have named these peptides adamtsostatin-4, adamtsostatin-16, adamtsostatin-18, cartilostatin-1, cartilostatin-2, fibulostatin-6.2, fibulostatin-6.3, papilostatin-1, papilostatin-2, properdistatin, scospondistatin, semastatin-5A.1, semastatin-5A.2, semastatin-5B, thrombostatin containing-1, thrombostatin contaning-3, thrombostatin contaning-6, and wispostatin-1 to reflect their origin. We further demonstrate that these peptides inhibit the proliferation and migration of human umbilical vein endothelial cells in vitro. The anti-proliferative and anti-migratory properties of the identified peptides may be important in maintaining angiogenic homeostasis in vivo and make these peptides suitable candidates for use as anti-angiogenic pharmaceutical agents in numerous therapeutic applications.

  6. Identifying Fracture Types and Relative Ages Using Fluid Inclusion Stratigraphy

    SciTech Connect

    Dilley, Lorie M.; Norman, David; Owens, Lara

    2008-06-30

    Enhanced Geothermal Systems (EGS) are designed to recover heat from the subsurface by mechanically creating fractures in subsurface rocks. Understanding the life cycle of a fracture in a geothermal system is fundamental to the development of techniques for creating fractures. Recognizing the stage of a fracture, whether it is currently open and transmitting fluids; if it recently has closed; or if it is an ancient fracture would assist in targeting areas for further fracture stimulation. Identifying dense fracture areas as well as large open fractures from small fracture systems will also assist in fracture stimulation selection. Geothermal systems are constantly generating fractures, and fluids and gases passing through rocks in these systems leave small fluid and gas samples trapped in healed microfractures. Fluid inclusions trapped in minerals as the fractures heal are characteristic of the fluids that formed them, and this signature can be seen in fluid inclusion gas analysis. Our hypothesis is that fractures over their life cycle have different chemical signatures that we can see in fluid inclusion gas analysis and by using the new method of fluid inclusion stratigraphy (FIS) the different stages of fractures, along with an estimate of fracture size can be identified during the well drilling process. We have shown with this study that it is possible to identify fracture locations using FIS and that different fractures have different chemical signatures however that signature is somewhat dependent upon rock type. Open, active fractures correlate with increase concentrations of CO2, N2, Ar, and to a lesser extent H2O. These fractures would be targets for further enhancement. The usefulness of this method is that it is low cost alternative to current well logging techniques and can be done as a well is being drilled.

  7. A Formal Method for Identifying Distinct States of Variability in Time-varying Sources: Sgr A* as an Example

    NASA Astrophysics Data System (ADS)

    Meyer, L.; Witzel, G.; Longstaff, F. A.; Ghez, A. M.

    2014-08-01

    Continuously time variable sources are often characterized by their power spectral density and flux distribution. These quantities can undergo dramatic changes over time if the underlying physical processes change. However, some changes can be subtle and not distinguishable using standard statistical approaches. Here, we report a methodology that aims to identify distinct but similar states of time variability. We apply this method to the Galactic supermassive black hole, where 2.2 μm flux is observed from a source associated with Sgr A* and where two distinct states have recently been suggested. Our approach is taken from mathematical finance and works with conditional flux density distributions that depend on the previous flux value. The discrete, unobserved (hidden) state variable is modeled as a stochastic process and the transition probabilities are inferred from the flux density time series. Using the most comprehensive data set to date, in which all Keck and a majority of the publicly available Very Large Telescope data have been merged, we show that Sgr A* is sufficiently described by a single intrinsic state. However, the observed flux densities exhibit two states: noise dominated and source dominated. Our methodology reported here will prove extremely useful to assess the effects of the putative gas cloud G2 that is on its way toward the black hole and might create a new state of variability.

  8. A formal method for identifying distinct states of variability in time-varying sources: SGR A* as an example

    SciTech Connect

    Meyer, L.; Witzel, G.; Ghez, A. M.; Longstaff, F. A.

    2014-08-10

    Continuously time variable sources are often characterized by their power spectral density and flux distribution. These quantities can undergo dramatic changes over time if the underlying physical processes change. However, some changes can be subtle and not distinguishable using standard statistical approaches. Here, we report a methodology that aims to identify distinct but similar states of time variability. We apply this method to the Galactic supermassive black hole, where 2.2 μm flux is observed from a source associated with Sgr A* and where two distinct states have recently been suggested. Our approach is taken from mathematical finance and works with conditional flux density distributions that depend on the previous flux value. The discrete, unobserved (hidden) state variable is modeled as a stochastic process and the transition probabilities are inferred from the flux density time series. Using the most comprehensive data set to date, in which all Keck and a majority of the publicly available Very Large Telescope data have been merged, we show that Sgr A* is sufficiently described by a single intrinsic state. However, the observed flux densities exhibit two states: noise dominated and source dominated. Our methodology reported here will prove extremely useful to assess the effects of the putative gas cloud G2 that is on its way toward the black hole and might create a new state of variability.

  9. Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

    PubMed Central

    Tan, Tuan Zea; Miow, Qing Hao; Huang, Ruby Yun-Ju; Wong, Meng Kang; Ye, Jieru; Lau, Jieying Amelia; Wu, Meng Chu; Bin Abdul Hadi, Luqman Hakim; Soong, Richie; Choolani, Mahesh; Davidson, Ben; Nesland, Jahn M; Wang, Ling-Zhi; Matsumura, Noriomi; Mandai, Masaki; Konishi, Ikuo; Goh, Boon-Cher; Chang, Jeffrey T; Thiery, Jean Paul; Mori, Seiichi

    2013-01-01

    Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi-A, Epi-B, Mes, Stem-A and Stem-B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype-specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor-prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule-related processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients. PMID:23666744

  10. Novel and Distinct Metabolites Identified Following a Single Oral Dose of α- or γ-Hexabromocyclododecane in Mice

    PubMed Central

    Szabo, David T.; Huwe, Janice; Diliberto, Janet; Birnbaum, Linda S.

    2013-01-01

    The metabolism of α- and γ-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. α- or γ-[14C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice were dosed and sacrificed 3 hours post-exposure to investigate tissue metabolite levels. Extractable and non-extractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to α-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, mice exposed to γ-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene in the feces while only a single monohydroxy-pentabromocyclododecane metabolite was measured in liver and adipose tissue. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as evidenced by high fecal non-extractables. Although the potential toxicity of these free and bound metabolites remains to be determined, the presence of distinct metabolic products from the two main HBCD stereoisomers should allow biomarkers to be selected that may aid in characterizing sources of HBCD exposure. PMID:23171393

  11. Improvement of the Owner Distinction Method for Healing-Type Pet Robots

    NASA Astrophysics Data System (ADS)

    Nambo, Hidetaka; Kimura, Haruhiko; Hara, Mirai; Abe, Koji; Tajima, Takuya

    In order to decrease human stress, Animal Assisted Therapy which applies pets to heal humans is attracted. However, since animals are insanitary and unsafe, it is difficult to practically apply animal pets in hospitals. For the reason, on behalf of animal pets, pet robots have been attracted. Since pet robots would have no problems in sanitation and safety, they are able to be applied as a substitute for animal pets in the therapy. In our previous study where pet robots distinguish their owners like an animal pet, we used a puppet type pet robot which has pressure type touch sensors. However, the accuracy of our method was not sufficient to practical use. In this paper, we propose a method to improve the accuracy of the distinction. The proposed method can be applied for capacitive touch sensors such as installed in AIBO in addition to pressure type touch sensors. Besides, this paper shows performance of the proposed method from experimental results and confirms the proposed method has improved performance of the distinction in the conventional method.

  12. It is not always tickling: distinct cerebral responses during perception of different laughter types.

    PubMed

    Szameitat, Diana P; Kreifelts, Benjamin; Alter, Kai; Szameitat, André J; Sterr, Annette; Grodd, Wolfgang; Wildgruber, Dirk

    2010-12-01

    Laughter is highly relevant for social interaction in human beings and non-human primates. In humans as well as in non-human primates laughter can be induced by tickling. Human laughter, however, has further diversified and encompasses emotional laughter types with various communicative functions, e.g. joyful and taunting laughter. Here, it was evaluated if this evolutionary diversification of ecological functions is associated with distinct cerebral responses underlying laughter perception. Functional MRI revealed a double-dissociation of cerebral responses during perception of tickling laughter and emotional laughter (joy and taunt) with higher activations in the anterior rostral medial frontal cortex (arMFC) when emotional laughter was perceived, and stronger responses in the right superior temporal gyrus (STG) during appreciation of tickling laughter. Enhanced activation of the arMFC for emotional laughter presumably reflects increasing demands on social cognition processes arising from the greater social salience of these laughter types. Activation increase in the STG for tickling laughter may be linked to the higher acoustic complexity of this laughter type. The observed dissociation of cerebral responses for emotional laughter and tickling laughter was independent of task-directed focusing of attention. These findings support the postulated diversification of human laughter in the course of evolution from an unequivocal play signal to laughter with distinct emotional contents subserving complex social functions. PMID:20600991

  13. Comparison of 17 genome types of adenovirus type 3 identified among strains recovered from six continents.

    PubMed Central

    Li, Q G; Wadell, G

    1988-01-01

    Restriction endonucleases BamHI, BclI, BglI, BglII, BstEII, EcoRI, HindIII, HpaI, SalI, SmalI, XbalI, and XholI were used to analyze 61 selected strains of adenovirus type 3 (Ad3) isolated from Africa, Asia, Australia, Europe, North America, and South America. It was noted that the use of BamHI, BclI, BglII, HpaI, SalI, and SmaI was sufficient to distinguish 17 genome types; 13 of them were newly identified. All 17 Ad3 genome types could be divided into three genomic clusters. Genome types of Ad3 cluster 1 occurred in Africa, Europe, South America, and North America. Genomic cluster 2 was identified in Africa; genomic cluster 3 was identified in Africa, Asia, Australia, Europe (a few), and North America. This was of interest because 15 identified genome types of Ad7 could also be divided into three genomic clusters. The degree of genetic relatedness between the 17 Ad3 and the 15 Ad7 genome types was analyzed and was expressed in a three-dimensional model. Images PMID:2838500

  14. Complexity analyses show two distinct types of nonlinear dynamics in short heart period variability recordings

    PubMed Central

    Porta, Alberto; Bari, Vlasta; Marchi, Andrea; De Maria, Beatrice; Cysarz, Dirk; Van Leeuwen, Peter; Takahashi, Anielle C. M.; Catai, Aparecida M.; Gnecchi-Ruscone, Tomaso

    2015-01-01

    Two diverse complexity metrics quantifying time irreversibility and local prediction, in connection with a surrogate data approach, were utilized to detect nonlinear dynamics in short heart period (HP) variability series recorded in fetuses, as a function of the gestational period, and in healthy humans, as a function of the magnitude of the orthostatic challenge. The metrics indicated the presence of two distinct types of nonlinear HP dynamics characterized by diverse ranges of time scales. These findings stress the need to render more specific the analysis of nonlinear components of HP dynamics by accounting for different temporal scales. PMID:25806002

  15. Comparative pathogenicity of three genetically distinct Trypanosoma congolense-types in inbred Balb/c mice.

    PubMed

    Bengaly, Z; Sidibe, I; Boly, H; Sawadogo, L; Desquesnes, M

    2002-04-30

    Inbred Balb/c mice were infected with three clones of Trypanosoma congolense (Sam.28.1, Dind.3.1 and K60.1A) corresponding, respectively, to the three genetically distinct types (savannah, forest and kilifi) defined within this species, for the purpose of comparing their pathogenicity for a better understanding of the epidemiology of African trypanosomosis. Another clone of savannah type, IL 3000, was also tested simultaneously to study a probable strain variation. Both the clones of savannah type were found of extreme virulence with loss of appetite, rough hair, rapid respiration, lethargy, and all mice died within a week. Parasitaemias evolved rapidly to the first peak by day 3-5 post-inoculation without any remission and the course of disease was correlated positively with the prepatent period. The clones of the forest type and the kilifi type were of low virulence with chronic infection and symptoms progressively less patent throughout the infection; only one mouse died in each experimental group. PMID:11900925

  16. Novel Human Embryonic Stem Cell Regulators Identified by Conserved and Distinct CpG Island Methylation State

    PubMed Central

    Pells, Steve; Koutsouraki, Eirini; Morfopoulou, Sofia; Valencia-Cadavid, Sara; Tomlinson, Simon R.; Kalathur, Ravi; Futschik, Matthias E.; De Sousa, Paul A.

    2015-01-01

    Human embryonic stem cells (hESCs) undergo epigenetic changes in vitro which may compromise function, so an epigenetic pluripotency “signature” would be invaluable for line validation. We assessed Cytosine-phosphate-Guanine Island (CGI) methylation in hESCs by genomic DNA hybridisation to a CGI array, and saw substantial variation in CGI methylation between lines. Comparison of hESC CGI methylation profiles to corresponding somatic tissue data and hESC mRNA expression profiles identified a conserved hESC-specific methylation pattern associated with expressed genes. Transcriptional repressors and activators were over-represented amongst genes whose associated CGIs were methylated or unmethylated specifically in hESCs, respectively. Knockdown of candidate transcriptional regulators (HMGA1, GLIS2, PFDN5) induced differentiation in hESCs, whereas ectopic expression in fibroblasts modulated iPSC colony formation. Chromatin immunoprecipitation confirmed interaction between the candidates and the core pluripotency transcription factor network. We thus identify novel pluripotency genes on the basis of a conserved and distinct epigenetic configuration in human stem cells. PMID:26151932

  17. Subtypes of batterers in treatment: empirical support for a distinction between type I, type II and type III.

    PubMed

    Graña, José Luis; Redondo, Natalia; Muñoz-Rivas, Marina J; Cantos, Arthur L

    2014-01-01

    This study explores the existence of different types of batterers in a sample of 266 men who had been court referred for intimate partner violence. The data collected in the assessment that have been used to perform a hierarchical and a two-step cluster analysis fall into three areas: aggression towards the partner, general aggression and presence of psychopathology and personality traits, more specifically, alcohol use, borderline and antisocial personality traits, psychopathy traits, state anger and trait anger, anger expression and control, anger, hostility, and, finally, impulsivity. The results show a typology consisting of 3 types of batterers on the basis of violence level and psychopathology: low (65%), moderate (27.8%) and high (7.1%). This study provides empirical support for the development of batterer typologies. These typologies will help achieve early detection of different types of batterers, allowing us to tailor interventions on the basis of the needs of each of the types. PMID:25329828

  18. Subtypes of Batterers in Treatment: Empirical Support for a Distinction between Type I, Type II and Type III

    PubMed Central

    Graña, José Luis; Redondo, Natalia; Muñoz-Rivas, Marina J.; Cantos, Arthur L.

    2014-01-01

    This study explores the existence of different types of batterers in a sample of 266 men who had been court referred for intimate partner violence. The data collected in the assessment that have been used to perform a hierarchical and a two-step cluster analysis fall into three areas: aggression towards the partner, general aggression and presence of psychopathology and personality traits, more specifically, alcohol use, borderline and antisocial personality traits, psychopathy traits, state anger and trait anger, anger expression and control, anger, hostility, and, finally, impulsivity. The results show a typology consisting of 3 types of batterers on the basis of violence level and psychopathology: low (65%), moderate (27.8%) and high (7.1%). This study provides empirical support for the development of batterer typologies. These typologies will help achieve early detection of different types of batterers, allowing us to tailor interventions on the basis of the needs of each of the types. PMID:25329828

  19. Perlecan Diversely Regulates the Migration and Proliferation of Distinct Cell Types in vitro.

    PubMed

    Nakamura, Ryosuke; Nakamura, Fumio; Fukunaga, Shigeharu

    2015-01-01

    Perlecan is a multifunctional component of the extracellular matrix. It shows different effects on distinct cell types, and therefore it is thought to show potential for therapies targeting multiple cell types. However, the full range of multifunctionality of perlecan remains to be elucidated. We cultured various cell types, which were derived from epithelial/endothelial, connective and muscle tissues, in the presence of either antiserum against perlecan or exogenous perlecan, and examined the effects of perlecan on cell migration and proliferation. Cell migration was determined using a scratch assay. Blocking of perlecan by anti-perlecan antiserum inhibited the migration of vascular endothelial cells (VECs) and bone marrow-derived mesenchymal stem cells, and exogenous perlecan added to the culture medium promoted the migration of these cell types. The migration of other cell types was inhibited or was not promoted by exogenous perlecan. Cell proliferation was measured using a water-soluble tetrazolium dye. When cells were cultured at low densities, perlecan blocking inhibited the proliferation of VECs, and exogenous perlecan promoted the proliferation of keratinocytes. In contrast, the proliferation of fibroblasts, pre-adipocytes and vascular smooth muscle cells cultured at low densities was inhibited by exogenous perlecan. When cells were cultured at high densities, perlecan blocking promoted the proliferation of most cell types, with the exception of skeletal system-derived cells (chondrocytes and osteoblasts), which were inhibited by exogenous perlecan. Our results provide an overview of the multiple functions of perlecan in various cell types, and implicate a potential role of perlecan to inhibit undesirable activities, such as fibrosis, obesity and intimal hyperplasia. PMID:26562025

  20. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

    PubMed

    Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun; Hernaez, Ruben; Kim, Lauren J; Palmer, Cameron D; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E; Launer, Lenore J; Nalls, Michael A; Clark, Jeanne M; Mitchell, Braxton D; Shuldiner, Alan R; Butler, Johannah L; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M; O'Donnell, Christopher J; Sahani, Dushyant V; Salomaa, Veikko; Schadt, Eric E; Schwartz, Stephen M; Siscovick, David S; Voight, Benjamin F; Carr, J Jeffrey; Feitosa, Mary F; Harris, Tamara B; Fox, Caroline S; Smith, Albert V; Kao, W H Linda; Hirschhorn, Joel N; Borecki, Ingrid B

    2011-03-01

    Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719

  1. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

    PubMed Central

    Palmer, Cameron D.; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E.; Launer, Lenore J.; Nalls, Michael A.; Clark, Jeanne M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Butler, Johannah L.; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Sahani, Dushyant V.; Salomaa, Veikko; Schadt, Eric E.; Schwartz, Stephen M.; Siscovick, David S.; Voight, Benjamin F.; Carr, J. Jeffrey; Feitosa, Mary F.; Harris, Tamara B.; Fox, Caroline S.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719

  2. A Newly Identified Extrinsic Input Triggers a Distinct Gastric Mill Rhythm via Activation of Modulatory Projection Neurons

    PubMed Central

    Blitz, Dawn M.; White, Rachel S.; Saideman, Shari R.; Cook, Aaron; Christie, Andrew E.; Nadim, Farzan; Nusbaum, Michael P.

    2008-01-01

    Neuronal network flexibility enables animals to respond appropriately to changes in their internal and external states. We are using the isolated crab stomatogastric nervous system to determine how extrinsic inputs contribute to network flexibility. The stomatogastric system includes the well-characterized gastric mill (chewing) and pyloric (filtering of chewed food) motor circuits in the stomatogastric ganglion. Projection neurons with somata in the commissural ganglia (CoGs) regulate these rhythms. Previous work characterized a unique gastric mill rhythm that occurred spontaneously in some preparations, but whose origin remained undetermined. This rhythm includes a distinct protractor phase activity pattern, during which all active gastric mill circuit and projection neurons fire in a pyloric rhythm-timed activity pattern instead of the tonic firing pattern exhibited by these neurons during previously studied gastric mill rhythms. Here we identify a new extrinsic input, the post-oesophageal commissure (POC) neurons, relatively brief stimulation (30 sec) of which triggers a long-lasting (tens of minutes) activation of this novel gastric mill rhythm at least in part via its lasting activation of CoG projection neurons, including the previously identified MCN1 and CPN2. Immunocytochemical and electrophysiological data suggest that the POC neurons excite MCN1 and CPN2 by release of the neuropeptide Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). These data further suggest that the CoG arborization of the POC neurons comprises the previously identified anterior commissural organ (ACO), a CabTRP Ia-containing neurohemal organ. This endocrine pathway thus appears to also have paracrine actions that include activation of a novel and lasting gastric mill rhythm. PMID:18310125

  3. Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics

    PubMed Central

    2010-01-01

    Introduction Breast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. Methods We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer. Results We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors

  4. Three subclasses of a Drosophila insulator show distinct and cell type-specific genomic distributions

    PubMed Central

    Bushey, Ashley M.; Ramos, Edward; Corces, Victor G.

    2009-01-01

    Insulators are protein-bound DNA elements that are thought to play a role in chromatin organization and the regulation of gene expression by mediating intra- and interchromosomal interactions. Suppressor of Hair-wing [Su(Hw)] and Drosophila CTCF (dCTCF) insulators are found at distinct loci throughout the Drosophila melanogaster genome and function by recruiting an additional protein, Centrosomal Protein 190 (CP190). We performed chromatin immunoprecipitation (ChIP) and microarray analysis (ChIP–chip) experiments with whole-genome tiling arrays to compare Su(Hw), dCTCF, boundary element-associated factor (BEAF), and CP190 localization on DNA in two different cell lines and found evidence that BEAF is a third subclass of CP190-containing insulators. The DNA-binding proteins Su(Hw), dCTCF, and BEAF show unique distribution patterns with respect to the location and expression level of genes, suggesting diverse roles for these three subclasses of insulators in genome organization. Notably, cell line-specific localization sites for all three DNA-binding proteins as well as CP190 indicate multiple levels at which insulators can be regulated to affect gene expression. These findings suggest a model in which insulator subclasses may have distinct functions that together organize the genome in a cell type-specific manner, resulting in differential regulation of gene expression. PMID:19443682

  5. Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation.

    PubMed

    Scott, Daniel C; Rhee, David Y; Duda, David M; Kelsall, Ian R; Olszewski, Jennifer L; Paulo, Joao A; de Jong, Annemieke; Ovaa, Huib; Alpi, Arno F; Harper, J Wade; Schulman, Brenda A

    2016-08-25

    Hundreds of human cullin-RING E3 ligases (CRLs) modify thousands of proteins with ubiquitin (UB) to achieve vast regulation. Current dogma posits that CRLs first catalyze UB transfer from an E2 to their client substrates and subsequent polyubiquitylation from various linkage-specific E2s. We report an alternative E3-E3 tagging cascade: many cellular NEDD8-modified CRLs associate with a mechanistically distinct thioester-forming RBR-type E3, ARIH1, and rely on ARIH1 to directly add the first UB and, in some cases, multiple additional individual monoubiquitin modifications onto CRL client substrates. Our data define ARIH1 as a component of the human CRL system, demonstrate that ARIH1 can efficiently and specifically mediate monoubiquitylation of several CRL substrates, and establish principles for how two distinctive E3s can reciprocally control each other for simultaneous and joint regulation of substrate ubiquitylation. These studies have broad implications for CRL-dependent proteostasis and mechanisms of E3-mediated UB ligation. PMID:27565346

  6. Distinct electrophysiological properties in subtypes of nonspiking olfactory local interneurons correlate with their cell type-specific Ca2+ current profiles.

    PubMed

    Husch, Andreas; Paehler, Moritz; Fusca, Debora; Paeger, Lars; Kloppenburg, Peter

    2009-11-01

    A diverse population of local interneurons (LNs) helps to process, structure, and spatially represent olfactory information in the insect antennal lobe. In Periplaneta americana, we identified two subtypes of nonspiking local interneurons (type II LNs) by their distinct morphological and intrinsic electrophysiological properties. As an important step toward a better understanding of the cellular mechanisms that mediate odor information processing, we present a detailed analysis of their distinct voltage-activated Ca(2+) currents, which clearly correlated with their distinct intrinsic electrophysiological properties. Both type II LNs did not posses voltage-activated Na(+) currents and apparently innervated all glomeruli including the macroglomerulus. Type IIa LNs had significant longer and thicker low-order neurites and innervated each glomerulus entirely and homogeneously, whereas type IIb LNs innervated only parts of each glomerulus. All type II LNs were broadly tuned and responded to odorants of many chemical classes with graded changes in the membrane potential. Type IIa LNs responded with odor-specific elaborate patterns of excitation that could also include "spikelets" riding on the depolarizations and periods of inhibition. In contrast, type IIb LNs responded mostly with sustained, relatively smooth depolarizations. Consistent with the strong active membrane properties of type IIa LNs versus type IIb LNs, the voltage-activated Ca(2+) current of type IIa LNs activated at more hyperpolarized membrane potentials and had a larger transient component. PMID:19759323

  7. A Global Genomic Characterization of Nairoviruses Identifies Nine Discrete Genogroups with Distinctive Structural Characteristics and Host-Vector Associations

    PubMed Central

    Walker, Peter J.; Widen, Steven G.; Wood, Thomas G.; Guzman, Hilda; Tesh, Robert B.; Vasilakis, Nikolaos

    2016-01-01

    Nairoviruses are primarily tick-borne bunyaviruses, some of which are known to cause mild-to-severe febrile illness in humans or livestock. We describe the genome sequences of 11 poorly characterized nairoviruses that have ecological associations with either birds (Farallon, Punta Salinas, Sapphire II, Zirqa, Avalon, Clo Mor, Taggert, and Abu Hammad viruses), rodents (Qalyub and Bandia viruses), or camels (Dera Ghazi Khan virus). Global phylogenetic analyses of proteins encoded in the L, M, and S RNA segments of these and 20 other available nairovirus genomes identified nine well-supported genogroups (Nairobi sheep disease, Thiafora, Sakhalin, Keterah, Qalyub, Kasokero, Dera Ghazi Khan, Hughes, and Tamdy). Genogroup-specific structural variations were evident, particularly in the M segment encoding a polyprotein from which virion envelope glycoproteins (Gn and Gc) are generated by proteolytic processing. Structural variations include the extension, abbreviation, or absence sequences encoding an O-glycosylated mucin-like protein in the N-terminal domain, distinctive patterns of conserved cysteine residues in the GP38-like domain, insertion of sequences encoding a double-membrane-spanning protein (NSm) between the Gn and Gc domains, and the presence of an alternative long open reading frame encoding a viroporin-like transmembrane protein (Gx). We also observed strong genogroup-specific associations with categories of hosts and tick vectors. PMID:26903607

  8. A Global Genomic Characterization of Nairoviruses Identifies Nine Discrete Genogroups with Distinctive Structural Characteristics and Host-Vector Associations.

    PubMed

    Walker, Peter J; Widen, Steven G; Wood, Thomas G; Guzman, Hilda; Tesh, Robert B; Vasilakis, Nikolaos

    2016-05-01

    Nairoviruses are primarily tick-borne bunyaviruses, some of which are known to cause mild-to-severe febrile illness in humans or livestock. We describe the genome sequences of 11 poorly characterized nairoviruses that have ecological associations with either birds (Farallon, Punta Salinas, Sapphire II, Zirqa, Avalon, Clo Mor, Taggert, and Abu Hammad viruses), rodents (Qalyub and Bandia viruses), or camels (Dera Ghazi Khan virus). Global phylogenetic analyses of proteins encoded in the L, M, and S RNA segments of these and 20 other available nairovirus genomes identified nine well-supported genogroups (Nairobi sheep disease, Thiafora, Sakhalin, Keterah, Qalyub, Kasokero, Dera Ghazi Khan, Hughes, and Tamdy). Genogroup-specific structural variations were evident, particularly in the M segment encoding a polyprotein from which virion envelope glycoproteins (Gn and Gc) are generated by proteolytic processing. Structural variations include the extension, abbreviation, or absence sequences encoding an O-glycosylated mucin-like protein in the N-terminal domain, distinctive patterns of conserved cysteine residues in the GP38-like domain, insertion of sequences encoding a double-membrane-spanning protein (NSm) between the Gn and Gc domains, and the presence of an alternative long open reading frame encoding a viroporin-like transmembrane protein (Gx). We also observed strong genogroup-specific associations with categories of hosts and tick vectors. PMID:26903607

  9. Natural diversity in the model legume Medicago truncatula allows identifying distinct genetic mechanisms conferring partial resistance to Verticillium wilt

    PubMed Central

    Gentzbittel, Laurent

    2013-01-01

    Verticillium wilt is a major threat to alfalfa (Medicago sativa) and many other crops. The model legume Medicago truncatula was used as a host for studying resistance and susceptibility to Verticillium albo-atrum. In addition to presenting well-established genetic resources, this wild plant species enables to investigate biodiversity of the response to the pathogen and putative crosstalk between disease and symbiosis. Symptom scoring after root inoculation and modelling of disease curves allowed assessing susceptibility levels in recombinant lines of three crosses between susceptible and resistant lines, in a core collection of 32 lines, and in mutants affected in symbiosis with rhizobia. A GFP-expressing V. albo-atrum strain was used to study colonization of susceptible plants. Symptoms and colonization pattern in infected M. truncatula plants were typical of Verticillium wilt. Three distinct major quantitative trait loci were identified using a multicross, multisite design, suggesting that simple genetic mechanisms appear to control Verticillium wilt resistance in M. truncatula lines A17 and DZA45.5. The disease functional parameters varied largely in lines of the core collection. This biodiversity with regard to disease response encourages the development of association genetics and ecological approaches. Several mutants of the resistant line, impaired in different steps of rhizobial symbiosis, were affected in their response to V. albo-atrum, which suggests that mechanisms involved in the establishment of symbiosis or disease might have some common regulatory control points. PMID:23213135

  10. Internal Transcribed Spacer 1 (ITS1) based sequence typing reveals phylogenetically distinct Ascaris population

    PubMed Central

    Das, Koushik; Chowdhury, Punam; Ganguly, Sandipan

    2015-01-01

    Taxonomic differentiation among morphologically identical Ascaris species is a debatable scientific issue in the context of Ascariasis epidemiology. To explain the disease epidemiology and also the taxonomic position of different Ascaris species, genome information of infecting strains from endemic areas throughout the world is certainly crucial. Ascaris population from human has been genetically characterized based on the widely used genetic marker, internal transcribed spacer1 (ITS1). Along with previously reported and prevalent genotype G1, 8 new sequence variants of ITS1 have been identified. Genotype G1 was significantly present among female patients aged between 10 to 15 years. Intragenic linkage disequilibrium (LD) analysis at target locus within our study population has identified an incomplete LD value with potential recombination events. A separate cluster of Indian isolates with high bootstrap value indicate their distinct phylogenetic position in comparison to the global Ascaris population. Genetic shuffling through recombination could be a possible reason for high population diversity and frequent emergence of new sequence variants, identified in present and other previous studies. This study explores the genetic organization of Indian Ascaris population for the first time which certainly includes some fundamental information on the molecular epidemiology of Ascariasis. PMID:26504510

  11. Internal Transcribed Spacer 1 (ITS1) based sequence typing reveals phylogenetically distinct Ascaris population.

    PubMed

    Das, Koushik; Chowdhury, Punam; Ganguly, Sandipan

    2015-01-01

    Taxonomic differentiation among morphologically identical Ascaris species is a debatable scientific issue in the context of Ascariasis epidemiology. To explain the disease epidemiology and also the taxonomic position of different Ascaris species, genome information of infecting strains from endemic areas throughout the world is certainly crucial. Ascaris population from human has been genetically characterized based on the widely used genetic marker, internal transcribed spacer1 (ITS1). Along with previously reported and prevalent genotype G1, 8 new sequence variants of ITS1 have been identified. Genotype G1 was significantly present among female patients aged between 10 to 15 years. Intragenic linkage disequilibrium (LD) analysis at target locus within our study population has identified an incomplete LD value with potential recombination events. A separate cluster of Indian isolates with high bootstrap value indicate their distinct phylogenetic position in comparison to the global Ascaris population. Genetic shuffling through recombination could be a possible reason for high population diversity and frequent emergence of new sequence variants, identified in present and other previous studies. This study explores the genetic organization of Indian Ascaris population for the first time which certainly includes some fundamental information on the molecular epidemiology of Ascariasis. PMID:26504510

  12. A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II*S⃞

    PubMed Central

    Alvino, Clair L.; McNeil, Kerrie A.; Ong, Shee Chee; Delaine, Carlie; Booker, Grant W.; Wallace, John C.; Whittaker, Jonathan; Forbes, Briony E.

    2009-01-01

    Very little is known about the residues important for the interaction of insulin-like growth factor II (IGF-II) with the type 1 IGF receptor (IGF-1R) and the insulin receptor (IR). Insulin, to which IGF-II is homologous, is proposed to cross-link opposite halves of the IR dimer through two receptor binding surfaces, site 1 and site 2. In the present study we have analyzed the contribution of IGF-II residues equivalent to insulin's two binding surfaces toward the interaction of IGF-II with the IGF-1R and IR. Four “site 1” and six “site 2” analogues were produced and analyzed in terms of IGF-1R and IR binding and activation. The results show that Val43, Phe28, and Val14 (equivalent to site 1) are critical to IGF-1R and IR binding, whereas mutation to alanine of Gln18 affects only IGF-1R and not IR binding. Alanine substitutions at Glu12, Asp15, Phe19, Leu53, and Glu57 analogues resulted in significant (>2-fold) decreases in affinity for both the IGF-1R and IR. Furthermore, taking a novel approach using a monomeric, single-chain minimized IGF-1R we have defined a distinct second binding surface formed by Glu12, Phe19, Leu53, and Glu57 that potentially engages the IGF-1R at one or more of the FnIII domains. PMID:19139090

  13. Mapping bundles of ecosystem services reveals distinct types of multifunctionality within a Swedish landscape.

    PubMed

    Queiroz, Cibele; Meacham, Megan; Richter, Kristina; Norström, Albert V; Andersson, Erik; Norberg, Jon; Peterson, Garry

    2015-01-01

    Ecosystem services (ES) is a valuable concept to be used in the planning and management of social-ecological landscapes. However, the understanding of the determinant factors affecting the interaction between services in the form of synergies or trade-offs is still limited. We assessed the production of 16 ES across 62 municipalities in the Norrström drainage basin in Sweden. We combined GIS data with publically available information for quantifying and mapping the distribution of services. Additionally, we calculated the diversity of ES for each municipality and used correlations and k-means clustering analyses to assess the existence of ES bundles. We found five distinct types of bundles of ES spatially agglomerated in the landscape that could be explained by regional social and ecological gradients. Human-dominated landscapes were highly multifunctional in our study area and urban densely populated areas were hotspots of cultural services. PMID:25576284

  14. Distinct Circular Single-Stranded DNA Viruses Exist in Different Soil Types

    PubMed Central

    Swanson, Maud M.; Cock, Peter J. A.; Dawson, Lorna; Freitag, Thomas E.; Singh, Brajesh K.; Torrance, Lesley; Mushegian, Arcady R.

    2015-01-01

    The potential dependence of virus populations on soil types was examined by electron microscopy, and the total abundance of virus particles in four soil types was similar to that previously observed in soil samples. The four soil types examined differed in the relative abundances of four morphological groups of viruses. Machair, a unique type of coastal soil in western Scotland and Ireland, differed from the others tested in having a higher proportion of tailed bacteriophages. The other soils examined contained predominantly spherical and thin filamentous virus particles, but the Machair soil had a more even distribution of the virus types. As the first step in looking at differences in populations in detail, virus sequences from Machair and brown earth (agricultural pasture) soils were examined by metagenomic sequencing after enriching for circular Rep-encoding single-stranded DNA (ssDNA) (CRESS-DNA) virus genomes. Sequences from the family Microviridae (icosahedral viruses mainly infecting bacteria) of CRESS-DNA viruses were predominant in both soils. Phylogenetic analysis of Microviridae major coat protein sequences from the Machair viruses showed that they spanned most of the diversity of the subfamily Gokushovirinae, whose members mainly infect obligate intracellular parasites. The brown earth soil had a higher proportion of sequences that matched the morphologically similar family Circoviridae in BLAST searches. However, analysis of putative replicase proteins that were similar to those of viruses in the Circoviridae showed that they are a novel clade of Circoviridae-related CRESS-DNA viruses distinct from known Circoviridae genera. Different soils have substantially different taxonomic biodiversities even within ssDNA viruses, which may be driven by physicochemical factors. PMID:25841004

  15. Distinct circular single-stranded DNA viruses exist in different soil types.

    PubMed

    Reavy, Brian; Swanson, Maud M; Cock, Peter J A; Dawson, Lorna; Freitag, Thomas E; Singh, Brajesh K; Torrance, Lesley; Mushegian, Arcady R; Taliansky, Michael

    2015-06-15

    The potential dependence of virus populations on soil types was examined by electron microscopy, and the total abundance of virus particles in four soil types was similar to that previously observed in soil samples. The four soil types examined differed in the relative abundances of four morphological groups of viruses. Machair, a unique type of coastal soil in western Scotland and Ireland, differed from the others tested in having a higher proportion of tailed bacteriophages. The other soils examined contained predominantly spherical and thin filamentous virus particles, but the Machair soil had a more even distribution of the virus types. As the first step in looking at differences in populations in detail, virus sequences from Machair and brown earth (agricultural pasture) soils were examined by metagenomic sequencing after enriching for circular Rep-encoding single-stranded DNA (ssDNA) (CRESS-DNA) virus genomes. Sequences from the family Microviridae (icosahedral viruses mainly infecting bacteria) of CRESS-DNA viruses were predominant in both soils. Phylogenetic analysis of Microviridae major coat protein sequences from the Machair viruses showed that they spanned most of the diversity of the subfamily Gokushovirinae, whose members mainly infect obligate intracellular parasites. The brown earth soil had a higher proportion of sequences that matched the morphologically similar family Circoviridae in BLAST searches. However, analysis of putative replicase proteins that were similar to those of viruses in the Circoviridae showed that they are a novel clade of Circoviridae-related CRESS-DNA viruses distinct from known Circoviridae genera. Different soils have substantially different taxonomic biodiversities even within ssDNA viruses, which may be driven by physicochemical factors. PMID:25841004

  16. Differential progression of structural and functional alterations in distinct retinal ganglion cell types in a mouse model of glaucoma.

    PubMed

    Della Santina, Luca; Inman, Denise M; Lupien, Caroline B; Horner, Philip J; Wong, Rachel O L

    2013-10-30

    Intraocular pressure (IOP) elevation is a principal risk factor for glaucoma. Using a microbead injection technique to chronically raise IOP for 15 or 30 d in mice, we identified the early changes in visual response properties of different types of retinal ganglion cells (RGCs) and correlated these changes with neuronal morphology before cell death. Microbead-injected eyes showed reduced optokinetic tracking as well as cell death. In such eyes, multielectrode array recordings revealed that four RGC types show diverse alterations in their light responses upon IOP elevation. OFF-transient RGCs exhibited a more rapid decline in both structural and functional organizations compared with other RGCs. In contrast, although the light-evoked responses of OFF-sustained RGCs were perturbed, the dendritic arbor of this cell type remained intact. ON-transient and ON-sustained RGCs had normal functional receptive field sizes but their spontaneous and light-evoked firing rates were reduced. ON- and OFF-sustained RGCs lost excitatory synapses across an otherwise structurally normal dendritic arbor. Together, our observations indicate that there are changes in spontaneous activity and light-evoked responses in RGCs before detectable dendritic loss. However, when dendrites retract, we found corresponding changes in receptive field center size. Importantly, the effects of IOP elevation are not uniformly manifested in the structure and function of diverse RGC populations, nor are distinct RGC types perturbed within the same time-frame by such a challenge. PMID:24174678

  17. Differential Progression of Structural and Functional Alterations in Distinct Retinal Ganglion Cell Types in a Mouse Model of Glaucoma

    PubMed Central

    Della Santina, Luca; Inman, Denise M.; Lupien, Caroline B.; Horner, Philip J.

    2013-01-01

    Intraocular pressure (IOP) elevation is a principal risk factor for glaucoma. Using a microbead injection technique to chronically raise IOP for 15 or 30 d in mice, we identified the early changes in visual response properties of different types of retinal ganglion cells (RGCs) and correlated these changes with neuronal morphology before cell death. Microbead-injected eyes showed reduced optokinetic tracking as well as cell death. In such eyes, multielectrode array recordings revealed that four RGC types show diverse alterations in their light responses upon IOP elevation. OFF-transient RGCs exhibited a more rapid decline in both structural and functional organizations compared with other RGCs. In contrast, although the light-evoked responses of OFF-sustained RGCs were perturbed, the dendritic arbor of this cell type remained intact. ON-transient and ON-sustained RGCs had normal functional receptive field sizes but their spontaneous and light-evoked firing rates were reduced. ON- and OFF-sustained RGCs lost excitatory synapses across an otherwise structurally normal dendritic arbor. Together, our observations indicate that there are changes in spontaneous activity and light-evoked responses in RGCs before detectable dendritic loss. However, when dendrites retract, we found corresponding changes in receptive field center size. Importantly, the effects of IOP elevation are not uniformly manifested in the structure and function of diverse RGC populations, nor are distinct RGC types perturbed within the same time-frame by such a challenge. PMID:24174678

  18. Identifying Aerosol Type/Mixture from Aerosol Absorption Properties Using AERONET

    NASA Technical Reports Server (NTRS)

    Giles, D. M.; Holben, B. N.; Eck, T. F.; Sinyuk, A.; Dickerson, R. R.; Thompson, A. M.; Slutsker, I.; Li, Z.; Tripathi, S. N.; Singh, R. P.; Zibordi, G.

    2010-01-01

    Aerosols are generated in the atmosphere through anthropogenic and natural mechanisms. These sources have signatures in the aerosol optical and microphysical properties that can be used to identify the aerosol type/mixture. Spectral aerosol absorption information (absorption Angstrom exponent; AAE) used in conjunction with the particle size parameterization (extinction Angstrom exponent; EAE) can only identify the dominant absorbing aerosol type in the sample volume (e.g., black carbon vs. iron oxides in dust). This AAE/EAE relationship can be expanded to also identify non-absorbing aerosol types/mixtures by applying an absorption weighting. This new relationship provides improved aerosol type distinction when the magnitude of absorption is not equal (e.g, black carbon vs. sulfates). The Aerosol Robotic Network (AERONET) data provide spectral aerosol optical depth and single scattering albedo - key parameters used to determine EAE and AAE. The proposed aerosol type/mixture relationship is demonstrated using the long-term data archive acquired at AERONET sites within various source regions. The preliminary analysis has found that dust, sulfate, organic carbon, and black carbon aerosol types/mixtures can be determined from this AAE/EAE relationship when applying the absorption weighting for each available wavelength (Le., 440, 675, 870nm). Large, non-spherical dust particles absorb in the shorter wavelengths and the application of 440nm wavelength absorption weighting produced the best particle type definition. Sulfate particles scatter light efficiently and organic carbon particles are small near the source and aggregate over time to form larger less absorbing particles. Both sulfates and organic carbon showed generally better definition using the 870nm wavelength absorption weighting. Black carbon generation results from varying combustion rates from a number of sources including industrial processes and biomass burning. Cases with primarily black carbon showed

  19. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. PMID:26847489

  20. Methylation Analysis in Distinct Immune Cell Subsets in Type 1 Diabetes.

    PubMed

    Dang, Mary N; Bradford, Claire M; Pozzilli, Paolo; Leslie, R David

    2016-01-01

    Epigenetics provides a mechanism in which the environment can interact with the genotype to produce a variety of phenotypes. These epigenetic modifications have been associated with altered gene expression and silencing of repetitive elements, and these modifications can be inherited mitotically. DNA methylation is the best characterized epigenetic mark and earlier studies have examined DNA methylation profiles in peripheral blood mononuclear cells in disease. However, any disease-related signatures identified would just display differences in the relative abundance of individual cell types as each cell subset generates a unique methylation profile. Therefore is it important to identify cell- or tissue-specific changes in DNA methylation, particularly in autoimmune diseases such as type 1 diabetes. PMID:26791360

  1. Characterization of KIR intermediate promoters reveals four promoter types associated with distinct expression patterns of KIR subtypes

    PubMed Central

    Li, Hongchuan; Wright, Paul W.; McCullen, Matthew; Anderson, Stephen K.

    2015-01-01

    The human KIR genes contain multiple promoters that control the process of gene activation and variegated expression of KIR on NK and T cells. Specific subfamilies of KIR genes have differences in the timing and tissue-specificity of expression: however, previous studies of the proximal KIR promoters have not shown significant differences in activity between differentially expressed KIR gene subsets. The recent identification of an intermediate KIR promoter (ProI) associated with KIR2DL1 expression suggested a central role for this element in KIR expression. The current study identifies ProI elements in all of the KIR genes, revealing four classes of ProI that correspond with four distinct expression phenotypes of KIR sub-groups: KIR2DL2/S2/L3 that are expressed early in reconstituting NK after transplant; KIR2DL4 that is expressed by CD56-bright NK in a non-variegated manner; KIR3DL3 that is not expressed by circulating NK cells; and the remaining KIR that are expressed by subsets of CD56-dim NK. The four classes of ProI are structurally diverse and display distinct functional properties. Altogether, these results indicate that KIR ProI elements contribute to the tissue/cell type specificity of KIR transcription, and cooperate with the probabilistic proximal promoter to control KIR expression. PMID:26656451

  2. Distinct Mutations Led to Inactivation of Type 1 Fimbriae Expression in Shigella spp.

    PubMed Central

    Bravo, Verónica; Puhar, Andrea; Sansonetti, Philippe; Parsot, Claude; Toro, Cecilia S.

    2015-01-01

    Shigella spp. are responsible for bacillary dysentery in humans. The acquisition or the modification of the virulence plasmid encoding factors promoting entry of bacteria into and dissemination within epithelial cells was a critical step in the evolution of these bacteria from their Escherichia coli ancestor(s). Incorporation of genomic islands (GI) and gene inactivation also shaped interactions between these pathogens and their human host. Sequence analysis of the GI inserted next to the leuX tRNA gene in S. boydii, S. dysenteriae, S. flexneri, S. sonnei and enteroinvasive E. coli (EIEC) suggests that this region initially carried the fec, yjhATS and fim gene clusters. The fim cluster encoding type I fimbriae is systematically inactivated in both reference strains and clinical isolates and distinct mutations are responsible for this inactivation in at least three phylogenetic groups. To investigate consequences of the presence of fimbriae on the outcome of the interaction of Shigella with host cells, we used a S. flexneri strain harboring a plasmid encoding the E. coli fim operon. Production of fimbriae by this recombinant strain increased the ability of bacteria to adhere to and enter into epithelial cells and had no effect on their ability to disseminate from cell to cell. The observations that production of type I fimbriae increases invasion of epithelial cells and that independent mutations abolish fimbriae production in Shigella suggest that these mutations correspond to pathoadaptive events. PMID:25811616

  3. Spatial firing correlates of physiologically distinct cell types of the rat dentate gyrus

    PubMed Central

    Neunuebel, Joshua P.; Knierim, James J.

    2012-01-01

    The dentate gyrus (DG) occupies a key position in information flow through the hippocampus. Its principal cell, the granule cell, has spatially selective place fields. However, the behavioral correlates of cells located in the hilus of the rat dentate gyrus are unknown. We report here that cells below the granule layer show spatially selective firing that consists of multiple subfields. Other cells recorded from the DG had single place fields. Compared to cells with multiple fields, cells with single fields fired at lower rates during sleep; were less bursty; and were more likely to be recorded simultaneously with large populations of neurons that were active during sleep and silent during behavior. We propose that cells with single fields are likely to be mature granule cells that use sparse encoding to potentially disambiguate input patterns. Furthermore, we hypothesize that cells with multiple fields might be cells of the hilus or newborn granule cells. These data are the first demonstration, based on physiological criteria, that single-field and multiple-field cells constitute at least two distinct cell classes in the DG. Because of the heterogeneity of firing correlates and cell types in the DG, understanding which cell types correspond to which firing patterns, and how these correlates change with behavioral state and between different environments, are critical questions for testing longstanding computational theories that the DG performs a pattern separation function using a very sparse coding strategy. PMID:22423105

  4. Distinct mutations led to inactivation of type 1 fimbriae expression in Shigella spp.

    PubMed

    Bravo, Verónica; Puhar, Andrea; Sansonetti, Philippe; Parsot, Claude; Toro, Cecilia S

    2015-01-01

    Shigella spp. are responsible for bacillary dysentery in humans. The acquisition or the modification of the virulence plasmid encoding factors promoting entry of bacteria into and dissemination within epithelial cells was a critical step in the evolution of these bacteria from their Escherichia coli ancestor(s). Incorporation of genomic islands (GI) and gene inactivation also shaped interactions between these pathogens and their human host. Sequence analysis of the GI inserted next to the leuX tRNA gene in S. boydii, S. dysenteriae, S. flexneri, S. sonnei and enteroinvasive E. coli (EIEC) suggests that this region initially carried the fec, yjhATS and fim gene clusters. The fim cluster encoding type I fimbriae is systematically inactivated in both reference strains and clinical isolates and distinct mutations are responsible for this inactivation in at least three phylogenetic groups. To investigate consequences of the presence of fimbriae on the outcome of the interaction of Shigella with host cells, we used a S. flexneri strain harboring a plasmid encoding the E. coli fim operon. Production of fimbriae by this recombinant strain increased the ability of bacteria to adhere to and enter into epithelial cells and had no effect on their ability to disseminate from cell to cell. The observations that production of type I fimbriae increases invasion of epithelial cells and that independent mutations abolish fimbriae production in Shigella suggest that these mutations correspond to pathoadaptive events. PMID:25811616

  5. The Co-Expression Pattern of Odorant Binding Proteins and Olfactory Receptors Identify Distinct Trichoid Sensilla on the Antenna of the Malaria Mosquito Anopheles gambiae

    PubMed Central

    Schultze, Anna; Pregitzer, Pablo; Walter, Marika F.; Woods, Daniel F.; Marinotti, Osvaldo; Breer, Heinz; Krieger, Jürgen

    2013-01-01

    The initial steps of odorant recognition in the insect olfactory system involve odorant binding proteins (OBPs) and odorant receptors (ORs). While large families of OBPs have been identified in the malaria vector A. gambiae, little is known about their expression pattern in the numerous sensory hairs of the female antenna. We applied whole mount fluorescence in Situ hybridization (WM-FISH) and fluorescence immunohistochemistry (WM-FIHC) to investigate the sensilla co-expression of eight A. gambiae OBPs (AgOBPs), most notably AgOBP1 and AgOBP4, which all have abundant transcripts in female antenna. WM-FISH analysis of female antennae using AgOBP-specific probes revealed marked differences in the number of cells expressing each various AgOBPs. Testing combinations of AgOBP probes in two-color WM-FISH resulted in distinct cellular labeling patterns, indicating a combinatorial expression of AgOBPs and revealing distinct AgOBP requirements for various functional sensilla types. WM-FIHC with antisera to AgOBP1 and AgOBP4 confirmed expression of the respective proteins by support cells and demonstrated a location of OBPs within sensilla trichodea. Based on the finding that AgOBP1 and AgOBP4 as well as the receptor type AgOR2 are involved in the recognition of indole, experiments were performed to explore if the AgOBP-types and AgOR2 are co-expressed in distinct olfactory sensilla. Applying two-color WM-FISH with AgOBP-specific probes and probes specific for AgOR2 revealed a close association of support cells bearing transcripts for AgOBP1 and AgOBP4 and neurons with a transcript for the receptor AgOR2. Moreover, combined WM-FISH/-FIHC approaches using an AgOR2-specific riboprobe and AgOBP-specific antisera revealed the expression of the “ligand-matched” AgOBP1, AgOBP4 and AgOR2 to single trichoid hairs. This result substantiates the notion that a specific response to indole is mediated by an interplay of the proteins. PMID:23861970

  6. Method for identifying type I diabetes mellitus in humans

    DOEpatents

    Metz, Thomas O [Kennewick, WA; Qian, Weijun [Richland, WA; Jacobs, Jon M [Pasco, WA

    2011-04-12

    A method and system for classifying subject populations utilizing predictive and diagnostic biomarkers for type I diabetes mellitus. The method including determining the levels of a variety of markers within the serum or plasma of a target organism and correlating this level to general populations as a screen for predisposition or progressive monitoring of disease presence or predisposition.

  7. Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas.

    PubMed

    Lassmann, Silke; Weis, Roland; Makowiec, Frank; Roth, Jasmine; Danciu, Mihai; Hopt, Ulrich; Werner, Martin

    2007-03-01

    DNA copy number changes represent molecular fingerprints of solid tumors and are as such relevant for better understanding of tumor development and progression. In this study, we applied genome-wide array comparative genomic hybridization (aCGH) to identify gene-specific DNA copy number changes in chromosomal (CIN)- and microsatellite (MIN)-unstable sporadic colorectal cancers (sCRC). Genomic DNA was extracted from microdissected, matching normal colorectal epithelium and invasive tumor cells of formalin-fixed and paraffin-embedded tissues of 22 cases with colorectal cancer (CIN = 11, MIN = 11). DNA copy number changes were determined by aCGH for 287 target sequences in tumor cell DNAs, using pooled normal DNAs as reference. aCGH data of tumor cell DNAs was confirmed by fluorescence in situ hybridization (FISH) for three genes on serial tissues as those used for aCGH. aCGH revealed DNA copy number changes previously described by metaphase CGH (gains 7, 8q, 13q, and 20q; losses 8p, 15q, 18q, and 17p). However, chromosomal regions 20q, 13q, 7, and 17p were preferentially altered in CIN-type tumors and included DNA amplifications of eight genes on chromosome 20q (TOP1, AIB1, MYBL2, CAS, PTPN1, STK15, ZNF217, and CYP24), two genes on chromosome 13q (BRCA2 and D13S25), and three genes on chromosome 7 (IL6, CYLN2, and MET) as well as DNA deletions of two genes on chromosome 17p (HIC1 and LLGL1). Finally, additional CIN-tumor-associated DNA amplifications were identified for EXT1 (8q24.11) and MYC (8q24.12) as well as DNA deletions for MAP2K5 (15q23) and LAMA3 (18q11.2). In contrast, distinct MIN-tumor-associated DNA amplifications were detected for E2F5 (8p22-q21.3), GARP (11q13.5-q14), ATM (11q22.3), KAL (Xp22.3), and XIST (Xq13.2) as well as DNA deletions for RAF1 (3p25), DCC (18q21.3), and KEN (21q tel). aCGH revealed distinct DNA copy number changes of oncogenes and tumor suppressor genes in CIN- and MIN-type sporadic colorectal carcinomas. The identified candidate

  8. Discovery of a Distinct Superfamily of Kunitz-Type Toxin (KTT) from Tarantulas

    PubMed Central

    Diao, Jian-Bo; Jiang, Li-Ping; Tang, Xing; Liang, Song-Ping

    2008-01-01

    Background Kuntiz-type toxins (KTTs) have been found in the venom of animals such as snake, cone snail and sea anemone. The main ancestral function of Kunitz-type proteins was the inhibition of a diverse array of serine proteases, while toxic activities (such as ion-channel blocking) were developed under a variety of Darwinian selection pressures. How new functions were grafted onto an old protein scaffold and what effect Darwinian selection pressures had on KTT evolution remains a puzzle. Principal Findings Here we report the presence of a new superfamily of KTTs in spiders (Tarantulas: Ornithoctonus huwena and Ornithoctonus hainana), which share low sequence similarity to known KTTs and is clustered in a distinct clade in the phylogenetic tree of KTT evolution. The representative molecule of spider KTTs, HWTX-XI, purified from the venom of O. huwena, is a bi-functional protein which is a very potent trypsin inhibitor (about 30-fold more strong than BPTI) as well as a weak Kv1.1 potassium channel blocker. Structural analysis of HWTX-XI in 3-D by NMR together with comparative function analysis of 18 expressed mutants of this toxin revealed two separate sites, corresponding to these two activities, located on the two ends of the cone-shape molecule of HWTX-XI. Comparison of non-synonymous/synonymous mutation ratios (ω) for each site in spider and snake KTTs, as well as PBTI like body Kunitz proteins revealed high Darwinian selection pressure on the binding sites for Kv channels and serine proteases in snake, while only on the proteases in spider and none detected in body proteins, suggesting different rates and patterns of evolution among them. The results also revealed a series of key events in the history of spider KTT evolution, including the formation of a novel KTT family (named sub-Kuntiz-type toxins) derived from the ancestral native KTTs with the loss of the second disulfide bridge accompanied by several dramatic sequence modifications. Conclusions

  9. On the possible cause of distinct El Niño types in the recent decades

    NASA Astrophysics Data System (ADS)

    Jadhav, Jyoti; Panickal, Swapna; Marathe, Shamal; Ashok, K.

    2015-11-01

    Distinct El Niño types have been observed in the recent decades with warm anomalies in the eastern Pacific (Canonical El Niño, EL) and central Pacific (El Niño Modoki, EM). Among these, a basinwide tropical Pacific (TP) warming is seen during 2009 and recently during 2014. We carried out data analysis and numerical simulation experiments to understand the possible cause for different El Niño flavours. The results reveal that the co-evolution of ocean-atmospheric conditions are critically important. Stronger boreal spring (Mar-May) through summer (June-September) westerly wind anomalies (WWA), with relatively stronger ocean pre-conditioning can lead to EL, weaker ocean pre-conditioning and weaker WWA can generate EM, while stronger ocean preconditioning and weaker WWA can lead to basinwide warming pattern. The strength of the WWA is crucial in determining the strength of the ocean dynamic response and the thermocline displacements in the Pacific. The study has important implications for understanding the nature of El Niño in advance.

  10. Distinct Structural Elements Dictate the Specificity of the Type III Pentaketide Synthase from Neurospora crassa

    SciTech Connect

    Rubin-Pitel, Sheryl B.; Zhang, Houjin; Vu, Trang; Brunzelle, Joseph S.; Zhao, Huimin; Nair, Satish K.

    2009-01-15

    The fungal type III polyketide synthase 2'-oxoalkylresorcyclic acid synthase (ORAS) primes with a range of acyl-Coenzyme A thioesters (C{sub 4}--C{sub 20}) and extends using malonyl-Coenzyme A to produce pyrones, resorcinols, and resorcylic acids. To gain insight into this unusual substrate specificity and product profile, we have determined the crystal structures of ORAS to 1.75 {angstrom} resolution, the Phe-252{yields}Gly site-directed mutant to 2.1 {angstrom} resolution, and a binary conplex of ORAS with eicosanoic acid to 2.0 {angstrom} resolution. The structures reveal a distinct rearrangement of structural elements near the active site that allows accomodation of long-chain fatty acid esters and a reorientation of the gating mechanism that controls cyclization and polyketide chain length. The roles of these structural elements are further elucidated by characterization of various structure-based site-directed variants. These studies establish an unexpected plasticity to the PKS fold, unanticipated from structural studies of other members of this enzyme family.

  11. Distinct Morphology of Human T-Cell Leukemia Virus Type 1-Like Particles

    PubMed Central

    Maldonado, José O.; Cao, Sheng; Zhang, Wei; Mansky, Louis M.

    2016-01-01

    The Gag polyprotein is the main retroviral structural protein and is essential for the assembly and release of virus particles. In this study, we have analyzed the morphology and Gag stoichiometry of human T-cell leukemia virus type 1 (HTLV-1)-like particles and authentic, mature HTLV-1 particles by using cryogenic transmission electron microscopy (cryo-TEM) and scanning transmission electron microscopy (STEM). HTLV-1-like particles mimicked the morphology of immature authentic HTLV-1 virions. Importantly, we have observed for the first time that the morphology of these virus-like particles (VLPs) has the unique local feature of a flat Gag lattice that does not follow the curvature of the viral membrane, resulting in an enlarged distance between the Gag lattice and the viral membrane. Other morphological features that have been previously observed with other retroviruses include: (1) a Gag lattice with multiple discontinuities; (2) membrane regions associated with the Gag lattice that exhibited a string of bead-like densities at the inner leaflet; and (3) an arrangement of the Gag lattice resembling a railroad track. Measurement of the average size and mass of VLPs and authentic HTLV-1 particles suggested a consistent range of size and Gag copy numbers in these two groups of particles. The unique local flat Gag lattice morphological feature observed suggests that HTLV-1 Gag could be arranged in a lattice structure that is distinct from that of other retroviruses characterized to date. PMID:27187442

  12. Distinct Morphology of Human T-Cell Leukemia Virus Type 1-Like Particles.

    PubMed

    Maldonado, José O; Cao, Sheng; Zhang, Wei; Mansky, Louis M

    2016-01-01

    The Gag polyprotein is the main retroviral structural protein and is essential for the assembly and release of virus particles. In this study, we have analyzed the morphology and Gag stoichiometry of human T-cell leukemia virus type 1 (HTLV-1)-like particles and authentic, mature HTLV-1 particles by using cryogenic transmission electron microscopy (cryo-TEM) and scanning transmission electron microscopy (STEM). HTLV-1-like particles mimicked the morphology of immature authentic HTLV-1 virions. Importantly, we have observed for the first time that the morphology of these virus-like particles (VLPs) has the unique local feature of a flat Gag lattice that does not follow the curvature of the viral membrane, resulting in an enlarged distance between the Gag lattice and the viral membrane. Other morphological features that have been previously observed with other retroviruses include: (1) a Gag lattice with multiple discontinuities; (2) membrane regions associated with the Gag lattice that exhibited a string of bead-like densities at the inner leaflet; and (3) an arrangement of the Gag lattice resembling a railroad track. Measurement of the average size and mass of VLPs and authentic HTLV-1 particles suggested a consistent range of size and Gag copy numbers in these two groups of particles. The unique local flat Gag lattice morphological feature observed suggests that HTLV-1 Gag could be arranged in a lattice structure that is distinct from that of other retroviruses characterized to date. PMID:27187442

  13. On the possible cause of distinct El Niño types in the recent decades.

    PubMed

    Jadhav, Jyoti; Panickal, Swapna; Marathe, Shamal; Ashok, K

    2015-01-01

    Distinct El Niño types have been observed in the recent decades with warm anomalies in the eastern Pacific (Canonical El Niño, EL) and central Pacific (El Niño Modoki, EM). Among these, a basinwide tropical Pacific (TP) warming is seen during 2009 and recently during 2014. We carried out data analysis and numerical simulation experiments to understand the possible cause for different El Niño flavours. The results reveal that the co-evolution of ocean-atmospheric conditions are critically important. Stronger boreal spring (Mar-May) through summer (June-September) westerly wind anomalies (WWA), with relatively stronger ocean pre-conditioning can lead to EL, weaker ocean pre-conditioning and weaker WWA can generate EM, while stronger ocean preconditioning and weaker WWA can lead to basinwide warming pattern. The strength of the WWA is crucial in determining the strength of the ocean dynamic response and the thermocline displacements in the Pacific. The study has important implications for understanding the nature of El Niño in advance. PMID:26598274

  14. On the possible cause of distinct El Niño types in the recent decades

    PubMed Central

    Jadhav, Jyoti; Panickal, Swapna; Marathe, Shamal; Ashok, K.

    2015-01-01

    Distinct El Niño types have been observed in the recent decades with warm anomalies in the eastern Pacific (Canonical El Niño, EL) and central Pacific (El Niño Modoki, EM). Among these, a basinwide tropical Pacific (TP) warming is seen during 2009 and recently during 2014. We carried out data analysis and numerical simulation experiments to understand the possible cause for different El Niño flavours. The results reveal that the co-evolution of ocean-atmospheric conditions are critically important. Stronger boreal spring (Mar-May) through summer (June-September) westerly wind anomalies (WWA), with relatively stronger ocean pre-conditioning can lead to EL, weaker ocean pre-conditioning and weaker WWA can generate EM, while stronger ocean preconditioning and weaker WWA can lead to basinwide warming pattern. The strength of the WWA is crucial in determining the strength of the ocean dynamic response and the thermocline displacements in the Pacific. The study has important implications for understanding the nature of El Niño in advance. PMID:26598274

  15. Variability in soil CO2 efflux across distinct urban land cover types

    NASA Astrophysics Data System (ADS)

    Weissert, Lena F.; Salmond, Jennifer A.; Schwendenmann, Luitgard

    2015-04-01

    As a main source of greenhouse gases urban areas play an important role in the global carbon cycle. To assess the potential role of urban vegetation in mitigating carbon emissions we need information on the magnitude of biogenic CO2 emissions and its driving factors. We examined how urban land use types (urban forest, parklands, sportsfields) vary in their soil CO2 efflux. We measured soil CO2 efflux and its isotopic signature, soil temperature and soil moisture over a complete growing season in Auckland, New Zealand. Soil physical and chemical properties and vegetation characteristics were also measured. Mean soil CO2 efflux ranged from 4.15 to 12 μmol m-2 s-1. We did not find significant differences in soil CO2 efflux among land cover types due to high spatial variability in soil CO2 efflux among plots. Soil (soil carbon and nitrogen density, texture, soil carbon:nitrogen ratio) and vegetation characteristics (basal area, litter carbon density, grass biomass) were not significantly correlated with soil CO2 efflux. We found a distinct seasonal pattern with significantly higher soil CO2 efflux in autumn (Apr/May) and spring (Oct). In urban forests and sportsfields over 80% of the temporal variation was explained by soil temperature and soil water content. The δ13C signature of CO2 respired from parklands and sportsfields (-20 permil - -25 permil) were more positive compared to forest plots (-29 permil) indicating that parkland and sportsfields had a considerable proportion of C4 grasses. Despite the large intra-urban variability, our results compare to values reported from other, often climatically different cities, supporting the hypothesis of homogenization across urban areas as a result of human management practices.

  16. Distinct impact of different types of aerosols on surface solar radiation in China

    NASA Astrophysics Data System (ADS)

    Yang, Xin; Zhao, Chuanfeng; Zhou, Lijing; Wang, Yang; Liu, Xiaohong

    2016-06-01

    Observations of surface direct solar radiation (DSR) and visibility, particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5), together with the aerosol optical thickness (AOT) taken from Moderate-Resolution Imaging Spectroradiometer and Multiangle Imaging Spectroradiometer, were investigated to gain insight into the impact of aerosol pollution on surface solar radiation in China. The surface DSR decreased during 2004-2014 compared with 1993~2003 over eastern China, but no clear reduction was observed in remote regions with cleaner air. Significant correlations of visibility, PM2.5, and regionally averaged AOT with the surface DSR over eastern China indicate that aerosol pollution greatly affects the energy available at the surface. The net loss of surface solar radiation also reduces the surface ground temperature over eastern China. However, the slope of the linear variation of the radiation with respect to atmospheric visibility is distinctly different at different stations, implying that the main aerosol type varies regionally. The largest slope value occurs at Zhengzhou and indicates that the aerosol absorption in central China is the highest, and lower slope values suggest relatively weakly absorbing types of aerosols at other locations. The spatial distribution of the linear slopes agrees well with the geographical distribution of the absorbing aerosols derived from the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations and Ozone Monitoring Instrument over China. The regional correlation between a larger slope value and higher absorbance properties of aerosols indicates that the net effects of aerosols on the surface solar energy and corresponding climatic effects are dependent on both aerosol amount and optical properties.

  17. Cardiomyocytes hypertrophic status after myocardial infarction determines distinct types of arrhythmia: role of the ryanodine receptor.

    PubMed

    Fauconnier, Jérémy; Pasquié, Jean-Luc; Bideaux, Patrice; Lacampagne, Alain; Richard, Sylvain

    2010-09-01

    The mechanisms responsible for sudden cardiac death in heart failure (HF) are unclear. We investigated early and delayed afterdepolarizations (EADs, DADs) in HF. Cardiomyocytes were enzymatically isolated from the right ventricle (RV) and the septum of rats 8 weeks after myocardial infarction (MI) and sham-operated animals. Membrane capacitance, action potentials (AP) and ionic currents were measured by whole-cell patch-clamp. The [Ca(2+)](i) transients and Ca(2+) sparks were recorded with Fluo-4 during fluorescence measurements. Arrhythmia was triggered in 40% of MI cells (not in sham) using trains of 5 stimulations at 2.0 Hz. EADs and DADs occurred in distinct cell populations both in the RV and the septum. EADs occurred in normal-sized PMI cells (<230 pF), whereas DADs occurred in hypertrophic PMI cells (>230 pF). All cells exhibited prolonged APs due to reduced I(to) current. However, additional modifications in Ca(2+)-dependent ionic currents occurred in hypertrophic cells: a decrease in the inward rectifier K(+) current I(K1), and a slowing of L-type Ca(2+) current inactivation which was responsible for the lack of adaptation of APs to abrupt changes in the pacing rate. The occurrence of spontaneous Ca(2+) sparks, reflecting ryanodine receptor (RyR2) diastolic activity, increased with hypertrophy. The [Ca(2+)](i) transient amplitude, sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) sparks amplitude were all inversely correlated with cell size. We conclude that the trophic status of cardiomyocytes determines the type of cellular arrhythmia in MI rats, based on differential electrophysiological remodeling which may reflect early-mild and late-severe or differential modifications in the RyR2 function. PMID:20109482

  18. Distinct types of tumors exhibit differential grade of inflammation and angiogenesis in mice.

    PubMed

    Viana, C T R; Campos, P P; Carvalho, L A; Cenedezi, J M; Lavall, L; Lopes, M T P; Ferreira, M A N D; Andrade, S P

    2013-03-01

    Inflammation, angiogenesis and cytokine production are common features of almost, if not all tumors. However, the extent of these processes induced by different types of tumors has not been evaluated. We investigated the growth pattern of the experimental metastatic tumors, B16F10 melanoma, CT26.WT colon and 4T1 mammary cells inoculated in the flank of syngeneic mice and determined the degree of inflammation, angiogenesis, and production level of pro-inflammatory and pro-angiogenic cytokines within the tumors. In addition, we have analyzed vascular changes in the interface between the tumors and the adjacent cutaneous tissue and levels of relevant pro-inflammatory and pro-angiogenic cytokines systemically. The weight of tumors 15 days post-inoculation of 10(6) cells was markedly different. Melanomas were 2 and 10-fold heavier than colon and mammary tumors, respectively. Locally, CT26.WT tumor cells induced more vessels in cutaneous tissue adjacent to the tumors but systemically, the plasma levels of VEGF were higher (approximately 2-fold) in 4T1 tumor-bearing mice compared with the other two tumors. Mammary tumors presented the most prominent inflammatory content as assessed by a range of markers (inflammatory enzymes and cytokines). The vascular index, as determined by the intra-tumor amount of hemoglobin and number of vessels in hot spot areas, was also higher (approximately 2-fold) in melanomas compared with the other two tumors. These findings showing that distinct tumor types determine differential grade of inflammation, angiogenesis and host interaction in mice may provide new insights to tailor differential therapeutic approach based on the status of tumor biomarkers. PMID:23253264

  19. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

    PubMed Central

    Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C.; Dinger, Katharina; Wempe, Frank; Wohl, Alexander P.; Imhof, Thomas; Wunderlich, F. Thomas; Bunck, Alexander C.; Nakamura, Tomoyuki; Koli, Katri; Bloch, Wilhelm; Ghanem, Alexander; Heinz, Andrea; von Melchner, Harald; Sengle, Gerhard; Sterner-Kock, Anja

    2015-01-01

    Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S−/−), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S−/− and Ltbp4-null (Ltbp4−/−) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C. PMID:25713297

  20. FAMA is an essential component for the differentiation of two distinct cell types, myrosin cells and guard cells, in Arabidopsis.

    PubMed

    Shirakawa, Makoto; Ueda, Haruko; Nagano, Atsushi J; Shimada, Tomoo; Kohchi, Takayuki; Hara-Nishimura, Ikuko

    2014-10-01

    Brassicales plants, including Arabidopsis thaliana, have an ingenious two-compartment defense system, which sequesters myrosinase from the substrate glucosinolate and produces a toxic compound when cells are damaged by herbivores. Myrosinase is stored in vacuoles of idioblast myrosin cells. The molecular mechanism that regulates myrosin cell development remains elusive. Here, we identify the basic helix-loop-helix transcription factor FAMA as an essential component for myrosin cell development along Arabidopsis leaf veins. FAMA is known as a regulator of stomatal development. We detected FAMA expression in myrosin cell precursors in leaf primordia in addition to stomatal lineage cells. FAMA deficiency caused defects in myrosin cell development and in the biosynthesis of myrosinases THIOGLUCOSIDE GLUCOHYDROLASE1 (TGG1) and TGG2. Conversely, ectopic FAMA expression conferred myrosin cell characteristics to hypocotyl and root cells, both of which normally lack myrosin cells. The FAMA interactors ICE1/SCREAM and its closest paralog SCREAM2/ICE2 were essential for myrosin cell development. DNA microarray analysis identified 32 candidate genes involved in myrosin cell development under the control of FAMA. This study provides a common regulatory pathway that determines two distinct cell types in leaves: epidermal guard cells and inner-tissue myrosin cells. PMID:25304202

  1. IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells.

    PubMed

    Saenz, Steven A; Siracusa, Mark C; Monticelli, Laurel A; Ziegler, Carly G K; Kim, Brian S; Brestoff, Jonathan R; Peterson, Lance W; Wherry, E John; Goldrath, Ananda W; Bhandoola, Avinash; Artis, David

    2013-08-26

    The predominantly epithelial cell-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) can promote CD4(+) Th2 cell-dependent immunity, inflammation, and tissue repair at barrier surfaces through the induction of multiple innate immune cell populations. IL-25 and IL-33 were previously shown to elicit four innate cell populations, named natural helper cells, nuocytes, innate type 2 helper cells, and multipotent progenitor type 2 (MPP(type2)) cells, now collectively termed group 2 innate lymphoid cells (ILC2). In contrast to other types of ILC2, MPP(type2) cells exhibit multipotent potential and do not express T1/ST2 or IL-7Rα, suggesting that MPP(type2) cells may be a distinct population. Here, we show that IL-33 elicits robust ILC2 responses, whereas IL-25 predominantly promotes MPP(type2) cell responses at multiple tissue sites with limited effects on ILC2 responses. MPP(type2) cells were distinguished from ILC2 by their differential developmental requirements for specific transcription factors, distinct genome-wide transcriptional profile, and functional potential. Furthermore, IL-25-induced MPP(type2) cells promoted Th2 cytokine-associated inflammation after depletion of ILC2. These findings indicate that IL-25 simultaneously elicits phenotypically and functionally distinct innate lymphoid- and nonlymphoid-associated cell populations and implicate IL-25-elicited MPP(type2) cells and extramedullary hematopoiesis in the promotion of Th2 cytokine responses at mucosal surfaces. PMID:23960191

  2. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex

    PubMed Central

    Kvitsiani, D.; Ranade, S.; Hangya, B.; Taniguchi, H.; Huang, JZ.; Kepecs, A.

    2013-01-01

    Neurons in prefrontal cortex exhibit diverse behavioural correlates1–4, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically-defined inhibitory interneuron classes, the perisomatically-targeting parvalbumin (Pv) and the dendritically-targeting somatostatin (Som) neurons5–8 in anterior cingulate cortex (ACC) of mice performing a reward foraging task. Here we show that Pv and a subtype of Som neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory impact and behavioural correlates. Out of a number of events pertaining to behaviour, a subtype of Som neurons selectively responded at reward approach, while Pv neurons responded at reward leaving encoding preceding stay duration. These behavioural correlates of Pv and Som neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to ACC9–11. Furthermore, Pv neurons could fire in millisecond synchrony exerting fast and powerful inhibition on principal cell firing, while the inhibitory impact of Som neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of and inputs to principal neurons12–16. These results suggest a connection between the circuit-level function of different interneuron-types in regulating the flow of information, and the behavioural functions served by the cortical circuits. Moreover these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity. PMID:23708967

  3. Distinct neural patterns enable grasp types decoding in monkey dorsal premotor cortex

    NASA Astrophysics Data System (ADS)

    Hao, Yaoyao; Zhang, Qiaosheng; Controzzi, Marco; Cipriani, Christian; Li, Yue; Li, Juncheng; Zhang, Shaomin; Wang, Yiwen; Chen, Weidong; Chiara Carrozza, Maria; Zheng, Xiaoxiang

    2014-12-01

    Objective. Recent studies have shown that dorsal premotor cortex (PMd), a cortical area in the dorsomedial grasp pathway, is involved in grasp movements. However, the neural ensemble firing property of PMd during grasp movements and the extent to which it can be used for grasp decoding are still unclear. Approach. To address these issues, we used multielectrode arrays to record both spike and local field potential (LFP) signals in PMd in macaque monkeys performing reaching and grasping of one of four differently shaped objects. Main results. Single and population neuronal activity showed distinct patterns during execution of different grip types. Cluster analysis of neural ensemble signals indicated that the grasp related patterns emerged soon (200-300 ms) after the go cue signal, and faded away during the hold period. The timing and duration of the patterns varied depending on the behaviors of individual monkey. Application of support vector machine model to stable activity patterns revealed classification accuracies of 94% and 89% for each of the two monkeys, indicating a robust, decodable grasp pattern encoded in the PMd. Grasp decoding using LFPs, especially the high-frequency bands, also produced high decoding accuracies. Significance. This study is the first to specify the neuronal population encoding of grasp during the time course of grasp. We demonstrate high grasp decoding performance in PMd. These findings, combined with previous evidence for reach related modulation studies, suggest that PMd may play an important role in generation and maintenance of grasp action and may be a suitable locus for brain-machine interface applications.

  4. Tectonically Undulating Terrestrial Geospheres and Concordant Development of Two Distinct Somatic Types of Man

    NASA Astrophysics Data System (ADS)

    Kochemasov, G. G.

    The human organisms in microgravity conditions loss Ca or become less dense. But variously dense men also develop on Earth due to varying tectonics. As any celestial body, Earth is not a billiard-ball but is complexly warped by a number of standing waves imprinted in the geoid shape. The fundamental wave (long 2π R, R- planet radius) makes tectonic dichotomy (an opposition of the eastern and western oceanic hemispheres), the first overtone (π R) makes sectoring: on the continental eastern hemisphere, for example, around the Pamirs-Hindukush converge 4 sectors. They are 2 opposed differently uplifted (African ++, Asian +) separated by 2 opposed differently subsided (Eurasian -, Indoceanic - -). In rotating Earth the alternating uplifts (++, +) and subsidences (- -, -) require materials of different densities: less dense for uplifts and denser for subsidences. This requirement concerns all geospheres including anthroposphere. The long development of Homo sapiens adapting to graviconditions of uplifting and subsiding blocks produced two distinct somatic types of man: long and narrow (slim) leptosomes and short and broad eirisomes. As shows F. Weidenreich [1], this fundamental division appeared very early in the human history and is observed in all great human races and even in apes. A block uplifting (an increase of the planetary radius) requires diminishing density. This is achieved by distributing the man's weight by the longer stature. Thus appears long and slim leptosome. On the contrary, a block subsidence (diminishing radius) requires increasing density: man is shorter and broader (eirisome). A long existence on intensively moving (up or down) blocks makes these somatic types characteristic of races. Thus, many African tribes developing on intensively moving up continent (more than one kilometer in a few mln. y. ) are leptosomatic; on the contrary, Indians of subsiding western hemisphere are typically eirisomatic with high Rohrer's index; Polynesians of

  5. Quantitative Morphometry of Electrophysiologically Identified CA3b Interneurons Reveals Robust Local Geometry and Distinct Cell Classes

    PubMed Central

    Ascoli, Giorgio A.; Brown, Kerry M.; Calixto, Eduardo; Card, J. Patrick; Galvan, E. J.; Perez-Rosello, T.; Barrionuevo, Germán

    2010-01-01

    The morphological and electrophysiological diversity of inhibitory cells in hippocampal area CA3 may underlie specific computational roles and is not yet fully elucidated. In particular, interneurons with somata in strata radiatum (R) and lacunosum-moleculare (L-M) receive converging stimulation from the dentate gyrus and entorhinal cortex as well as within CA3. Although these cells express different forms of synaptic plasticity, their axonal trees and connectivity are still largely unknown. We investigated the branching and spatial patterns, plus the membrane and synaptic properties, of rat CA3b R and L-M interneurons digitally reconstructed after intracellular labeling. We found considerable variability within but no difference between the two layers, and no correlation between morphological and biophysical properties. Nevertheless, two cell types were identified based on the number of dendritic bifurcations, with significantly different anatomical and electrophysiological features. Axons generally branched an order of magnitude more than dendrites. However, interneurons on both sides of the R/L-M boundary revealed surprisingly modular axo-dendritic arborizations with consistently uniform local branch geometry. Both axons and dendrites followed a lamellar organization, and axons displayed a spatial preference towards the fissure. Moreover, only a small fraction of the axonal arbor extended to the outer portion of the invaded volume, and tended to return towards the proximal region. In contrast, dendritic trees demonstrated more limited but isotropic volume occupancy. These results suggest a role of predominantly local feedforward and lateral inhibitory control for both R and L-M interneurons. Such role may be essential to balance the extensive recurrent excitation of area CA3 underlying hippocampal autoassociative memory function. PMID:19496174

  6. Identifying distinct phytoplankton regions based on ocean colour data supplemented by in-situ and model data

    NASA Astrophysics Data System (ADS)

    Eliasen, Solva; Hátún, Hjálmar; Margretha Larsen, Karin; Hansen, Bogi

    2016-04-01

    The Faroe Shelf hosts a rich and diverse marine ecosystem, which sustains a large portion of the economy of the Islands. The primary production, even though often referred to as being important to the higher trophic levels, is still not thoroughly understood. A high resolution chlorophyll time series from coastal station S, dating back to 1997, has given valuable information about the phytoplankton concentrations on the central shelf, and interannual fluctuations (with a factor of 4-5) in this time series have been linked to several other biological indicators. However, with regards to phytoplankton and primary production farther off-shore, only CTD fluorescence observations from research cruises are available and a thorough analysis of these temporally and spatially scattered data is difficult to conduct and yet to be done. Thus, the spatial extent of the region, for which the station S phytoplankton concentrations are representative, is not well defined. In this study we compare satellite ocean colour data from 1998-2015 with in-situ data from station S and identify the region which station S represents. Moreover, we use the ocean colour data to identity biogeographical regions in which phytoplankton is uniquely and coherently varying and compare these with the breeding and feeding grounds of commercially important fish stocks. The surface chlorophyll pattern does not necessarily represent the primary production in the water column. We therefore supplement the results with hydrographic observations and model simulations and from these extract information about the total carbon production in the various regions. The ocean colour data are consistent with the in-situ observations and the results from combining these with the other data types have enhanced our understanding of timing and strength of the phytoplankton spring bloom farther off-shore and contribute to the understanding of the shelf ecosystem in general.

  7. Spread of distinct human immunodeficiency virus type 1 AG recombinant lineages in Africa.

    PubMed

    Cornelissen, M; van Den Burg, R; Zorgdrager, F; Goudsmit, J

    2000-02-01

    To identify new subtype G human immunodeficiency virus type 1 (HIV-1) strains and AG recombinant forms, we collected 28 serum samples from immigrants to the Netherlands from 12 countries throughout Africa. Based on the gag sequences 22 isolates were identified as subtype A or G. Phylogenetic analysis of discontinuous regions of the gag (726 nt), pol (1176 nt) and env (276 nt) genes revealed 13 AG recombinants with the mosaic structure A(gag)/G(pol)/A(env), three with A(gag)/G(pol)/G(env) and one other with A(gag) /G(pol)/G(env), in addition to 'pure' subtypes A(gag)/A(pol)/A(env) (n=1) and G(gag)/G(pol)/G(env) (n=4). To analyse the crossover points in more detail, a new RT-PCR was developed resulting in a large contiguous sequence of 2600 nt from the gag region to half the pol region. All the 13 A(gag)/G(pol)/A(env) recombinants appeared to belong to the circulating recombinant form (CRF) AG (IbNG). The three A(gag)/G(pol) /G(env) recombinants differed from the CRF AG (IbNG) subtype, suggesting the identification of a new CRF subtype. The recovery of AG recombinants from African countries a thousand miles apart indicates the active spread of new recombinants. PMID:10644851

  8. Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers

    PubMed Central

    Harryman, William L; Pond, Erika; Singh, Parminder; Little, Andrew S; Eschbacher, Jennifer M; Nagle, Raymond B; Cress, Anne E

    2016-01-01

    .0432*). Querying the in vitro drug resistance profiles with the LBI signature demonstrated a positive correlation with cells resistant to inhibitors of HDAC (Vorinostat, Panobinostat) and topoisomerase II (Irinotecan). No correlation was found with the following agents: Bleomycin, Doxorubicin, Methotrexate, Gemcitabine, Docetaxel, Bortezomib, and Shikonen. Conclusions: Our work has identified epithelial-types of human cancer that have significant CNA in our selected five-gene signature, which was based on the essential and genetically-defined functions of the protein product networks (in this case, the LBI axis). CNA of the gene signature not only predicted overall survival in bladder, cervical, and endocervical adenocarcinoma but also response to chemotherapy. This work suggests that future studies designed to optimize the gene signature are warranted. General Significance: The copy number alteration of structural components of the LBI axis in epithelial-type tumors may be promising biomarkers and rational targets for personalized therapy in preventing or arresting metastatic spread. PMID:27158381

  9. Integrating Diverse Types of Genomic Data to Identify Genes that Underlie Adverse Pregnancy Phenotypes

    PubMed Central

    Hirbo, Jibril; Eidem, Haley; Rokas, Antonis; Abbot, Patrick

    2015-01-01

    Progress in understanding complex genetic diseases has been bolstered by synthetic approaches that overlay diverse data types and analyses to identify functionally important genes. Pre-term birth (PTB), a major complication of pregnancy, is a leading cause of infant mortality worldwide. A major obstacle in addressing PTB is that the mechanisms controlling parturition and birth timing remain poorly understood. Integrative approaches that overlay datasets derived from comparative genomics with function-derived ones have potential to advance our understanding of the genetics of birth timing, and thus provide insights into the genes that may contribute to PTB. We intersected data from fast evolving coding and non-coding gene regions in the human and primate lineage with data from genes expressed in the placenta, from genes that show enriched expression only in the placenta, as well as from genes that are differentially expressed in four distinct PTB clinical subtypes. A large fraction of genes that are expressed in placenta, and differentially expressed in PTB clinical subtypes (23–34%) are fast evolving, and are associated with functions that include adhesion neurodevelopmental and immune processes. Functional categories of genes that express fast evolution in coding regions differ from those linked to fast evolution in non-coding regions. Finally, there is a surprising lack of overlap between fast evolving genes that are differentially expressed in four PTB clinical subtypes. Integrative approaches, especially those that incorporate evolutionary perspectives, can be successful in identifying potential genetic contributions to complex genetic diseases, such as PTB. PMID:26641094

  10. Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer.

    PubMed

    Koski, Taru A; Lehtonen, Heli J; Jee, Kowan J; Ninomiya, Shinsuke; Joosse, Simon A; Vahteristo, Pia; Kiuru, Maija; Karhu, Auli; Sammalkorpi, Heli; Vanharanta, Sakari; Lehtonen, Rainer; Edgren, Henrik; Nederlof, Petra M; Hietala, Marja; Aittomäki, Kristiina; Herva, Riitta; Knuutila, Sakari; Aaltonen, Lauri A; Launonen, Virpi

    2009-07-01

    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome with cutaneous and uterine leiomyomatosis as well as renal cell cancer (RCC) as its clinical manifestations. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (fumarase) gene. In this study, we used array comparative genomic hybridization to identify the specific copy number changes characterizing the HLRCC-associated RCCs. The study material comprised formalin-fixed paraffin-embedded renal tumors obtained from Finnish patients with HLRCC. All 11 investigated tumors displayed the papillary type 2 histopathology typical for HLRCC renal tumors. The most frequent copy number changes detected in at least 3/11 (27%) of the tumors were gains in chromosomes 2, 7, and 17, and losses in 13q12.3-q21.1, 14, 18, and X. These findings provide genetic evidence for a distinct copy number profile in HLRCC renal tumors compared with sporadic RCC tumors of the same histopathological subtype, and delineate chromosomal regions that associate with this very aggressive form of RCC. PMID:19373782

  11. Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip

    PubMed Central

    FitzGerald, Edward A.; Park, Tae-Eun; Sleeboom, Jelle J. F.; Ingber, Donald E.

    2016-01-01

    Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel’s inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types. PMID:26930059

  12. Distinct photoluminescence and Raman spectroscopy signatures for identifying highly crystalline WS2 monolayers produced by different growth methods

    DOE PAGESBeta

    McCreary, Amber; Berkdemir, Ayse; Wang, Junjie; Nguyen, Minh An; Elías, Ana Laura; Perea-López, Néstor; Fujisawa, Kazunori; Kabius, Bernd; Carozo, Victor; Cullen, David A.; et al

    2016-03-08

    We report that transition metal dichalcogenides (TMDs) such as WS2 show exciting promise in electronic and optoelectronic applications. Significant variations in the transport, Raman, and photoluminescence (PL) can be found in the literature, yet it is rarely addressed why this is. In this report, Raman and PL of monolayered WS2 produced via different methods are studied and distinct features that indicate the degree of crystallinity of the material are observed. While the intensity of the LA(M) Raman mode is found to be a useful indicator to assess the crystallinity, PL is drastically more sensitive to the quality of the materialmore » than Raman spectroscopy. We also show that even exfoliated crystals, which are usually regarded as the most pristine material, can contain large amounts of defects that would not be apparent without Raman and PL measurements. Ultimately, these findings can be applied to the understanding of other two-dimensional heterostructured systems.« less

  13. Comparative pathogenicity of three genetically distinct types of Trypanosoma congolense in cattle: clinical observations and haematological changes.

    PubMed

    Bengaly, Z; Sidibe, I; Ganaba, R; Desquesnes, M; Boly, H; Sawadogo, L

    2002-08-30

    The pathology of African bovine trypanosomosis was compared in Zebu cattle subcutaneously inoculated with three clones of trypanosomes corresponding to the three genetically distinct types of Trypanosoma congolense; savannah-type, west African riverine/forest-type and kilifi-type. All inoculated animals became parasitaemic between 7 and 11 days post-infection (dpi). The savannah-type showed consistently higher levels of parasitaemia and lower packed red cell volume percentages and leukocyte counts than the other two types. The syndrome was also more severe in the savannah-type and led inexorably to death between 29 and 54 dpi while animals with the forest or the kilifi-types recovered from earlier symptoms and haematological alterations after 3 months of infection. By the end of the experiment, the animals self-cured from the forest-type infection and the kilifi-type passed under control. The results of the present study indicated clear difference in pathogenicity between the three types of T. congolense; the savannah-type was virulent while the forest-type was of low pathogenicity and the kilifi-type was non-pathogenic. PMID:12191895

  14. Mutant Thyroid Hormone Receptors (TRs) Isolated from Distinct Cancer Types Display Distinct Target Gene Specificities: a Unique Regulatory Repertoire Associated with Two Renal Clear Cell Carcinomas

    PubMed Central

    Rosen, Meghan D.; Chan, Ivan H.

    2011-01-01

    Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that regulate a diverse array of biological activities, including metabolism, homeostasis, and development. TRs also serve as tumor suppressors, and aberrant TR function (via mutation, deletion, or altered expression) is associated with a spectrum of both neoplastic and endocrine diseases. A particularly high frequency of TR mutations has been reported in renal clear cell carcinoma (RCCC) and in hepatocellular carcinoma (HCC). We have shown that HCC-TR mutants regulate only a fraction of the genes targeted by wild-type TRs but have gained the ability to regulate other, unique, targets. We have suggested that this altered gene recognition may contribute to the neoplastic phenotype. Here, to determine the generality of this phenomenon, we examined a distinct set of TR mutants associated with RCCC. We report that two different TR mutants, isolated from independent RCCC tumors, possess greatly expanded target gene specificities that extensively overlap one another, but only minimally overlap that of the wild-type TRs, or those of two HCC-TR mutants. Many of the genes targeted by either or both RCCC-TR mutants have been previously implicated in RCCC and include a series of metallothioneins, solute carriers, and genes involved in glycolysis and energy metabolism. We propose as a hypothesis that TR mutations from RCCC and HCC may play tissue-specific roles in carcinogenesis, and that the divergent target gene recognition patterns of TR mutants isolated from the two different types of tumors may arise from different selective pressures during development of RCCC vs. HCC. PMID:21622534

  15. Steady state or non-steady state? Identifying driving mechanisms of oxygen isotope signatures of leaf transpiration in functionally distinct plant species

    NASA Astrophysics Data System (ADS)

    Dubbert, Maren; Kübert, Angelika; Cuntz, Matthias; Werner, Christiane

    2015-04-01

    Isotope techniques are widely applied in ecosystem studies. For example, isoflux models are used to separate soil evaporation from transpiration in ecosystems. These models often assume that plant transpiration occurs at isotopic steady state, i.e. that the transpired water shows the same isotopic signature as the source water. Yet, several studies found that transpiration did not occur at isotopic steady state, under both controlled and field conditions. Here we focused on identifying the internal and external factors which drive the isotopic signature of leaf transpiration. Using cavity ring-down spectroscopy (CRDS), the effect of both environmental variables and leaf physiological traits on δ18OT was investigated under controlled conditions. Six plant species with distinct leaf physiological traits were exposed to step changes in relative air humidity (RH), their response in δ18OT and gas exchange parameters and their leaf physiological traits were assessed. Moreover, two functionally distinct plant types (tree, i.e. Quercus suber, and grassland) of a semi-arid Mediterranean oak-woodland where observed under natural conditions throughout an entire growth period in the field. The species differed substantially in their leaf physiological traits and their turn-over times of leaf water. They could be grouped in species with fast (<60 min.), intermediate (ca. 120 min.) and slow (>240 min.) turn-over times, mostly due to differences in stomatal conductance, leaf water content or a combination of both. Changes in RH caused an immediate response in δ18OT, which were similarly strong in all species, while leaf physiological traits affected the subsequent response in δ18OT. The turn-over time of leaf water determined the speed of return to the isotopic steady or a stable δ18OT value (Dubbert & Kübert et al., in prep.). Under natural conditions, changes in environmental conditions over the diurnal cycle had a huge impact on the diurnal development of δ18OT in both

  16. A genome-wide RNAi screen identifies factors required for distinct stages of C. elegans piRNA biogenesis

    PubMed Central

    Goh, Wee-Siong Sho; Seah, Jun Wen Eugene; Harrison, Emily J.; Chen, Caifu; Hammell, Christopher M.; Hannon, Gregory J.

    2014-01-01

    In animals, piRNAs and their associated Piwi proteins guard germ cell genomes against mobile genetic elements via an RNAi-like mechanism. In Caenorhabditis elegans, 21U-RNAs comprise the piRNA class, and these collaborate with 22G RNAs via unclear mechanisms to discriminate self from nonself and selectively and heritably silence the latter. Recent work indicates that 21U-RNAs are post-transcriptional processing products of individual transcription units that produce ∼26-nucleotide capped precursors. However, nothing is known of how the expression of precursors is controlled or how primary transcripts give rise to mature small RNAs. We conducted a genome-wide RNAi screen to identify components of the 21U biogenesis machinery. Screening by direct, quantitative PCR (qPCR)-based measurements of mature 21U-RNA levels, we identified 22 genes important for 21U-RNA production, termed TOFUs (Twenty-One-u Fouled Ups). We also identified seven genes that normally repress 21U production. By measuring mature 21U-RNA and precursor levels for the seven strongest hits from the screen, we assigned factors to discrete stages of 21U-RNA production. Our work identifies for the first time factors separately required for the transcription of 21U precursors and the processing of these precursors into mature 21U-RNAs, thereby providing a resource for studying the biogenesis of this important small RNA class. PMID:24696458

  17. Occurrence of two distinct types of tissue inhibitors of metallo-proteinases-2 in Fugu rubripes

    NASA Astrophysics Data System (ADS)

    Yokoyama, Yoshihiro; Tsukamoto, Hiroshi; Suzuki, Tohru; Mizuta, Shohshi; Yoshinaka, Reiji

    2005-07-01

    In this study, genes of two distinct tissue inhibitors of metalloproteinases-2 (TIMP-2) from Japanese puffer fish Fugu rubripes, Fugu TIMP-2a and TIMP-2b, were cloned. The open reading frames of Fugu TIMP-2a and TIMP-2b cDNAs are composed of 660 and 657 nucleotides and 220 and 219 amino acids, respectively. Both Fugu TIMP-2s contain 12 cysteine residues, which might form six disulfide bonds as in other animals’ TIMP-2s. Reverse-transcribed polymerase chain reaction analysis showed the mRNAs of Fugu TIMP-2a and TIMP-2b to be expressed in some tissues examined with different expression patterns. These findings suggest that the two distinct Fugu TIMP-2s might perform different functions in Fugu tissues.

  18. Distinct facilitated diffusion mechanisms by E. coli Type II restriction endonucleases.

    PubMed

    Pollak, Adam J; Chin, Aaron T; Reich, Norbert O

    2014-11-18

    The passive search by proteins for particular DNA sequences involving nonspecific DNA is essential for gene regulation, DNA repair, phage defense, and diverse epigenetic processes. Distinct mechanisms contribute to these searches, and it remains unresolved as to which mechanism or blend of mechanisms best suits a particular protein and, more importantly, its biological role. To address this, we compare the translocation properties of two well-studied bacterial restriction endonucleases (ENases), EcoRI and EcoRV. These dimeric, magnesium-dependent enzymes hydrolyze related sites (EcoRI ENase, 5'-GAATTC-3'; EcoRV ENase, 5'-GATATC-3'), leaving overhangs and blunt DNA segments, respectively. Here, we demonstrate that the extensive sliding by EcoRI ENase, involving sliding up to ∼600 bp prior to dissociating from the DNA, contrasts with a larger reliance on hopping mechanism(s) by EcoRV ENase. The mechanism displayed by EcoRI ENase results in a highly thorough search of DNA, whereas the EcoRV ENase mechanism results in an extended, yet less rigorous, interrogation of DNA sequence space. We describe how these mechanistic distinctions are complemented by other aspects of these endonucleases, such as the 10-fold higher in vivo concentrations of EcoRI ENase compared to that of EcoRV ENase. Further, we hypothesize that the highly diverse enzyme arsenal that bacteria employ against foreign DNA involves seemingly similar enzymes that rely on distinct but complementary search mechanisms. Our comparative approach reveals how different proteins utilize distinct site-locating strategies. PMID:25350874

  19. Reciprocal Phosphorylation of Yeast Glycerol-3-Phosphate Dehydrogenases in Adaptation to Distinct Types of Stress

    PubMed Central

    Lee, Yong Jae; Jeschke, Grace R.; Roelants, Françoise M.; Thorner, Jeremy

    2012-01-01

    Eukaryotic cells have evolved mechanisms for ensuring growth and survival in the face of stress caused by a fluctuating environment. Saccharomyces cerevisiae has two homologous glycerol-3-phosphate dehydrogenases, Gpd1 and Gpd2, that are required to endure various stresses, including hyperosmotic shock and hypoxia. These enzymes are only partially redundant, and their unique functions were attributed previously to differential transcriptional regulation and localization. We find that Gpd1 and Gpd2 are negatively regulated through phosphorylation by distinct kinases under reciprocal conditions. Gpd2 is phosphorylated by the AMP-activated protein kinase Snf1 to curtail glycerol production when nutrients are limiting. Gpd1, in contrast, is a target of TORC2-dependent kinases Ypk1 and Ypk2. Inactivation of Ypk1 by hyperosmotic shock results in dephosphorylation and activation of Gpd1, accelerating recovery through increased glycerol production. Gpd1 dephosphorylation acts synergistically with its transcriptional upregulation, enabling long-term growth at high osmolarity. Phosphorylation of Gpd1 and Gpd2 by distinct kinases thereby enables rapid adaptation to specific stress conditions. Introduction of phosphorylation motifs targeted by distinct kinases provides a general mechanism for functional specialization of duplicated genes during evolution. PMID:22988299

  20. Distinct firing patterns of identified basket and dendrite-targeting interneurons in the prefrontal cortex during hippocampal theta and local spindle oscillations.

    PubMed

    Hartwich, Katja; Pollak, Thomas; Klausberger, Thomas

    2009-07-29

    The medial prefrontal cortex is involved in working memory and executive control. However, the collective spatiotemporal organization of the cellular network has not been possible to explain during different brain states. We show that pyramidal cells in the prelimbic cortex fire synchronized to hippocampal theta and local spindle oscillations in anesthetized rats. To identify which types of interneurons contribute to the synchronized activity, we recorded and juxtacellularly labeled parvalbumin- and calbindin-expressing (PV+/CB+) basket cells and CB-expressing, PV-negative (CB+/PV-) dendrite-targeting interneurons during both network oscillations. All CB+/PV- dendrite-targeting cells strongly decreased their firing rate during hippocampal theta oscillations. Most PV+/CB+ basket cells fired at the peak of dorsal CA1 theta cycles, similar to prefrontal pyramidal cells. We show that pyramidal cells in the ventral hippocampus also fire around the peak of dorsal CA1 theta cycles, in contrast to previously reported dorsal hippocampal pyramidal cells. Therefore, prefrontal neurons might be driven by monosynaptic connections from the ventral hippocampus during theta oscillations. During prefrontal spindle oscillations, the majority of pyramidal cells and PV+/CB+ basket cells fired preferentially at the trough and early ascending phase, but CB+/PV- dendrite-targeting cells fired uniformly at all phases. We conclude that PV+/CB+ basket cells contribute to rhythmic responses of prefrontal pyramidal cells in relation to hippocampal and thalamic inputs and CB+/PV- dendrite-targeting cells modulate the excitability of dendrites and spines regardless of these field rhythms. Distinct classes of GABAergic interneuron in the prefrontal cortex contribute differentially to the synchronization of pyramidal cells during network oscillations. PMID:19641119

  1. Cluster Analysis in the COPDGene Study Identifies Subtypes of Smokers with Distinct Patterns of Airway Disease and Emphysema

    PubMed Central

    Castaldi, Peter J; Dy, Jennifer; Ross, James; Chang, Yale; Washko, George R; Curran-Everett, Douglas; Williams, Andre; Lynch, David A; Make, Barry J; Crapo, James D; Bowler, Russ P; Regan, Elizabeth A; Hokanson, John E; Kinney, Greg L; Han, Meilan K; Soler, Xavier; Ramsdell, Joseph W; Barr, R Graham; Foreman, Marilyn; van Beek, Edwin; Casaburi, Richard; Criner, Gerald J; Lutz, Sharon M; Rennard, Steven I; Santorico, Stephanie; Sciurba, Frank C; DeMeo, Dawn L; Hersh, Craig P; Silverman, Edwin K; Cho, Michael H

    2014-01-01

    Background There is notable heterogeneity in the clinical presentation of patients with COPD. To characterize this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene Study. Methods We applied a clustering method, k-means, to data from 10,192 smokers in the COPDGene Study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. Findings We identified four clusters that can be characterized as 1) relatively resistant smokers (i.e. no/mild obstruction and minimal emphysema despite heavy smoking), 2) mild upper zone emphysema predominant, 3) airway disease predominant, and 4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Interpretation Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants. PMID:24563194

  2. Connectivity from OR37 expressing olfactory sensory neurons to distinct cell types in the hypothalamus.

    PubMed

    Bader, Andrea; Klein, Bettina; Breer, Heinz; Strotmann, Jörg

    2012-01-01

    Olfactory sensory neurons (OSNs) which express a member from the OR37 subfamily of odorant receptor (OR) genes are wired to the main olfactory bulb (MOB) in a unique monoglomerular fashion; from these glomeruli an untypical connectivity into higher brain centers exists. In the present study we have investigated by DiI and transsynaptic tracing approaches how the connection pattern from these glomeruli into distinct hypothalamic nuclei is organized. The application of DiI onto the ventral domain of the bulb which harbors the OR37 glomeruli resulted in the labeling of fibers within the paraventricular nucleus (PVN) and supraoptic nucleus (SO) of the hypothalamus; some of these fibers were covered with varicose-like structures. No DiI-labeled cell somata were detectable in these nuclei. The data indicate that projection neurons which originate in the OR37 region of the MOB form direct connections into these nuclei. The cells that were labeled by the transsynaptic tracer WGA in these nuclei were further characterized. Their distribution pattern in the paraventricular nucleus was reminiscent of cells which produce distinct neuropeptides. Double labeling experiments confirmed that they contained vasopressin, but not the related neuropeptide oxytocin. Morphological analysis revealed that they comprise of magno- and parvocellular cells. A comparative investigation of the WGA-positive cells in the SO demonstrated that these were vasopressin-positive, as well, whereas oxytocin-producing cells of this nucleus also contained no transsynaptic tracer. Together, the data demonstrates a connectivity from OR37 expressing sensory neurons to distinct hypothalamic neurons with the same neuropeptide content. PMID:23162434

  3. Connectivity from OR37 expressing olfactory sensory neurons to distinct cell types in the hypothalamus

    PubMed Central

    Bader, Andrea; Klein, Bettina; Breer, Heinz; Strotmann, Jörg

    2012-01-01

    Olfactory sensory neurons (OSNs) which express a member from the OR37 subfamily of odorant receptor (OR) genes are wired to the main olfactory bulb (MOB) in a unique monoglomerular fashion; from these glomeruli an untypical connectivity into higher brain centers exists. In the present study we have investigated by DiI and transsynaptic tracing approaches how the connection pattern from these glomeruli into distinct hypothalamic nuclei is organized. The application of DiI onto the ventral domain of the bulb which harbors the OR37 glomeruli resulted in the labeling of fibers within the paraventricular nucleus (PVN) and supraoptic nucleus (SO) of the hypothalamus; some of these fibers were covered with varicose-like structures. No DiI-labeled cell somata were detectable in these nuclei. The data indicate that projection neurons which originate in the OR37 region of the MOB form direct connections into these nuclei. The cells that were labeled by the transsynaptic tracer WGA in these nuclei were further characterized. Their distribution pattern in the paraventricular nucleus was reminiscent of cells which produce distinct neuropeptides. Double labeling experiments confirmed that they contained vasopressin, but not the related neuropeptide oxytocin. Morphological analysis revealed that they comprise of magno- and parvocellular cells. A comparative investigation of the WGA-positive cells in the SO demonstrated that these were vasopressin-positive, as well, whereas oxytocin-producing cells of this nucleus also contained no transsynaptic tracer. Together, the data demonstrates a connectivity from OR37 expressing sensory neurons to distinct hypothalamic neurons with the same neuropeptide content. PMID:23162434

  4. Multilocus sequence typing identifies epidemic clones of Flavobacterium psychrophilum in Nordic countries.

    PubMed

    Nilsen, Hanne; Sundell, Krister; Duchaud, Eric; Nicolas, Pierre; Dalsgaard, Inger; Madsen, Lone; Aspán, Anna; Jansson, Eva; Colquhoun, Duncan J; Wiklund, Tom

    2014-05-01

    Flavobacterium psychrophilum is the causative agent of bacterial cold water disease (BCWD), which affects a variety of freshwater-reared salmonid species. A large-scale study was performed to investigate the genetic diversity of F. psychrophilum in the four Nordic countries: Denmark, Finland, Norway, and Sweden. Multilocus sequence typing of 560 geographically and temporally disparate F. psychrophilum isolates collected from various sources between 1983 and 2012 revealed 81 different sequence types (STs) belonging to 12 clonal complexes (CCs) and 30 singleton STs. The largest CC, CC-ST10, which represented almost exclusively isolates from rainbow trout and included the most predominant genotype, ST2, comprised 65% of all isolates examined. In Norway, with a shorter history (<10 years) of BCWD in rainbow trout, ST2 was the only isolated CC-ST10 genotype, suggesting a recent introduction of an epidemic clone. The study identified five additional CCs shared between countries and five country-specific CCs, some with apparent host specificity. Almost 80% of the singleton STs were isolated from non-rainbow trout species or the environment. The present study reveals a simultaneous presence of genetically distinct CCs in the Nordic countries and points out specific F. psychrophilum STs posing a threat to the salmonid production. The study provides a significant contribution toward mapping the genetic diversity of F. psychrophilum globally and support for the existence of an epidemic population structure where recombination is a significant driver in F. psychrophilum evolution. Evidence indicating dissemination of a putatively virulent clonal complex (CC-ST10) with commercial movement of fish or fish products is strengthened. PMID:24561585

  5. Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.

    PubMed

    Michaut, Magali; Chin, Suet-Feung; Majewski, Ian; Severson, Tesa M; Bismeijer, Tycho; de Koning, Leanne; Peeters, Justine K; Schouten, Philip C; Rueda, Oscar M; Bosma, Astrid J; Tarrant, Finbarr; Fan, Yue; He, Beilei; Xue, Zheng; Mittempergher, Lorenza; Kluin, Roelof J C; Heijmans, Jeroen; Snel, Mireille; Pereira, Bernard; Schlicker, Andreas; Provenzano, Elena; Ali, Hamid Raza; Gaber, Alexander; O'Hurley, Gillian; Lehn, Sophie; Muris, Jettie J F; Wesseling, Jelle; Kay, Elaine; Sammut, Stephen John; Bardwell, Helen A; Barbet, Aurélie S; Bard, Floriane; Lecerf, Caroline; O'Connor, Darran P; Vis, Daniël J; Benes, Cyril H; McDermott, Ultan; Garnett, Mathew J; Simon, Iris M; Jirström, Karin; Dubois, Thierry; Linn, Sabine C; Gallagher, William M; Wessels, Lodewyk F A; Caldas, Carlos; Bernards, Rene

    2016-01-01

    Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies. PMID:26729235

  6. Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

    PubMed Central

    Michaut, Magali; Chin, Suet-Feung; Majewski, Ian; Severson, Tesa M.; Bismeijer, Tycho; de Koning, Leanne; Peeters, Justine K.; Schouten, Philip C.; Rueda, Oscar M.; Bosma, Astrid J.; Tarrant, Finbarr; Fan, Yue; He, Beilei; Xue, Zheng; Mittempergher, Lorenza; Kluin, Roelof J.C.; Heijmans, Jeroen; Snel, Mireille; Pereira, Bernard; Schlicker, Andreas; Provenzano, Elena; Ali, Hamid Raza; Gaber, Alexander; O’Hurley, Gillian; Lehn, Sophie; Muris, Jettie J.F.; Wesseling, Jelle; Kay, Elaine; Sammut, Stephen John; Bardwell, Helen A.; Barbet, Aurélie S.; Bard, Floriane; Lecerf, Caroline; O’Connor, Darran P.; Vis, Daniël J.; Benes, Cyril H.; McDermott, Ultan; Garnett, Mathew J.; Simon, Iris M.; Jirström, Karin; Dubois, Thierry; Linn, Sabine C.; Gallagher, William M.; Wessels, Lodewyk F.A.; Caldas, Carlos; Bernards, Rene

    2016-01-01

    Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies. PMID:26729235

  7. Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt-Jakob disease in cell-protein misfolding cyclic amplification.

    PubMed

    Takeuchi, Atsuko; Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Morita, Masanori; Uno, Shusei; Kitamoto, Tetsuyuki

    2016-05-01

    There are two distinct subtypes of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with methionine homozygosity at codon 129 of the PRNP gene. The majority of cases is represented by a non-plaque-type (np-dCJD) resembling sporadic CJD (sCJD)-MM1 or -MV1, while the minority by a plaque-type (p-dCJD). p-dCJD shows distinctive phenotypic features, namely numerous kuru plaques and an abnormal isoform of prion protein (PrP(Sc)) intermediate in size between types 1 and 2. Transmission studies have shown that the unusual phenotypic features of p-dCJD are linked to the V2 prion strain that is associated with sCJD subtypes VV2 or -MV2. In this study, we applied protein misfolding cyclic amplification (PMCA) using recombinant human prion protein as a substrate and demonstrated that p-dCJD prions show amplification features that are distinct from those of np-dCJD. Although no amplification of np-dCJD prions was observed with either 129 M or 129 V substrate, p-dCJD prions were drastically amplified with the 129 V substrates, despite the PRNP codon 129 incompatibility between seed and substrate. Moreover, by using a type 2 PrP(Sc)-specific antibody not recognizing PrP(Sc) in p-dCJD, we found that type 2 products are generated de novo from p-dCJD prions during PMCA with the 129 V substrates. These findings suggest that our cell-PMCA is a useful tool for easily and rapidly identifying acquired CJD associated with the transmission of the V2 CJD strain to codon 129 methionine homozygotes, based on the preference for the 129 V substrate and the type of the amplified products. PMID:26878132

  8. Implement of the Owner Distinction Function for Healing-Type Pet Robots

    NASA Astrophysics Data System (ADS)

    Nambo, Hidetaka; Kimura, Haruhiko; Hirose, Sadaki

    In recent years, a robotics technology is extremely progressive, and robots are widely applied in many fields. One of the most typical robots is a pet robot. The pet robot is based on an animal pet, such as a dog or a cat. Also, it is known that an animal pet has a healing effect. Therefore, the study to apply pet robots to Animal Assisted Therapy instead of an animal pet has begun to be investigated. We, also, have investigated a method of an owner distinction for pet robot, to emphasize a healing effect of pet robots. In this paper, taking account of implementation into pet robots, a real-time owner distinction method is proposed. In the concrete, the method provides a real-time matching algorithm and an oblivion mechanism. The real-time matching means that a matching and a data acquisition are processed simultaneously. The oblivion mechanism is deleting features of owners in the database of the pet robots. Additionally, the mechanism enables to reduce matching costs or size of database and it enables to follow a change of owners. Furthermore, effectivity and a practicality of the method are evaluated by experiments.

  9. Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease.

    PubMed

    Butler, Timothy M; Johnson-Camacho, Katherine; Peto, Myron; Wang, Nicholas J; Macey, Tara A; Korkola, James E; Koppie, Theresa M; Corless, Christopher L; Gray, Joe W; Spellman, Paul T

    2015-01-01

    The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient's resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor. PMID:26317216

  10. Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease

    PubMed Central

    Butler, Timothy M.; Johnson-Camacho, Katherine; Peto, Myron; Wang, Nicholas J.; Macey, Tara A.; Korkola, James E.; Koppie, Theresa M.; Corless, Christopher L.; Gray, Joe W.; Spellman, Paul T.

    2015-01-01

    The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient’s resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor. PMID:26317216

  11. Identification of Four Distinct Subunit Types in the Unique 6×6 Hemocyanin of the Centipede Scutigera coleoptrata

    NASA Astrophysics Data System (ADS)

    Gebauer, W.; Markl, J.

    We isolated 6×6 hemocyanin, dissociated it into subunits, and examined it by electron microscopy. The subunits were separated by native polyacrylamide gel electrophoresis (PAGE), sodium dodecyl sulfate PAGE, and crossed immunoelectrophoresis. Single subunits were isolated by gel cutting from native PAGE and identified as hemocyanin by measuring their ultraviolet spectrum. A total of four distinct hemocyanin subunits were identified, and the subunit pattern of the three electrophoresis systems assigned to each other. The relative proportion of subunits a:b:c:d were 2 : 2 :>: 1 as determined by densitometry. Presumably, c and d act as linkers between hexamers.

  12. An EST-based analysis identifies new genes and reveals distinctive gene expression features of Coffea arabica and Coffea canephora

    PubMed Central

    2011-01-01

    Background Coffee is one of the world's most important crops; it is consumed worldwide and plays a significant role in the economy of producing countries. Coffea arabica and C. canephora are responsible for 70 and 30% of commercial production, respectively. C. arabica is an allotetraploid from a recent hybridization of the diploid species, C. canephora and C. eugenioides. C. arabica has lower genetic diversity and results in a higher quality beverage than C. canephora. Research initiatives have been launched to produce genomic and transcriptomic data about Coffea spp. as a strategy to improve breeding efficiency. Results Assembling the expressed sequence tags (ESTs) of C. arabica and C. canephora produced by the Brazilian Coffee Genome Project and the Nestlé-Cornell Consortium revealed 32,007 clusters of C. arabica and 16,665 clusters of C. canephora. We detected different GC3 profiles between these species that are related to their genome structure and mating system. BLAST analysis revealed similarities between coffee and grape (Vitis vinifera) genes. Using KA/KS analysis, we identified coffee genes under purifying and positive selection. Protein domain and gene ontology analyses suggested differences between Coffea spp. data, mainly in relation to complex sugar synthases and nucleotide binding proteins. OrthoMCL was used to identify specific and prevalent coffee protein families when compared to five other plant species. Among the interesting families annotated are new cystatins, glycine-rich proteins and RALF-like peptides. Hierarchical clustering was used to independently group C. arabica and C. canephora expression clusters according to expression data extracted from EST libraries, resulting in the identification of differentially expressed genes. Based on these results, we emphasize gene annotation and discuss plant defenses, abiotic stress and cup quality-related functional categories. Conclusion We present the first comprehensive genome-wide transcript

  13. Benchmark data for identifying multi-functional types of membrane proteins.

    PubMed

    Wan, Shibiao; Mak, Man-Wai; Kung, Sun-Yuan

    2016-09-01

    Identifying membrane proteins and their multi-functional types is an indispensable yet challenging topic in proteomics and bioinformatics. In this article, we provide data that are used for training and testing Mem-ADSVM (Wan et al., 2016. "Mem-ADSVM: a two-layer multi-label predictor for identifying multi-functional types of membrane proteins" [1]), a two-layer multi-label predictor for predicting multi-functional types of membrane proteins. PMID:27294176

  14. Promoter Hypermethylation Profiling Identifies Subtypes of Head and Neck Cancer with Distinct Viral, Environmental, Genetic and Survival Characteristics

    PubMed Central

    Choudhury, Javed Hussain; Ghosh, Sankar Kumar

    2015-01-01

    Background Epigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor-related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status. Methodology The study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex-PCR respectively. Principal Findings Unsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival. Conclusions Promoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC. PMID:26098903

  15. Two distinct types of the inhibition of vasculogenesis by different species of charged particles

    PubMed Central

    2013-01-01

    Background Charged particle radiation is known to be more biologically effective than photon radiation. One example of this is the inhibition of the formation of human blood vessels. This effect is an important factor influencing human health and is relevant to space travel as well as to cancer radiotherapy. We have previously shown that ion particles with a high energy deposition, or linear energy transfer (LET) are more than four times more effective at disrupting mature vessel tissue models than particles with a lower LET. For vasculogenesis however, the relative biological effectiveness between particles is the same. This unexpected result prompted us to investigate whether the inhibition of vasculogenesis was occurring by distinct mechanisms. Methods Using 3-Dimensional human vessel models, we developed assays that determine at what stage angiogenesis is inhibited. Vessel morphology, the presence of motile tip structures, and changes in the matrix architecture were assessed. To confirm that the mechanisms are distinct, stimulation of Protein Kinase C (PKC) with phorbol ester (PMA) was employed to selectively restore vessel formation in cultures where early motile tip activity was inhibited. Results Endothelial cells in 3-D culture exposed to low LET protons failed to make connections with other cells but eventually developed a central lumen. Conversely, cells exposed to high LET Fe charged particles extended cellular processes and made connections to other cells but did not develop a central lumen. The microtubule and actin cytoskeletons indicated that motility at the extending tips of endothelial cells is inhibited by low LET but not high LET particles. Actin-rich protrusive structures that contain bundled microtubules showed a 65% decrease when exposed to low LET particles but not high LET particles, with commensurate changes in the matrix architecture. Stimulation of PKC with PMA restored tip motility and capillary formation in low but not high LET particle

  16. The distinction of 'psychosomatogenic family types' based on parents' self reported questionnaire information: a cluster analysis.

    PubMed

    Rousseau, Sofie; Grietens, Hans; Vanderfaeillie, Johan; Ceulemans, Eva; Hoppenbrouwers, Karel; Desoete, Annemie; Van Leeuwen, Karla

    2014-06-01

    The theory of 'psychosomatogenic family types' is often used in treatment of somatizing adolescents. This study investigated the validity of distinguishing 'psychosomatogenic family types' based on parents' self-reported family features. The study included a Flemish general population sample of 12-year olds (n = 1428). We performed cluster analysis on 3 variables concerning parents' self-reported problems in family functioning. The distinguished clusters were examined for differences in marital problems, parental emotional problems, professional help for family members, demographics, and adolescents' somatization. Results showed the existence of 5 family types: 'chaotic family functioning,' 'average amount of family functioning problems,' 'few family functioning problems,' 'high amount of support and communication problems,' and 'high amount of sense of security problems' clusters. Membership of the 'chaotic family functioning' and 'average amount of family functioning problems' cluster was significantly associated with higher levels of somatization, compared with 'few family functioning problems' cluster membership. Among additional variables, only marital and parental emotional problems distinguished somatization relevant from non relevant clusters: parents in 'average amount of family functioning problems' and 'chaotic family functioning' clusters reported higher problems. The data showed that 'apparently perfect' or 'enmeshed' patterns of family functioning may not be assessed by means of parent report as adopted in this study. In addition, not only adolescents from 'extreme' types of family functioning may suffer from somatization. Further, professionals should be careful assuming that families in which parents report average to high amounts of family functioning problems also show different demographic characteristics. PMID:24749676

  17. Distinct Neural Correlates for Two Types of Inhibition in Bilinguals: Response Inhibition versus Interference Suppression

    ERIC Educational Resources Information Center

    Luk, Gigi; Anderson, John A. E.; Craik, Fergus I. M.; Grady, Cheryl; Bialystok, Ellen

    2010-01-01

    To examine the effects of bilingualism on cognitive control, we studied monolingual and bilingual young adults performing a flanker task with functional MRI. The trial types of primary interest for this report were incongruent and no-go trials, representing interference suppression and response inhibition, respectively. Response times were similar…

  18. Position-dependent plasticity of distinct progenitor types in the primitive streak

    PubMed Central

    Wymeersch, Filip J; Huang, Yali; Blin, Guillaume; Cambray, Noemí; Wilkie, Ron; Wong, Frederick CK; Wilson, Valerie

    2016-01-01

    The rostrocaudal (head-to-tail) axis is supplied by populations of progenitors at the caudal end of the embryo. Despite recent advances characterising one of these populations, the neuromesodermal progenitors, their nature and relationship to other populations remains unclear. Here we show that neuromesodermal progenitors are a single Sox2lowTlow entity whose choice of neural or mesodermal fate is dictated by their position in the progenitor region. The choice of mesoderm fate is Wnt/β-catenin dependent. Wnt/β-catenin signalling is also required for a previously unrecognised phase of progenitor expansion during mid-trunk formation. Lateral/ventral mesoderm progenitors represent a distinct committed state that is unable to differentiate to neural fates, even upon overexpression of the neural transcription factor Sox2. They do not require Wnt/β-catenin signalling for mesoderm differentiation. This information aids the correct interpretation of in vivo genetic studies and the development of in vitro protocols for generating physiologically-relevant cell populations of clinical interest. DOI: http://dx.doi.org/10.7554/eLife.10042.001 PMID:26780186

  19. The Shaping of Two Distinct Dendritic Spikes by A-Type Voltage-Gated K+ Channels

    PubMed Central

    Yang, Sungchil; Tang, Cha-Min; Yang, Sunggu

    2015-01-01

    Dendritic ion channels have been a subject of intense research in neuroscience because active ion channels in dendrites shape input signals. Ca2+-permeable channels including NMDA receptors (NMDARs) have been implicated in supralinear dendritic integration, and the IA conductance in sublinear integration. Despite their essential roles in dendritic integration, it has remained uncertain whether these conductance coordinate with, or counteract, each other in the process of dendritic integration. To address this question, experiments were designed in hippocampal CA1 neurons with a recent 3D digital holography system that has shown excellent performance for spatial photoactivation. The results demonstrated a role of IA as a key modulator for two distinct dendritic spikes, low- and high-threshold Ca2+ spikes, through a preferential action of IA on Ca2+-permeable channel-mediated currents, over fast AMPAR-mediated currents. It is likely that the rapid kinetics of IA provides feed-forward inhibition to counteract the regenerative Ca2+ channel-mediated dendritic excitability. This research reveals one dynamic ionic mechanism of dendritic integration, and may contribute to a new understanding of neuronal hyperexcitability embedded in several neural diseases such as epilepsy, fragile X syndrome and Alzheimer’s disease. PMID:26696828

  20. Position-dependent plasticity of distinct progenitor types in the primitive streak.

    PubMed

    Wymeersch, Filip J; Huang, Yali; Blin, Guillaume; Cambray, Noemí; Wilkie, Ron; Wong, Frederick Ck; Wilson, Valerie

    2016-01-01

    The rostrocaudal (head-to-tail) axis is supplied by populations of progenitors at the caudal end of the embryo. Despite recent advances characterising one of these populations, the neuromesodermal progenitors, their nature and relationship to other populations remains unclear. Here we show that neuromesodermal progenitors are a single Sox2(low)T(low) entity whose choice of neural or mesodermal fate is dictated by their position in the progenitor region. The choice of mesoderm fate is Wnt/β-catenin dependent. Wnt/β-catenin signalling is also required for a previously unrecognised phase of progenitor expansion during mid-trunk formation. Lateral/ventral mesoderm progenitors represent a distinct committed state that is unable to differentiate to neural fates, even upon overexpression of the neural transcription factor Sox2. They do not require Wnt/β-catenin signalling for mesoderm differentiation. This information aids the correct interpretation of in vivo genetic studies and the development of in vitro protocols for generating physiologically-relevant cell populations of clinical interest. PMID:26780186

  1. Different types of laughter modulate connectivity within distinct parts of the laughter perception network.

    PubMed

    Wildgruber, Dirk; Szameitat, Diana P; Ethofer, Thomas; Brück, Carolin; Alter, Kai; Grodd, Wolfgang; Kreifelts, Benjamin

    2013-01-01

    Laughter is an ancient signal of social communication among humans and non-human primates. Laughter types with complex social functions (e.g., taunt and joy) presumably evolved from the unequivocal and reflex-like social bonding signal of tickling laughter already present in non-human primates. Here, we investigated the modulations of cerebral connectivity associated with different laughter types as well as the effects of attention shifts between implicit and explicit processing of social information conveyed by laughter using functional magnetic resonance imaging (fMRI). Complex social laughter types and tickling laughter were found to modulate connectivity in two distinguishable but partially overlapping parts of the laughter perception network irrespective of task instructions. Connectivity changes, presumably related to the higher acoustic complexity of tickling laughter, occurred between areas in the prefrontal cortex and the auditory association cortex, potentially reflecting higher demands on acoustic analysis associated with increased information load on auditory attention, working memory, evaluation and response selection processes. In contrast, the higher degree of socio-relational information in complex social laughter types was linked to increases of connectivity between auditory association cortices, the right dorsolateral prefrontal cortex and brain areas associated with mentalizing as well as areas in the visual associative cortex. These modulations might reflect automatic analysis of acoustic features, attention direction to informative aspects of the laughter signal and the retention of those in working memory during evaluation processes. These processes may be associated with visual imagery supporting the formation of inferences on the intentions of our social counterparts. Here, the right dorsolateral precentral cortex appears as a network node potentially linking the functions of auditory and visual associative sensory cortices with those of the

  2. Distinct Human Papillomavirus Type 16 Methylomes in Cervical Cells at Different Stages of Premalignancy

    PubMed Central

    Brandsma, Janet L.; Sun, Ying; Lizardi, Paul M.; Tuck, David P.; Zelterman, Daniel; Haines, G. Kenneth; Martel, Maritza; Harigopal, Malini; Schofield, Kevin; Neapolitano, Matthew

    2009-01-01

    Human papillomavirus (HPV) gene expression is dramatically altered during cervical carcinogenesis. Because dysregulated genes frequently show abnormal patterns of DNA methylation, we hypothesized that comprehensive mapping of the HPV methylomes in cervical samples at different stages of progression would reveal patterns of clinical significance. To test this hypothesis, thirteen HPV16-positive samples were obtained from women undergoing routine cervical cancer screening. Complete methylation data were obtained for 98.7% of the HPV16 CpGs in all samples by bisulfite-sequencing. Most HPV16 CpGs were unmethylated or methylated in only one sample. The other CpGs were methylated at levels ranging from 11% to 100% of the HPV16 copies per sample. The results showed three major patterns and two variants of one pattern. The patterns showed minimal or no methylation (A), low level methylation in the E1 and E6 genes (B), and high level methylation at many CpGs in the E5/L2/L1 region (C). Generally, pattern A was associated with negative cytology, pattern B with low-grade lesions, and pattern C with high-grade lesions. The severity of the cervical lesions was then ranked by the HPV16 DNA methylation patterns and, independently, by the pathologic diagnoses. Statistical analysis of the two rating methods showed highly significant agreement. In conclusion, analysis of the HPV16 DNA methylomes in clinical samples of cervical cells led to the identification of distinct methylation patterns which, after validation in larger studies, could have potential utility as biomarkers of neoplastic cervical progression. PMID:19443004

  3. Teleost leukocyte immune-type receptors activate distinct phagocytic modes for target acquisition and engulfment.

    PubMed

    Lillico, Dustin M E; Zwozdesky, Myron A; Pemberton, Joshua G; Deutscher, Julianna M; Jones, Lena O; Chang, John P; Stafford, James L

    2015-08-01

    Channel catfish (Ictalurus punctatus) IpLITRs belong to the Ig superfamily and regulate innate immune cell effector responses. This study tested the hypothesis that ITAM-dependent and ITAM-independent phagocytic pathways are engaged by different subtypes of the IpLITR family. When stably expressed in RBL-2H3 cells, the ITAM-containing fusion-construct IpLITR 2.6b/IpFcRγ-L stimulated phagocytic responses that were abrogated at suboptimal incubation temperatures and by pharmacological inhibitors of the classic signaling components of the mammalian FcR-dependent phagocytic pathway. Interestingly, the ITIM-containing receptor IpLITR 1.1b also induced phagocytosis through an actin-dependent mechanism, but this process was insensitive to the pharmacological inhibitors tested and remained functional at temperatures as low as 22°C. The IpLITR 1.1b also displayed a unique target-acquisition phenotype that consisted of complex, membranous protrusions, which captured targets in phagocytic cup-like structures but often failed to completely engulf targets. Taken together, these findings suggest that teleost immunoregulatory receptors that associate with ITAM-containing adaptors can engage conserved components of the phagocytic machinery to engulf extracellular targets akin to the classic FcR-mediated response in mammals. Alternatively, IpLITR 1.1b displays a stalled phagocytic phenotype that is likely dependent on the selective recruitment of the minimal molecular machinery required for target capture but results in incomplete target engulfment. Overall, this study demonstrates that IpLITRs can selectively engage distinct components of the phagocytic process and provides important new information regarding the target acquisition as well as internalization mechanisms involved in controlling phagocytic responses across vertebrates. PMID:25977286

  4. Distinct Microbial Communities within the Endosphere and Rhizosphere of Populus deltoides Roots across Contrasting Soil Types.

    SciTech Connect

    Gottel, Neil R; Castro Gonzalez, Hector F; Kerley, Marilyn K; Yang, Zamin; Pelletier, Dale A; Podar, Mircea; Karpinets, Tatiana V; Uberbacher, Edward C; Tuskan, Gerald A; Vilgalys, Rytas; Doktycz, Mitchel John; Schadt, Christopher Warren

    2011-01-01

    The root-rhizosphere interface of Populus is the nexus of a variety of associations between bacteria, fungi, and the host plant and an ideal model for studying interactions between plants and microorganisms. However, such studies have generally been confined to greenhouse and plantation systems. Here we analyze microbial communities from the root endophytic and rhizospheric habitats of Populus deltoides in mature natural trees from both upland and bottomland sites in central Tennessee. Community profiling utilized 454 pyrosequencing with separate primers targeting the V4 region for bacterial 16S rRNA and the D1/D2 region for fungal 28S rRNA genes. Rhizosphere bacteria were dominated by Acidobacteria (31%) and Alphaproteobacteria (30%), whereas most endophytes were from the Gammaproteobacteria (54%) as well as Alphaproteobacteria (23%). A single Pseudomonas-like operational taxonomic unit (OTU) accounted for 34% of endophytic bacterial sequences. Endophytic bacterial richness was also highly variable and 10-fold lower than in rhizosphere samples originating from the same roots. Fungal rhizosphere and endophyte samples had approximately equal amounts of the Pezizomycotina (40%), while the Agaricomycotina were more abundant in the rhizosphere (34%) than endosphere (17%). Both fungal and bacterial rhizosphere samples were highly clustered compared to the more variable endophyte samples in a UniFrac principal coordinates analysis, regardless of upland or bottomland site origin. Hierarchical clustering of OTU relative abundance patterns also showed that the most abundant bacterial and fungal OTUs tended to be dominant in either the endophyte or rhizosphere samples but not both. Together, these findings demonstrate that root endophytic communities are distinct assemblages rather than opportunistic subsets of the rhizosphere.

  5. Functional Proteomics Screen Enables Enrichment of Distinct Cell Types from Human Pancreatic Islets

    PubMed Central

    Sharivkin, Revital; Walker, Michael D.; Soen, Yoav

    2015-01-01

    The current world-wide epidemic of diabetes has prompted attempts to generate new sources of insulin-producing cells for cell replacement therapy. An inherent challenge in many of these strategies is the lack of cell-surface markers permitting isolation and characterization of specific cell types from differentiating stem cell populations. Here we introduce an iterative proteomics procedure allowing tag-free isolation of cell types based on their function. Our method detects and associates specific cell-surface markers with particular cell functionality by coupling cell capture on antibody arrays with immunofluorescent labeling. Using this approach in an iterative manner, we discovered marker combinations capable of enriching for discrete pancreatic cell subtypes from human islets of Langerhans: insulin-producing beta cells (CD9high/CD56+), glucagon-producing alpha cells (CD9- /CD56+) and trypsin-producing acinar cells (CD9- /CD56-). This strategy may assist future beta cell research and the development of diagnostic tools for diabetes. It can also be applied more generally for function-based purification of desired cell types from other limited and heterogeneous biological samples. PMID:25706282

  6. A Visual Screen of a Gfp-Fusion Library Identifies a New Type of Nuclear Envelope Membrane Protein

    PubMed Central

    Rolls, Melissa M.; Stein, Pascal A.; Taylor, Stephen S.; Ha, Edward; McKeon, Frank; Rapoport, Tom A.

    1999-01-01

    The nuclear envelope (NE) is a distinct subdomain of the ER, but few membrane components have been described that are specific to it. We performed a visual screen in tissue culture cells to identify proteins targeted to the NE. This approach does not require assumptions about the nature of the association with the NE or the physical separation of NE and ER. We confirmed that screening a library of fusions to the green fluorescent protein can be used to identify proteins targeted to various subcompartments of mammalian cells, including the NE. With this approach, we identified a new NE membrane protein, named nurim. Nurim is a multispanning membrane protein without large hydrophilic domains that is very tightly associated with the nucleus. Unlike the known NE membrane proteins, it is neither associated with nuclear pores, nor targeted like lamin-associated membrane proteins. Thus, nurim is a new type of NE membrane protein that is localized to the NE by a distinct mechanism. PMID:10402458

  7. CALTECH CORE-COLLAPSE PROJECT (CCCP) OBSERVATIONS OF TYPE II SUPERNOVAE: EVIDENCE FOR THREE DISTINCT PHOTOMETRIC SUBTYPES

    SciTech Connect

    Arcavi, Iair; Gal-Yam, Avishay; Yaron, Ofer; Cenko, S. Bradley; Becker, Adam B.; Fox, Derek B.; Leonard, Douglas C.; Moon, Dae-Sik; Sand, David J.; Soderberg, Alicia M.; Kiewe, Michael; Scheps, Raphael; Birenbaum, Gali; Chamudot, Daniel; Zhou, Jonathan

    2012-09-10

    We present R-band light curves of Type II supernovae (SNe) from the Caltech Core-Collapse Project (CCCP). With the exception of interacting (Type IIn) SNe and rare events with long rise times, we find that most light curve shapes belong to one of three apparently distinct classes: plateau, slowly declining, and rapidly declining events. The last class is composed solely of Type IIb SNe which present similar light curve shapes to those of SNe Ib, suggesting, perhaps, similar progenitor channels. We do not find any intermediate light curves, implying that these subclasses are unlikely to reflect variance of continuous parameters, but rather might result from physically distinct progenitor systems, strengthening the suggestion of a binary origin for at least some stripped SNe. We find a large plateau luminosity range for SNe IIP, while the plateau lengths seem rather uniform at approximately 100 days. As analysis of additional CCCP data goes on and larger samples are collected, demographic studies of core-collapse SNe will likely continue to provide new constraints on progenitor scenarios.

  8. Turtle Dorsal Cortex Pyramidal Neurons Comprise Two Distinct Cell Types with Indistinguishable Visual Responses

    PubMed Central

    Crockett, Thomas; Wright, Nathaniel; Thornquist, Stephen; Ariel, Michael; Wessel, Ralf

    2015-01-01

    A detailed inventory of the constituent pieces in cerebral cortex is considered essential to understand the principles underlying cortical signal processing. Specifically, the search for pyramidal neuron subtypes is partly motivated by the hypothesis that a subtype-specific division of labor could create a rich substrate for computation. On the other hand, the extreme integration of individual neurons into the collective cortical circuit promotes the hypothesis that cellular individuality represents a smaller computational role within the context of the larger network. These competing hypotheses raise the important question to what extent the computational function of a neuron is determined by its individual type or by its circuit connections. We created electrophysiological profiles from pyramidal neurons within the sole cellular layer of turtle visual cortex by measuring responses to current injection using whole-cell recordings. A blind clustering algorithm applied to these data revealed the presence of two principle types of pyramidal neurons. Brief diffuse light flashes triggered membrane potential fluctuations in those same cortical neurons. The apparently network driven variability of the visual responses concealed the existence of subtypes. In conclusion, our results support the notion that the importance of diverse intrinsic physiological properties is minimized when neurons are embedded in a synaptic recurrent network. PMID:26633877

  9. Yeast GAL11 protein is a distinctive type transcription factor that enhances basal transcription in vitro.

    PubMed Central

    Sakurai, H; Hiraoka, Y; Fukasawa, T

    1993-01-01

    The yeast auxiliary transcription factor GAL11, a candidate for the coactivator, was partially purified from yeast cells, and its function was characterized in a cell-free transcription system. The partially purified GAL11 protein stimulated basal transcription from the CYC1 core promoter by a factor of 4-5 at the step of preinitiation complex formation. GAL11 protein also enhanced transcription activated by general regulatory factor 1, GAL4-AH, or GAL4-VP16 to the same extent as the basal transcription. Therefore, the apparent potentiation of the activators by GAL11 was attributable to the stimulation of basal transcription. The wild-type GAL11 protein (but not a mutant-type protein) produced in bacteria stimulated transcription as effectively as GAL11 from yeast. These results suggest that GAL11 functions as a positive cofactor of basal and activator-induced transcription in a cell-free transcription system. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8378310

  10. Distinct Functional Properties of Isoamylase-Type Starch Debranching Enzymes in Monocot and Dicot Leaves1[C][W][OPEN

    PubMed Central

    Facon, Maud; Lin, Qiaohui; Azzaz, Abdelhamid M.; Hennen-Bierwagen, Tracie A.; Myers, Alan M.; Putaux, Jean-Luc; Roussel, Xavier; D’Hulst, Christophe; Wattebled, Fabrice

    2013-01-01

    Isoamylase-type starch debranching enzymes (ISA) play important roles in starch biosynthesis in chloroplast-containing organisms, as shown by the strict conservation of both catalytically active ISA1 and the noncatalytic homolog ISA2. Functional distinctions exist between species, although they are not understood yet. Numerous plant tissues require both ISA1 and ISA2 for normal starch biosynthesis, whereas monocot endosperm and leaf exhibit nearly normal starch metabolism without ISA2. This study took in vivo and in vitro approaches to determine whether organism-specific physiology or evolutionary divergence between monocots and dicots is responsible for distinctions in ISA function. Maize (Zea mays) ISA1 was expressed in Arabidopsis (Arabidopsis thaliana) lacking endogenous ISA1 or lacking both native ISA1 and ISA2. The maize protein functioned in Arabidopsis leaves to support nearly normal starch metabolism in the absence of any native ISA1 or ISA2. Analysis of recombinant enzymes showed that Arabidopsis ISA1 requires ISA2 as a partner for enzymatic function, whereas maize ISA1 was active by itself. The electrophoretic mobility of recombinant and native maize ISA differed, suggestive of posttranslational modifications in vivo. Sedimentation equilibrium measurements showed recombinant maize ISA1 to be a dimer, in contrast to previous gel permeation data that estimated the molecular mass as a tetramer. These data demonstrate that evolutionary divergence between monocots and dicots is responsible for the distinctions in ISA1 function. PMID:24027240

  11. Distinction between S-type and peraluminous I-type granites: Zircon versus whole-rock geochemistry

    NASA Astrophysics Data System (ADS)

    Gao, Peng; Zheng, Yong-Fei; Zhao, Zi-Fu

    2016-08-01

    Biotite and two-mica granites are common in continental crust. Although they are generally peraluminous in lithochemistry, their petrogenesis has been controversial. Because they often show a negative correlation between P2O5 and SiO2 and a positive correlation between A/CNK and SiO2, they are commonly considered as the I-type granites of metaigneous origin. However, such lithochemical consideration is not certain in view of their other geochemical characteristics. To constrain the source nature of peraluminous granites, we performed a combined study of in situ U-Pb age, O isotope, and trace element for synmagmatic and relict zircons from Triassic biotite and two-mica granites in the Nanling Range, South China. Zircon U-Pb dating yields concordant ages of 230 ± 3 to 237 ± 3 Ma for synmagmatic zircons, and 335-2379 Ma for relict zircons with two clusters at ca. 440 Ma and ca. 800 Ma, respectively. Both the synmagmatic zircons and the ~ 440 Ma relict zircons are characterized by high δ18O values of 8.8-11.4‰ and 8.6-10.3‰, respectively. In contrast, the majority of the other relict zircons show relatively low δ18O values of 5.1-7.9‰. The high δ18O values for synmagmatic zircons indicate that the Triassic granites were originated from metasedimentary sources. The two age clusters for relict zircons overlap with two episodes of granitic magmatism, respectively, in the early Paleozoic and the middle Neoproterozoic in South China, suggesting their inheritance from the metasedimentary sources. Thus, these Triassic granites were derived from partial melting of metasedimentary rocks rather than metaigneous rocks; they belong to S-type granite although their lithochemical relationships are akin to common I-type granites. As such, the zircon in situ geochemical analyses have the capacity to unravel the source nature of controversial granites. Our data indicate that fractional crystallization of heterogeneous magmas is the possible mechanism for the decoupling

  12. Distinct Representation and Distribution of Visual Information by Specific Cell Types in Mouse Superficial Superior Colliculus

    PubMed Central

    Gale, Samuel D.

    2014-01-01

    The superficial superior colliculus (sSC) occupies a critical node in the mammalian visual system; it is one of two major retinorecipient areas, receives visual cortical input, and innervates visual thalamocortical circuits. Nonetheless, the contribution of sSC neurons to downstream neural activity and visually guided behavior is unknown and frequently neglected. Here we identified the visual stimuli to which specific classes of sSC neurons respond, the downstream regions they target, and transgenic mice enabling class-specific manipulations. One class responds to small, slowly moving stimuli and projects exclusively to lateral posterior thalamus; another, comprising GABAergic neurons, responds to the sudden appearance or rapid movement of large stimuli and projects to multiple areas, including the lateral geniculate nucleus. A third class exhibits direction-selective responses and targets deeper SC layers. Together, our results show how specific sSC neurons represent and distribute diverse information and enable direct tests of their functional role. PMID:25274823

  13. Functional genomics identifies neural stem cell sub-type expression profiles and genes regulating neuroblast homeostasis

    PubMed Central

    Carney, Travis D.; Miller, Michael R.; Robinson, Kristin J.; Bayraktar, Omer A.; Osterhout, Jessica A.; Doe, Chris Q.

    2014-01-01

    The Drosophila larval central brain contains about 10,000 differentiated neurons and 200 scattered neural progenitors (neuroblasts), which can be further subdivided into ~95 type I neuroblasts and eight type II neuroblasts per brain lobe. Only type II neuroblasts generate self-renewing intermediate neural progenitors (INPs), and consequently each contributes more neurons to the brain, including much of the central complex. We characterized six different mutant genotypes that lead to expansion of neuroblast numbers; some preferentially expand type II or type I neuroblasts. Transcriptional profiling of larval brains from these mutant genotypes versus wild-type allowed us to identify small clusters of transcripts enriched in type II or type I neuroblasts, and we validated these clusters by gene expression analysis. Unexpectedly, only a few genes were found to be differentially expressed between type I/II neuroblasts, suggesting that these genes play a large role in establishing the different cell types. We also identified a large group of genes predicted to be expressed in all neuroblasts but not neurons. We performed a neuroblast-specific, RNAi-based functional screen and identified 84 genes that are required to maintain proper neuroblast numbers; all have conserved mammalian orthologs. These genes are excellent candidates for regulating neural progenitor self-renewal in Drosophila and mammals. PMID:22061480

  14. Distribution of human papillomavirus types in genital lesions from two temporally distinct populations determined by in situ hybridization.

    PubMed

    Anderson, S M; Brooke, P K; Van Eyck, S L; Noell, H; Frable, W J

    1993-05-01

    We examined 341 paraffin-embedded cervical tissues for human papillomavirus (HPV) DNA by in situ hybridization. The genital lesions examined represented tissue biopsies from two temporally distinct populations (1964 to 1965 and 1988 to 1989). Biotinylated probes to 14 different HPV types were used in our analysis: HPV types 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, and 56. The number of HPV DNA-positive specimens and the distributions of HPV types were similar for these two populations. Human papillomavirus DNA sequences were detected in approximately 50% of the tissues from each time period. Of the low-grade lesions (condyloma/cervical intraepithelial neoplasia 1 [CIN 1]) 52% (1964 to 1965) and 35% (1988 to 1989) were positive for HPV DNA by in situ hybridization. Among the high-grade lesions (CIN 2/CIN 3), 41% (1964 to 1965) and 67% (1988 to 1989) had detectable HPV sequences. Approximately 15% of the tissues with minimal histopathologic changes also contained HPV DNA. Human papillomavirus types 16 and/or 18 were the most common viral types in lesions from both time periods, followed by types 31/33/35; 6/11, 51/52; and 42/43/44, 45/46. Types 16 and/or 18 were strongly associated with high-grade lesions. Five percent of the HPV-positive lesions demonstrated evidence of multiple infections. Our results indicate that HPV DNA sequences can be detected readily by in situ hybridization in archival materials, even those prepared more than 25 years ago. In addition, analysis of HPV type distributions demonstrates that recently isolated HPV types (42, 43, 44, 45, 51, 52, and 56) were equally represented in tissues from both time periods. PMID:8387959

  15. Narrow-Host-Range Bacteriophages That Infect Rhizobium etli Associate with Distinct Genomic Types

    PubMed Central

    Santamaría, Rosa Isela; Bustos, Patricia; Sepúlveda-Robles, Omar; Lozano, Luis; Rodríguez, César; Fernández, José Luis; Juárez, Soledad; Kameyama, Luis; Guarneros, Gabriel; Dávila, Guillermo

    2014-01-01

    In this work, we isolated and characterized 14 bacteriophages that infect Rhizobium etli. They were obtained from rhizosphere soil of bean plants from agricultural lands in Mexico using an enrichment method. The host range of these phages was narrow but variable within a collection of 48 R. etli strains. We obtained the complete genome sequence of nine phages. Four phages were resistant to several restriction enzymes and in vivo cloning, probably due to nucleotide modifications. The genome size of the sequenced phages varied from 43 kb to 115 kb, with a median size of ∼45 to 50 kb. A large proportion of open reading frames of these phage genomes (65 to 70%) consisted of hypothetical and orphan genes. The remainder encoded proteins needed for phage morphogenesis and DNA synthesis and processing, among other functions, and a minor percentage represented genes of bacterial origin. We classified these phages into four genomic types on the basis of their genomic similarity, gene content, and host range. Since there are no reports of similar sequences, we propose that these bacteriophages correspond to novel species. PMID:24185856

  16. Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type.

    PubMed

    Nagel, R L; Fabry, M E; Pagnier, J; Zohoun, I; Wajcman, H; Baudin, V; Labie, D

    1985-04-01

    Patients with sickle cell anemia vary in the hematologic and clinical features of their disease, in part because of variability in the presence of linked and unlinked genes that modify the expression of the disease. The hemoglobin S gene is strongly linked to three different haplotypes of polymorphic endonuclease-restriction sites of the beta-like gene cluster (genes in the vicinity of the beta-globin gene)--one prevalent in Atlantic West Africa, another in central West Africa, and yet another in Bantu-speaking Africa (equatorial, East, and southern Africa). We have studied the differences in the hematologic characteristics of patients with sickle cell anemia from the first two geographical areas. We find that the Senegalese (Atlantic West Africa) patients have higher levels of hemoglobin F, a preponderance of G gamma chains in hemoglobin F, a lower proportion of very dense red cells, and a lower percentage of irreversibly sickled cells than those from Benin (central West Africa). We interpret these data to mean that the gamma-chain composition and the hemoglobin F level are haplotype linked and that the decrease in the percentage of dense cells and irreversibly sickled cells is secondary to the elevation in the hemoglobin F level. Patients with sickle cell anemia in the New World probably correspond to various combinations of these types, in addition to the still hematologically undefined haplotype associated with sickle cell anemia in the Bantu-speaking areas of Africa. PMID:2579336

  17. Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

    PubMed

    Uibo, Raivo; Panarina, Marina; Teesalu, Kaupo; Talja, Ija; Sepp, Epp; Utt, Meeme; Mikelsaar, Marika; Heilman, Kaire; Uibo, Oivi; Vorobjova, Tamara

    2011-03-01

    Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. PMID:21317917

  18. Different types of spinal afferent nerve endings in stomach and esophagus identified by anterograde tracing from dorsal root ganglia.

    PubMed

    Spencer, Nick J; Kyloh, Melinda; Beckett, Elizabeth A; Brookes, Simon; Hibberd, Tim

    2016-10-15

    In visceral organs of mammals, most noxious (painful) stimuli as well as innocuous stimuli are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRGs). One of the major unresolved questions is the location, morphology, and neurochemistry of the nerve endings of spinal afferents that actually detect these stimuli in the viscera. In the upper gastrointestinal (GI) tract, there have been many anterograde tracing studies of vagal afferent endings, but none on spinal afferent endings. Recently, we developed a technique that now provides selective labeling of only spinal afferents. We used this approach to identify spinal afferent nerve endings in the upper GI tract of mice. Animals were anesthetized, and injections of dextran-amine were made into thoracic DRGs (T8-T12). Seven days post surgery, mice were euthanized, and the stomach and esophagus were removed, fixed, and stained for calcitonin gene-related peptide (CGRP). Spinal afferent axons were identified that ramified extensively through many rows of myenteric ganglia and formed nerve endings in discrete anatomical layers. Most commonly, intraganglionic varicose endings (IGVEs) were identified in myenteric ganglia of the stomach and varicose simple-type endings in the circular muscle and mucosa. Less commonly, nerve endings were identified in internodal strands, blood vessels, submucosal ganglia, and longitudinal muscle. In the esophagus, only IGVEs were identified in myenteric ganglia. No intraganglionic lamellar endings (IGLEs) were identified in the stomach or esophagus. We present the first identification of spinal afferent endings in the upper GI tract. Eight distinct types of spinal afferent endings were identified in the stomach, and most of them were CGRP immunoreactive. J. Comp. Neurol. 524:3064-3083, 2016. © 2016 Wiley Periodicals, Inc. PMID:27019197

  19. Development of the Theta Comparative Cell Scoring Method to Quantify Diverse Phenotypic Responses Between Distinct Cell Types

    PubMed Central

    Warchal, Scott J.; Dawson, John C.

    2016-01-01

    Abstract In this article, we have developed novel data visualization tools and a Theta comparative cell scoring (TCCS) method, which supports high-throughput in vitro pharmacogenomic studies across diverse cellular phenotypes measured by multiparametric high-content analysis. The TCCS method provides a univariate descriptor of divergent compound-induced phenotypic responses between distinct cell types, which can be used for correlation with genetic, epigenetic, and proteomic datasets to support the identification of biomarkers and further elucidate drug mechanism-of-action. Application of these methods to compound profiling across high-content assays incorporating well-characterized cells representing known molecular subtypes of disease supports the development of personalized healthcare strategies without prior knowledge of a drug target. We present proof-of-principle data quantifying distinct phenotypic response between eight breast cancer cells representing four disease subclasses. Application of the TCCS method together with new advances in next-generation sequencing, induced pluripotent stem cell technology, gene editing, and high-content phenotypic screening are well placed to advance the identification of predictive biomarkers and personalized medicine approaches across a broader range of disease types and therapeutic classes. PMID:27552144

  20. Development of the Theta Comparative Cell Scoring Method to Quantify Diverse Phenotypic Responses Between Distinct Cell Types.

    PubMed

    Warchal, Scott J; Dawson, John C; Carragher, Neil O

    2016-09-01

    In this article, we have developed novel data visualization tools and a Theta comparative cell scoring (TCCS) method, which supports high-throughput in vitro pharmacogenomic studies across diverse cellular phenotypes measured by multiparametric high-content analysis. The TCCS method provides a univariate descriptor of divergent compound-induced phenotypic responses between distinct cell types, which can be used for correlation with genetic, epigenetic, and proteomic datasets to support the identification of biomarkers and further elucidate drug mechanism-of-action. Application of these methods to compound profiling across high-content assays incorporating well-characterized cells representing known molecular subtypes of disease supports the development of personalized healthcare strategies without prior knowledge of a drug target. We present proof-of-principle data quantifying distinct phenotypic response between eight breast cancer cells representing four disease subclasses. Application of the TCCS method together with new advances in next-generation sequencing, induced pluripotent stem cell technology, gene editing, and high-content phenotypic screening are well placed to advance the identification of predictive biomarkers and personalized medicine approaches across a broader range of disease types and therapeutic classes. PMID:27552144

  1. Comparative analysis of somatic copy-number alterations across different human cancer types reveals two distinct classes of breakpoint hotspots

    PubMed Central

    Li, Yudong; Zhang, Li; Ball, Robyn L.; Liang, Xinle; Li, Jianrong; Lin, Zhenguo; Liang, Han

    2012-01-01

    Somatic copy-number alterations (SCNAs) play a crucial role in the development of human cancer. However, it is not well understood what evolutionary mechanisms contribute to the global patterns of SCNAs in cancer genomes. Taking advantage of data recently available through The Cancer Genome Atlas, we performed a systematic analysis on genome-wide SCNA breakpoint data for eight cancer types. First, we observed a high degree of overall similarity among the SCNA breakpoint landscapes of different cancer types. Then, we compiled 19 genomic features and evaluated their effects on the observed SCNA patterns. We found that evolutionary indel and substitution rates between species (i.e. humans and chimpanzees) consistently show the strongest correlations with breakpoint frequency among all the surveyed features; whereas the effects of some features are quite cancer-type dependent. Focusing on SCNA breakpoint hotspots, we found that cancer-type-specific breakpoint hotspots and common hotspots show distinct patterns. Cancer-type-specific hotspots are enriched with known cancer genes but are poorly predicted from genomic features; whereas common hotspots show the opposite patterns. This contrast suggests that explaining high-frequency SCNAs in cancer may require different evolutionary models: positive selection driven by cancer genes, and non-adaptive evolution related to an intrinsically unstable genomic context. Our results not only present a systematic view of the effects of genetic factors on genome-wide SCNA patterns, but also provide deep insights into the evolutionary process of SCNAs in cancer. PMID:22899649

  2. Allocation of Klebsiella pneumoniae Bloodstream Isolates into Four Distinct Groups by ompK36 Typing in a Taiwanese University Hospital

    PubMed Central

    Zheng, Po-Xing; Wang, Ming-Cheng; Tsai, Shu-Huei; Wang, Li-Rong; Wu, Jiunn-Jong

    2015-01-01

    The OmpK36 porin plays a role in carbapenem resistance and may contribute to bacterial virulence in Klebsiella pneumoniae. This study aimed to investigate the characteristics of different groups of K. pneumoniae separated by ompK36 typing. Among 226 nonduplicate K. pneumoniae bloodstream isolates collected at a Taiwanese hospital in 2011, four ompK36 types, designated types A, B, C, and D, were identified by PCR in 61, 28, 100, and 36 isolates, respectively; 1 isolate was untypeable. Statistical analysis showed significantly higher rates of antimicrobial resistance (all tested antibiotics except meropenem), extended-spectrum β-lactamases or DHA-1 (47.5% together), Qnr-type quinolone resistance determinants (50.8%), and IncFIIA-type plasmids (49.2%) in group A than in others. Seventeen isolates were identified as belonging to 3 international high-risk clones (4 sequence type 11 [ST11], 10 ST15, and 3 ST147 isolates); all isolates but 1 ST15 isolate were classified in group A. The significant characteristics of group C were hypermucoviscosity (62.0%) and a higher virulence gene content. This group included all serotype K1 (n = 30), K2 (n = 25), and K5 (n = 3) isolates, 6 of 7 K57 isolates, all isolates of major clones associated with pyogenic liver abscesses (29 ST23, 11 ST65, 5 ST86, 7 ST373, and 1 ST375 isolates), and 16 (94.1%) of 17 isolates causing bacteremic liver abscesses. Twelve (42.9%) of the group B isolates were responsible for bacteremic biliary tract infections. Group D was predominant (83.3%) among 12 K20 isolates. This study suggests that most clinical K. pneumoniae isolates can be allocated into four groups with distinct characteristics based on ompK36 types. PMID:26224840

  3. Discovering Massive Runaway Stars with Infrared Bowshock Nebulae: Identifying Twelve New Early-Type Stars using SMOG

    NASA Astrophysics Data System (ADS)

    Chick, William T.; Andrews, Julian E.; Kobulnicky, Henry A.; Povich, Matthew S.; Dale, Daniel A.; Munari, Stephan; Olivier, Grace M.; Schurhammer, Danielle; Sorber, Rebecca L.; Wernke, Heather N.

    2016-01-01

    Massive O and B type stars are crucial to the evolution of the interstellar medium, dominating the production of ionizing radiation, mechanical energy, and heavy elements. However, due to their short lives and relative scarcity, these stars are some of the least well understood and are difficult to locate outside of large star forming regions. A small but significant fraction of these massive stars have been observed to be high-velocity runaway stars moving rapidly away from their origin. When these stars encounter nebular gas they create characteristic arc-shaped bowshocks of heated compressed dust and gas. Using the distinct infrared emission morphology of the hot dust, these bowshock nebulae are predicted to give the location of the massive early type stars.Visual inspection of 24-micron band images from the Spitzer Mapping of the Outer Galaxy (SMOG) revealed 12 new bowshock nebula candidates. Follow up optical spectroscopy from the Wyoming Infrared Observatory confirmed that all 12 of the associated stellar sources are early-type stars. Combined with related results from visual searches for bowshock nebulae using WISE and Spitzer surveys in the inner Galaxy, we have identified over 85 new early type bowshock supporting stellar sources, a 95% success rate. We conclude that morphological selection of arc-shared infrared nebulae with a symmetrically placed star is an efficient way to discover early type stars.This work is supported by the National Science Foundation under grants AST-1063146 (REU), AST-1411851 (RUI), and AST-1412845.

  4. Molecular changes in mitochondrial respiratory activity and metabolic enzyme activity in muscle of four pig breeds with distinct metabolic types.

    PubMed

    Liu, Xuan; Trakooljul, Nares; Muráni, Eduard; Krischek, Carsten; Schellander, Karl; Wicke, Michael; Wimmers, Klaus; Ponsuksili, Siriluck

    2016-02-01

    Skeletal muscles are metabolically active and have market value in meat-producing farm animals. A better understanding of biological pathways affecting energy metabolism in skeletal muscle could advance the science of skeletal muscle. In this study, comparative pathway-focused gene expression profiling in conjunction with muscle fiber typing were analyzed in skeletal muscles from Duroc, Pietrain, and Duroc-Pietrain crossbred pigs. Each breed type displayed a distinct muscle fiber-type composition. Mitochondrial respiratory activity and glycolytic and oxidative enzyme activities were comparable among genotypes, except for significantly lower complex I activity in Pietrain pigs homozygous-positive for malignant hyperthermia syndrome. At the transcriptional level, lactate dehydrogenase B showed breed specificity, with significantly lower expression in Pietrain pigs homozygous-positive for malignant hyperthermia syndrome. A similar mRNA expression pattern was shown for several subunits of oxidative phosphorylation complexes, including complex I, complex II, complex IV, and ATP synthase. Significant correlations were observed between mRNA expression of genes in focused pathways and enzyme activities in a breed-dependent manner. Moreover, expression patterns of pathway-focused genes were well correlated with muscle fiber-type composition. These results stress the importance of regulation of transcriptional rate of genes related to oxidative and glycolytic pathways in the metabolic capacity of muscle fibers. Overall, the results further the breed-specific understanding of the molecular basis of metabolic enzyme activities, which directly impact meat quality. PMID:26759028

  5. Comparative analysis of Edwardsiella isolates from fish in the eastern United States identifies two distinct genetic taxa amongst organisms phenotypically classified as E. tarda

    USGS Publications Warehouse

    Griffin, Matt J.; Quiniou, Sylvie M.; Cody, Theresa; Tabuchi, Maki; Ware, Cynthia; Cipriano, Rocco C.; Mauel, Michael J.; Soto, Esteban

    2013-01-01

    Edwardsiella tarda, a Gram-negative member of the family Enterobacteriaceae, has been implicated in significant losses in aquaculture facilities worldwide. Here, we assessed the intra-specific variability of E. tarda isolates from 4 different fish species in the eastern United States. Repetitive sequence mediated PCR (rep-PCR) using 4 different primer sets (ERIC I & II, ERIC II, BOX, and GTG5) and multi-locus sequence analysis of 16S SSU rDNA, groEl, gyrA, gyrB, pho, pgi, pgm, and rpoA gene fragments identified two distinct genotypes of E. tarda (DNA group I; DNA group II). Isolates that fell into DNA group II demonstrated more similarity to E. ictaluri than DNA group I, which contained the reference E. tarda strain (ATCC #15947). Conventional PCR analysis using published E. tarda-specific primer sets yielded variable results, with several primer sets producing no observable amplification of target DNA from some isolates. Fluorometric determination of G + C content demonstrated 56.4% G + C content for DNA group I, 60.2% for DNA group II, and 58.4% for E. ictaluri. Surprisingly, these isolates were indistinguishable using conventional biochemical techniques, with all isolates demonstrating phenotypic characteristics consistent with E. tarda. Analysis using two commercial test kits identified multiple phenotypes, although no single metabolic characteristic could reliably discriminate between genetic groups. Additionally, anti-microbial susceptibility and fatty acid profiles did not demonstrate remarkable differences between groups. The significant genetic variation (<90% similarity at gyrA, gyrB, pho, phi and pgm; <40% similarity by rep-PCR) between these groups suggests organisms from DNA group II may represent an unrecognized, genetically distinct taxa of Edwardsiella that is phenotypically indistinguishable from E. tarda.

  6. 1 + 1 = 3: Development and validation of a SNP-based algorithm to identify genetic contributions from three distinct inbred mouse strains.

    PubMed

    Gorham, James D; Ranson, Matthew S; Smith, Janebeth C; Gorham, Beverly J; Muirhead, Kristen-Ashley

    2012-12-01

    State-of-the-art, genome-wide assessment of mouse genetic background uses single nucleotide polymorphism (SNP) PCR. As SNP analysis can use multiplex testing, it is amenable to high-throughput analysis and is the preferred method for shared resource facilities that offer genetic background assessment of mouse genomes. However, a typical individual SNP query yields only two alleles (A vs. B), limiting the application of this methodology to distinguishing contributions from no more than two inbred mouse strains. By contrast, simple sequence length polymorphism (SSLP) analysis yields multiple alleles but is not amenable to high-throughput testing. We sought to devise a SNP-based technique to identify donor strain origins when three distinct mouse strains potentially contribute to the genetic makeup of an individual mouse. A computational approach was used to devise a three-strain analysis (3SA) algorithm that would permit identification of three genetic backgrounds while still using a binary-output SNP platform. A panel of 15 mosaic mice with contributions from BALB/c, C57Bl/6, and DBA/2 genetic backgrounds was bred and analyzed using a genome-wide SNP panel using 1449 markers. The 3SA algorithm was applied and then validated using SSLP. The 3SA algorithm assigned 85% of 1449 SNPs as informative for the C57Bl/6, BALB/c, or DBA/2 backgrounds, respectively. Testing the panel of 15 F2 mice, the 3SA algorithm predicted donor strain origins genome-wide. Donor strain origins predicted by the 3SA algorithm correlated perfectly with results from individual SSLP markers located on five different chromosomes (n=70 tests). We have established and validated an analysis algorithm based on binary SNP data that can successfully identify the donor strain origins of chromosomal regions in mice that are bred from three distinct inbred mouse strains. PMID:23204929

  7. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection.

    PubMed

    Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L; Langeveld, Jan; Telling, Glenn C; Kong, Qingzhong; Safar, Jiri G

    2013-10-11

    The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrP(Sc)). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrP(Sc) particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrP(Sc) particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrP(C) substrate, the dominant PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrP(Sc) is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. PMID:23974118

  8. Charge transport in C60-based dumbbell-type molecules: mechanically induced switching between two distinct conductance states.

    PubMed

    Moreno-García, Pavel; La Rosa, Andrea; Kolivoška, Viliam; Bermejo, Daniel; Hong, Wenjing; Yoshida, Koji; Baghernejad, Masoud; Filippone, Salvatore; Broekmann, Peter; Wandlowski, Thomas; Martín, Nazario

    2015-02-18

    Single molecule charge transport characteristics of buckminsterfullerene-capped symmetric fluorene-based dumbbell-type compound 1 were investigated by scanning tunneling microscopy break junction (STM-BJ), current sensing atomic force microscopy break junction (CS-AFM-BJ), and mechanically controlled break junction (MCBJ) techniques, under ambient conditions. We also show that compound 1 is able to form highly organized defect-free surface adlayers, allowing the molecules on the surface to be addressed specifically. Two distinct single molecule conductance states (called high G(H)(1) and low G(L)(1)) were observed, depending on the pressure exerted by the probe on the junction, thus allowing molecule 1 to function as a mechanically driven molecular switch. These two distinct conductance states were attributed to the electron tunneling through the buckminsterfullerene anchoring group and fully extended molecule 1, respectively. The assignment of conductance features to these configurations was further confirmed by control experiments with asymmetrically designed buckminsterfullerene derivative 2 as well as pristine buckminsterfullerene 3, both lacking the G(L) feature. PMID:25651069

  9. Classifiers utilized to enhance acoustic based sensors to identify round types of artillery/mortar

    NASA Astrophysics Data System (ADS)

    Grasing, David; Desai, Sachi; Morcos, Amir

    2008-04-01

    Feature extraction methods based on the statistical analysis of the change in event pressure levels over a period and the level of ambient pressure excitation facilitate the development of a robust classification algorithm. The features reliably discriminates mortar and artillery variants via acoustic signals produced during the launch events. Utilizing acoustic sensors to exploit the sound waveform generated from the blast for the identification of mortar and artillery variants as type A, etcetera through analysis of the waveform. Distinct characteristics arise within the different mortar/artillery variants because varying HE mortar payloads and related charges emphasize varying size events at launch. The waveform holds various harmonic properties distinct to a given mortar/artillery variant that through advanced signal processing and data mining techniques can employed to classify a given type. The skewness and other statistical processing techniques are used to extract the predominant components from the acoustic signatures at ranges exceeding 3000m. Exploiting these techniques will help develop a feature set highly independent of range, providing discrimination based on acoustic elements of the blast wave. Highly reliable discrimination will be achieved with a feedforward neural network classifier trained on a feature space derived from the distribution of statistical coefficients, frequency spectrum, and higher frequency details found within different energy bands. The processes that are described herein extend current technologies, which emphasis acoustic sensor systems to provide such situational awareness.

  10. Linking structural features from mitochondrial and bacterial F-type ATP synthases to their distinct mechanisms of ATPase inhibition.

    PubMed

    Krah, Alexander

    2015-10-01

    ATP synthases are molecular motors, which synthesize ATP, the ubiquitous energy source in all living cells. They use an electrochemical gradient to drive a rotation in the membrane embedded Fo domain, namely the c-ring, causing a conformational change in the soluble F1 domain which leads to the catalytic event. In the opposite fashion, they can also hydrolyse ATP to maintain the ion gradient across the membrane. To prevent wasteful ATP hydrolysis, bacteria and mammals have developed peculiar mechanistic features in addition to a common one, namely MgADP inhibition. Here I discuss the distinct ATPase inhibition mechanism in mitochondrial (IF1) and bacterial (subunits ε and ζ) F-type ATP synthases, based on available structural, biophysical and biochemical data. PMID:26140992

  11. Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis.

    PubMed

    Börner, Kenneth; Becker, Peter B

    2016-09-01

    SWR1-type nucleosome remodeling factors replace histone H2A by variants to endow chromatin locally with specialized functionality. In Drosophila melanogaster a single H2A variant, H2A.V, combines functions of mammalian H2A.Z and H2A.X in transcription regulation and the DNA damage response. A major role in H2A.V incorporation for the only SWR1-like enzyme in flies, Domino, is assumed but not well documented in vivo. It is also unclear whether the two alternatively spliced isoforms, DOM-A and DOM-B, have redundant or specialized functions. Loss of both DOM isoforms compromises oogenesis, causing female sterility. We systematically explored roles of the two DOM isoforms during oogenesis using a cell type-specific knockdown approach. Despite their ubiquitous expression, DOM-A and DOM-B have non-redundant functions in germline and soma for egg formation. We show that chromatin incorporation of H2A.V in germline and somatic cells depends on DOM-B, whereas global incorporation in endoreplicating germline nurse cells appears to be independent of DOM. By contrast, DOM-A promotes the removal of H2A.V from stage 5 nurse cells. Remarkably, therefore, the two DOM isoforms have distinct functions in cell type-specific development and H2A.V exchange. PMID:27578180

  12. Flexible or leaky attention in creative people? Distinct patterns of attention for different types of creative thinking.

    PubMed

    Zabelina, Darya; Saporta, Arielle; Beeman, Mark

    2016-04-01

    Creativity has been putatively linked to distinct forms of attention, but which aspects of creativity and which components of attention remains unclear. Two experiments examined how divergent thinking and creative achievement relate to visual attention. In both experiments, participants identified target letters (S or H) within hierarchical stimuli (global letters made of local letters), after being cued to either the local or global level. In Experiment 1, participants identified the targets more quickly following valid cues (80% of trials) than following invalid cues. However, this smaller validity effect was associated with higher divergent thinking, suggesting that divergent thinking was related to quicker overcoming of invalid cues, and thus to flexible attention. Creative achievement was unrelated to the validity effect. Experiment 2 examined whether divergent thinking (or creative achievement) is related to "leaky attention," so that when cued to one level of a stimulus, some information is still processed, or leaks in, from the non-cued level. In this case, the cued stimulus level always contained a target, and the non-cued level was congruent, neutral, or incongruent with the target. Divergent thinking did not relate to stimulus congruency. In contrast, high creative achievement was related to quicker responses to the congruent than to the incongruent stimuli, suggesting that real-world creative achievement is indeed associated with leaky attention, whereas standard laboratory tests of divergent thinking are not. Together, these results elucidate distinct patterns of attention for different measures of creativity. Specifically, creative achievers may have leaky attention, as suggested by previous literature, whereas divergent thinkers have selective yet flexible attention. PMID:26527210

  13. IFN-β-inducing, unusual viral RNA species produced by paramyxovirus infection accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner

    PubMed Central

    Yoshida, Asuka; Kawabata, Ryoko; Honda, Tomoyuki; Tomonaga, Keizo; Sakaguchi, Takemasa; Irie, Takashi

    2015-01-01

    The interferon (IFN) system is one of the most important defensive responses of mammals against viruses, and is rapidly evoked when the pathogen-associated molecular patterns (PAMPs) of viruses are sensed. Non-self, virus-derived RNA species have been identified as the PAMPs of RNA viruses. In the present study, we compared different types of IFN-β-inducing and -non-inducing viruses in the context of Sendai virus infection. We found that some types of unusual viral RNA species were produced by infections with IFN-β-inducing viruses and accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner. One of these structures was similar to the so-called antiviral stress granules (avSGs) formed by an infection with IFN-inducing viruses whose C proteins were knocked-out or mutated. Non-encapsidated, unusual viral RNA harboring the 5′-terminal region of the viral genome as well as RIG-I and typical SG markers accumulated in these granules. Another was a non-SG-like inclusion formed by an infection with the Cantell strain; a copyback-type DI genome, but not an authentic viral genome, specifically accumulated in the inclusion, whereas RIG-I and SG markers did not. The induction of IFN-β was closely associated with the production of these unusual RNAs as well as the formation of the cytoplasmic structures. PMID:26300870

  14. Common Marker Genes Identified from Various Sample Types for Systemic Lupus Erythematosus

    PubMed Central

    Wang, Lan; Zhang, Yong-Hong; Lei, Shu-Feng; Deng, Fei-Yan

    2016-01-01

    Objective Systemic lupus erythematosus (SLE) is a complex auto-immune disease. Gene expression studies have been conducted to identify SLE-related genes in various types of samples. It is unknown whether there are common marker genes significant for SLE but independent of sample types, which may have potentials for follow-up translational research. The aim of this study is to identify common marker genes across various sample types for SLE. Methods Based on four public microarray gene expression datasets for SLE covering three representative types of blood-born samples (monocyte; peripheral blood mononuclear cell, PBMC; whole blood), we utilized three statistics (fold-change, FC; t-test p value; false discovery rate adjusted p value) to scrutinize genes simultaneously regulated with SLE across various sample types. For common marker genes, we conducted the Gene Ontology enrichment analysis and Protein-Protein Interaction analysis to gain insights into their functions. Results We identified 10 common marker genes associated with SLE (IFI6, IFI27, IFI44L, OAS1, OAS2, EIF2AK2, PLSCR1, STAT1, RNASE2, and GSTO1). Significant up-regulation of IFI6, IFI27, and IFI44L with SLE was observed in all the studied sample types, though the FC was most striking in monocyte, compared with PBMC and whole blood (8.82–251.66 vs. 3.73–74.05 vs. 1.19–1.87). Eight of the above 10 genes, except RNASE2 and GSTO1, interact with each other and with known SLE susceptibility genes, participate in immune response, RNA and protein catabolism, and cell death. Conclusion Our data suggest that there exist common marker genes across various sample types for SLE. The 10 common marker genes, identified herein, deserve follow-up studies to dissert their potentials as diagnostic or therapeutic markers to predict SLE or treatment response. PMID:27257790

  15. Analysis of the type II-A CRISPR-Cas system of Streptococcus agalactiae reveals distinctive features according to genetic lineages

    PubMed Central

    Lier, Clément; Baticle, Elodie; Horvath, Philippe; Haguenoer, Eve; Valentin, Anne-Sophie; Glaser, Philippe; Mereghetti, Laurent; Lanotte, Philippe

    2015-01-01

    CRISPR-Cas systems (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) are found in 90% of archaea and about 40% of bacteria. In this original system, CRISPR arrays comprise short, almost unique sequences called spacers that are interspersed with conserved palindromic repeats. These systems play a role in adaptive immunity and participate to fight non-self DNA such as integrative and conjugative elements, plasmids, and phages. In Streptococcus agalactiae, a bacterium implicated in colonization and infections in humans since the 1960s, two CRISPR-Cas systems have been described. A type II-A system, characterized by proteins Cas9, Cas1, Cas2, and Csn2, is ubiquitous, and a type I–C system, with the Cas8c signature protein, is present in about 20% of the isolates. Unlike type I–C, which appears to be non-functional, type II-A appears fully functional. Here we studied type II-A CRISPR-cas loci from 126 human isolates of S. agalactiae belonging to different clonal complexes that represent the diversity of the species and that have been implicated in colonization or infection. The CRISPR-cas locus was analyzed both at spacer and repeat levels. Major distinctive features were identified according to the phylogenetic lineages previously defined by multilocus sequence typing, especially for the sequence type (ST) 17, which is considered hypervirulent. Among other idiosyncrasies, ST-17 shows a significantly lower number of spacers in comparison with other lineages. This characteristic could reflect the peculiar virulence or colonization specificities of this lineage. PMID:26124774

  16. GenoType NTM-DR for Identifying Mycobacterium abscessus Subspecies and Determining Molecular Resistance.

    PubMed

    Kehrmann, Jan; Kurt, Nermin; Rueger, Kai; Bange, Franz-Christoph; Buer, Jan

    2016-06-01

    We studied the performance of a new line probe assay for identifying the subspecies and determining the macrolide and aminoglycoside resistance levels of 50 Mycobacterium abscessus isolates. Agreement of GenoType NTM-DR results with sequencing and phenotypic resistance results was 92% for subspecies identification and 98% for determining molecular and phenotypic resistance. PMID:27030487

  17. Potential of infrared spectroscopy in combination with extended canonical variate analysis for identifying different paper types

    NASA Astrophysics Data System (ADS)

    Riba, Jordi-Roger; Canals, Trini; Cantero, Rosa; Iturriaga, Hortensia

    2011-02-01

    The increasing use of secondary fiber in papermaking has led to the production of paper containing a wide range of contaminants. Wastepaper mills need to develop quality control methods for evaluating the incoming wastepaper stock as well as testing the specifications of the final product. The goal of this work is to present a fast and successful methodology for identifying different paper types. In this way, undesirable paper types can be refused, thus improving the runnability of the paper machine and the quality of the paper manufactured. In this work we examine various types of paper using information obtained by an appropriate chemometric treatment of infrared spectral data. For this purpose, we studied a large number of paper sheets of three different types (namely coated, offset and cast-coated) supplied by several paper manufacturers. We recorded Fourier transform infrared (FTIR) spectra with the aid of an attenuated total reflectance (ATR) module and near-infrared (NIR) reflectance spectra by means of fiber optics. Both techniques proved expeditious and required no sample pretreatment. The primary objective of this work was to develop a methodology for the accurate identification of samples of different paper types. For this purpose, we used the chemometric discrimination technique extended canonical variate analysis (ECVA) in combination with the k nearest neighbor (kNN) method to classify samples in the prediction set. Use of the NIR and FTIR techniques under these conditions allowed paper types to be identified with 100% success in prediction samples.

  18. A multivariate spatial crash frequency model for identifying sites with promise based on crash types.

    PubMed

    Jonathan, Aguero-Valverde; Wu, Kun-Feng Ken; Donnell, Eric T

    2016-02-01

    Many studies have proposed the use of a systemic approach to identify sites with promise (SWiPs). Proponents of the systemic approach to road safety management suggest that it is more effective in reducing crash frequency than the traditional hot spot approach. The systemic approach aims to identify SWiPs by crash type(s) and, therefore, effectively connects crashes to their corresponding countermeasures. Nevertheless, a major challenge to implementing this approach is the low precision of crash frequency models, which results from the systemic approach considering subsets (crash types) of total crashes leading to higher variability in modeling outcomes. This study responds to the need for more precise statistical output and proposes a multivariate spatial model for simultaneously modeling crash frequencies for different crash types. The multivariate spatial model not only induces a multivariate correlation structure between crash types at the same site, but also spatial correlation among adjacent sites to enhance model precision. This study utilized crash, traffic, and roadway inventory data on rural two-lane highways in Pennsylvania to construct and test the multivariate spatial model. Four models with and without the multivariate and spatial correlations were tested and compared. The results show that the model that considers both multivariate and spatial correlation has the best fit. Moreover, it was found that the multivariate correlation plays a stronger role than the spatial correlation when modeling crash frequencies in terms of different crash types. PMID:26615494

  19. Detection of a Distinctive Genomic Signature in Rhabdoid Glioblastoma, A Rare Disease Entity Identified by Whole Exome Sequencing and Whole Transcriptome Sequencing123

    PubMed Central

    Koh, Youngil; Park, Inho; Sun, Chung-Hyun; Lee, Seungmook; Yun, Hongseok; Park, Chul-Kee; Park, Sung-Hye; Park, Joo Kyung; Lee, Se-Hoon

    2015-01-01

    We analyzed the genome of a rhabdoid glioblastoma (R-GBM) tumor, a very rare variant of GBM. A surgical specimen of R-GBM from a 20-year-old woman was analyzed using whole exome sequencing (WES), whole transcriptome sequencing (WTS), single nucleotide polymorphism array, and array comparative genomic hybridization. The status of gene expression in R-GBM tissue was compared with that of normal brain tissue and conventional GBM tumor tissue. We identified 23 somatic non-synonymous small nucleotide variants with WES. We identified the BRAF V600E mutation and possible functional changes in the mutated genes, ISL1 and NDRG2. Copy number alteration analysis revealed gains of chromosomes 3, 7, and 9. We found loss of heterozygosity and focal homozygous deletion on 9q21, which includes CDKN2A and CDKN2B. In addition, WTS revealed that CDK6, MET, EZH2, EGFR, and NOTCH1, which are located on chromosomes 7 and 9, were over-expressed, whereas CDKN2A/2B were minimally expressed. Fusion gene analysis showed 14 candidate genes that may be functionally involved in R-GBM, including TWIST2, and UPK3BL. The BRAF V600E mutation, CDKN2A/2B deletion, and EGFR/MET copy number gain were observed. These simultaneous alterations are very rarely found in GBM. Moreover, the NDRG2 mutation was first identified in this study as it has never been reported in GBM. We observed a unique genomic signature in R-GBM compared to conventional GBM, which may provide insight regarding R-GBM as a distinct disease entity among the larger group of GBMs. PMID:26310374

  20. Chromatin marks identify critical cell types for fine mapping complex trait variants.

    PubMed

    Trynka, Gosia; Sandor, Cynthia; Han, Buhm; Xu, Han; Stranger, Barbara E; Liu, X Shirley; Raychaudhuri, Soumya

    2013-02-01

    If trait-associated variants alter regulatory regions, then they should fall within chromatin marks in relevant cell types. However, it is unclear which of the many marks are most useful in defining cell types associated with disease and fine mapping variants. We hypothesized that informative marks are phenotypically cell type specific; that is, SNPs associated with the same trait likely overlap marks in the same cell type. We examined 15 chromatin marks and found that those highlighting active gene regulation were phenotypically cell type specific. Trimethylation of histone H3 at lysine 4 (H3K4me3) was the most phenotypically cell type specific (P < 1 × 10(-6)), driven by colocalization of variants and marks rather than gene proximity (P < 0.001). H3K4me3 peaks overlapped with 37 SNPs for plasma low-density lipoprotein concentration in the liver (P < 7 × 10(-5)), 31 SNPs for rheumatoid arthritis within CD4(+) regulatory T cells (P = 1 × 10(-4)), 67 SNPs for type 2 diabetes in pancreatic islet cells (P = 0.003) and the liver (P = 0.003), and 14 SNPs for neuropsychiatric disease in neuronal tissues (P = 0.007). We show how cell type-specific H3K4me3 peaks can inform the fine mapping of associated SNPs to identify causal variation. PMID:23263488

  1. Characterization of type 2 diacylglycerol acyltransferases in Chlamydomonas reinhardtii reveals their distinct substrate specificities and functions in triacylglycerol biosynthesis.

    PubMed

    Liu, Jin; Han, Danxiang; Yoon, Kangsup; Hu, Qiang; Li, Yantao

    2016-04-01

    Diacylglycerol acyltransferases (DGATs) catalyze a rate-limiting step of triacylglycerol (TAG) biosynthesis in higher plants and yeast. The genome of the green alga Chlamydomonas reinhardtii has multiple genes encoding type 2 DGATs (DGTTs). Here we present detailed functional and biochemical analyses of Chlamydomonas DGTTs. In vitro enzyme analysis using a radiolabel-free assay revealed distinct substrate specificities of three DGTTs: CrDGTT1 preferred polyunsaturated acyl CoAs, CrDGTT2 preferred monounsaturated acyl CoAs, and CrDGTT3 preferred C16 CoAs. When diacylglycerol was used as the substrate, CrDGTT1 preferred C16 over C18 in the sn-2 position of the glycerol backbone, but CrDGTT2 and CrDGTT3 preferred C18 over C16. In vivo knockdown of CrDGTT1, CrDGTT2 or CrDGTT3 resulted in 20-35% decreases in TAG content and a reduction of specific TAG fatty acids, in agreement with the findings of the in vitro assay and fatty acid feeding test. These results demonstrate that CrDGTT1, CrDGTT2 and CrDGTT3 possess distinct specificities toward acyl CoAs and diacylglycerols, and may work in concert spatially and temporally to synthesize diverse TAG species in C. reinhardtii. CrDGTT1 was shown to prefer prokaryotic lipid substrates and probably resides in both the endoplasmic reticulum and chloroplast envelope, indicating its role in prokaryotic and eukaryotic TAG biosynthesis. Based on these findings, we propose a working model for the role of CrDGTT1 in TAG biosynthesis. This work provides insight into TAG biosynthesis in C. reinhardtii, and paves the way for engineering microalgae for production of biofuels and high-value bioproducts. PMID:26919811

  2. Amiloride-Insensitive Salt Taste Is Mediated by Two Populations of Type III Taste Cells with Distinct Transduction Mechanisms

    PubMed Central

    Sukumaran, Sunil K.; Margolskee, Robert F.; Bachmanov, Alexander A.

    2016-01-01

    Responses in the amiloride-insensitive (AI) pathway, one of the two pathways mediating salty taste in mammals, are modulated by the size of the anion of a salt. This “anion effect” has been hypothesized to result from inhibitory transepithelial potentials (TPs) generated across the lingual epithelium as cations permeate through tight junctions and leave their larger and less permeable anions behind (Ye et al., 1991). We tested directly the necessity of TPs for the anion effect by measuring responses to NaCl and Na-gluconate (small and large anion sodium salts, respectively) in isolated taste cells from mouse circumvallate papillae. Using calcium imaging, we identified AI salt-responsive type III taste cells and demonstrated that they compose a subpopulation of acid-responsive taste cells. Even in the absence of TPs, many (66%) AI salt-responsive type III taste cells still exhibited the anion effect, demonstrating that some component of the transduction machinery for salty taste in type III cells is sensitive to anion size. We hypothesized that osmotic responses could explain why a minority of type III cells (34%) had AI salt responses but lacked anion sensitivity. All AI type III cells had osmotic responses to cellobiose, which were significantly modulated by extracellular sodium concentration, suggesting the presence of a sodium-conducting osmotically sensitive ion channel. However, these responses were significantly larger in AI type III cells that did not exhibit the anion effect. These findings indicate that multiple mechanisms could underlie AI salt responses in type III taste cells, one of which may contribute to the anion effect. SIGNIFICANCE STATEMENT Understanding the mechanisms underlying salty taste will help inform strategies to combat the health problems associated with NaCl overconsumption by humans. Of the two pathways underlying salty taste in mammals, the amiloride-insensitive (AI) pathway is the least understood. Using calcium imaging of

  3. Multilocus Sequence Typing Supports the Hypothesis that Cow- and Human-Associated Salmonella Isolates Represent Distinct and Overlapping Populations▿ †

    PubMed Central

    Alcaine, S. D.; Soyer, Y.; Warnick, L. D.; Su, W.-L.; Sukhnanand, S.; Richards, J.; Fortes, E. D.; McDonough, P.; Root, T. P.; Dumas, N. B.; Gröhn, Y.; Wiedmann, M.

    2006-01-01

    A collection of 179 human and 156 bovine clinical Salmonella isolates obtained from across New York state over the course of 1 year was characterized using serotyping and a multilocus sequence typing (MLST) scheme based on the sequencing of three genes (fimA, manB, and mdh). The 335 isolates were differentiated into 52 serotypes and 72 sequence types (STs). Analyses of bovine isolates collected on different farms over time indicated that specific subtypes can persist over time on a given farm; in particular, a number of farms showed evidence for the persistence of a specific Salmonella enterica serotype Newport sequence type. Serotypes and STs were not randomly distributed among human and bovine isolates, and selected serotypes and STs were associated exclusively with either human or bovine sources. A number of common STs were geographically widespread. For example, ST6, which includes isolates representing serotype Typhimurium as well as the emerging serotype 4,5,12:i:-, was found among human and bovine isolates in a number of counties in New York state. Phylogenetic analyses supported the possibility that serotype 4,5,12:i:- is closely related to Salmonella serotype Typhimurium. Salmonella serotype Newport was found to represent two distinct evolutionary lineages that differ in their frequencies among human and bovine isolates. A number of Salmonella isolates carried two copies of manB (33 isolates) or showed small deletion events in fimA (nine isolates); these duplication and deletion events may provide mechanisms for the rapid diversification of Salmonella surface molecules. We conclude that the combined use of an economical three-gene MLST scheme and serotyping can provide considerable new insights into the evolution and transmission of Salmonella. PMID:17028236

  4. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity?

    PubMed

    Shia, Jinru; Tang, Laura H; Weiser, Martin R; Brenner, Baruch; Adsay, N Volkan; Stelow, Edward B; Saltz, Leonard B; Qin, Jing; Landmann, Ron; Leonard, Gregory D; Dhall, Deepti; Temple, Larissa; Guillem, Jose G; Paty, Philip B; Kelsen, David; Wong, W Douglas; Klimstra, David S

    2008-05-01

    %), whereas most involving the glandular mucosa were large cell (53%) or mixed (82%) type; associated adenocarcinomas were more frequent in large cell (61%) or mixed (36%) type than in small cell type (26%); and focal intracytoplasmic mucin was seen only in large cell or mixed type. As a group, the 2-year disease-specific survival for patients with HGNEC was 25.4% (median follow-up time, 11.3 mo). No significant survival difference was observed among the different histologic subtypes. In conclusion, our study demonstrates the existence of both small cell and nonsmall cell types of HGNEC in the GI tract, and provides a detailed illustration of their morphologic spectrum. There are differences in certain pathologic features between small cell and nonsmall cell types, whereas the differences between the subtypes of nonsmall cell category (large cell versus mixed) are less distinct. Given the current uncertainty as to whether large cell neuroendocrine carcinoma is as chemosensitive as small cell carcinoma even in the lung, our data provide further evidence in favor of a dichotomous classification scheme (small cell vs. nonsmall cell) for HGNEC of the GI tract. Separation of nonsmall cell type into large cell and mixed subtypes may not be necessary. These tumors are clinically aggressive. Prospective studies using defined diagnostic criteria are needed to determine their biologic characteristics and optimal management. PMID:18360283

  5. Targeting N-glycan cryptic sugar moieties for broad-spectrum virus neutralization: progress in identifying conserved molecular targets in viruses of distinct phylogenetic origins.

    PubMed

    Wang, Denong; Tang, Jin; Tang, Jiulai; Wang, Lai-Xi

    2015-01-01

    Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA), for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV), and human cytomegalovirus (HCMV). In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9)-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn). These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation. PMID:25774492

  6. Four new type I restriction enzymes identified in Escherichia coli clinical isolates

    PubMed Central

    Kasarjian, Julie K. A.; Kodama, Yoshiaki; Iida, Masatake; Matsuda, Katsura; Ryu, Junichi

    2005-01-01

    Using a plasmid transformation method and the RM search computer program, four type I restriction enzymes with new recognition sites and two isoschizomers (EcoBI and Eco377I) were identified in a collection of clinical Escherichia coli isolates. These new enzymes were designated Eco394I, Eco826I, Eco851I and Eco912I. Their recognition sequences were determined to be GAC(5N)RTAAY, GCA(6N)CTGA, GTCA(6N)TGAY and CAC(5N)TGGC, respectively. A methylation sensitivity assay, using various synthetic oligonucleotides, was used to identify the adenines that prevent cleavage when methylated (underlined). These results suggest that type I enzymes are abundant in E.coli and many other bacteria, as has been inferred from bacterial genome sequencing projects. PMID:16040596

  7. Distinct types of protease systems are involved in homeostasis regulation of mitochondrial morphology via balanced fusion and fission.

    PubMed

    Saita, Shotaro; Ishihara, Takaya; Maeda, Maki; Iemura, Shun-Ichiro; Natsume, Tohru; Mihara, Katsuyoshi; Ishihara, Naotada

    2016-05-01

    Mitochondrial morphology is dynamically regulated by fusion and fission. Several GTPase proteins control fusion and fission, and posttranslational modifications of these proteins are important for the regulation. However, it has not been clarified how the fusion and fission is balanced. Here, we report the molecular mechanism to regulate mitochondrial morphology in mammalian cells. Ablation of the mitochondrial fission, by repression of Drp1 or Mff, or by over-expression of MiD49 or MiD51, results in a reduction in the fusion GTPase mitofusins (Mfn1 and Mfn2) in outer membrane and long form of OPA1 (L-OPA1) in inner membrane. RNAi- or CRISPR-induced ablation of Drp1 in HeLa cells enhanced the degradation of Mfns via the ubiquitin-proteasome system (UPS). We further found that UPS-related protein BAT3/BAG6, here we identified as Mfn2-interacting protein, was implicated in the turnover of Mfns in the absence of mitochondrial fission. Ablation of the mitochondrial fission also enhanced the proteolytic cleavage of L-OPA1 to soluble S-OPA1, and the OPA1 processing was reversed by inhibition of the inner membrane protease OMA1 independent on the mitochondrial membrane potential. Our findings showed that the distinct degradation systems of the mitochondrial fusion proteins in different locations are enhanced in response to the mitochondrial morphology. PMID:26935475

  8. p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients.

    PubMed

    Pasqualim, G; Ribeiro, M G; da Fonseca, G G G; Szlago, M; Schenone, A; Lemes, A; Rojas, M V M; Matte, U; Giugliani, R

    2015-10-01

    Mucopolysaccharidosis type I is a rare autosomal recessive disorder caused by deficiency of α-l-iduronidase (IDUA) which leads to a wide spectrum of clinical severity. Here, we describe the case of four male patients who present the previously undescribed p.L18P mutation. Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, claw hands and underwent bilateral carpal tunnel surgery at 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented claw hands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptide to 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease, or cognitive impairment. PMID:25256405

  9. An Active Type I-E CRISPR-Cas System Identified in Streptomyces avermitilis

    PubMed Central

    Qiu, Yi; Wang, Shiwei; Chen, Zhi; Guo, Yajie; Song, Yuan

    2016-01-01

    CRISPR-Cas systems, the small RNA-dependent immune systems, are widely distributed in prokaryotes. However, only a small proportion of CRISPR-Cas systems have been identified to be active in bacteria. In this work, a naturally active type I-E CRISPR-Cas system was found in Streptomyces avermitilis. The system shares many common genetic features with the type I-E system of Escherichia coli, and meanwhile shows unique characteristics. It not only degrades plasmid DNA with target protospacers, but also acquires new spacers from the target plasmid DNA. The naive features of spacer acquisition in the type I-E system of S. avermitilis were investigated and a completely conserved PAM 5’-AAG-3’ was identified. Spacer acquisition displayed differential strand bias upstream and downstream of the priming spacer, and irregular integrations of new spacers were observed. In addition, introduction of this system into host conferred phage resistance to some extent. This study will give new insights into adaptation mechanism of the type I-E systems in vivo, and meanwhile provide theoretical foundation for applying this system on the genetic modification of S. avermitilis. PMID:26901661

  10. Vision System To Identify Car Body Types For Spray Painting Robot

    NASA Astrophysics Data System (ADS)

    Uartlam, Peter; Neilson, Geoff

    1984-02-01

    The automation of car body spray booth operations employing paint spraying robots generally requires the robots to execute one of a number of defined routines according to the car body type. A vision system is described which identifies a car body type by its shape and provides an identity code to the robot controller thus enabling the correct routine to be executed. The vision system consists of a low cost linescan camera, a flucrescens light source and a microprocessor image analyser and is an example of a cost effective, reliable, industrially engineered robot vision system for a demanding production environment. Extension of the system with additional cameras will increase the application to the other automatic operations on a car assembly line where it becomes essential to reliably differentiate between up to 40 vatiations of body types.