Sample records for typing identifies distinct

  1. Two Types of Identified Ascending Interneurons With Distinct GABA Receptors in the Crayfish Terminal Abdominal Ganglion

    E-print Network

    Nagayama, Toshiki

    Two Types of Identified Ascending Interneurons With Distinct GABA Receptors in the Crayfish the CNS is therefore necessary to discriminate receptors in the crayfish terminal abdominal ganglion. J of the identified About 130 ascending interneurons originate in the crayfish ascending interneurons originating

  2. Identifying distinct thermal components of a creek

    NASA Astrophysics Data System (ADS)

    Boughton, David A.; Hatch, Christine; Mora, Ethan

    2012-09-01

    Statistical and heat budget methods for analyzing temperature dynamics of creeks are limited by the ability to resolve thermal processes and fine-grained thermal structures, respectively. Here we describe a hybrid method that identifies distinct thermal components in a stream's heat budget using only temperature data and an algorithm that employs mutual information to "unmix" signals in the temperature data. Spatial resolution is limited only by the number of temperature-logging sensors, which can be quite high for distributed-temperature sensors. Process resolution is at the level of thermal components, defined as distinct collections of heat flux elements sharing coordinated (nonindependent) dynamics. Inference can be used to relate thermal components to meteorological forcing and structural heterogeneity in the fluvial system and to suggest novel hypotheses for further testing with targeted heat budget studies. Applying the method to a small, arid-land creek produced two novel hypotheses: (1) lateral conduction of heat from adjacent dry land (bed, terraces) appeared to cause a substantial heating of the stream, augmented by off-channel flow paths, and (2) riparian vegetation was associated with a subtraction of heat from the stream at a rate proportionate to solar insolation, exceeding the maximum decoupling effect of shade by at least 2°C at midday, and suggesting upwelling heat flux from water to tree canopy proportional to sunlight. The method appears useful for generating new hypotheses, for selecting informative sites for detailed heat budgets, for determining the dimensionality of heat budgets in natural streams, and more broadly for associating thermal components to fluvial structure and processes.

  3. ADHD Combined Type and ADHD Predominantly Inattentive Type Are Distinct and Unrelated Disorders

    Microsoft Academic Search

    Richard Milich; Amy C. Balentine; Donald R. Lynam

    2001-01-01

    We comprehensively reviewed research assessing differences in attention-deficit hyperactivity disorder (ADHD) subtypes to examine the possibility that ADHD\\/ combined type (ADHD\\/Q and ADHD\\/predominantly inattentive type (ADHD\\/I) are distinct and unrelated disorders. Differences among subtypes were examined along dimensions identified as being important in documenting the distinctiveness of two disorders. These include essential and associated features, demographics, measures of cognitive and

  4. 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

  5. Propionibacterium acnes types I and II represent phylogenetically distinct groups.

    PubMed

    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

  6. 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

  7. Distinct signaling properties identify functionally different CD4 epitopes.

    PubMed

    Baldari, C T; Milia, E; Di Somma, M M; Baldoni, F; Valitutti, S; Telford, J L

    1995-07-01

    The CD4 coreceptor interacts with non-polymorphic regions of major histocompatibility complex class II molecules on antigen-presenting cells and contributes to T cell activation. We have investigated the effect of CD4 triggering on T cell activating signals in a lymphoma model using monoclonal antibodies (mAb) which recognize different CD4 epitopes. We demonstrate that CD4 triggering delivers signals capable of activating the NF-AT transcription factor which is required for interleukin-2 gene expression. Whereas different anti-CD4 mAb or HIV-1 gp120 could all trigger activation of the protein tyrosine kinases p56lck and p59fyn and phosphorylation of the Shc adaptor protein, which mediates signals to Ras, they differed significantly in their ability to activate NF-AT. Lack of full activation of NF-AT could be correlated to a dramatically reduced capacity to induce calcium flux and could be complemented with a calcium ionophore. The results identify functionally distinct epitopes on the CD4 coreceptor involved in activation of the Ras/protein kinase C and calcium pathways. PMID:7542591

  8. Constructing Taxonomies to Identify Distinctive Forms of Primary Healthcare Organizations

    PubMed Central

    Borgès Da Silva, Roxane; Pineault, Raynald; Hamel, Marjolaine; Levesque, Jean-Frédéric; Roberge, Danièle; Lamarche, Paul

    2013-01-01

    Background. Primary healthcare (PHC) renewal gives rise to important challenges for policy makers, managers, and researchers in most countries. Evaluating new emerging forms of organizations is therefore of prime importance in assessing the impact of these policies. This paper presents a set of methods related to the configurational approach and an organizational taxonomy derived from our analysis. Methods. In 2005, we carried out a study on PHC in two health and social services regions of Quebec that included urban, suburban, and rural areas. An organizational survey was conducted in 473 PHC practices. We used multidimensional nonparametric statistical methods, namely, multiple correspondence and principal component analyses, and an ascending hierarchical classification method to construct a taxonomy of organizations. Results. PHC organizations were classified into five distinct models: four professional and one community. Study findings indicate that the professional integrated coordination and the community model have great potential for organizational development since they are closest to the ideal type promoted by current reforms. Conclusion. Results showed that the configurational approach is useful to assess complex phenomena such as the organization of PHC. The analysis highlights the most promising organizational models. Our study enhances our understanding of organizational change in health services organizations. PMID:24959575

  9. 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

  10. 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

  11. Identifying elemental genomic track types and representing them uniformly

    PubMed Central

    2011-01-01

    Background With the recent advances and availability of various high-throughput sequencing technologies, data on many molecular aspects, such as gene regulation, chromatin dynamics, and the three-dimensional organization of DNA, are rapidly being generated in an increasing number of laboratories. The variation in biological context, and the increasingly dispersed mode of data generation, imply a need for precise, interoperable and flexible representations of genomic features through formats that are easy to parse. A host of alternative formats are currently available and in use, complicating analysis and tool development. The issue of whether and how the multitude of formats reflects varying underlying characteristics of data has to our knowledge not previously been systematically treated. Results We here identify intrinsic distinctions between genomic features, and argue that the distinctions imply that a certain variation in the representation of features as genomic tracks is warranted. Four core informational properties of tracks are discussed: gaps, lengths, values and interconnections. From this we delineate fifteen generic track types. Based on the track type distinctions, we characterize major existing representational formats and find that the track types are not adequately supported by any single format. We also find, in contrast to the XML formats, that none of the existing tabular formats are conveniently extendable to support all track types. We thus propose two unified formats for track data, an improved XML format, BioXSD 1.1, and a new tabular format, GTrack 1.0. Conclusions The defined track types are shown to capture relevant distinctions between genomic annotation tracks, resulting in varying representational needs and analysis possibilities. The proposed formats, GTrack 1.0 and BioXSD 1.1, cater to the identified track distinctions and emphasize preciseness, flexibility and parsing convenience. PMID:22208806

  12. 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.

  13. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

    E-print Network

    Capecchi, Mario R.

    The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified contiguous crypts and villi. Clonogenic culture of isolated single Bmi1+ ISCs yields long-lived self

  14. Identifying marker typing incompatibilities in linkage analysis

    SciTech Connect

    Stringham, H.M.; Boehnke, M. [Univ. of Michigan, Ann Arbor, MI (United States)

    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.

  15. Multiple Genetically Distinct Groups Revealed among Clinical Isolates Identified as Atypical Aspergillus fumigatus

    Microsoft Academic Search

    Margaret E. Katz; Annette M. Dougall; Brian F. Cheetham

    2005-01-01

    To investigate whether genetic variants of A. fumigatus are found among clinical isolates, four isolates that were originally identified as poorly sporulating strains of Aspergillus fumigatus were subjected to molecular analysis. DNA sequence analysis of the alkaline protease genes of these isolates showed that each is genetically distinct and each shows substantial variation (7 to 11%) from the A. fumigatus

  16. A Distinct Repertoire of Autoantibodies in Hepatocellular Carcinoma Identified by Proteomic Analysis

    Microsoft Academic Search

    Francois Le Naour; Franck Brichory; David E. Misek; Christian Brechot; Samir M. Hanash; Laura Beretta

    2002-01-01

    Chronic infections with hepatitis B (HBV) and hepatitis C (HCV) viruses are major risk factors for hepatocellular carcinoma (HCC). We have utilized a proteomic approach to determine whether a distinct repertoire of autoantibod- ies can be identified in HCC. Sera from 37 patients with HCC and 31 subjects chronically infected with HBV or HCV without HCC were investigated. Sera from

  17. Principal Component Analysis of Dynamically distinct D-Type Asteroids.

    NASA Astrophysics Data System (ADS)

    Nedic, Sanja; Ziffer, J.; Campins, H.; Fernandez, Y. R.; Walker, M.

    2008-09-01

    Principal Component Analysis (PCA), a common statistically based classification technique, has been used to classify asteroids into broad spectral categories. In some cases, a spectral superclass considered in isolation may undergo sub-classification (e.g. S-type subclasses). Since D-type asteroids populate at least three distinct dynamical regions in the asteroid belt -- namely Hilda, L4 Trojans and L5 Trojans, and since the recently-developed "Nice” model (Morbidelli et al. 2005. Nature 435, 462; Levison et al. 2008, ACM 2008 abstract #8156) hypothesizes that these regions may share a common origin, examining the appropriateness of a D-type sub-classification scheme is warranted. Toward this end, we performed PCA on the D-type L4, L5, and Hilda asteroids. Our PCA was based on the Sloan Digital Sky Survey broadband colors (u - g, g - r, r - i, and i - z) of 31 L4, 24 L5, and 32 Hilda asteroids with radii ranging from approximately 5 to 45 km. PCA showed 90.2% of the variance in the spectra could be condensed into the first two principal components, PC1 and PC2, with the first and second component accounting for 50.7% and 39.4% respectively. No significant clustering is observed on a PC1 vs. PC2 plot suggesting the D-type L4, L5, and Hilda asteroids do not form three independent groups, but rather are spectrally indistinguishable. We performed several statistical analyses of the means and variances of the principal components to test the validity of this conclusion. No statistically significant difference in the means among the three groups was found, nor was there any such difference in the variances, although the statistic comparing the L4 Trojans and Hildas was close to the critical value. Further measurements of colors of both large and small Trojans and Hildas will let us continue to investigate the spectral diversity of these objects.

  18. Distinct lipid compositions of two types of human prostasomes.

    PubMed

    Brouwers, Jos F; Aalberts, Marian; Jansen, Jeroen W A; van Niel, Guillaume; Wauben, Marca H; Stout, Tom A E; Helms, J Bernd; Stoorvogel, Willem

    2013-05-01

    Prostasomes are vesicles secreted by prostate epithelial cells and found in abundance in seminal plasma. They regulate aspects of sperm cell function and are also thought to prevent immune-mediated destruction of sperm cells within the female reproductive tract. In a previous study, we isolated two distinct populations of prostasomes, differing both in size and protein composition, from the seminal fluid of vasectomized men. In the current study, we characterized the lipid content of these two prostasome populations. Both prostasome types had an unusual lipid composition, with high levels of sphingomyelin (SM), cholesterol, and glycosphingolipids at the expense of, in particular, phosphatidylcholine. The different classes of glycerophospholipids consisted mainly of mono-unsaturated species. The sphingosine-based lipids, SM and the hexosylceramides, were characterized by a near absence of unsaturated species. The two types of prostasome differed in lipid composition, particularly with regard to the relative contributions of SM and hexosylceramides. Potential implications of the lipid compositions of prostasomes for the mechanisms of their formation and function are discussed. PMID:23404715

  19. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods

    PubMed Central

    Reese, Jessica A.; Li, Xiaoning; Hauben, Manfred; Aster, Richard H.; Bougie, Daniel W.; Curtis, Brian R.; George, James N.

    2010-01-01

    Drug-induced immune thrombocytopenia (DITP) is often suspected in patients with acute thrombocytopenia unexplained by other causes, but documenting that a drug is the cause of thrombocytopenia can be challenging. To provide a resource for diagnosis of DITP and for drug safety surveillance, we analyzed 3 distinct methods for identifying drugs that may cause thrombocytopenia. (1) Published case reports of DITP have described 253 drugs suspected of causing thrombocytopenia; using defined clinical criteria, 87 (34%) were identified with evidence that the drug caused thrombocytopenia. (2) Serum samples from patients with suspected DITP were tested for 202 drugs; drug-dependent, platelet-reactive antibodies were identified for 67 drugs (33%). (3) The Food and Drug Administration's Adverse Event Reporting System database was searched for drugs associated with thrombocytopenia by use of data mining algorithms; 1444 drugs had at least 1 report associated with thrombocytopenia, and 573 (40%) drugs demonstrated a statistically distinctive reporting association with thrombocytopenia. Among 1468 drugs suspected of causing thrombocytopenia, 102 were evaluated by all 3 methods, and 23 of these 102 drugs had evidence for an association with thrombocytopenia by all 3 methods. Multiple methods, each with a distinct perspective, can contribute to the identification of drugs that can cause thrombocytopenia. PMID:20530792

  20. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods.

    PubMed

    Reese, Jessica A; Li, Xiaoning; Hauben, Manfred; Aster, Richard H; Bougie, Daniel W; Curtis, Brian R; George, James N; Vesely, Sara K

    2010-09-23

    Drug-induced immune thrombocytopenia (DITP) is often suspected in patients with acute thrombocytopenia unexplained by other causes, but documenting that a drug is the cause of thrombocytopenia can be challenging. To provide a resource for diagnosis of DITP and for drug safety surveillance, we analyzed 3 distinct methods for identifying drugs that may cause thrombocytopenia. (1) Published case reports of DITP have described 253 drugs suspected of causing thrombocytopenia; using defined clinical criteria, 87 (34%) were identified with evidence that the drug caused thrombocytopenia. (2) Serum samples from patients with suspected DITP were tested for 202 drugs; drug-dependent, platelet-reactive antibodies were identified for 67 drugs (33%). (3) The Food and Drug Administration's Adverse Event Reporting System database was searched for drugs associated with thrombocytopenia by use of data mining algorithms; 1444 drugs had at least 1 report associated with thrombocytopenia, and 573 (40%) drugs demonstrated a statistically distinctive reporting association with thrombocytopenia. Among 1468 drugs suspected of causing thrombocytopenia, 102 were evaluated by all 3 methods, and 23 of these 102 drugs had evidence for an association with thrombocytopenia by all 3 methods. Multiple methods, each with a distinct perspective, can contribute to the identification of drugs that can cause thrombocytopenia. PMID:20530792

  1. A Framework for Identifying Distinct Multipollutant Profiles in Air Pollution Data

    PubMed Central

    Austin, Elena; Coull, Brent; Thomas, Dylan; Koutrakis, Petros

    2013-01-01

    BACKGROUND The importance of describing, understanding and regulating multi-pollutant mixtures has been highlighted by the US National Academy of Science and the Environmental Protection Agency. Furthering our understanding of the health effects associated with exposure to mixtures of pollutants will lead to the development of new multi-pollutant National Air Quality Standards. OBJECTIVES Introduce a framework within which diagnostic methods that are based on our understanding of air pollution mixtures are used to validate the distinct air pollutant mixtures identified using cluster analysis. METHODS: S ix years of daily gaseous and particulate air pollution data collected in Boston, MA were classified solely on their concentration profiles. Classification was performed using k-means partitioning and hierarchical clustering. Diagnostic strategies were developed to identify the most optimal clustering. RESULTS The optimal solution used k-means analysis and contained five distinct groups of days. Pollutant concentrations and elemental ratios were computed in order to characterize the differences between clusters. Time-series regression confirmed that the groups differed in their chemical compositions. The mean values of meteorological parameters were estimated for each group and air mass origin between clusters was examined using back-trajectory analysis. This allowed us to link the distinct physico-chemical characteristics of each cluster to characteristic weather patterns and show that different clusters were associated with distinct air mass origins. CONCLUSIONS This analysis yielded a solution that was robust to outlier points and interpretable based on chemical, physical and meteorological characteristics. This novel method provides an exciting tool with which to identify and further investigate multi-pollutant mixtures and link them directly to health effects studies. PMID:22584082

  2. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

    PubMed Central

    Yan, Kelley S.; Chia, Luis A.; Li, Xingnan; Ootani, Akifumi; Su, James; Lee, Josephine Y.; Su, Nan; Luo, Yuling; Heilshorn, Sarah C.; Amieva, Manuel R.; Sangiorgi, Eugenio; Capecchi, Mario R.; Kuo, Calvin J.

    2012-01-01

    The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1+ ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1+ ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5+ ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration. PMID:22190486

  3. Distinct trajectories of multimorbidity in primary care were identified using latent class growth analysis?

    PubMed Central

    Strauss, Vicky Y.; Jones, Peter W.; Kadam, Umesh T.; Jordan, Kelvin P.

    2014-01-01

    Objectives To investigate the use of latent class growth analysis (LCGA) in understanding onset and changes in multimorbidity over time in older adults. Study Design and Setting This study used primary care consultations for 42 consensus-defined chronic morbidities over 3 years (2003–2005) by 24,615 people aged >50 years at 10 UK general practices, which contribute to the Consultations in Primary Care Archive database. Distinct groups of people who had similar progression of multimorbidity over time were identified using LCGA. These derived trajectories were tested in another primary care consultation data set with linked self-reported health status. Results Five clusters of people representing different trajectories were identified: those who had no recorded chronic problems (40%), those who developed a first chronic morbidity over 3 years (10%), a developing multimorbidity group (37%), a group with increasing number of chronic morbidities (12%), and a multi-chronic group with many chronic morbidities (1%). These trajectories were also identified using another consultation database and associated with self-reported physical and mental health. Conclusion There are distinct trajectories in the development of multimorbidity in primary care populations, which are associated with poor health. Future research needs to incorporate such trajectories when assessing progression of disease and deterioration of health. PMID:25063556

  4. Latent Class Analysis Identifies Distinct Phenotypes of Primary Graft Dysfunction After Lung Transplantation

    PubMed Central

    Diamond, Joshua M.; Cantu, Edward; Lee, James C.; Lederer, David J.; Lama, Vibha N.; Orens, Jonathan; Weinacker, Ann; Wilkes, David S.; Bhorade, Sangeeta; Wille, Keith M.; Ware, Lorraine B.; Palmer, Scott M.; Crespo, Maria; Localio, A. Russell; Demissie, Ejigayehu; Kawut, Steven M.; Bellamy, Scarlett L.; Christie, Jason D.

    2013-01-01

    Background: There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and patterns of resolution. Methods: Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. Results: Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent dysfunction (class 1), (2) complete resolution of dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P < .001). Conclusions: There are distinct phenotypes of resolution of dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of graft dysfunction. PMID:23429890

  5. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia

    PubMed Central

    Papaemmanuil, Elli; Ambaglio, Ilaria; Elena, Chiara; Gallì, Anna; Della Porta, Matteo G.; Travaglino, Erica; Pietra, Daniela; Pascutto, Cristiana; Ubezio, Marta; Bono, Elisa; Da Vià, Matteo C.; Brisci, Angela; Bruno, Francesca; Cremonesi, Laura; Ferrari, Maurizio; Boveri, Emanuela; Invernizzi, Rosangela; Campbell, Peter J.; Cazzola, Mario

    2014-01-01

    Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible. PMID:24970933

  6. Identifying land cover variability distinct from land cover change: Cheatgrass in the Great Basin

    E-print Network

    Bradley, Bethany

    that ecosystems dominated by non-native cheatgrass (Bromus tectorum) show an inter-annual amplified response Basin; Cheatgrass; Bromus tectorum; Invasive species; Time series; NDVI; Inter-annual variability 1 is prominent in land cover types dominated by cheatgrass (Bromus tectorum). Correctly identifying

  7. 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 these limitations is greatly needed. PMID:25287854

  8. Novel and Distinct Metabolites Identified Following a Single Oral Dose of ?- or ?-Hexabromocyclododecane in Mice

    PubMed Central

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

    2013-01-01

    The metabolism of ?- and ?-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. ?- or ?-[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 ?-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 ?-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

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

    PubMed

    Nandi, Tannistha; 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

  10. Valence Parity Renders z -Type Ions Chemically Distinct

    E-print Network

    Craciun, Gheorghe

    ppm mass accuracy a unique chemical composition can only be determined for peptides having masses less-type series).8 In practice, however, such assign- ments are difficult to make, even for high mass accuracy that no c-type ion shall have the same chemical composition, and by extension mass, as a z· -type ion

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

    PubMed

    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

  12. 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

  13. bodies [4, 12]. In honeybee queens, several types of glands have been identified [6, 15,

    E-print Network

    Paris-Sud XI, Université de

    bodies [4, 12]. In honeybee queens, several types of glands have been identified [6, 15, 17, 28 no differences in gland location or structure in the honeybee queens of both races. However capen- sis workers further emphasises the distinctiveness of Cape honeybees. A. m. capensis / A. m. scutellata / tergal gland

  14. Gene-expression profiling of microdissected breast cancer microvasculature identifies distinct tumor vascular subtypes

    PubMed Central

    2012-01-01

    Introduction Angiogenesis represents a potential therapeutic target in breast cancer. However, responses to targeted antiangiogenic therapies have been reported to vary among patients. This suggests that the tumor vasculature may be heterogeneous and that an appropriate choice of treatment would require an understanding of these differences. Methods To investigate whether and how the breast tumor vasculature varies between individuals, we isolated tumor-associated and matched normal vasculature from 17 breast carcinomas by laser-capture microdissection, and generated gene-expression profiles. Because microvessel density has previously been associated with disease course, tumors with low (n = 9) or high (n = 8) microvessel density were selected for analysis to maximize heterogeneity for this feature. Results We identified differences between tumor and normal vasculature, and we describe two subtypes present within tumor vasculature. These subtypes exhibit distinct gene-expression signatures that reflect features including hallmarks of vessel maturity. Potential therapeutic targets (MET, ITGAV, and PDGFR?) are differentially expressed between subtypes. Taking these subtypes into account has allowed us to derive a vascular signature associated with disease outcome. Conclusions Our results further support a role for tumor microvasculature in determining disease progression. Overall, this study provides a deeper molecular understanding of the heterogeneity existing within the breast tumor vasculature and opens new avenues toward the improved design and targeting of antiangiogenic therapies. PMID:22906178

  15. In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors.

    PubMed

    Xiang, Jie; Wu, Dai-Chen; Chen, Yuanting; Paulson, Robert F

    2015-03-12

    Tissue hypoxia induces a systemic response designed to increase oxygen delivery to tissues. One component of this response is increased erythropoiesis. Steady-state erythropoiesis is primarily homeostatic, producing new erythrocytes to replace old erythrocytes removed from circulation by the spleen. In response to anemia, the situation is different. New erythrocytes must be rapidly made to increase hemoglobin levels. At these times, stress erythropoiesis predominates. Stress erythropoiesis is best characterized in the mouse, where it is extramedullary and utilizes progenitors and signals that are distinct from steady-state erythropoiesis. In this report, we use an in vitro culture system that recapitulates the in vivo development of stress erythroid progenitors. We identify cell-surface markers that delineate a series of stress erythroid progenitors with increasing maturity. In addition, we use this in vitro culture system to expand human stress erythroid progenitor cells that express analogous cell-surface markers. Consistent with previous suggestions that human stress erythropoiesis is similar to fetal erythropoiesis, we demonstrate that human stress erythroid progenitors express fetal hemoglobin upon differentiation. These data demonstrate that similar to murine bone marrow, human bone marrow contains cells that can generate BMP4-dependent stress erythroid burst-forming units when cultured under stress erythropoiesis conditions. PMID:25608563

  16. TGF-?1 activates two distinct type I receptors in neurons

    PubMed Central

    König, Hans-Georg; Kögel, Donat; Rami, Abdelhaq; Prehn, Jochen H.M.

    2005-01-01

    Transforming growth factor-?s (TGF-?s) are pleiotropic cytokines involved in development and maintenance of the nervous system. In several neural lesion paradigms, TGF-?1 exerts potent neuroprotective effects. Neurons treated with TGF-?1 activated the canonical TGF-? receptor I/activin-like kinase receptor 5 (ALK5) pathway. The transcription factor nuclear factor-?B (NF-?B) plays a fundamental role in neuroprotection. Treatment with TGF-?1 enhanced NF-?B activity in gelshift and reporter gene analyses. However, ectopic expression of a constitutively active ALK5 failed to mimic these effects. ALK1 has been described as an alternative TGF-? receptor in endothelial cells. Interestingly, we detected significant basal expression of ALK1 and its injury-induced up-regulation in neurons. Treatment with TGF-?1 also induced a pronounced increase in downstream Smad1 phosphorylation. Overexpression of a constitutively active ALK1 mimicked the effect of TGF-?1 on NF-?B activation and neuroprotection. Our data suggest that TGF-?1 simultaneously activates two distinct receptor pathways in neurons and that the ALK1 pathway mediates TGF-?1–induced NF-?B survival signaling. PMID:15781474

  17. Adenovirus Vectors Targeting Distinct Cell Types in the Retina

    PubMed Central

    Sweigard, J. Harry; Cashman, Siobhan M.

    2010-01-01

    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 (Ad5?RGD). 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 Ad5?RGD was detected. Photoreceptor-specific transgene expression from the 257-bp mouse opsin promoter in the context of Ad5?RGD 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 Ad5?RGD vectors. PMID:19892875

  18. Single nucleotide polymorphism array profiling identifies distinct chromosomal aberration patterns across colorectal adenomas and carcinomas.

    PubMed

    Zarzour, Peter; Boelen, Lies; Luciani, Fabio; Beck, Dominik; Sakthianandeswaren, Anuratha; Mouradov, Dmitri; Sieber, Oliver M; Hawkins, Nicholas J; Hesson, Luke B; Ward, Robyn L; Wong, Jason W H

    2015-05-01

    The progression of benign colorectal adenomas into cancer is associated with the accumulation of chromosomal aberrations. Even though patterns and frequencies of chromosomal aberrations have been well established in colorectal carcinomas, corresponding patterns of aberrations in adenomas are less well documented. The aim of this study was to profile chromosomal aberrations across colorectal adenomas and carcinomas to provide a better insight into key changes during tumor initiation and progression. Single nucleotide polymorphism array analysis was performed on 216 colorectal tumor/normal matched pairs, comprising 60 adenomas and 156 carcinomas. While many chromosomal aberrations were specific to carcinomas, those with the highest frequency in carcinomas (amplification of chromosome 7, 13q, and 20q; deletion of 17p and chromosome 18; LOH of 1p, chromosome 4, 5q, 8p, 17p, chromosome 18, and 20p) were also identified in adenomas. Hierarchical clustering using chromosomal aberrations revealed three distinct subtypes. Interestingly, these subtypes were only partially dependent on tumor staging. A cluster of colorectal cancer patients with frequent chromosomal deletions had the least favorable prognosis, and a number of adenomas (n?=?9) were also present in the cluster suggesting that, at least in some tumors, the chromosomal aberration pattern is determined at a very early stage of tumor formation. Finally, analysis of LOH events revealed that copy-neutral/gain LOH (CN/G-LOH) is frequent (>10%) in carcinomas at 5q, 11q, 15q, 17p, chromosome 18, 20p, and 22q. Deletion of the corresponding region is sometimes present in adenomas, suggesting that LOH at these loci may play an important role in tumor initiation. © 2015 Wiley Periodicals, Inc. PMID:25726927

  19. Evidence for two distinct populations of type Ia supernovae.

    PubMed

    Wang, Xiaofeng; Wang, Lifan; Filippenko, Alexei V; Zhang, Tianmeng; Zhao, Xulin

    2013-04-12

    Type Ia supernovae (SNe Ia) have been used as excellent standardizable candles for measuring cosmic expansion, but their progenitors are still elusive. Here, we report that the spectral diversity of SNe Ia is tied to their birthplace environments. We found that those with high-velocity ejecta are substantially more concentrated in the inner and brighter regions of their host galaxies than are normal-velocity SNe Ia. Furthermore, the former tend to inhabit larger and more luminous hosts. These results suggest that high-velocity SNe Ia likely originate from relatively younger and more metal-rich progenitors than do normal-velocity SNe Ia and are restricted to galaxies with substantial chemical evolution. PMID:23470733

  20. Characterization of the Proteomes Associating with Three Distinct Membrane Raft Sub-types in Murine Sperm

    PubMed Central

    Asano, Atsushi; Nelson, Jacquelyn L.; Zhang, Sheng; Travis, Alexander J.

    2010-01-01

    Mammalian sperm are transcriptionally and translationally inactive. To meet changing needs in the epididymis and female tract, they rely heavily on post-translational modifications and protein acquisition/degradation. Membrane rafts are sterol and sphingolipid-enriched micro-domains that organize and regulate various pathways. Rafts have significance in sperm by transducing the stimulus of sterol efflux into changes in intracellular signaling that confer fertilization competence. We recently characterized 3 biochemically distinct sub-types of sperm rafts, and now present profiles for proteins targeting to and associating with these sub-types, along with a fraction largely comprised of “non-raft” domains. Proteomics analysis using a gel-based LC-MS/MS approach identified 190 strictly validated proteins in the raft sub-types. Interestingly, many of these are known to be expressed in the epididymis, where sperm membrane composition matures. To investigate potential roles for rafts in epididymal protein acquisition, we compared the expression and localization of 2 different sterol-interacting proteins, apolipoprotein-A1 and prominin-1 in sperm from different zones. We found that apolipoprotein-A1 was gradually added to the plasma membrane overlying the acrosome, whereas prominin-1 was not, suggesting different mechanisms for raft protein acquisition. Our results define raft-associating proteins, demonstrate functional similarities and differences among raft sub-types, and provide insights into raft-mediated epididymal protein acquisition. PMID:20815087

  1. RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms

    PubMed Central

    Qin, Yue; Zhou, Mao-Tian; Hu, Ming-Ming; Hu, Yun-Hong; Zhang, Jing; Guo, Lin; Zhong, Bo; Shu, Hong-Bing

    2014-01-01

    Viral infection triggers induction of type I interferons (IFNs), which are critical mediators of innate antiviral immune response. Mediator of IRF3 activation (MITA, also called STING) is an adapter essential for virus-triggered IFN induction pathways. How post-translational modifications regulate the activity of MITA is not fully elucidated. In expression screens, we identified RING finger protein 26 (RNF26), an E3 ubiquitin ligase, could mediate polyubiquitination of MITA. Interestingly, RNF26 promoted K11-linked polyubiquitination of MITA at lysine 150, a residue also targeted by RNF5 for K48-linked polyubiquitination. Further experiments indicated that RNF26 protected MITA from RNF5-mediated K48-linked polyubiquitination and degradation that was required for quick and efficient type I IFN and proinflammatory cytokine induction after viral infection. On the other hand, RNF26 was required to limit excessive type I IFN response but not proinflammatory cytokine induction by promoting autophagic degradation of IRF3. Consistently, knockdown of RNF26 inhibited the expression of IFNB1 gene in various cells at the early phase and promoted it at the late phase of viral infection, respectively. Furthermore, knockdown of RNF26 inhibited viral replication, indicating that RNF26 antagonizes cellular antiviral response. Our findings thus suggest that RNF26 temporally regulates innate antiviral response by two distinct mechanisms. PMID:25254379

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

    PubMed Central

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

    2015-01-01

    Summary Vascular development begins with formation of a primary capillary plexus that is later remodeled to give rise to the definitive vasculature. While 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 Angiopoietin2 (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

  3. 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.

  4. Comparative genomic analysis reveals distinct genotypic features of the emerging pathogen Haemophilus influenzae type f

    PubMed Central

    2014-01-01

    Background The incidence of invasive disease caused by encapsulated Haemophilus influenzae type f (Hif) has increased in the post-H. influenzae type b (Hib) vaccine era. We previously annotated the first complete Hif genome from a clinical isolate (KR494) that caused septic shock and necrotizing myositis. Here, the full genome of Hif KR494 was compared to sequenced reference strains Hib 10810, capsule type d (Hid) Rd Kw20, and finally nontypeable H. influenzae 3655. The goal was to identify possible genomic characteristics that may shed light upon the pathogenesis of Hif. Results The Hif KR494 genome exhibited large regions of synteny with other H. influenzae, but also distinct genome rearrangements. A predicted Hif core genome of 1390 genes was shared with the reference strains, and 6 unique genomic regions comprising half of the 191 unique coding sequences were revealed. The majority of these regions were inserted genetic fragments, most likely derived from the closely-related Haemophilus spp. including H. aegyptius, H. haemolyticus and H. parainfluenzae. Importantly, the KR494 genome possessed several putative virulence genes that were distinct from non-type f strains. These included the sap2 operon, aef3 fimbriae, and genes for kanamycin nucleotidyltranserase, iron-utilization proteins, and putative YadA-like trimeric autotransporters that may increase the bacterial virulence. Furthermore, Hif KR494 lacked a hisABCDEFGH operon for de novo histidine biosynthesis, hmg locus for lipooligosaccharide biosynthesis and biofilm formation, the Haemophilus antibiotic resistance island and a Haemophilus secondary molybdate transport system. We confirmed the histidine auxotrophy and kanamycin resistance in Hif by functional experiments. Moreover, the pattern of unique or missing genes of Hif KR494 was similar in 20 Hif clinical isolates obtained from different years and geographical areas. A cross-species comparison revealed that the Hif genome shared more characteristics with H. aegyptius than Hid and NTHi. Conclusions The genomic comparative analyses facilitated identification of genotypic characteristics that may be related to the specific virulence of Hif. In relation to non-type f H. influenzae strains, the Hif genome contains differences in components involved in metabolism and survival that may contribute to its invasiveness. PMID:24438474

  5. Will Jets Identify the Progenitors of Type Ia Supernovae?

    E-print Network

    Mario Livio; Adam Riess; William Sparks

    2002-04-26

    We use the fact that a Type Ia supernova has been serendipitously discovered near the jet of the active galaxy 3C 78 to examine the question of whether jets can enhance accretion onto white dwarfs. One interesting outcome of such a jet-induced accretion process is an enhanced rate of novae in the vicinity of jets. We present results of observations of the jet in M87 which appear to have indeed discovered 11 novae in close proximity to the jet. We show that a confirmation of the relation between jets and novae and Type Ia supernovae can finally identify the elusive progenitors of Type Ia supernovae.

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

    PubMed Central

    Bernatík, Ond?ej; Šedová, Kate?ina; Schille, Carolin; Ganji, Ranjani Sri; ?ervenka, Igor; Trantírek, Lukáš; Schambony, Alexandra; Zdráhal, Zbyn?k; Bryja, Vít?zslav

    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 1? (CK1?) 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 CK1?. Our analysis revealed >50 phosphorylation sites on Dvl3; only a minority of these sites was found dynamically induced after co-expression of CK1?, 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 CK1? 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 CK1? acts via phosphorylation of distinct residues as the activator as well as the shut-off signal of Wnt/?-catenin signaling and (ii) suggest that CK1? acts on Dvl via different mechanism than Fzd5. PMID:24993822

  7. 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

  8. Functional analysis of dishevelled-3 phosphorylation identifies distinct mechanisms driven by casein kinase 1? and frizzled5.

    PubMed

    Bernatík, Ond?ej; Šedová, Kate?ina; Schille, Carolin; Ganji, Ranjani Sri; ?ervenka, Igor; Trantírek, Lukáš; Schambony, Alexandra; Zdráhal, Zbyn?k; Bryja, Vít?zslav

    2014-08-22

    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 1? (CK1?) 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 CK1?. Our analysis revealed >50 phosphorylation sites on Dvl3; only a minority of these sites was found dynamically induced after co-expression of CK1?, 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 CK1? 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 CK1? acts via phosphorylation of distinct residues as the activator as well as the shut-off signal of Wnt/?-catenin signaling and (ii) suggest that CK1? acts on Dvl via different mechanism than Fzd5. PMID:24993822

  9. Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses.

    PubMed

    Vogazianou, Artemis P; Chan, Raymond; Bäcklund, L Magnus; Pearson, Danita M; Liu, Lu; Langford, Cordelia F; Gregory, Simon G; Collins, V Peter; Ichimura, Koichi

    2010-07-01

    We studied the status of chromosomes 1 and 19 in 363 astrocytic and oligodendroglial tumors. Whereas the predominant pattern of copy number abnormality was a concurrent loss of the entire 1p and 19q regions (total 1p/19q loss) among oligodendroglial tumors and partial deletions of 1p and/or 19q in astrocytic tumors, a subset of apparently astrocytic tumors also had total 1p/19q loss. The presence of total 1p/19q loss was associated with longer survival of patients with all types of adult gliomas independent of age and diagnosis (P = .041). The most commonly deleted region on 19q in astrocytic tumors spans 885 kb in 19q13.33-q13.41, which is telomeric to the previously proposed region. Novel regions of homozygous deletion, including a part of DPYD (1p21.3) or the KLK cluster (19q13.33), were observed in anaplastic oligodendrogliomas. Amplifications encompassing AKT2 (19q13.2) or CCNE1 (19q12) were identified in some glioblastomas. Deletion mapping of the centromeric regions of 1p and 19q in the tumors that had total 1p/19q loss, indicating that the breakpoints lie centromeric to NOTCH2 within the pericentromeric regions of 1p and 19q. Thus, we show that the copy number abnormalities of 1p and 19q in human gliomas are complex and have distinct patterns that are prognostically predictive independent of age and pathological diagnosis. An accurate identification of total 1p/19q loss and discriminating this from other 1p/19q changes is, however, critical when the 1p/19q copy number status is used to stratify patients in clinical trials. PMID:20164239

  10. Porcine Skin-Derived Progenitor (SKP) Spheres and Neurospheres: Distinct “Stemness” Identified by Microarray Analysis

    PubMed Central

    Zhao, Ming-Tao; Whitworth, Kristin M.; Lin, Hui; Zhang, Xia; Isom, S. Clay; Dobbs, Kyle B.; Bauer, Bethany; Zhang, Yong

    2010-01-01

    Abstract Skin-derived progenitors (SKP) are neural crest derived and can generate neural and mesodermal progeny in vitro, corresponding to the multipotency of neural crest stem cells. Likewise, neural stem/progenitor cells (displaying as neurospheres) have the capacity of self-renewing, and can produce most phenotypes in the nervous system. Both form spheres when cultured with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Although the “stemness” of neural stem/progenitor cells has been extensively investigated, the molecular comparison of SKP spheres and neurospheres has not been elucidated. Here, SKP spheres and neurospheres from the same individual porcine fetuses were isolated with the same culture medium, and the multipotency was tested by in vitro differentiation assays. Microarray analysis was used to illustrate the “stemness” of SKP spheres and neurospheres. The upregulated genes that were in common in the SKP spheres and neurospheres are involved in ribosome, tight junction, gap junction, cell communication, calcium signaling, ErbB signaling, JAK–STAT signaling, MAPK signaling, etc. The differentially expressed genes between SKP spheres and neurospheres are mainly involved in ECM–receptor interaction and the transforming growth factor-beta (TGF-?) signaling pathway. Finally, treatment with leukemia inhibitory factor (LIF) or MEK inhibitor results in a distinctive impact on the “stemness” and differentiation genes of SKP spheres and neurospheres. Thus, the cell-intrinsic genetic program may contribute to the innate “stemness” of SKP spheres and neurospheres in a similar local microenvironment. PMID:20694160

  11. Distinct Stages of Stimulated Fc?RI Receptor Clustering and Immobilization Are Identified through Superresolution Imaging

    PubMed Central

    Shelby, Sarah A.; Holowka, David; Baird, Barbara; Veatch, Sarah L.

    2013-01-01

    Recent advances in fluorescence localization microscopy have made it possible to image chemically fixed and living cells at 20 nm lateral resolution. We apply this methodology to simultaneously record receptor organization and dynamics on the ventral surface of live RBL-2H3 mast cells undergoing antigen-mediated signaling. Cross-linking of IgE bound to Fc?RI by multivalent antigen initiates mast cell activation, which leads to inflammatory responses physiologically. We quantify receptor organization and dynamics as cells are stimulated at room temperature (22°C). Within 2 min of antigen addition, receptor diffusion coefficients decrease by an order of magnitude, and single-particle trajectories are confined. Within 5 min of antigen addition, receptors organize into clusters containing ?100 receptors with average radii of ?70 nm. By comparing simultaneous measurements of clustering and mobility, we determine that there are two distinct stages of receptor clustering. In the first stage, which precedes stimulated Ca2+ mobilization, receptors slow dramatically but are not tightly clustered. In the second stage, receptors are tightly packed and confined. We find that stimulation-dependent changes in both receptor clustering and mobility can be reversed by displacing multivalent antigen with monovalent ligands, and that these changes can be modulated through enrichment or reduction in cellular cholesterol levels. PMID:24268146

  12. Sequence analysis of 96 genomic regions identifies distinct evolutionary lineages within CC156, the largest Streptococcus pneumoniae clonal complex in the MLST database.

    PubMed

    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

  13. Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma

    Microsoft Academic Search

    Bernd Kubista; Florian Klinglmueller; Martin Bilban; Martin Pfeiffer; Richard Lass; Alexander Giurea; Phillipp T. Funovics; Cyril Toma; Martin Dominkus; Rainer Kotz; Theresia Thalhammer; Klemens Trieb; Teresa Zettl; Christian F. Singer

    2011-01-01

    Osteosarcoma is the most common primary malignant bone tumour. Currently osteosarcoma classification is based on histological\\u000a appearance. It was the aim of this study to use a more systematic approach to osteosarcoma classification based on gene expression\\u000a analysis and to identify subtype specific differentially expressed genes. We analysed the global gene expression profiles\\u000a of ten osteosarcoma samples using Affymetrix U133A

  14. 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

  15. Two Types of Human Mast Cells That Have Distinct Neutral Protease Compositions

    Microsoft Academic Search

    A. A. Irani; N. M. Schechter; S. S. Craig; G. Deblois; L. B. Schwartz

    1986-01-01

    Two human mast cell types were identified by immunohistochemical techniques in skin, lung, and small intestine. One type contains the neutral proteases, tryptase and chymotryptic proteinase, and is termed the TC mast cell. The second type contains only tryptase and is termed the T mast cell. Both types are fixed better by Carnoy's fluid than by formalin. The percentage of

  16. N-Glycoprotein Surfaceomes of Four Developmentally Distinct Mouse Cell Types

    PubMed Central

    Kropp, Erin M.; Bhattacharya, Subarna; Waas, Matthew; Chuppa, Sandra L.; Hadjantonakis, Anna-Katerina; Boheler, Kenneth R.; Gundry, Rebekah L.

    2014-01-01

    Purpose Detailed knowledge of cell surface proteins present during early embryonic development remains limited for most cell lineages. Due to the relevance of cell surface proteins in their functional roles controlling cell signaling and their utility as accessible, non-genetic markers for cell identification and sorting, the goal of this study was to provide new information regarding the cell surface proteins present during early mouse embryonic development. Experimental Design Using the Cell Surface Capture Technology, the cell surface N-glycoproteomes of three cell lines and one in vitro differentiated cell type representing distinct cell fates and stages in mouse embryogenesis were assessed. Results Altogether, more than 600 cell surface N-glycoproteins were identified represented by >5500 N-glycopeptides. Conclusions and Clinical Relevance The development of new, informative cell surface markers for the reliable identification and isolation of functionally defined subsets of cells from early developmental stages will advance the use of stem cell technologies for mechanistic developmental studies, including disease modeling and drug discovery. PMID:24920426

  17. 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...

  18. Parallel circuits mediating distinct emotional coping reactions to different types of stress

    Microsoft Academic Search

    Kevin A. Keay; Richard Bandler

    2001-01-01

    All animals, including humans, react with distinct emotional coping strategies to different types of stress. Active coping strategies (e.g. confrontation, fight, escape) are evoked if the stressor is controllable or escapable. Passive coping strategies (e.g. quiescence, immobility, decreased responsiveness to the environment) are usually elicited if the stressor is inescapable and help to facilitate recovery and healing. Neural substrates mediating

  19. 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, ...

  20. On two distinct types of drag-reducing fluids, diameter scaling, and turbulent profiles

    Microsoft Academic Search

    K. Gasljevic; G. Aguilar; E. F. Matthys

    2001-01-01

    Two distinct scaling procedures were found to predict the diameter effect for different types of drag-reducing fluids. The first one, which correlates the relative drag reduction (DR) with flow bulk velocity (V), appears applicable to fluids that comply with the 3-layers velocity profile model. This model has been applied to many polymer solutions; but the drag reduction versus V scaling

  1. A Pascal type triangle for the number of topologically distinct many-electron Feynman graphs

    Microsoft Academic Search

    F. Battaglia; F. George

    1988-01-01

    By expressing the Green function for a many-body system in terms of a perturbative expansion written as a sutra over all connected and topologically distinct Feynnian graphs, it is shown that the number of such diagrams can be iteratively obtained from a Pascal-type triangle, The key to the problem is to notice that it is possible to define on the

  2. Distinct transcriptional regulatory modules underlie STAT3’s cell type-independent and cell type-specific functions

    PubMed Central

    Hutchins, Andrew Paul; Diez, Diego; Takahashi, Yoshiko; Ahmad, Shandar; Jauch, Ralf; Tremblay, Michel Lucien; Miranda-Saavedra, Diego

    2013-01-01

    Transcription factors (TFs) regulate gene expression by binding to short DNA sequence motifs, yet their binding specificities alone cannot explain how certain TFs drive a diversity of biological processes. In order to investigate the factors that control the functions of the pleiotropic TF STAT3, we studied its genome-wide binding patterns in four different cell types: embryonic stem cells, CD4+ T cells, macrophages and AtT-20 cells. We describe for the first time two distinct modes of STAT3 binding. First, a small cell type-independent mode represented by a set of 35 evolutionarily conserved STAT3-binding sites that collectively regulate STAT3’s own functions and cell growth. We show that STAT3 is recruited to sites with E2F1 already pre-bound before STAT3 activation. Second, a series of different transcriptional regulatory modules (TRMs) assemble around STAT3 to drive distinct transcriptional programs in the four cell types. These modules recognize cell type-specific binding sites and are associated with factors particular to each cell type. Our study illustrates the versatility of STAT3 to regulate both universal- and cell type-specific functions by means of distinct TRMs, a mechanism that might be common to other pleiotropic TFs. PMID:23295670

  3. 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

  4. Differential expression of vesicular glutamate transporters 1 and 2 may identify distinct modes of glutamatergic transmission in the macaque visual system

    PubMed Central

    Balaram, Pooja; Hackett, Troy A.; Kaas, Jon H.

    2013-01-01

    Glutamate is the primary neurotransmitter utilized by the mammalian visual system for excitatory neurotransmission. The sequestration of glutamate into synaptic vesicles, and the subsequent transport of filled vesicles to the presynaptic terminal membrane, is regulated by a family of proteins known as vesicular glutamate transporters (VGLUTs). Two VGLUT proteins, VGLUT1 and VGLUT2, characterize distinct sets of glutamatergic projections between visual structures in rodents and prosimian primates, yet little is known about their distributions in the visual system of anthropoid primates. We have examined the mRNA and protein expression patterns of VGLUT1 and VGLUT2 in the visual system of macaque monkeys, an Old World anthropoid primate, in order to determine their relative distributions in the superior colliculus, lateral geniculate nucleus, pulvinar complex, V1 and V2. Distinct expression patterns for both VGLUT1 and VGLUT2 identified architectonic boundaries in all structures, as well as anatomical subdivisions of the superior colliculus, pulvinar complex, and V1. These results suggest that VGLUT1 and VGLUT2 clearly identify regions of glutamatergic input in visual structures, and may identify common architectonic features of visual areas and nuclei across the primate radiation. Additionally, we find that VGLUT1 and VGLUT2 characterize distinct subsets of glutamatergic projections in the macaque visual system; VGLUT2 predominates in driving or feedforward projections from lower order to higher order visual structures while VGLUT1 predominates in modulatory or feedback projections from higher order to lower order visual structures. The distribution of these two proteins suggests that VGLUT1 and VGLUT2 may identify class 1 and class 2 type glutamatergic projections within the primate visual system (Sherman and Guillery, 2006). PMID:23524295

  5. Genetic errors identified in 12 major cancer types

    Cancer.gov

    Examining 12 major types of cancer, scientists at Washington University School of Medicine in St. Louis (home of the Alvin J. Siteman Cancer Center) have identified 127 repeatedly mutated genes that appear to drive the development and progression of a range of tumors in the body. The discovery sets the stage for devising new diagnostic tools and more personalized cancer treatments. The research, published Oct. 17 in Nature, shows that some of the same genes commonly mutated in certain cancers also occur in seemingly unrelated tumors.

  6. ON IDENTIFYING THE PROGENITORS OF Type Ia SUPERNOVAE

    SciTech Connect

    Livio, Mario; Pringle, J. E., E-mail: mlivio@stsci.edu [Space Telescope Science Institute, Baltimore, MD (United States)

    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.

  7. Beige Adipocytes are a Distinct Type of Thermogenic Fat Cell in Mouse and Human

    PubMed Central

    Wu, Jun; Boström, Pontus; Sparks, Lauren M.; Ye, Li; Choi, Jang Hyun; Giang, An-Hoa; Khandekar, Melin; Nuutila, Pirjo; Schaart, Gert; Huang, Kexin; Tu, Hua; van Marken Lichtenbelt, Wouter D.; Hoeks, Joris; Enerbäck, Sven; Schrauwen, Patrick; Spiegelman, Bruce M.

    2012-01-01

    Summary Brown fat defends against hypothermia and obesity through thermogenesis mediated by mitochondrial UCP1. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here we report the cloning of “beige” cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we show that deposits of brown fat previously observed in adult humans are composed of beige adipose cells. These data illustrate a new cell type with therapeutic potential in mouse and human. PMID:22796012

  8. Gene expression profiling identifies different sub-types of retinoblastoma

    PubMed Central

    Kapatai, G; Brundler, M-A; Jenkinson, H; Kearns, P; Parulekar, M; Peet, A C; McConville, C M

    2013-01-01

    Background: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. Methods: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. Results: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. Conclusion: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics. PMID:23756868

  9. 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

  10. 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 susceptibility. The data provide strong evidence for distinct differences in temperature tolerance between C3 and C15 Symbiodinium types when in- hospite; however, future studies addressing the confounding effect of host species would help to confirm this.

  11. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.

    PubMed

    Wang, Tianjiao; Feldman, Andrew L; Wada, David A; Lu, Ye; Polk, Avery; Briski, Robert; Ristow, Kay; Habermann, Thomas M; Thomas, Dafydd; Ziesmer, Steven C; Wellik, Linda E; Lanigan, Thomas M; Witzig, Thomas E; Pittelkow, Mark R; Bailey, Nathanael G; Hristov, Alexandra C; Lim, Megan S; Ansell, Stephen M; Wilcox, Ryan A

    2014-05-01

    The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas. PMID:24497534

  12. 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

  13. Animal models of GWAS-identified type 2 diabetes genes.

    PubMed

    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

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

    SciTech Connect

    Karagiannis, Emmanouil D. [Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, 613 Traylor Building, 720 Rultland Avenue, Baltimore, MD 21205 (United States)]. E-mail: ekaragi1@jhmi.edu; Popel, Aleksander S. [Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, 613 Traylor Building, 720 Rultland Avenue, Baltimore, MD 21205 (United States)

    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.

  15. 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.

  16. 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.

  17. An infant with human parechovirus type 3 infection with a distinctive rash on the extremities.

    PubMed

    Shoji, Kensuke; Komuro, Hisako; Kobayashi, Yoshinori; Shike, Tatsuhiko; Funaki, Takanori; Katsuta, Tomohiro; Miyata, Ippei; Saitoh, Akihiko

    2014-01-01

    Human parechovirus type 3 (HPeV3) is known to cause sepsis-like syndrome and meningoencephalitis in neonates and young infants. We herein report a neonatal case of sepsis-like syndrome due to HPeV3 infection, diagnosed using polymerase chain reaction (PCR), with a distinctive erythematous rash present mainly on the soles and palms that helped in the diagnosis of the disease. Combining the unique characteristics of rash and confirmation by PCR at the early stage of the disease led to the diagnosis of HPeV3, distinguishing it from sepsis and other critical disease conditions, and allowing for appropriate, rapid management. PMID:22938181

  18. Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B

    PubMed Central

    Schwabe, Georg C.; Tinschert, Sigrid; Buschow, Christian; Meinecke, Peter; Wolff, Gerhard; Gillessen-Kaesbach, Gabriele; Oldridge, Michael; Wilkie, Andrew O. M.; Kömec, Reyhan; Mundlos, Stefan

    2000-01-01

    Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect—features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome. PMID:10986040

  19. The Actinomycete Thermobispora bispora Contains Two Distinct Types of Transcriptionally Active 16S rRNA Genes

    Microsoft Academic Search

    YUE WANG; ZHENSHUI ZHANG; NARENDRAKUMAR RAMANAN

    1997-01-01

    Here we present the first description of the presence of two distinct types of 16S rRNA genes in the genome of a (eu)bacterium, Thermobispora bispora. We cloned and determined the nucleotide sequences of all four rRNA operons of T. bispora. Sequence comparisons revealed that the genome of T. bispora contains two distinct types of 16S rRNA genes, each type consisting

  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. Specific T-type calcium channel isoforms are associated with distinct burst phenotypes

    E-print Network

    Turner, Ray

    of the three different T-type channel isoforms (Cav3.1, Cav3.2, and Cav3.3) in cerebellar neurons and focus detected expression of one or more Cav3 channel isoforms in a wide range of cerebellar neurons the Cav3 channel expression pattern with the electrophysiological profile of identified DCN cells, we show

  2. 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 improved definition in the 870nm wavelength absorption weighting due to the increased absorption in the near-infrared wavelengths, while the 440nm wavelength provided better definition when black carbon mixed with dust. Utilization of this particle type scheme provides necessary information for remote sensing applications, which needs a priori knowledge of aerosol type to model the retrieved properties especially over semi-bright surfaces. In fact, this analysis reveals that the aerosol types occurred in mixtures with varying magnitudes of absorption and requires the use of more than one assumed aerosol mixture model. Furthermore, this technique will provide the aerosol transport model community a data set for validating aerosol type.

  3. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling

    Microsoft Academic Search

    Ash A. Alizadeh; Michael B. Eisen; R. Eric Davis; Izidore S. Lossos; Andreas Rosenwald; Jennifer C. Boldrick; Hajeer Sabet; Truc Tran; Xin Yu; John I. Powell; Liming Yang; Gerald E. Marti; Troy Moore; James Hudson Jr; Lisheng Lu; David B. Lewis; Robert Tibshirani; Gavin Sherlock; Wing C. Chan; Timothy C. Greiner; Dennis D. Weisenburger; James O. Armitage; Roger Warnke; Ronald Levy; Wyndham Wilson; Michael R. Grever; John C. Byrd; David Botstein; Patrick O. Brown; Louis M. Staudt

    2000-01-01

    12 Pathology and Microbiology, and 13 Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have

  4. 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

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

    PubMed

    Ben, Cécile; Toueni, Maoulida; Montanari, Sara; Tardin, Marie-Claire; Fervel, Magalie; Negahi, Azam; Saint-Pierre, Laure; Mathieu, Guillaume; Gras, Marie-Christine; Noël, Dominique; Prospéri, Jean-Marie; Pilet-Nayel, Marie-Laure; Baranger, Alain; Huguet, Thierry; Julier, Bernadette; Rickauer, Martina; 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

  6. 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

  7. 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

  8. Differences in HIV Type 1 Neutralization Breadth in 2 Geographically Distinct Cohorts in Africa.

    PubMed

    Bandawe, Gama P; Moore, Penny L; Werner, Lise; Gray, Elin S; Sheward, Daniel J; Madiga, Maphuti; Nofemela, Andile; Thebus, Ruwayhida; Marais, Jinny C; Maboko, Leonard; Abdool Karim, Salim S; Hoelscher, Michael; Morris, Lynn; Williamson, Carolyn

    2015-05-01

    To investigate whether distinct populations have differing human immunodeficiency virus type 1 (HIV) neutralizing antibody responses, we compared 20 women from Tanzania's HIV Superinfection Study (HISIS) cohort, who were infected multiple HIV subtypes, and 22 women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) cohort, who were infected exclusively with HIV subtype C. By 2 years after infection, 35% of HISIS subjects developed neutralization breadth, compared with 9% of CAPRISA subjects (P = .0131). Cumulative viral loads between 3 and 12 months were higher in the HISIS group (P = .046) and strongly associated with breadth (P < .0001). While viral load was the strongest predictor, other factors may play a role, as the odds of developing breadth remained higher in HISIS even after correction for viral load. PMID:25398460

  9. Lateral Hypothalamus Contains Two Types of Palatability-Related Taste Responses with Distinct Dynamics

    PubMed Central

    Yoshida, Takashi; Monk, Kevin J.; Katz, Donald B.

    2013-01-01

    The taste of foods, in particular the palatability of these tastes, exerts a powerful influence on our feeding choices. Although the lateral hypothalamus (LH) has long been known to regulate feeding behavior, taste processing in LH remains relatively understudied. Here, we examined single-unit LH responses in rats subjected to a battery of taste stimuli that differed in both chemical composition and palatability. Like neurons in cortex and amygdala, LH neurons produced a brief epoch of nonspecific responses followed by a protracted period of taste-specific firing. Unlike in cortex, however, where palatability-related information only appears 500 ms after the onset of taste-specific firing, taste specificity in LH was dominated by palatability-related firing, consistent with LH's role as a feeding center. Upon closer inspection, taste-specific LH neurons fell reliably into one of two subtypes: the first type showed a reliable affinity for palatable tastes, low spontaneous firing rates, phasic responses, and relatively narrow tuning; the second type showed strongest modulation to aversive tastes, high spontaneous firing rates, protracted responses, and broader tuning. Although neurons producing both types of responses were found within the same regions of LH, cross-correlation analyses suggest that they may participate in distinct functional networks. Our data shed light on the implementation of palatability processing both within LH and throughout the taste circuit, and may ultimately have implications for LH's role in the formation and maintenance of taste preferences and aversions. PMID:23719813

  10. BIOCHEMICAL CHARACTERIZATION OF MEMBRANE FRACTIONS IN MURINE SPERM: IDENTIFICATION OF THREE DISTINCT SUB-TYPES OF MEMBRANE RAFTS

    PubMed Central

    Asano, Atsushi; Selvaraj, Vimal; Buttke, Danielle E.; Nelson, Jacquelyn L.; Green, Karin M.; Evans, James E.; Travis, Alexander J.

    2009-01-01

    Despite enormous interest in membrane raft microdomains, no studies in any cell type have defined the relative compositions of the raft fractions on the basis of their major components—sterols, phospholipids, and proteins—or additional raft-associating lipids such as the ganglioside, GM1. Our previous localization data in live sperm showed that the plasma membrane overlying the acrosome represents a stabilized platform enriched in GM1 and sterols. These findings, along with the physiological requirement for sterol efflux for sperm to function, prompted us to characterize sperm membrane fractions biochemically. After confirming limitations of commonly-used detergent-based approaches, we utilized a non-detergent-based method, separating membrane fractions that were reproducibly distinct based on sterol, GM1, phospholipid and protein compositions (both mass amounts and molar ratios). Based on fraction buoyancy and biochemical composition, we identified at least three highly reproducible subtypes of membrane raft. Electron microscopy revealed that raft fractions were free of visible contaminants and were separated by buoyancy rather than morphology. Quantitative proteomic comparisons and fluorescence localization of lipids suggested that different organelles contributed differentially to individual raft sub-types, but that multiple membrane microdomain sub-types could exist within individual domains. This has important implications for scaffolding functions broadly associated with rafts. Most importantly, we show that the common practice of characterizing membrane domains as either “raft” or “non-raft” oversimplifies the actual biochemical complexity of cellular membranes. PMID:19006178

  11. Identification of a Distinct, Cryptic Heparosan Synthase from Pasteurella multocida Types A, D, and F

    PubMed Central

    DeAngelis, Paul L.; White, Carissa L.

    2004-01-01

    The extracellular polysaccharide capsules of Pasteurella multocida types A, D, and F are composed of hyaluronan, N-acetylheparosan (heparosan or unsulfated, unepimerized heparin), and unsulfated chondroitin, respectively. Previously, a type D heparosan synthase, a glycosyltransferase that forms the repeating disaccharide heparosan backbone, was identified. Here, a ?73% identical gene product that is encoded outside of the capsule biosynthesis locus was also shown to be a functional heparosan synthase. Unlike PmHS1, the PmHS2 enzyme was not stimulated greatly by the addition of an exogenous polymer acceptor and yielded smaller- molecular-weight-product size distributions. Virtually identical hssB genes are found in most type A, D, and F isolates. The occurrence of multiple polysaccharide synthases in a single strain invokes the potential for capsular variation. PMID:15576804

  12. cis-acting elements in human immunodeficiency virus type 1 RNAs direct viral transcripts to distinct intranuclear locations.

    PubMed Central

    Berthold, E; Maldarelli, F

    1996-01-01

    Two distinct intranuclear locations were identified for alternatively spliced RNA transcripts expressed from the pNL4-3 infectious molecular clone of human immunodeficiency virus (HIV) type 1. Multiply spliced HIV RNA encoding tat was detected within the nucleus in large clusters; immunostaining and colocalization studies using laser-scanning confocal microscopy revealed that these structures contained the non-small nuclear ribonucleoprotein RNA processing factor, SC35. In contrast, unspliced gag RNA was detected in much smaller granules distributed throughout the nucleus, with little or no association with SC35-containing granules. Analyses of nuclear RNA expressed from recombinant plasmids encoding gag (pCMVgag-2) alone or tat (pCMVtat-2) alone revealed distributions corresponding to those obtained with pNL4-3, indicating that expression within the context of the HIV provirus was not required for the distinct RNA locations detected for these transcripts. The presence of unspliced gag RNA in small granules was confirmed in infections of H9 T-lymphocytic cells, indicating that gag localization was not restricted to transient expression systems. The intranuclear distribution of gag RNA was dependent on specific RNA sequences. Deletion of a portion of the gag gene of pCMVgag-2, containing a cis-repressing inhibitory region, resulted in redirection of unspliced gag RNA from small granules into large SC35-containing clusters. The addition of the Rev-responsive element, RRE, to the deleted pCMVgag-2 construct resulted in RNA transcripts which were no longer associated with SC35. We also identified a cellular intron, rabbit beta-globin-intervening sequence 2 (IVS-2) which, when introduced into pCMVgag-2, redirected unspliced gag RNA into SC35-containing granules and permitted rev-independent Gag expression. These findings suggest that redirecting intranuclear RNA localization may influence gene expression. Color micrographs from this article are available for view at http//128.231.216.2/lmmhome.htm. PMID:8676493

  13. 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

  14. Growth of equilibrium structures built from a large number of distinct component types

    E-print Network

    Lester O. Hedges; Ranjan V. Mannige; Stephen Whitelam

    2014-05-09

    We use simple analytic arguments and lattice-based computer simulations to study the growth of structures made from a large number of distinct component types. Components possess 'designed' interactions, chosen to stabilize an equilibrium target structure in which each component type has a defined spatial position, and 'undesigned' interactions that allow components to bind in a compositionally-disordered way. We find that high-fidelity growth of the equilibrium target structure can happen in the presence of substantial attractive undesigned interactions, as long as the energy scale of the set of designed interactions is chosen appropriately. This observation may help explain why equilibrium DNA 'brick' structures self-assemble even if undesigned interactions are not suppressed [Ke et al. Science 338, 1177 (2012)]. We also find that high-fidelity growth of the target structure is most probable when designed interactions are drawn from a distribution that is as narrow as possible. We use this result to suggest how to choose complementary DNA sequences in order to maximize the fidelity of multicomponent self-assembly mediated by complementary DNA interactions. We also comment on the prospect of growing macroscopic structures in this manner

  15. Distinct activities of Bartonella henselae type IV secretion effector proteins modulate capillary-like sprout formation.

    PubMed

    Scheidegger, F; Ellner, Y; Guye, P; Rhomberg, T A; Weber, H; Augustin, H G; Dehio, C

    2009-07-01

    The zoonotic pathogen Bartonella henselae (Bh) can lead to vasoproliferative tumour lesions in the skin and inner organs known as bacillary angiomatosis and bacillary peliosis. The knowledge on the molecular and cellular mechanisms involved in this pathogen-triggered angiogenic process is confined by the lack of a suitable animal model and a physiologically relevant cell culture model of angiogenesis. Here we employed a three-dimensional in vitro angiogenesis assay of collagen gel-embedded endothelial cell (EC) spheroids to study the angiogenic properties of Bh. Spheroids generated from Bh-infected ECs displayed a high capacity to form sprouts, which represent capillary-like projections into the collagen gel. The VirB/VirD4 type IV secretion system and a subset of its translocated Bartonella effector proteins (Beps) were found to profoundly modulate this Bh-induced sprouting activity. BepA, known to protect ECs from apoptosis, strongly promoted sprout formation. In contrast, BepG, triggering cytoskeletal rearrangements, potently inhibited sprouting. Hence, the here established in vitro model of Bartonella- induced angiogenesis revealed distinct and opposing activities of type IV secretion system effector proteins, which together with a VirB/VirD4-independent effect may control the angiogenic activity of Bh during chronic infection of the vasculature. PMID:19416269

  16. Identifying Cell Types from Spatially Referenced Single-Cell Expression Datasets

    PubMed Central

    Achim, Kaia; Richardson, Sylvia; Azizi, Lamiae; Marioni, John

    2014-01-01

    Complex tissues, such as the brain, are composed of multiple different cell types, each of which have distinct and important roles, for example in neural function. Moreover, it has recently been appreciated that the cells that make up these sub-cell types themselves harbour significant cell-to-cell heterogeneity, in particular at the level of gene expression. The ability to study this heterogeneity has been revolutionised by advances in experimental technology, such as Wholemount in Situ Hybridizations (WiSH) and single-cell RNA-sequencing. Consequently, it is now possible to study gene expression levels in thousands of cells from the same tissue type. After generating such data one of the key goals is to cluster the cells into groups that correspond to both known and putatively novel cell types. Whilst many clustering algorithms exist, they are typically unable to incorporate information about the spatial dependence between cells within the tissue under study. When such information exists it provides important insights that should be directly included in the clustering scheme. To this end we have developed a clustering method that uses a Hidden Markov Random Field (HMRF) model to exploit both quantitative measures of expression and spatial information. To accurately reflect the underlying biology, we extend current HMRF approaches by allowing the degree of spatial coherency to differ between clusters. We demonstrate the utility of our method using simulated data before applying it to cluster single cell gene expression data generated by applying WiSH to study expression patterns in the brain of the marine annelid Platynereis dumereilii. Our approach allows known cell types to be identified as well as revealing new, previously unexplored cell types within the brain of this important model system. PMID:25254363

  17. Identifying cell types from spatially referenced single-cell expression datasets.

    PubMed

    Pettit, Jean-Baptiste; Tomer, Raju; Achim, Kaia; Richardson, Sylvia; Azizi, Lamiae; Marioni, John

    2014-09-01

    Complex tissues, such as the brain, are composed of multiple different cell types, each of which have distinct and important roles, for example in neural function. Moreover, it has recently been appreciated that the cells that make up these sub-cell types themselves harbour significant cell-to-cell heterogeneity, in particular at the level of gene expression. The ability to study this heterogeneity has been revolutionised by advances in experimental technology, such as Wholemount in Situ Hybridizations (WiSH) and single-cell RNA-sequencing. Consequently, it is now possible to study gene expression levels in thousands of cells from the same tissue type. After generating such data one of the key goals is to cluster the cells into groups that correspond to both known and putatively novel cell types. Whilst many clustering algorithms exist, they are typically unable to incorporate information about the spatial dependence between cells within the tissue under study. When such information exists it provides important insights that should be directly included in the clustering scheme. To this end we have developed a clustering method that uses a Hidden Markov Random Field (HMRF) model to exploit both quantitative measures of expression and spatial information. To accurately reflect the underlying biology, we extend current HMRF approaches by allowing the degree of spatial coherency to differ between clusters. We demonstrate the utility of our method using simulated data before applying it to cluster single cell gene expression data generated by applying WiSH to study expression patterns in the brain of the marine annelid Platynereis dumereilii. Our approach allows known cell types to be identified as well as revealing new, previously unexplored cell types within the brain of this important model system. PMID:25254363

  18. 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.

  19. Rocket observations of two distinct types of dispersive features of auroral HF waves

    NASA Astrophysics Data System (ADS)

    Colpitts, C. A.; Samara, M.; LaBelle, J.; Yoon, P.

    2009-05-01

    Two dispersive auroral HF emissions have been observed on two sounding rockets 5 years apart, employing different sensors with different effective antenna lengths and payload orientations. Both the SIERRA and CHARM rockets were launched to ˜735 km over active auroral substorms from Poker Flat, Alaska. On both flights, two distinct types of dispersed features occurred, each of which exhibited a frequency-time structure characterized by an impulsive signal at one end of the frequency range, with progressively greater dispersion as the emission frequency approached a bounding frequency from either above or below. The first type of emissions, called “swishers,” occurred in the frequency range 1200-1500 kHz, with a characteristic signature whereby the signal is progressively more delayed as its frequency approaches a lower bound from above. The second type of emissions, called “hooks,” were observed in the frequency range 600-1100 kHz and were progressively more delayed as their frequency approached an upper bound from below. Qualitatively, hooks and swishers might both be explained purely by wave propagation: As the wave frequency approaches the lower cutoff of the Langmuir, O-mode, or Z-mode (in the case of swishers) or the upper cutoff of the whistler mode (in the case of hooks), the group velocity becomes small and the signals are delayed. In the case of hooks, ray-tracing calculations support this explanation by showing that wave dispersion can explain the observed signature, if the emission originates on the whistler mode resonance cone on the 60° invariant field line. In the case of swishers, ray-tracing calculations suggest that wave dispersion alone cannot explain the observed signature for any possible mode.

  20. Store-depletion and hyperforin activate distinct types of Ca(2+)-conducting channels in cortical neurons.

    PubMed

    Gibon, Julien; Tu, Peng; Bouron, Alexandre

    2010-06-01

    Cortical neurons embryos (E13) from murine brain have a wide diversity of plasma membrane Ca(2+)-conducting channels. For instance, they express several types of transient receptor potential channels of C-type (TRPC) and hyperforin, a potent TRPC6-channel activator, controls the activity of TRPC6-like channels. In addition, E13 cortical neurons possess plasma membrane channels activated in response to the depletion of internal Ca(2+) pools. Since some TRPC channels seem to be involved in the activity of store-depletion-activated channels, we investigated whether hyperforin and the depletion of the Ca(2+) stores control similar or distinct Ca(2+) routes. Calcium imaging experiments performed with the fluorescent Ca(2+) indicator Fluo-4 showed that the TRPC3 channel blocker Pyr3 potently inhibits with an IC(50) of 0.5microM the entry of Ca(2+) triggered in response to the thapsigargin-dependent depletion of the Ca(2+) stores. On the other hand, Pyr3 does not block the hyperforin-sensitive Ca(2+) entry. In contrast to the hyperforin responses, the Ca(2+) entry through the store-depletion-activated channels is down-regulated by the competitive tyrosine kinase inhibitors genistein and PP2. In addition, the immunosuppressant FK506, known to modulate several classes of Ca(2+)-conducting channels, strongly attenuates the entry of Ca(2+) through the store-depletion-activated channels, leaving the hyperforin-sensitive responses unaffected. Hence, the Zn(2+) chelator TPEN markedly attenuated the hyperforin-sensitive responses without modifying the thapsigargin-dependent Ca(2+) signals. Pyr3-insensitive channels are key components of the hyperforin-sensitive channels, whereas the thapsigargin-dependent depletion of the Ca(2+) stores of the endoplasmic reticulum activates Pyr3-sensitive channels. Altogether, these data support the notion that hyperforin and the depletion of the Ca(2+) pools control distinct plasma membrane Ca(2+)-conducting channels. This report further illustrates that, at the beginning of the corticogenesis, immature cortical neurons express diverse functional Ca(2+) channels. PMID:20621761

  1. 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

  2. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.

    PubMed

    Merrill, Amy E; Sarukhanov, Anna; Krejci, Pavel; Idoni, Brian; Camacho, Natalia; Estrada, Kristine D; Lyons, Karen M; Deixler, Hannah; Robinson, Haynes; Chitayat, David; Curry, Cynthia J; Lachman, Ralph S; Wilcox, William R; Krakow, Deborah

    2012-03-01

    Fibroblast growth factor receptor 2 (FGFR2) is a crucial regulator of bone formation during embryonic development. Both gain and loss-of-function studies in mice have shown that FGFR2 maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells. We have identified de novo FGFR2 mutations in a sporadically occurring perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Histological analysis of the long bones revealed that the growth plate contained smaller hypertrophic chondrocytes and a thickened hypercellular periosteum. Four unrelated affected individuals were found to be heterozygous for missense mutations that introduce a polar amino acid into the hydrophobic transmembrane domain of FGFR2. Using diseased chondrocytes and a cell-based assay, we determined that these mutations selectively reduced plasma-membrane levels of FGFR2 and markedly diminished the receptor's responsiveness to extracellular FGF. All together, these clinical and molecular findings are separate from previously characterized FGFR2 disorders and represent a distinct skeletal dysplasia. PMID:22387015

  3. Invasive micropapillary carcinoma: A distinct type of adenocarcinomas in the gastrointestinal tract

    PubMed Central

    Guzi?ska-Ustymowicz, Katarzyna; Niewiarowska, Katarzyna; Pryczynicz, Anna

    2014-01-01

    Invasive micropapillary carcinoma (IMPC) is a rare histological type of tumor, first described in invasive ductal breast cancer, than in malignancies in other organs such as lungs, urinary bladder, ovaries or salivary glands. Recent literature data shows that this histological lesion has also been found in cancers of the gastrointestinal system. The micropapillary components are clusters of neoplastic cells that closely adhere to each other and are located in distinct empty spaces. Moreover, clusters of neoplastic cells do not have a fibrous-vascular core. The IMPC cells show reverse polarity resulting in typical ‘’inside-out’’ structures that determines secretary properties, disturbs adhesion and conditions grade of malignancy in gastrointestinal (GI) tract. Invasive micropapillary carcinoma in this location is associated with metastases to local lymph nodes and lymphovascular invasion. IMPC can be a prognostic factor for patients with cancers of the stomach, pancreas and with colorectal cancer since it is related with disease-free and overall survival. The purpose of this review is to present the characterization of invasive micropapillary carcinoma in colon, rectum, stomach and others site of GI tract, and to determine the immunohistological indentification of IMPC in those localization. PMID:24782612

  4. 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. (UIUC); (NWU)

    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.

  5. Fat- and fiber-related diet behavior among type 2 diabetes patients from distinct regions

    PubMed Central

    Hendrychova, Tereza; Vytrisalova, Magda; Alwarafi, Abdullah; Duintjer Tebbens, Jurjen; Vankatova, Helena; Leal, Sandra; Kubena, Ales Antonin; Smahelova, Alena; Vlcek, Jiri

    2015-01-01

    Purpose Diet and eating habits are of key importance in patients with type 2 diabetes mellitus (T2DM). The purpose of this comparative study was to analyze fat- and fiber-related behavior (FFB) in patients with T2DM from distinct cultural areas. Patients and methods Observational study was carried out in the Czech Republic (CR) (n=200), the US (n=207), and Yemen (n=200). Patients completed the Fat- and Fiber-related Diet Behavior Questionnaire (FFBQ). Results Differences in all aspects of FFB among countries were found (P<0.05). The best fat-related behavior reported was from patients from the CR. Patients from the US showed the worst fat-related behavior in total. On the other hand, patients from the US reported the best fiber-related behavior. Patients from Yemen reached the worst scores in all fat-related domains. Patients from all studied countries reported the best results in the “modify meat” and “avoid fat as flavoring” and the worst in the “substitute high fiber” subscales. Conclusion Professionals involved in the diet education of T2DM patients should be aware of the specificity of diet in their country when advising patients keeping general recommendations. We suggest them to be as specific as possible and concentrate on fiber-related behavior. PMID:25737634

  6. 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

  7. The Cancer Genome Atlas Identifies Distinct Subtypes of Deadly Brain Cancer That May Lead to New Treatment Strategies

    Cancer.gov

    The most common form of malignant brain cancer in adults, glioblastoma multiforme, is not a single disease but appears to be four distinct molecular subtypes, according to a study by the Cancer Genome Atlas (TCGA) Research Network. The researchers of this study also found that response to aggressive chemotherapy and radiation differed by subtype.

  8. The Cancer Genome Atlas Identifies Distinct Subtypes of Deadly Brain Cancer That May Lead to New Treatment Strategies

    Cancer.gov

    The most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is not a single disease but appears to be four distinct molecular subtypes, according to a study by The Cancer Genome Atlas (TCGA) Research Network. The researchers of this study also found that response to aggressive chemotherapy and radiation differed by subtype.

  9. Marked Genomic Differences Characterize Primary and Secondary Glioblastoma Subtypes and Identify Two Distinct Molecular and Clinical Secondary Glioblastoma Entities

    Microsoft Academic Search

    Elizabeth A. Maher; Cameron Brennan; Patrick Y. Wen; Laura Durso; Keith L. Ligon; Aaron Richardson; Deepak Khatry; Raktim Sinha; David N. Louis; John Quackenbush; Lynda Chin; Ronald A. DePinho

    2006-01-01

    Glioblastoma is classified into two subtypes on the basis of clinical history: ''primary glioblastoma'' arising de novo without detectable antecedent disease and ''secondary glio- blastoma'' evolving from a low-grade astrocytoma. Despite their distinctive clinical courses, they arrive at an indistin- guishable clinical and pathologic end point highlighted by widespread invasion and resistance to therapy and, as such, are managed clinically

  10. A newly identified hepatitis B type virus in tree squirrels.

    PubMed

    Feitelson, M A; Millman, I; Halbherr, T; Simmons, H; Blumberg, B S

    1986-04-01

    Virus-associated particles have been isolated from the livers of three common gray tree squirrels (Sciurus carolinensis pennsylvanicus) that have histological evidence of hepatitis. Two of these livers were also positive by orcein staining, suggesting the presence of surface antigen in the cytoplasm of hepatocytes. Fractionation of these particles by CsCl density equilibrium gradient centrifugation and assay of the fractions for surface antigen, core antigen, and DNA polymerase activities demonstrate the presence of all three at an approximate density peak of 1.27. Electron microscopic examination of purified virus preparations showed spherical particles with a mean diameter of 25 nm. Initial characterization of the DNA polymerase product by gel electrophoresis showed a single DNase I sensitive band, migrating slightly faster than the woodchuck hepatitis virus DNA polymerase product. The presence of apparently cross-reacting antibodies was demonstrated by purified hepatitis B surface and/or core antigens binding to some squirrel sera in solid phase assays. Infected tree squirrels appear to lack detectable antigen in their sera. These results suggest that the tree squirrels studied are chronic carriers of a hepatitis B type virus. The host-virus interaction described herein may be useful in understanding the chronic carrier state associated with hepatitis B in man. PMID:3457384

  11. Quantitative morphometry of electrophysiologically identified CA3b interneurons reveals robust local geometry and distinct cell classes.

    PubMed

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

    2009-08-20

    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 axodendritic arborizations with consistently uniform local branch geometry. Both axons and dendrites followed a lamellar organization, and axons displayed a spatial preference toward the fissure. Moreover, only a small fraction of the axonal arbor extended to the outer portion of the invaded volume, and tended to return toward 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 a role may be essential to balance the extensive recurrent excitation of area CA3 underlying hippocampal autoassociative memory function. PMID:19496174

  12. 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.

  13. 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 2? R, R- planet radius) makes tectonic dichotomy (an opposition of the eastern and western oceanic hemispheres), the first overtone (? 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 Pacific are high but corpulent, the Rohrer' index is also high. Short in time cosmic experiments (abrupt uplifting) with a sharp drop in gravity produce noticeable effect of Ca leaching out of organism making it less dense. Sure, changing gravity influences not only bones but also flesh, blood, hairs and eventually genes. The frequencies of genetic markers of Rh-system in blood of inhabitants of 4 variously leveled sectors and subsided western hemisphere are clearly different. References: [1] F. Weidenreich. Rasse und Körperbau (in Russian translation, State Publishing House, Moscow-Leningrad, 1929, 271 pp.).

  14. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases.

    PubMed

    Dieter, Sebastian M; Ball, Claudia R; Hoffmann, Christopher M; Nowrouzi, Ali; Herbst, Friederike; Zavidij, Oksana; Abel, Ulrich; Arens, Anne; Weichert, Wilko; Brand, Karsten; Koch, Moritz; Weitz, Jürgen; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno

    2011-10-01

    Human colon cancer harbors a small subfraction of tumor-initiating cells (TICs) that is assumed to be a functionally homogeneous stem-cell-like population driving tumor maintenance and metastasis formation. We found unexpected cellular heterogeneity within the TIC compartment, which contains three types of TICs. Extensively self-renewing long-term TICs (LT-TICs) maintained tumor formation in serial xenotransplants. Tumor transient amplifying cells (T-TACs) with limited or no self-renewal capacity contributed to tumor formation only in primary mice. Rare delayed contributing TICs (DC-TICs) were exclusively active in secondary or tertiary mice. Bone marrow was identified as an important reservoir of LT-TICs. Metastasis formation was almost exclusively driven by self-renewing LT-TICs. Our results demonstrate that tumor initiation, self-renewal, and metastasis formation are limited to particular subpopulations of TICs in primary human colon cancer. We identify LT-TICs as a quantifiable target for therapies aimed toward eradication of self-renewing tumorigenic and metastatic colon cancer cells. PMID:21982235

  15. An archaeal CRISPR type III-B system exhibiting distinctive RNA targeting features and mediating dual RNA and DNA interference

    PubMed Central

    Peng, Wenfang; Feng, Mingxia; Feng, Xu; Liang, Yun Xiang; She, Qunxin

    2015-01-01

    CRISPR-Cas systems provide a small RNA-based mechanism to defend against invasive genetic elements in archaea and bacteria. To investigate the in vivo mechanism of RNA interference by two type III-B systems (Cmr-? and Cmr-?) in Sulfolobus islandicus, a genetic assay was developed using plasmids carrying an artificial mini-CRISPR (AC) locus with a single spacer. After pAC plasmids were introduced into different strains, Northern analyses confirmed that mature crRNAs were produced from the plasmid-borne CRISPR loci, which then guided gene silencing to target gene expression. Spacer mutagenesis identified a trinucleotide sequence in the 3?-region of crRNA that was crucial for RNA interference. Studying mutants lacking Cmr-? or Cmr-? system showed that each Cmr complex exhibited RNA interference. Strikingly, these analyses further revealed that the two Cmr systems displayed distinctive interference features. Whereas Cmr-? complexes targeted transcripts and could be recycled in RNA cleavage, Cmr-? complexes probably targeted nascent RNA transcripts and remained associated with the substrate. Moreover, Cmr-? exhibited much stronger RNA cleavage activity than Cmr-?. Since we previously showed that S. islandicus Cmr-? mediated transcription-dependent DNA interference, the Cmr-? constitutes the first CRISPR system exhibiting dual targeting of RNA and DNA. PMID:25505143

  16. In Asia, there are two distinct types of chum salmon (Oncorhynchus

    E-print Network

    - ing Kamchatka, the Sea of Okhotsk, the east coast of Sakhalin Island, and the Amur River. Later, and populations from Pri- morye, Sakhalin Island, and north- east Russia were the most distinct. Microsatellite

  17. Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations.

    PubMed

    Glossop, John R; Emes, Richard D; Nixon, Nicola B; Haworth, Kim E; Packham, Jon C; Dawes, Peter T; Fryer, Anthony A; Mattey, Derek L; Farrell, William E

    2014-09-01

    Changes to the DNA methylome have been described in patients with rheumatoid arthritis (RA). In previous work, we reported genome-wide methylation differences in T-lymphocyte and B-lymphocyte populations from healthy individuals. Now, using HumanMethylation450 BeadChips to interrogate genome-wide DNA methylation, we have determined disease-associated methylation changes in blood-derived T- and B-lymphocyte populations from 12 female patients with seropositive established RA, relative to 12 matched healthy individuals. Array data were analyzed using NIMBL software and bisulfite pyrosequencing was used to validate array candidates. Genome-wide DNA methylation, determined by analysis of LINE-1 sequences, revealed higher methylation in B-lymphocytes compared with T-lymphocytes (P ? 0.01), which is consistent with our findings in healthy individuals. Moreover, loci-specific methylation differences that distinguished T-lymphocytes from B-lymphocytes in healthy individuals were also apparent in RA patients. However, disease-associated methylation differences were also identified in RA. In these cases, we identified 509 and 252 CpGs in RA-derived T- and B-lymphocytes, respectively, that showed significant changes in methylation compared with their cognate healthy counterparts. Moreover, this included a restricted set of 32 CpGs in T-lymphocytes and 20 CpGs in B-lymphocytes (representing 15 and 10 genes, respectively, and including two, MGMT and CCS, that were common to both cell types) that displayed more substantial changes in methylation. These changes, apparent as hyper- or hypo-methylation, were independently confirmed by pyrosequencing analysis. Validation by pyrosequencing also revealed additional sites in some candidate genes that also displayed altered methylation in RA. In this first study of genome-wide DNA methylation in individual T- and B-lymphocyte populations in RA patients, we report disease-associated methylation changes that are distinct to each cell type and which support a role for discrete epigenetic regulation in this disease. PMID:25147922

  18. Lung Adenocarcinoma Global Profiling Identifies Type II Transforming Growth Factor Receptor as a Repressor of Invasiveness

    Microsoft Academic Search

    Alain C. Borczuk; Han K. Kim; Hilary A. Yegen; Richard A. Friedman; Charles A. Powell

    2005-01-01

    Rationale: Lung adenocarcinoma histology and clinical outcome are heterogeneous and associated with tumor invasiveness. Objectives: We hypothesized that invasiveness is associated with a distinct mo- lecular signature and that genes differentially expressed in tumor or adjacent stroma will identify cell surface signal transduction and matrixremodelingpathwaysassociatedwiththeacquisitionofinva- siveness in lung adenocarcinoma. Main Results: Microarray analysis of microdissected noninvasive bronchioloalveolar carcinoma (BAC) and

  19. Marker genes identify three somatic cell types in the fetal mouse ovary.

    PubMed

    Rastetter, Raphael H; Bernard, Pascal; Palmer, James S; Chassot, Anne-Amandine; Chen, Huijun; Western, Patrick S; Ramsay, Robert G; Chaboissier, Marie-Christine; Wilhelm, Dagmar

    2014-10-15

    The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility. PMID:25158167

  20. Wisconsin Card Sorting Revisited: Distinct Neural Circuits Participating in Different Stages of the Task Identified by Event Related Functional Magnetic Resonance Imaging

    Microsoft Academic Search

    Oury Monchi; Michael Petrides; Valentina Petre; Keith Worsley; Alain Dagher

    2001-01-01

    The Wisconsin Card Sorting Task (WCST) has been used to assess dysfunction of the prefrontal cortex and basal ganglia. Previous brain imaging studies have focused on identifying activity related to the set-shifting requirement of the WCST. The present study used event-related functional magnetic reso- nance imaging (fMRI) to study the pattern of activation during four distinct stages in the performance

  1. Essential role of EBF1 in the generation and function of distinct mature B cell types

    PubMed Central

    Vilagos, Bojan; Hoffmann, Mareike; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilic, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus

    2012-01-01

    The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity. PMID:22473956

  2. Full Genome Sequencing and Genetic Characterization of Eubenangee Viruses Identify Pata Virus as a Distinct Species within the Genus Orbivirus

    Microsoft Academic Search

    Manjunatha N. Belaganahalli; Sushila Maan; Narender S. Maan; Kyriaki Nomikou; Ian Pritchard; Ross Lunt; Peter D. Kirkland; Houssam Attoui; Joe Brownlie; Peter P. C. Mertens

    2012-01-01

    Eubenangee virus has previously been identified as the cause of Tammar sudden death syndrome (TSDS). Eubenangee virus (EUBV), Tilligery virus (TILV), Pata virus (PATAV) and Ngoupe virus (NGOV) are currently all classified within the Eubenangee virus species of the genus Orbivirus, family Reoviridae. Full genome sequencing confirmed that EUBV and TILV (both of which are from Australia) show high levels

  3. Proteomic Profiling Identifies Distinct Protein Patterns in Acute Myelogenous Leukemia CD34+CD38- Stem-Like Cells

    PubMed Central

    Kornblau, Steven M.; Qutub, Amina; Yao, Hui; York, Heather; Qiu, Yi Hua; Graber, David; Ravandi, Farhad; Cortes, Jorge; Andreeff, Michael; Zhang, Nianxiang; Coombes, Kevin R.

    2013-01-01

    Acute myeloid leukemia (AML) is believed to arise from leukemic stem-like cells (LSC) making understanding the biological differences between LSC and normal stem cells (HSC) or common myeloid progenitors (CMP) crucial to understanding AML biology. To determine if protein expression patterns were different in LSC compared to other AML and CD34+ populations, we measured the expression of 121 proteins by Reverse Phase Protein Arrays (RPPA) in 5 purified fractions from AML marrow and blood samples: Bulk (CD3/CD19 depleted), CD34-, CD34+(CMP), CD34+CD38+ and CD34+CD38-(LSC). LSC protein expression differed markedly from Bulk (n=31 cases, 93/121 proteins) and CD34+ cells (n= 30 cases, 88/121 proteins) with 54 proteins being significantly different (31 higher, 23 lower) in LSC than in either Bulk or CD34+ cells. Sixty-seven proteins differed significantly between CD34+ and Bulk blasts (n=69 cases). Protein expression patterns in LSC and CD34+ differed markedly from normal CD34+ cells. LSC were distinct from CD34+ and Bulk cells by principal component and by protein signaling network analysis which confirmed individual protein analysis. Potential targetable submodules in LSC included the proteins PU.1(SP1), P27, Mcl1, HIF1?, cMET, P53, Yap, and phospho-Stats 1, 5 and 6. Protein expression and activation in LSC differs markedly from other blast populations suggesting that studies of AML biology should be performed in LSC. PMID:24223100

  4. Multilocus Sequence Typing Identifies Epidemic Clones of Flavobacterium psychrophilum in Nordic Countries

    PubMed Central

    Duchaud, Eric; Nicolas, Pierre; Dalsgaard, Inger; Madsen, Lone; Aspán, Anna; Jansson, Eva; Colquhoun, Duncan J.; Wiklund, Tom

    2014-01-01

    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. John von Neumann Institute for Computing Different Types of Protein Folding Identified with

    E-print Network

    Janke, Wolfhard

    John von Neumann Institute for Computing Different Types of Protein Folding Identified://www.fz-juelich.de/nic-series/volume40 #12;Different Types of Protein Folding Identified with a Coarse-Grained Heteropolymer Model Stefan The identification of folding channels is one of the key tasks of protein folding studies. While secondary structures

  6. Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype: LI-cadherin is associated with intestinal phenotype.

    PubMed

    Motoshita, Junichi; Nakayama, Hirofumi; Taniyama, Kiyomi; Matsusaki, Keisuke; Yasui, Wataru

    2006-04-01

    Gastric carcinomas (GC) are classified into four phenotypes on the basis of the mucin expression profile: G type (gastric or foveolar phenotype), I type (intestinal phenotype), GI type (intestinal and gastric mixed phenotype) and N type (neither gastric nor intestinal phenotype). Immunohistochemistry was used to examine the expression of epidermal growth factor receptor (EGFR), E-cadherin, liver-intestine (LI)-cadherin, CD44v9 and p53 and correlation of these molecules with mucin phenotype and tumor stage was evaluated. Overexpression of EGFR and LI-cadherin, reduced expression of E-cadherin and abnormal expression of p53 were observed more frequently in advanced GC than in early GC. Among I-type GC, overexpression of EGFR and reduced expression of E-cadherin were observed more frequently in advanced tumors than in early tumors. Among G-type GC, reduced expression of E-cadherin was significantly associated with advanced tumors. With respect to the relationship between mucin phenotype and expression of cancer-related molecules, overexpression of LI-cadherin was observed more frequently in I-type (12/25, 48.0%) than in G-type (1/14, 7.1%) GC. I-type GC tended to express LI-cadherin more frequently than GI-type GC. These results provide insights into the molecular characteristics of the distinct mucin phenotype of differentiated-type GC and suggest that LI-cadherin may contribute to the biological behavior of I-type GC. PMID:16634965

  7. In vivo electrophysiological recordings in amygdala subnuclei reveal selective and distinct responses to a behaviorally identified predator odor.

    PubMed

    Govic, Antonina; Paolini, Antonio G

    2015-03-01

    Chemosensory cues signaling predators reliably stimulate innate defensive responses in rodents. Despite the well-documented role of the amygdala in predator odor-induced fear, evidence for the relative contribution of the specific nuclei that comprise this structurally heterogeneous structure is conflicting. In an effort to clarify this we examined neural activity, via electrophysiological recordings, in amygdala subnuclei to controlled and repeated presentations of a predator odor: cat urine. Defensive behaviors, characterized by avoidance, decreased exploration, and increased risk assessment, were observed in adult male hooded Wistar rats (n = 11) exposed to a cloth impregnated with cat urine. Electrophysiological recordings of the amygdala (777 multiunit clusters) were subsequently obtained in freely breathing anesthetized rats exposed to cat urine, distilled water, and eugenol via an air-dilution olfactometer. Recorded units selectively responded to cat urine, and frequencies of responses were distributed differently across amygdala nuclei; medial amygdala (MeA) demonstrated the greatest frequency of responses to cat urine (51.7%), followed by the basolateral and basomedial nuclei (18.8%) and finally the central amygdala (3.0%). Temporally, information transduction occurred primarily from the cortical amygdala and MeA (ventral divisions) to other amygdala nuclei. Interestingly, MeA subnuclei exhibited distinct firing patterns to predator urine, potentially revealing aspects of the underlying neurocircuitry of predator odor processing and defensiveness. These findings highlight the critical involvement of the MeA in processing olfactory cues signaling predator threat and converge with previous studies to indicate that amygdala regulation of predator odor-induced fear is restricted to a particular set of subnuclei that primarily include the MeA, particularly the ventral divisions. PMID:25475347

  8. IS3 profiling identifies the enterohaemorrhagic Escherichia coli O-island 62 in a distinct enteroaggregative E. coli lineage

    Microsoft Academic Search

    Iruka N Okeke; Louissa R Macfarlane-Smith; Jonathan N Fletcher; Anna M Snelling

    2011-01-01

    Background  Enteroaggregative Escherichia coli (EAEC) are important diarrhoeal pathogens that are defined by a HEp-2 adherence assay performed in specialist laboratories.\\u000a Multilocus sequence typing (MLST) has revealed that aggregative adherence is convergent, providing an explanation for why\\u000a not all EAEC hybridize with the plasmid-derived probe for this category, designated CVD432. Some EAEC lineages are globally\\u000a disseminated or more closely associated with

  9. Cross-Species Analyses Identify the BNIP-2 and Cdc42GAP Homology (BCH) Domain as a Distinct Functional Subclass of the CRAL_TRIO/Sec14 Superfamily

    PubMed Central

    Gupta, Anjali Bansal; Wee, Liang En; Zhou, Yi Ting; Hortsch, Michael; Low, Boon Chuan

    2012-01-01

    The CRAL_TRIO protein domain, which is unique to the Sec14 protein superfamily, binds to a diverse set of small lipophilic ligands. Similar domains are found in a range of different proteins including neurofibromatosis type-1, a Ras GTPase-activating Protein (RasGAP) and Rho guanine nucleotide exchange factors (RhoGEFs). Proteins containing this structural protein domain exhibit a low sequence similarity and ligand specificity while maintaining an overall characteristic three-dimensional structure. We have previously demonstrated that the BNIP-2 and Cdc42GAP Homology (BCH) protein domain, which shares a low sequence homology with the CRAL_TRIO domain, can serve as a regulatory scaffold that binds to Rho, RhoGEFs and RhoGAPs to control various cell signalling processes. In this work, we investigate 175 BCH domain-containing proteins from a wide range of different organisms. A phylogenetic analysis with ?100 CRAL_TRIO and similar domains from eight representative species indicates a clear distinction of BCH-containing proteins as a novel subclass within the CRAL_TRIO/Sec14 superfamily. BCH-containing proteins contain a hallmark sequence motif R(R/K)h(R/K)(R/K)NL(R/K)xhhhhHPs (‘h’ is large and hydrophobic residue and ‘s’ is small and weekly polar residue) and can be further subdivided into three unique subtypes associated with BNIP-2-N, macro- and RhoGAP-type protein domains. A previously unknown group of genes encoding ‘BCH-only’ domains is also identified in plants and arthropod species. Based on an analysis of their gene-structure and their protein domain context we hypothesize that BCH domain-containing genes evolved through gene duplication, intron insertions and domain swapping events. Furthermore, we explore the point of divergence between BCH and CRAL-TRIO proteins in relation to their ability to bind small GTPases, GAPs and GEFs and lipid ligands. Our study suggests a need for a more extensive analysis of previously uncharacterized BCH, ‘BCH-like’ and CRAL_TRIO-containing proteins and their significance in regulating signaling events involving small GTPases. PMID:22479462

  10. Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Target Distinct Phases of Early Reverse Transcription

    Microsoft Academic Search

    C. WILLIAM HOOKER; WILLIAM B. LOTT; DAVID HARRICH

    2001-01-01

    Early HIV-1 reverse transcription can be separated into initiation and elongation phases. Here we show, using PCR analysis of negative-strand strong-stop DNA ((2)ssDNA) synthesis in intact virus, that different reverse transcriptase (RT) inhibitors affect distinct phases of early natural endogenous reverse transcription (NERT). The effects of nevirapine on NERT were consistent with a mechanism of action including both specific and

  11. Significance of two distinct types of tryptophan synthase beta chain in Bacteria, Archaea and higher plants

    Microsoft Academic Search

    Gary Xie; Christian Forst; Carol Bonner; Roy A Jensen

    2001-01-01

    BACKGROUND: Tryptophan synthase consists of two subunits, ? and ?. Two distinct subgroups of ? chain exist. The major group (TrpEb_1) includes the well-studied ? chain of Salmonella typhimurium. The minor group of ? chain (TrpEb_2) is most frequently found in the Archaea. Most of the amino-acid residues important for catalysis are highly conserved between both TrpE subfamilies. RESULTS: Conserved

  12. Transcriptomic analysis identifies gene networks regulated by estrogen receptor ? (ER?) and ER? that control distinct effects of different botanical estrogens

    PubMed Central

    Gong, Ping; Madak-Erdogan, Zeynep; Li, Jilong; Cheng, Jianlin; Greenlief, C. Michael; Helferich, William G.; Katzenellenbogen, John A.

    2014-01-01

    The estrogen receptors (ERs) ER? and ER? mediate the actions of endogenous estrogens as well as those of botanical estrogens (BEs) present in plants. BEs are ingested in the diet and also widely consumed by postmenopausal women as dietary supplements, often as a substitute for the loss of endogenous estrogens at menopause. However, their activities and efficacies, and similarities and differences in gene expression programs with respect to endogenous estrogens such as estradiol (E2) are not fully understood. Because gene expression patterns underlie and control the broad physiological effects of estrogens, we have investigated and compared the gene networks that are regulated by different BEs and by E2. Our aim was to determine if the soy and licorice BEs control similar or different gene expression programs and to compare their gene regulations with that of E2. Gene expression was examined by RNA-Seq in human breast cancer (MCF7) cells treated with control vehicle, BE or E2. These cells contained three different complements of ERs, ER? only, ER?+ER?, or ER? only, reflecting the different ratios of these two receptors in different human breast cancers and in different estrogen target cells. Using principal component, hierarchical clustering, and gene ontology and interactome analyses, we found that BEs regulated many of the same genes as did E2. The genes regulated by each BE, however, were somewhat different from one another, with some genes being regulated uniquely by each compound. The overlap with E2 in regulated genes was greatest for the soy isoflavones genistein and S-equol, while the greatest difference from E2 in gene expression pattern was observed for the licorice root BE liquiritigenin. The gene expression pattern of each ligand depended greatly on the cell background of ERs present. Despite similarities in gene expression pattern with E2, the BEs were generally less stimulatory of genes promoting proliferation and were more pro-apoptotic in their gene regulations than E2. The distinctive patterns of gene regulation by the individual BEs and E2 may underlie differences in the activities of these soy and licorice-derived BEs in estrogen target cells containing different levels of the two ERs. PMID:25363786

  13. A Distinct and Divergent Lineage of Genomic Island-Associated Type IV Secretion Systems in Legionella

    PubMed Central

    Wee, Bryan A.; Woolfit, Megan; Beatson, Scott A.; Petty, Nicola K.

    2013-01-01

    Legionella encodes multiple classes of Type IV Secretion Systems (T4SSs), including the Dot/Icm protein secretion system that is essential for intracellular multiplication in amoebal and human hosts. Other T4SSs not essential for virulence are thought to facilitate the acquisition of niche-specific adaptation genes including the numerous effector genes that are a hallmark of this genus. Previously, we identified two novel gene clusters in the draft genome of Legionella pneumophila strain 130b that encode homologues of a subtype of T4SS, the genomic island-associated T4SS (GI-T4SS), usually associated with integrative and conjugative elements (ICE). In this study, we performed genomic analyses of 14 homologous GI-T4SS clusters found in eight publicly available Legionella genomes and show that this cluster is unusually well conserved in a region of high plasticity. Phylogenetic analyses show that Legionella GI-T4SSs are substantially divergent from other members of this subtype of T4SS and represent a novel clade of GI-T4SSs only found in this genus. The GI-T4SS was found to be under purifying selection, suggesting it is functional and may play an important role in the evolution and adaptation of Legionella. Like other GI-T4SSs, the Legionella clusters are also associated with ICEs, but lack the typical integration and replication modules of related ICEs. The absence of complete replication and DNA pre-processing modules, together with the presence of Legionella-specific regulatory elements, suggest the Legionella GI-T4SS-associated ICE is unique and may employ novel mechanisms of regulation, maintenance and excision. The Legionella GI-T4SS cluster was found to be associated with several cargo genes, including numerous antibiotic resistance and virulence factors, which may confer a fitness benefit to the organism. The in-silico characterisation of this new T4SS furthers our understanding of the diversity of secretion systems involved in the frequent horizontal gene transfers that allow Legionella to adapt to and exploit diverse environmental niches. PMID:24358157

  14. 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 profile study of C. arabica and C. canephora, which can be freely assessed by the scientific community at http://www.lge.ibi.unicamp.br/coffea. Our data reveal the presence of species-specific/prevalent genes in coffee that may help to explain particular characteristics of these two crops. The identification of differentially expressed transcripts offers a starting point for the correlation between gene expression profiles and Coffea spp. developmental traits, providing valuable insights for coffee breeding and biotechnology, especially concerning sugar metabolism and stress tolerance. PMID:21303543

  15. Taurine-, aspartate- and glutamate-like immunoreactivity identifies chemically distinct subdivisions of Kenyon cells in the cockroach mushroom body.

    PubMed

    Sinakevitch, I; Farris, S M; Strausfeld, N J

    2001-10-22

    The lobes of the mushroom bodies of the cockroach Periplaneta americana consist of longitudinal modules called laminae. These comprise repeating arrangements of Kenyon cell axons, which like their dendrites and perikarya have an affinity to one of three antisera: to taurine, aspartate, or glutamate. Taurine-immunopositive laminae alternate with immunonegative ones. Aspartate-immunopositive Kenyon cell axons are distributed across the lobes. However, smaller leaf-like ensembles of axons that reveal particularly high affinities to anti-aspartate are embedded within taurine-positive laminae and occur in the immunonegative laminae between them. Together, these arrangements reveal a complex architecture of repeating subunits whose different levels of immunoreactivity correspond to broader immunoreactive layers identified by sera against the neuromodulator FMRFamide. Throughout development and in the adult, the most posterior lamina is glutamate immunopositive. Its axons arise from the most recently born Kenyon cells that in the adult retain their juvenile character, sending a dense system of collaterals to the front of the lobes. Glutamate-positive processes intersect aspartate- and taurine-immunopositive laminae and are disposed such that they might play important roles in synaptogenesis or synapse modification. Glutamate immunoreactivity is not seen in older, mature axons, indicating that Kenyon cells show plasticity of neurotransmitter phenotype during development. Aspartate may be a universal transmitter substance throughout the lobes. High levels of taurine immunoreactivity occur in broad laminae containing the high concentrations of synaptic vesicles. PMID:11596059

  16. Cytokinetic nodes in fission yeast arise from two distinct types of nodes that merge during interphase.

    PubMed

    Akamatsu, Matthew; Berro, Julien; Pu, Kai-Ming; Tebbs, Irene R; Pollard, Thomas D

    2014-03-17

    We investigated the assembly of cortical nodes that generate the cytokinetic contractile ring in fission yeast. Observations of cells expressing fluorescent fusion proteins revealed two types of interphase nodes. Type 1 nodes containing kinase Cdr1p, kinase Cdr2p, and anillin Mid1p form in the cortex around the nucleus early in G2. Type 2 nodes with protein Blt1p, guanosine triphosphate exchange factor Gef2p, and kinesin Klp8p emerge from contractile ring remnants. Quantitative measurements and computer simulations showed that these two types of nodes come together by a diffuse-and-capture mechanism: type 2 nodes diffuse to the equator and are captured by stationary type 1 nodes. During mitosis, cytokinetic nodes with Mid1p and all of the type 2 node markers incorporate into the contractile ring, whereas type 1 nodes with Cdr1p and Cdr2p follow the separating nuclei before dispersing into the cytoplasm, dependent on septation initiation network signaling. The two types of interphase nodes follow parallel branches of the pathway to prepare nodes for cytokinesis. PMID:24637325

  17. The culture of olfactory ensheathing cells (OECs)—a distinct glial cell type

    PubMed Central

    Higginson, Jennifer R.; Barnett, Susan C.

    2011-01-01

    Olfactory ensheathing cells (OECs) have become a popular candidate for the transplant-mediated repair of the damaged CNS. In this review a description is made of the origins of these cells and a historical development of their purification and maintenance in culture. In addition, we illustrate the cellular and molecular characteristics of OECs and emphasise that although they share many properties with Schwann cells, they possess several inherent differences which may allow them to be more beneficial for CNS repair. In summary, OECs are distinct glial cells and the detailed understanding of their biological and molecular properties is essential in ensuring their clinical efficacy after cell transplantation. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID:20816825

  18. The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction 

    E-print Network

    Gourley, David G; Shrive, Annette K; Polikarpov, Igor; Krell, Tino; Coggins, John R; Hawkins, Alastair R; Isaacs, Neil W; Sawyer, Lindsay

    The structures of enzymes catalyzing the reactions in central metabolic pathways are generally well conserved as are their catalytic mechanisms. The two types of 3-dehydroquinate dehydratase (DHQase) are therefore most ...

  19. Activation of Type I Interferon Pathway in Systemic Lupus Erythematosus: Association with Distinct Clinical Phenotypes

    PubMed Central

    Karageorgas, Theophanis P.; Tseronis, Dimitrios D.; Mavragani, Clio P.

    2011-01-01

    Growing evidence over the last few years suggests a central role of type I IFN pathway in the pathogenesis of systemic autoimmune disorders. Data from clinical and genetic studies in patients with systemic lupus erythematosus (SLE) and lupus-prone mouse models, indicates that the type I interferon system may play a pivotal role in the pathogenesis of several lupus and associated clinical features, such as nephritis, neuropsychiatric and cutaneous lupus, premature atherosclerosis as well as lupus-specific autoantibodies particularly against ribonucleoproteins. In the current paper, our aim is to summarize the latest findings supporting the association of type I IFN pathway with specific clinical manifestations in the setting of SLE providing insights on the potential use of type I IFN as a therapeutic target. PMID:22162633

  20. 38 CFR 74.25 - What types of personally identifiable information will VA collect?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...VETERANS AFFAIRS (CONTINUED) VETERANS SMALL BUSINESS REGULATIONS Records Management § 74.25 What types of personally identifiable...ownership and control interests in a specific business seeking to obtain verified...

  1. 38 CFR 74.25 - What types of personally identifiable information will VA collect?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...VETERANS AFFAIRS (CONTINUED) VETERANS SMALL BUSINESS REGULATIONS Records Management § 74.25 What types of personally identifiable...ownership and control interests in a specific business seeking to obtain verified...

  2. 38 CFR 74.25 - What types of personally identifiable information will VA collect?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...VETERANS AFFAIRS (CONTINUED) VETERANS SMALL BUSINESS REGULATIONS Records Management § 74.25 What types of personally identifiable...ownership and control interests in a specific business seeking to obtain verified...

  3. 38 CFR 74.25 - What types of personally identifiable information will VA collect?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...VETERANS AFFAIRS (CONTINUED) VETERANS SMALL BUSINESS REGULATIONS Records Management § 74.25 What types of personally identifiable...ownership and control interests in a specific business seeking to obtain verified...

  4. 38 CFR 74.25 - What types of personally identifiable information will VA collect?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...VETERANS AFFAIRS (CONTINUED) VETERANS SMALL BUSINESS REGULATIONS Records Management § 74.25 What types of personally identifiable...ownership and control interests in a specific business seeking to obtain verified...

  5. Store-depletion and hyperforin activate distinct types of Ca 2+-conducting channels in cortical neurons

    Microsoft Academic Search

    Julien Gibon; Peng Tu; Alexandre Bouron

    2010-01-01

    Cortical neurons embryos (E13) from murine brain have a wide diversity of plasma membrane Ca2+-conducting channels. For instance, they express several types of transient receptor potential channels of C-type (TRPC) and hyperforin, a potent TRPC6-channel activator, controls the activity of TRPC6-like channels. In addition, E13 cortical neurons possess plasma membrane channels activated in response to the depletion of internal Ca2+

  6. 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 treated cultures. Conclusion Low LET charged particles inhibit the early stages of vasculogenesis when tip cells have motile protrusive structures and are creating pioneer guidance tunnels through the matrix. High LET charged particles do not affect the early stages of vasculogenesis but they do affect the later stages when the endothelial cells migrate to form tubes. PMID:24044765

  7. Multilocus sequence typing of Mycoplasma hyorhinis strains identified by a real-time TaqMan PCR assay.

    PubMed

    Tocqueville, Véronique; Ferré, Séverine; Nguyen, Ngoc Hong Phuc; Kempf, Isabelle; Marois-Créhan, Corinne

    2014-05-01

    A real-time TaqMan PCR assay based on the gene encoding the protein p37 was developed to detect Mycoplasma hyorhinis. Its specificity was validated with 29 epidemiologically unrelated M. hyorhinis strains (28 field strains and one reference strain) and other mycoplasma species or with other microorganisms commonly found in pigs. The estimated detection limit of this qPCR assay was 125 microorganism equivalents/?l. The same 29 epidemiologically unrelated M. hyorhinis strains and four previously fully sequenced strains were typed by two portable typing methods, the sequencing of the p37 gene and a multilocus sequence typing (MLST) scheme. The first method revealed 18 distinct nucleotide sequences and insufficient discriminatory power (0.934). The MLST scheme was developed with the sequenced genomes of the M. hyorhinis strains HUB-1, GDL-1, MCLD, and SK76 and based on the genes dnaA, rpoB, gyrB, gltX, adk, and gmk. In total, 2,304 bp of sequence was analyzed for each strain. MLST was capable of subdividing the 33 strains into 29 distinct sequence types. The discriminatory power of the method was >0.95, which is the threshold value for interpreting typing results with confidence (D=0.989). Population analysis showed that recombination in M. hyorhinis occurs and that strains are diverse but with a certain clonality (one unique clonal complex was identified). The new qPCR assay and the robust MLST scheme are available for the acquisition of new knowledge on M. hyorhinis epidemiology. A web-accessible database has been set up for the M. hyorhinis MLST scheme at http://pubmlst.org/mhyorhinis/. PMID:24622092

  8. Multilocus Sequence Typing of Mycoplasma hyorhinis Strains Identified by a Real-Time TaqMan PCR Assay

    PubMed Central

    Tocqueville, Véronique; Ferré, Séverine; Nguyen, Ngoc Hong Phuc

    2014-01-01

    A real-time TaqMan PCR assay based on the gene encoding the protein p37 was developed to detect Mycoplasma hyorhinis. Its specificity was validated with 29 epidemiologically unrelated M. hyorhinis strains (28 field strains and one reference strain) and other mycoplasma species or with other microorganisms commonly found in pigs. The estimated detection limit of this qPCR assay was 125 microorganism equivalents/?l. The same 29 epidemiologically unrelated M. hyorhinis strains and four previously fully sequenced strains were typed by two portable typing methods, the sequencing of the p37 gene and a multilocus sequence typing (MLST) scheme. The first method revealed 18 distinct nucleotide sequences and insufficient discriminatory power (0.934). The MLST scheme was developed with the sequenced genomes of the M. hyorhinis strains HUB-1, GDL-1, MCLD, and SK76 and based on the genes dnaA, rpoB, gyrB, gltX, adk, and gmk. In total, 2,304 bp of sequence was analyzed for each strain. MLST was capable of subdividing the 33 strains into 29 distinct sequence types. The discriminatory power of the method was >0.95, which is the threshold value for interpreting typing results with confidence (D = 0.989). Population analysis showed that recombination in M. hyorhinis occurs and that strains are diverse but with a certain clonality (one unique clonal complex was identified). The new qPCR assay and the robust MLST scheme are available for the acquisition of new knowledge on M. hyorhinis epidemiology. A web-accessible database has been set up for the M. hyorhinis MLST scheme at http://pubmlst.org/mhyorhinis/. PMID:24622092

  9. Pathologically and Biologically Distinct Types of Epithelium in Intraductal Papillary Mucinous Neoplasms Delineation of an \\

    Microsoft Academic Search

    N. Volkan Adsay; Kambiz Merati; Olca Basturk; Christine Iacobuzio-Donahue; Edi Levi; Jeanette D. Cheng; Fazlul H. Sarkar; Ralph H. Hruban; David S. Klimstra

    Although general characteristics of intraductal papillary mucinous neoplasms (IPMNs) and their delineation from other pan- creatic tumors have been well established, several issues regarding their biology and management remain unresolved. It has been noted briefly by us and other authors that there are different types of papillae in IPMNs; however, their frequency, biologic significance, and clini- cal relevance are unknown.

  10. 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…

  11. Asbestos Body Formation in the Human Lung: Distinctions, by Type and Size

    Microsoft Academic Search

    Yoshihiro Murai; Masanobu Kitagawa; Takesuke Hiraoka

    1995-01-01

    The fraction of fibers coated in a total of 3 800 asbestos fibers from 38 patients with disease related to asbestos (100 fibers per patient) was determined, according to asbestos fiber type and size parameters. Among the 3 800 fibers, 638 (16.8%) were coated and 3 162 were uncoated. All fibers were analyzed at 2 000x magnification (lower limit of

  12. 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 [Department of Particle Physics and Astrophysics, Weizmann Institute of Science, Rehovot 76100 (Israel); Cenko, S. Bradley; Becker, Adam B. [Department of Astronomy, University of California, Berkeley, CA 94720-3411 (United States); Fox, Derek B. [Department of Astronomy and Astrophysics, Pennsylvania State University, University Park, PA 16802 (United States); Leonard, Douglas C. [Department of Astronomy, San Diego State University, San Diego, CA 92182 (United States); Moon, Dae-Sik [Department of Astronomy and Astrophysics, University of Toronto, Toronto, ON M5S 3H4 (Canada); Sand, David J. [Las Cumbres Observatory Global Telescope Network, Santa Barbara, CA 93117 (United States); Soderberg, Alicia M. [Harvard-Smithsonian Center for Astrophysics, Cambridge, MA 02138 (United States); Kiewe, Michael [Department of Physics, University of Wisconsin, Madison, WI 53706 (United States); Scheps, Raphael [King's College, University of Cambridge, Cambridge CB2 1ST (United Kingdom); Birenbaum, Gali [12 Amos St, Ramat Chen, Ramat Gan 52233 (Israel); Chamudot, Daniel [20 Chen St, Petach Tikvah 49520 (Israel); Zhou, Jonathan, E-mail: iair.arcavi@weizmann.ac.il [101 Dunster Street, Box 398, Cambridge, MA 02138 (United States)

    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.

  13. Type III IFNs in Pteropid Bats: Differential Expression Patterns Provide Evidence for Distinct Roles in Antiviral Immunity

    PubMed Central

    Zhou, Peng; Cowled, Chris; Todd, Shawn; Crameri, Gary; Virtue, Elena R.; Marsh, Glenn A.; Klein, Reuben; Shi, Zhengli; Wang, Lin-Fa; Baker, Michelle L.

    2011-01-01

    Bats are known to harbor a number of emerging and re-emerging zoonotic viruses, many of which are highly pathogenic in other mammals but result in no clinical symptoms in bats. The ability of bats to coexist with viruses may be the result of rapid control of viral replication early in the immune response. IFNs provide the first line of defense against viral infection in vertebrates. Type III IFNs (IFN-?s) are a recently identified IFN family that share similar antiviral activities with type I IFNs. To our knowledge, we demonstrate the first functional analysis of type III IFNs from any species of bat, with the investigation of two IFN-? genes from the pteropid bat, Pteropus alecto. Our results demonstrate that bat type III IFN has similar antiviral activity to type I and III IFNs from other mammals. In addition, the two bat type III IFNs are differentially induced relative to each other and to type I IFNs after treatment or transfection with synthetic dsRNA. Infection with the bat paramyxovirus, Tioman virus, resulted in no upregulation of type I IFN production in bat splenocytes but was capable of inducing a type III IFN response in three of the four bats tested. To our knowledge, this is the first report to describe the simultaneous suppression of type I IFN and induction of type III IFN after virus infection. These results may have important implications for the role of type III IFNs in the ability of bats to coexist with viruses. PMID:21278349

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

    SciTech Connect

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

    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.

  15. Distinction of Staphylococcal Cassette Chromosome mec type V elements from Staphylococcus aureus ST398.

    PubMed

    Chlebowicz, Monika A; Bosch, Thijs; Sabat, Artur J; Arends, Jan P; Grundmann, Hajo; van Dijl, Jan Maarten; Buist, Girbe

    2013-12-01

    Methicillin resistant S. aureus (MRSA) is a major threat for human health and well-being. In recent years, it has become clear that livestock is a potential reservoir for MRSA, most livestock-associated isolates belonging to the ST398 lineage. Importantly, ST398 strains were also reported as causative agents of severe invasive infections in humans with no evidence for livestock associations. Here we document the sequence of the J1 region of the type V (5C2&5) SCCmec element and its right chromosomal junction in the clinical PVL-positive ST398 MRSA isolate UMCG-M4. Sequence comparisons show that this SCCmec element and related type V elements from other S. aureus isolates share a common core structure, but differ substantially in the so-called J1 region. Additional PCR analyses and typing studies indicate that the J1 region of strain UMCG-M4 is specific for SCCmec elements of PVL-positive ST398 isolates. Lastly, we show that the sequenced right chromosomal junction is invariant in strains of the ST398 lineage. PMID:23786828

  16. Functional proteomics screen enables enrichment of distinct cell types from human pancreatic islets.

    PubMed

    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

  17. 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

  18. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors

    PubMed Central

    Mortensen, Martin; Ebert, Bjarke; Wafford, Keith; Smart, Trevor G

    2010-01-01

    The activation characteristics of synaptic and extrasynaptic GABAA receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of ?1?3?2, ?4?3?2 and ?4?3? receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At ? subunit-containing extrasynaptic-type GABAA receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on ?4?3? receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. PMID:20176630

  19. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.

    PubMed

    Mortensen, Martin; Ebert, Bjarke; Wafford, Keith; Smart, Trevor G

    2010-04-15

    The activation characteristics of synaptic and extrasynaptic GABA(A) receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of alpha 1 beta 3 gamma 2, alpha 4 beta 3 gamma 2 and alpha 4 beta 3 delta receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At delta subunit-containing extrasynaptic-type GABA(A) receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on alpha 4 beta 3 delta receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. PMID:20176630

  20. Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

    PubMed Central

    Pietropaolo, Massimo; Towns, Roberto; Eisenbarth, George S.

    2012-01-01

    Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic ? cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated ?-cell injury and, in turn, preserving ?-cell function in type 1 diabetes mellitus. PMID:23028135

  1. 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

  2. Distinct representation and distribution of visual information by specific cell types in mouse superficial superior colliculus.

    PubMed

    Gale, Samuel D; Murphy, Gabe J

    2014-10-01

    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

  3. Two distinct types of neuronal asymmetries are controlled by the Caenorhabditis elegans zinc finger transcription factor die-1

    PubMed Central

    Cochella, Luisa; Tursun, Baris; Hsieh, Yi-Wen; Galindo, Samantha; Johnston, Robert J.; Chuang, Chiou-Fen; Hobert, Oliver

    2014-01-01

    Left/right asymmetric features of animals are either randomly distributed on either the left or right side within a population (“antisymmetries”) or found stereotypically on one particular side of an animal (“directional asymmetries”). Both types of asymmetries can be found in nervous systems, but whether the regulatory programs that establish these asymmetries share any mechanistic features is not known. We describe here an unprecedented molecular link between these two types of asymmetries in Caenorhabditis elegans. The zinc finger transcription factor die-1 is expressed in a directionally asymmetric manner in the gustatory neuron pair ASE left (ASEL) and ASE right (ASER), while it is expressed in an antisymmetric manner in the olfactory neuron pair AWC left (AWCL) and AWC right (AWCR). Asymmetric die-1 expression is controlled in a fundamentally distinct manner in these two neuron pairs. Importantly, asymmetric die-1 expression controls the directionally asymmetric expression of gustatory receptor proteins in the ASE neurons and the antisymmetric expression of olfactory receptor proteins in the AWC neurons. These asymmetries serve to increase the ability of the animal to discriminate distinct chemosensory inputs. PMID:24361693

  4. Calcium-permeable AMPA receptors provide a common mechanism for LTP in glutamatergic synapses of distinct hippocampal interneuron types.

    PubMed

    Szabo, Andras; Somogyi, Jozsef; Cauli, Bruno; Lambolez, Bertrand; Somogyi, Peter; Lamsa, Karri P

    2012-05-01

    Glutamatergic synapses on some hippocampal GABAergic interneurons exhibit activity-induced long-term potentiation (LTP). Interneuron types within the CA1 area expressing mutually exclusive molecular markers differ in LTP responses. Potentiation that depends on calcium-permeable (CP) AMPA receptors has been characterized in oriens-lacunosum moleculare (O-LM) interneurons, which express parvalbumin and somatostatin (SM). However, it is unknown how widely CP-AMPAR-dependent plasticity is expressed among different GABAergic interneuron types. Here we examine synaptic plasticity in rat hippocampal O-LM cells and two other interneuron types expressing either nitric oxide synthase (NOS) or cholecystokinin (CCK), which are known to be physiologically and developmentally distinct. We report similar CP-AMPAR-dependent LTP in NOS-immunopositive ivy cells and SM-expressing O-LM cells to afferent fiber theta burst stimulation. The potentiation in both cell types is induced at postsynaptic membrane potentials below firing threshold, and induction is blocked by intense spiking simultaneously with afferent stimulation. The strong inward rectification and calcium permeability of AMPARs is explained by a low level of GluA2 subunit mRNA expression. LTP is not elicited in CCK-expressing Schaffer collateral-associated cells, which lack CP-AMPARs and express high levels of the GluA2 subunit. The results show that CP-AMPAR-mediated synaptic potentiation is common in hippocampal interneuron types and occurs in interneurons of both feedforward and feedback inhibitory pathways. PMID:22573673

  5. The hippocampal CA3 region can generate two distinct types of sharp wave-ripple complexes, in vitro.

    PubMed

    Hofer, Katharina T; Kandrács, Ágnes; Ulbert, István; Pál, Ildikó; Szabó, Csilla; Héja, László; Wittner, Lucia

    2015-02-01

    Hippocampal sharp wave-ripples (SPW-Rs) occur during slow wave sleep and behavioral immobility and are thought to play an important role in memory formation. We investigated the cellular and network properties of SPW-Rs with simultaneous laminar multielectrode and intracellular recordings in a rat hippocampal slice model, using physiological bathing medium. Spontaneous SPW-Rs were generated in the dentate gyrus (DG), CA3, and CA1 regions. These events were characterized by a local field potential gradient (LFPg) transient, increased fast oscillatory activity and increased multiple unit activity (MUA). Two types of SPW-Rs were distinguished in the CA3 region based on their different LFPg and current source density (CSD) pattern. Type 1 (T1) displayed negative LFPg transient in the pyramidal cell layer, and the associated CSD sink was confined to the proximal dendrites. Type 2 (T2) SPW-Rs were characterized by positive LFPg transient in the cell layer, and showed CSD sinks involving both the apical and basal dendrites. In both types, consistent with the somatic CSD source, only a small subset of CA3 pyramidal cells fired, most pyramidal cells were hyperpolarized, while most interneurons increased firing rate before the LFPg peak. Different neuronal populations, with different proportions of pyramidal cells and distinct subsets of interneurons were activated during T1 and T2 SPW-Rs. Activation of specific inhibitory cell subsets-with the possible leading role of perisomatic interneurons-seems to be crucial to synchronize distinct ensembles of CA3 pyramidal cells finally resulting in the expression of different SPW-R activities. This suggests that the hippocampus can generate dynamic changes in its activity stemming from the same excitatory and inhibitory circuits, and so, might provide the cellular and network basis for an input-specific and activity-dependent information transmission. PMID:25209976

  6. Distinctive patterns of autoimmune response induced by different types of mineral oil.

    PubMed

    Kuroda, Yoshiki; Akaogi, Jun; Nacionales, Dina C; Wasdo, Scott C; Szabo, Nancy J; Reeves, Westley H; Satoh, Minoru

    2004-04-01

    Although mineral oils are generally considered nontoxic and have a long history of use in humans, the mineral oil Bayol F (incomplete Freund's adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane) induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice. In the present study, we investigated whether medicinal mineral oils can induce other types of autoantibodies and whether structural features of hydrocarbons influence autoantibody specificity. Female 3-month-old BALB/c (16-45/group) mice each received an i.p. injection of pristane (C19), squalene (C30), IFA, three medicinal mineral oils (MO-F, MO-HT, MO-S), or PBS. Sera were tested for autoantibodies and immunoglobulin levels. Hydrocarbons were analyzed by gas chromatography/mass spectrometry. IFA contained mainly C15-C25 hydrocarbons, whereas MO-HT and MO-S contained C20-C40, and MO-F contained C15-C40. Pristane and n-hexadecane were found in IFA (0.17% and 0.10% w/v, respectively) and MOs (0.0026-0.027%). At 3 months, pristane and IFA induced mainly IgG2a, squalene IgG1, and MOs IgG3 and IgM in sera. Anti-cytoplasmic antibodies were common in mice treated with MO-F, as well as those treated with pristane, squalene, and IFA. Anti-ssDNA and -chromatin antibodies were higher in MO-F and MO-S than in untreated/PBS, squalene-, or IFA-treated mice, suggesting that there is variability in the induction of anti-nRNP/Sm versus -chromatin/DNA antibodies. The preferential induction of anti-chromatin/ssDNA antibodies without anti-nRNP/Sm/Su by MO-S and MO-F is consistent with the idea that different types of autoantibodies are regulated differently. Induction of autoantibodies by mineral oils considered nontoxic also may have pathogenetic implications in human autoimmune diseases. PMID:14718649

  7. 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.

  8. Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31

    PubMed Central

    Yoshida, Kunihiro; Asakawa, Mika; Suzuki-Kouyama, Emi; Tabata, Kenichi; Shintaku, Masayuki; Ikeda, Shu-ichi; Oyanagi, Kiyomitsu

    2014-01-01

    Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant form of pure cerebellar ataxia that is caused by a disease-specific insertion containing penta-nucleotide repeats (TGGAA)n. Neuropathologically, cerebellar Purkinje cells are preferentially affected and reduced in number in SCA31, and they are often surrounded by halo-like amorphous materials. In the present study, we performed neuropathological analyses on two SCA31 brains, and discussed the serial morphological changes of Purkinje cells in SCA31.We found that bent, elongated, often folded nuclei were observed frequently in degenerating Purkinje cells with the halo-like structure. Conversely, Purkinje cells without this structure developed marked atrophy with severely slender and condensed nuclei. On the basis of these pathological findings, we propose two different processes for Purkinje cell degeneration in SCA31, namely, shrinkage of Purkinje cells with or without the halo-like amorphous materials. The former, but not the latter, was considered to be specific to SCA31. Correspondingly, fragmentation of the Golgi apparatus was observed more frequently in Purkinje cells with the halo-like structure than in those without this structure. We consider that the profound nuclear deformity and fragmentation of the Golgi apparatus are closely linked with the formation of the halo-like structure in SCA31. PMID:24344778

  9. A Distinct Type of Heterochromatin at the Telomeric Region of the Drosophila melanogaster Y Chromosome

    PubMed Central

    Wang, Sidney H.; Nan, Ruth; Accardo, Maria C.; Sentmanat, Monica; Dimitri, Patrizio; Elgin, Sarah C. R.

    2014-01-01

    Heterochromatin assembly and its associated phenotype, position effect variegation (PEV), provide an informative system to study chromatin structure and genome packaging. In the fruit fly Drosophila melanogaster, the Y chromosome is entirely heterochromatic in all cell types except the male germline; as such, Y chromosome dosage is a potent modifier of PEV. However, neither Y heterochromatin composition, nor its assembly, has been carefully studied. Here, we report the mapping and characterization of eight reporter lines that show male-specific PEV. In all eight cases, the reporter insertion sites lie in the telomeric transposon array (HeT-A and TART-B2 homologous repeats) of the Y chromosome short arm (Ys). Investigations of the impact on the PEV phenotype of mutations in known heterochromatin proteins (i.e., modifiers of PEV) show that this Ys telomeric region is a unique heterochromatin domain: it displays sensitivity to mutations in HP1a, EGG and SU(VAR)3-9, but no sensitivity to Su(z)2 mutations. It appears that the endo-siRNA pathway plays a major targeting role for this domain. Interestingly, an ectopic copy of 1360 is sufficient to induce a piRNA targeting mechanism to further enhance silencing of a reporter cytologically localized to the Ys telomere. These results demonstrate the diversity of heterochromatin domains, and the corresponding variation in potential targeting mechanisms. PMID:24475122

  10. iCTX-Type: A Sequence-Based Predictor for Identifying the Types of Conotoxins in Targeting Ion Channels

    PubMed Central

    Ding, Hui; Deng, En-Ze; Liu, Li; Chou, Kuo-Chen

    2014-01-01

    Conotoxins are small disulfide-rich neurotoxic peptides, which can bind to ion channels with very high specificity and modulate their activities. Over the last few decades, conotoxins have been the drug candidates for treating chronic pain, epilepsy, spasticity, and cardiovascular diseases. According to their functions and targets, conotoxins are generally categorized into three types: potassium-channel type, sodium-channel type, and calcium-channel types. With the avalanche of peptide sequences generated in the postgenomic age, it is urgent and challenging to develop an automated method for rapidly and accurately identifying the types of conotoxins based on their sequence information alone. To address this challenge, a new predictor, called iCTX-Type, was developed by incorporating the dipeptide occurrence frequencies of a conotoxin sequence into a 400-D (dimensional) general pseudoamino acid composition, followed by the feature optimization procedure to reduce the sample representation from 400-D to 50-D vector. The overall success rate achieved by iCTX-Type via a rigorous cross-validation was over 91%, outperforming its counterpart (RBF network). Besides, iCTX-Type is so far the only predictor in this area with its web-server available, and hence is particularly useful for most experimental scientists to get their desired results without the need to follow the complicated mathematics involved. PMID:24991545

  11. Biased Signaling of the Angiotensin II Type 1 Receptor Can Be Mediated through Distinct Mechanisms

    PubMed Central

    Bonde, Marie Mi; Hansen, Jonas Tind; Sanni, Samra Joke; Haunsø, Stig; Gammeltoft, Steen; Lyngsø, Christina; Hansen, Jakob Lerche

    2010-01-01

    Background Seven transmembrane receptors (7TMRs) can adopt different active conformations facilitating a selective activation of either G protein or ?-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given receptor. Several studies on pathway separation have been performed, many of these on the Angiotensin II type 1 receptor (AT1R). It has been shown that certain ligands or mutations facilitate internalization and/or recruitment of ?-arrestins without activation of G proteins. However, the underlying molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit ?-arrestins. Since uncoupling of G proteins by increased ability to recruit ?-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms. Methodology/Principal Findings We studied five AT1R mutants previously published to display pathway separation: D74N, DRY/AAY, Y292F, N298A, and Y302F (Ballesteros-Weinstein numbering: 2.50, 3.49–3.51, 7.43, 7.49, and 7.53). We find that D74N, DRY/AAY, and N298A mutants are more prone to ?-arrestin recruitment than WT. In contrast, receptor mutants Y292F and Y302F showed impaired ability to recruit ?-arrestin in response to Sar1-Ile4-Ile8 (SII) Ang II, a ligand solely activating the ?-arrestin pathway. Conclusions/Significance Our analysis reveals that the underlying conformations induced by these AT1R mutants most likely represent principally different mechanisms of uncoupling the G protein, which for some mutants may be due to their increased ability to recruit ?-arrestin2. Hereby, these findings have important implications for drug discovery and 7TMR biology and illustrate the necessity of uncovering the exact molecular determinants for G protein-coupling and ?-arrestin recruitment, respectively. PMID:21152433

  12. Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection*

    PubMed Central

    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.

    2013-01-01

    The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). 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 PrPSc 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 PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc 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 PrPSc 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 PrPSc conformers. PMID:23974118

  13. 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

  14. 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 GH(1) and low GL(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 GL feature. PMID:25651069

  15. N-glycosylated proteins and distinct lipooligosaccharide glycoforms of Campylobacter jejuni target the human C-type lectin receptor MGL.

    PubMed

    van Sorge, Nina M; Bleumink, Nancy M C; van Vliet, Sandra J; Saeland, Eirikur; van der Pol, W-Ludo; van Kooyk, Yvette; van Putten, Jos P M

    2009-12-01

    An increasing number of bacterial pathogens produce an array of glycoproteins of unknown function. Here we report that Campylobacter jejuni proteins that are modified by the N-linked glycosylation machinery encoded by the pgl locus bind the human Macrophage Galactose-type lectin (MGL). MGL receptor binding was abrogated by EDTA and N-acetylgalactosamine (GalNAc) and was successfully transferred to Escherichia coli by introducing the C. jejuni pgl locus together with a glycan acceptor protein. In addition to glycoproteins, C. jejuni lipooligosaccharide with a terminal GalNAc residue was recognized by MGL. Recombinant E. coli expressing the C. jejuni pgl locus in the absence of a suitable glycan acceptor protein produced altered lipopolysaccharide glycoforms that gained MGL reactivity. Infection assays demonstrated high levels of GalNAc-dependent interaction of the recombinant E. coli with MGL-transfected mammalian cells. In addition, interleukin-6 production by human dendritic cells was enhanced by C. jejuni lacking N-linked glycans compared with wild-type bacteria. Collectively, our results provide evidence that both N-linked glycoproteins and distinct lipooligosaccharide glycoforms of C. jejuni are ligands for the human C-type lectin MGL and that the C. jejuni N-glycosylation machinery can be exploited to target recombinant bacteria to MGL-expressing eukaryotic cells. PMID:19681908

  16. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and ?? T cells.

    PubMed

    Van Dyken, Steven J; Mohapatra, Alexander; Nussbaum, Jesse C; Molofsky, Ari B; Thornton, Emily E; Ziegler, Steven F; McKenzie, Andrew N J; Krummel, Matthew F; Liang, Hong-Erh; Locksley, Richard M

    2014-03-20

    Chitin, a polysaccharide constituent of many allergens and parasites, initiates innate type 2 lung inflammation through incompletely defined pathways. We show that inhaled chitin induced expression of three epithelial cytokines, interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP), which nonredundantly activated resident innate lymphoid type 2 cells (ILC2s) to express IL-5 and IL-13 necessary for accumulation of eosinophils and alternatively activated macrophages (AAMs). In the absence of all three epithelial cytokines, ILC2s normally populated the lung but failed to increase IL-5 and IL-13. Although eosinophils and AAMs were attenuated, neutrophil influx remained normal without these epithelial cytokines. Genetic ablation of ILC2s, however, enhanced IL-1?, TNF?, and IL-23 expression, increased activation of IL-17A-producing ?? T cells, and prolonged neutrophil influx. Thus, chitin elicited patterns of innate cytokines that targeted distinct populations of resident lymphoid cells, revealing divergent but interacting pathways underlying the tissue accumulation of specific types of inflammatory myeloid cells. PMID:24631157

  17. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 (ILC2) and ?? T cells

    PubMed Central

    Van Dyken, Steven J.; Mohapatra, Alexander; Nussbaum, Jesse C.; Molofsky, Ari B.; Thornton, Emily E.; Ziegler, Steven F.; McKenzie, Andrew N. J.; Krummel, Matthew F.; Liang, Hong-Erh; Locksley, Richard M.

    2014-01-01

    SUMMARY Chitin, a polysaccharide constituent of many allergens and parasites, initiates innate type 2 lung inflammation through incompletely defined pathways. We show that inhaled chitin induced expression of three epithelial cytokines, interleukin-25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP), which non-redundantly activated resident innate lymphoid type 2 cells (ILC2) to express IL-5 and IL-13 necessary for accumulation of eosinophils and alternatively activated macrophages (AAMs). In the absence of all three epithelial cytokines, ILC2 normally populated the lung but failed to increase IL-5 and IL-13. Although eosinophils and AAMs were attenuated, neutrophil influx remained normal without these epithelial cytokines. Genetic ablation of ILC2, however, enhanced IL-1?, TNF? and IL-23 expression, increased activation of IL-17A-producing ?? T cells, and prolonged neutrophil influx. Thus, chitin elicited patterns of innate cytokines that targeted distinct populations of resident lymphoid cells, revealing divergent but interacting pathways underlying the tissue accumulation of specific types of inflammatory myeloid cells. PMID:24631157

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

    PubMed

    Johnson, Michael E; Mahoney, J Matthew; Taroni, Jaclyn; Sargent, Jennifer L; Marmarelis, Eleni; Wu, Ming-Ru; Varga, John; Hinchcliff, Monique E; Whitfield, Michael L

    2015-01-01

    Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFN? signaling showed a strong association with early disease, while TGF? signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-?B. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGF? and TNF?. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFN? is involved in early disease pathology, and disease severity is associated with active TGF? signaling. PMID:25607805

  19. Specific Genomic Regions Are Differentially Affected by Copy Number Alterations across Distinct Cancer Types, in Aggregated Cytogenetic Data

    PubMed Central

    von Mering, Christian; Baudis, Michael

    2012-01-01

    Background Regional genomic copy number alterations (CNA) are observed in the vast majority of cancers. Besides specifically targeting well-known, canonical oncogenes, CNAs may also play more subtle roles in terms of modulating genetic potential and broad gene expression patterns of developing tumors. Any significant differences in the overall CNA patterns between different cancer types may thus point towards specific biological mechanisms acting in those cancers. In addition, differences among CNA profiles may prove valuable for cancer classifications beyond existing annotation systems. Principal Findings We have analyzed molecular-cytogenetic data from 25579 tumors samples, which were classified into 160 cancer types according to the International Classification of Disease (ICD) coding system. When correcting for differences in the overall CNA frequencies between cancer types, related cancers were often found to cluster together according to similarities in their CNA profiles. Based on a randomization approach, distance measures from the cluster dendrograms were used to identify those specific genomic regions that contributed significantly to this signal. This approach identified 43 non-neutral genomic regions whose propensity for the occurrence of copy number alterations varied with the type of cancer at hand. Only a subset of these identified loci overlapped with previously implied, highly recurrent (hot-spot) cytogenetic imbalance regions. Conclusions Thus, for many genomic regions, a simple null-hypothesis of independence between cancer type and relative copy number alteration frequency can be rejected. Since a subset of these regions display relatively low overall CNA frequencies, they may point towards second-tier genomic targets that are adaptively relevant but not necessarily essential for cancer development. PMID:22937079

  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. Fourier Transform Infrared Imaging and Infrared Fiber Optic Probe Spectroscopy Identify Collagen Type in Connective Tissues

    PubMed Central

    Hanifi, Arash; McCarthy, Helen; Roberts, Sally; Pleshko, Nancy

    2013-01-01

    Hyaline cartilage and mechanically inferior fibrocartilage consisting of mixed collagen types are frequently found together in repairing articular cartilage. The present study seeks to develop methodology to identify collagen type and other tissue components using Fourier transform infrared (FTIR) spectral evaluation of matrix composition in combination with multivariate analyses. FTIR spectra of the primary molecular components of repair cartilage, types I and II collagen, and aggrecan, were used to develop multivariate spectral models for discrimination of the matrix components of the tissues of interest. Infrared imaging data were collected from bovine bone, tendon, normal cartilage, meniscus and human repair cartilage tissues, and composition predicted using partial least squares analyses. Histology and immunohistochemistry results were used as standards for validation. Infrared fiber optic probe spectral data were also obtained from meniscus (a tissue with mixed collagen types) to evaluate the potential of this method for identification of collagen type in a minimally-invasive clinical application. Concentration profiles of the tissue components obtained from multivariate analysis were in excellent agreement with histology and immunohistochemistry results. Bone and tendon showed a uniform distribution of predominantly type I collagen through the tissue. Normal cartilage showed a distribution of type II collagen and proteoglycan similar to the known composition, while in repair cartilage, the spectral distribution of both types I and II collagen were similar to that observed via immunohistochemistry. Using the probe, the outer and inner regions of the meniscus were shown to be primarily composed of type I and II collagen, respectively, in accordance with immunohistochemistry data. In summary, multivariate analysis of infrared spectra can indeed be used to differentiate collagen type I and type II, even in the presence of proteoglycan, in connective tissues, using both imaging and fiber optic methodology. This has great potential for clinical in situ applications for monitoring tissue repair. PMID:23717662

  2. Human T-cell leukemia virus type 1 Tax protein transforms rat fibroblasts via two distinct pathways.

    PubMed Central

    Matsumoto, K; Shibata, H; Fujisawa, J I; Inoue, H; Hakura, A; Tsukahara, T; Fujii, M

    1997-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates the transcription of several cellular genes. This function is thought to play a critical role in the Tax-dependent transformation step in HTLV-1 leukemogenesis. Tax activates transcription via three enhancers: the cyclic AMP response element (CRE)-like sequence, the kappaB element, and the CArG box. Their involvement in the transformation of rat fibroblasts by Tax was examined by colony formation of Rat-1 cells in soft agar and Ras cooperative focus formation of rat embryo fibroblasts (REF). Among Tax mutants, those retaining activity for the CArG box transformed REF like wild-type Tax, while those inactive for the CArG box did not. Thus, the activation of the CArG box pathway is essential for the transformation of REF by Tax. In contrast, activation of the kappaB element correlated with the transformation of Rat-1 by Tax. These results show that Tax transforms rat fibroblasts via two distinct pathways. PMID:9151835

  3. 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

  4. Mating type idiomorphs from a French population of the wheat pathogen Mycosphaerella graminicola: widespread equal distribution and low but distinct levels of molecular polymorphism.

    PubMed

    Siah, Ali; Tisserant, Benoit; El Chartouni, Léa; Duyme, Florent; Deweer, Caroline; Roisin-Fichter, Céline; Sanssené, Jean; Durand, Roger; Reignault, Philippe; Halama, Patrice

    2010-01-01

    Septoria tritici blotch caused by the heterothallic ascomycete Mycosphaerella graminicola is currently the most frequent and the most economically damaging disease on wheat worldwide. Five hundred and ten strains of this fungus were sampled from 16 geographical locations representing the major wheat producing areas in France. Multiplex PCR amplification, PCR-RFLP-SSCP screening and sequencing of parts of mating type encoding sequences were performed in order to assess the distribution and molecular polymorphism of the mating type idiomorphs. The two idiomorphs were scored at similar frequencies within all sampled locations. Both mating types were also identified at the leaf spatial scale, on 42% of leaves from which two or three strains were isolated. No correlation was found between distribution of mating types and either host cultivars from which the sampling was carried out or in vitro colony phenotypes observed during the culture of strains on potato dextrose agar (PDA) medium. PCR-RFLP-SSCP assay highlighted only one MAT1-1 strain exhibiting a profile distinct from all other MAT1-1 strains, whereas ten MAT1-2 strains (among which two and four with same profiles, respectively) showed profiles differing from the other MAT1-2 strains. Sequencing revealed that all polymorphisms corresponded to single nucleotide variations and all strains displaying the same single strand conformation polymorphism (SSCP) profiles showed identical nucleotide sequences, thereby confirming the high sensitivity of SSCP. Only two out of the disclosed nucleotide variations were nonsynonymous. This study strongly suggests a large potential for sexual reproduction in the French population of M. graminicola and reports a high conservation of mating type sequences in the fungus at both nucleotide and population levels, with a great difference in molecular variability between the two idiomorphs. PMID:21036342

  5. Identification and characterization of a new and distinct molecular subtype of human T-cell lymphotropic virus type 2.

    PubMed Central

    Eiraku, N; Novoa, P; da Costa Ferreira, M; Monken, C; Ishak, R; da Costa Ferreira, O; Zhu, S W; Lorenco, R; Ishak, M; Azvedo, V; Guerreiro, J; de Oliveira, M P; Loureiro, P; Hammerschlak, N; Ijichi, S; Hall, W M

    1996-01-01

    Molecular studies have demonstrated the existence of at least two major subtypes of human T-cell lymphotropic virus type 2 (HTLV-2), designated HTLV-2a and HTLV-2b. To further investigate the heterogeneity of this family of viruses, we have characterized the HTLV-2 subtypes present in several urban areas in Brazil. DNAs from peripheral blood mononuclear cells of a large number of infected individuals, the majority of whom were intravenous drug abusers, were analyzed by using PCR with restriction fragment length polymorphism and nucleotide sequencing analysis. Restriction fragment length polymorphism analysis of the env region suggested that all individuals were infected with the HTLV-2a subtype, and this was confirmed by nucleotide sequence analysis. In contrast, nucleotide sequence analysis of the long terminal repeat demonstrated that although the viruses were more related to the HTLV-2a than to the HTLV-2b subtype, they clustered in a distinct phylogenetic group, suggesting that they may represent a new and distinct molecular subtype of HTLV-2. This conclusion was supported by nucleotide sequence analysis of the pX region, which demonstrated that the Tax proteins of the Brazilian viruses differed from that of prototype HTLV-2a isolates but were more similar to that of HTLV-2b in that they would be expected to have an additional 25 amino acids at the carboxy terminus. In transient expression assays, the extended Tax protein of the prototype HTLV-2a subtype. The studies suggest that the Brazilian viruses analyzed in this study, while being phylogenetically related to the prototypic HTLV-2a seen in North America, are phenotypically more related to HTLV-2b and can be justifiably classified as a new molecular subtype, which has been tentatively designated HTLV-2c. PMID:8627666

  6. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene

    Microsoft Academic Search

    Hakon Hakonarson; Struan F. A. Grant; Jonathan P. Bradfield; Luc Marchand; Cecilia E. Kim; Joseph T. Glessner; Rosemarie Grabs; Tracy Casalunovo; Shayne P. Taback; Edward C. Frackelton; Margaret L. Lawson; Luke J. Robinson; Robert Skraban; Yang Lu; Rosetta M. Chiavacci; Charles A. Stanley; Susan E. Kirsch; Eric F. Rappaport; Jordan S. Orange; Dimitri S. Monos; Marcella Devoto; Hui-Qi Qu; Constantin Polychronakos

    2007-01-01

    Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a

  7. Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib

    Microsoft Academic Search

    Stéphanie Maupetit-Méhouas; Virginie Mariot; Christelle Reynès; Guylène Bertrand; Francois Feillet; Jean-Claude Carel; Dominique Simon; Hélène Bihan; Vincent Gajdos; Eve Devouge; Savitha Shenoy; Placide Agbo-Kpati; Anne Ronan; Catherine Naud-Saudreau; Anne Lienhardt; Caroline Silve; Agnès Linglart

    2010-01-01

    BackgroundPseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A\\/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR.ObjectiveTo investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib.Design and methodsIn 19 patients

  8. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

    Microsoft Academic Search

    Benjamin F Voight; Laura J Scott; Valgerdur Steinthorsdottir; Andrew P Morris; Christian Dina; Ryan P Welch; Eleftheria Zeggini; Cornelia Huth; Yurii S Aulchenko; Gudmar Thorleifsson; Laura J McCulloch; Teresa Ferreira; Harald Grallert; Najaf Amin; Guanming Wu; Cristen J Willer; Soumya Raychaudhuri; Steve A McCarroll; Claudia Langenberg; Oliver M Hofmann; Josée Dupuis; Lu Qi; Ayellet V Segrè; Mandy van Hoek; Pau Navarro; Kristin Ardlie; Beverley Balkau; Rafn Benediktsson; Amanda J Bennett; Roza Blagieva; Eric Boerwinkle; Lori L Bonnycastle; Kristina Bengtsson Boström; Bert Bravenboer; Suzannah Bumpstead; Noisël P Burtt; Guillaume Charpentier; Peter S Chines; Marilyn Cornelis; David J Couper; Gabe Crawford; Alex S F Doney; Katherine S Elliott; Amanda L Elliott; Michael R Erdos; Caroline S Fox; Christopher S Franklin; Martha Ganser; Christian Gieger; Niels Grarup; Todd Green; Simon Griffin; Christopher J Groves; Candace Guiducci; Samy Hadjadj; Neelam Hassanali; Christian Herder; Bo Isomaa; Anne U Jackson; Paul R V Johnson; Torben Jørgensen; Wen H L Kao; Norman Klopp; Augustine Kong; Peter Kraft; Johanna Kuusisto; Torsten Lauritzen; Man Li; Aloysius Lieverse; Cecilia M Lindgren; Valeriya Lyssenko; Michel Marre; Thomas Meitinger; Kristian Midthjell; Mario A Morken; Narisu Narisu; Peter Nilsson; Katharine R Owen; Felicity Payne; John R B Perry; Ann-Kristin Petersen; Carl Platou; Christine Proença; Inga Prokopenko; Wolfgang Rathmann; N William Rayner; Neil R Robertson; Ghislain Rocheleau; Michael Roden; Michael J Sampson; Richa Saxena; Beverley M Shields; Peter Shrader; Gunnar Sigurdsson; Thomas Sparsø; Klaus Strassburger; Heather M Stringham; Qi Sun; Amy J Swift; Barbara Thorand; Jean Tichet; Tiinamaija Tuomi; Rob M van Dam; Timon W van Haeften; Thijs van Herpt; Jana V van Vliet-Ostaptchouk; G Bragi Walters; Michael N Weedon; Cisca Wijmenga; Jacqueline Witteman; Richard N Bergman; Stephane Cauchi; Francis S Collins; Anna L Gloyn; Ulf Gyllensten; Torben Hansen; Winston A Hide; Graham A Hitman; Albert Hofman; David J Hunter; Kristian Hveem; Markku Laakso; Karen L Mohlke; Andrew D Morris; Colin N A Palmer; Peter P Pramstaller; Igor Rudan; Eric Sijbrands; Lincoln D Stein; Jaakko Tuomilehto; Andre Uitterlinden; Mark Walker; Nicholas J Wareham; Richard M Watanabe; Gonçalo R Abecasis; Bernhard O Boehm; Harry Campbell; Mark J Daly; Andrew T Hattersley; Frank B Hu; James B Meigs; James S Pankow; Oluf Pedersen; H-Erich Wichmann; Inês Barroso; Jose C Florez; Timothy M Frayling; Leif Groop; Rob Sladek; Unnur Thorsteinsdottir; James F Wilson; Thomas Illig; Philippe Froguel; Cornelia M van Duijn; Kari Stefansson; David Altshuler; Michael Boehnke; Mark I McCarthy

    2010-01-01

    By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 × 10?8. These include a second independent signal at the KCNQ1 locus; the first

  9. 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

  10. Targeting surface nucleolin with multivalent HB-19 and related Nucant pseudopeptides results in distinct inhibitory mechanisms depending on the malignant tumor cell type

    PubMed Central

    2011-01-01

    Background Nucleolin expressed at the cell surface is a binding protein for a variety of ligands implicated in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal RGG domain of nucleolin, the HB-19 pseudopeptide, we recently reported that targeting surface nucleolin with HB-19 suppresses progression of established human breast tumor cells in the athymic nude mice, and delays development of spontaneous melanoma in the RET transgenic mice. Methods By the capacity of HB-19 to bind stably surface nucleolin, we purified and identified nucleolin partners at the cell surface. HB-19 and related multivalent Nucant pseudopeptides, that present pentavalently or hexavalently the tripeptide Lys?(CH2N)-Pro-Arg, were then used to show that targeting surface nucleolin results in distinct inhibitory mechanisms on breast, prostate, colon carcinoma and leukemia cells. Results Surface nucleolin exists in a 500-kDa protein complex including several other proteins, which we identified by microsequencing as two Wnt related proteins, Ku86 autoantigen, signal recognition particle subunits SRP68/72, the receptor for complement component gC1q-R, and ribosomal proteins S4/S6. Interestingly, some of the surface-nucleolin associated proteins are implicated in cell signaling, tumor cell adhesion, migration, invasion, cell death, autoimmunity, and bacterial infections. Surface nucleolin in the 500-kDa complex is highly stable. Surface nucleolin antagonists, HB-19 and related multivalent Nucant pseudopeptides, exert distinct inhibitory mechanisms depending on the malignant tumor cell type. For example, in epithelial tumor cells they inhibit cell adhesion or spreading and induce reversion of the malignant phenotype (BMC cancer 2010, 10:325) while in leukemia cells they trigger a rapid cell death associated with DNA fragmentation. The fact that these pseudopeptides do not cause cell death in epithelial tumor cells indicates that cell death in leukemia cells is triggered by a specific signaling mechanism, rather than nonspecific cellular injury. Conclusions Our results suggest that targeting surface nucleolin could change the organization of the 500-kDa complex to interfere with the proper functioning of surface nucleolin and the associated proteins, and thus lead to distinct inhibitory mechanisms. Consequently, HB-19 and related Nucant pseudopeptides provide novel therapeutic opportunities in treatment of a wide variety of cancers and related malignancies. PMID:21812966

  11. On Identifying Clusters Within the C-type Asteroids of the Sloan Digital Sky Survey

    NASA Astrophysics Data System (ADS)

    Poole, Renae; Ziffer, J.; Harvell, T.

    2012-10-01

    We applied AutoClass, a data mining technique based upon Bayesian Classification, to C-group asteroid colors in the Sloan Digital Sky Survey (SDSS). Previous taxonomic studies relied mostly on Principal Component Analysis (PCA) to differentiate asteroids within the C-group (e.g. B, G, F, Ch, Cg and Cb). AutoClass's advantage is that it calculates the most probable classification for us, removing the human factor from this part of the analysis. In our results, AutoClass divided the C-groups into two large classes and six smaller classes. The two large classes (n=4974 and 2033, respectively) display distinct regions with some overlap in color-vs-color plots. Each cluster's average spectrum is compared to 'typical' spectra of the C-group subtypes as defined by Tholen (1989) and each cluster's members are evaluated for consistency with previous taxonomies. Of the 117 asteroids classified as B-type in previous taxonomies, only 12 were found with SDSS colors that matched our criteria of having less than 0.1 magnitude error in u and 0.05 magnitude error in g, r, i, and z colors. Although this is a relatively small group, 11 of the 12 B-types were placed by AutoClass in the same cluster. By determining the C-group sub-classifications in the large SDSS database, this research furthers our understanding of the stratigraphy and composition of the main-belt.

  12. Membrane properties of type II spiral ganglion neurones identified in a neonatal rat cochlear slice

    PubMed Central

    Jagger, Daniel J; Housley, Gary D

    2003-01-01

    Neuro-anatomical studies in the mammalian cochlea have previously identified a subpopulation of approximately 5% of primary auditory neurones, designated type II spiral ganglion neurones (sgnII). These neurones project to outer hair cells and their supporting cells, within the ‘cochlear amplifier’ region. Physiological characterization of sgnII has proven elusive. Whole-cell patch clamp of spiral ganglion neurones in P7-P10 rat cochlear slices provided functional characterization of sgnII, identified by biocytin or Lucifer yellow labelling of their peripheral neurite projections (outer spiral fibres) subsequent to electrophysiological characterisation. SgnII terminal fields comprised multiple outer hair cells and supporting cells, located up to 370 ?m basal to their soma. SgnII firing properties were defined by rapidly inactivating A-type-like potassium currents that suppress burst firing of action potentials. Type I spiral ganglion neurones (sgnI), had shorter radial projections to single inner hair cells and exhibited larger potassium currents with faster activation and slower inactivation kinetics, compatible with the high temporal firing fidelity seen in auditory nerve coding. Based on these findings, sgnII may be identified in future by the A-type current. Glutamate-gated somatic currents in sgnII were more potentiated by cyclothiazide than those in sgnI, suggesting differential AMPA receptor expression. ATP-activated desensitising inward currents were comparable in sgn II and sgnI. These data support a role for sgnII in providing integrated afferent feedback from the cochlear amplifier. PMID:14561834

  13. Transcriptome Profiling Identifies Candidate Genes Associated with the Accumulation of Distinct Sulfur ?-Glutamyl Dipeptides in Phaseolus vulgaris and Vigna mungo Seeds.

    PubMed

    Liao, Dengqun; Cram, Dustin; Sharpe, Andrew G; Marsolais, Frédéric

    2013-01-01

    Common bean (Phaseolus vulgaris) and black gram (Vigna mungo) accumulate ?-Glutamyl-S-methylcysteine and ?-Glutamyl-methionine in seed, respectively. Transcripts were profiled by 454 pyrosequencing data at a similar developmental stage coinciding with the beginning of the accumulation of these metabolites. Expressed sequence tags were assembled into Unigenes, which were assigned to specific genes in the early release chromosomal assembly of the P. vulgaris genome. Genes involved in multiple sulfur metabolic processes were expressed in both species. Expression of Sultr3 members was predominant in P. vulgaris, whereas expression of Sultr5 members predominated in V. mungo. Expression of the cytosolic SERAT1;1 and -1;2 was approximately fourfold higher in P. vulgaris while expression of the plastidic SERAT2;1 was twofold higher in V. mungo. Among BSAS family members, BSAS4;1, encoding a cytosolic cysteine desulfhydrase, and BSAS1;1, encoding a cytosolic O-acetylserine sulphydrylase were most highly expressed in both species. This was followed by BSAS3;1 encoding a plastidic ?-cyanoalanine synthase which was more highly expressed by 10-fold in P. vulgaris. The data identify BSAS3;1 as a candidate enzyme for the biosynthesis of S-methylcysteine through the use of methanethiol as substrate instead of cyanide. Expression of GLC1 would provide a complete sequence leading to the biosynthesis of ?-Glutamyl-S-methylcysteine in plastids. The detection of S-methylhomoglutathione in P. vulgaris suggested that homoglutathione synthetase may accept, to some extent, ?-Glutamyl-S-methylcysteine as substrate, which might lead to the formation of S-methylated phytochelatins. In conclusion, 454 sequencing was effective at revealing differences in the expression of sulfur metabolic genes, providing information on candidate genes for the biosynthesis of distinct sulfur amino acid ?-Glutamyl dipeptides between P. vulgaris and V. mungo. PMID:23532826

  14. Transcriptome Profiling Identifies Candidate Genes Associated with the Accumulation of Distinct Sulfur ?-Glutamyl Dipeptides in Phaseolus vulgaris and Vigna mungo Seeds

    PubMed Central

    Liao, Dengqun; Cram, Dustin; Sharpe, Andrew G.; Marsolais, Frédéric

    2013-01-01

    Common bean (Phaseolus vulgaris) and black gram (Vigna mungo) accumulate ?-Glutamyl-S-methylcysteine and ?-Glutamyl-methionine in seed, respectively. Transcripts were profiled by 454 pyrosequencing data at a similar developmental stage coinciding with the beginning of the accumulation of these metabolites. Expressed sequence tags were assembled into Unigenes, which were assigned to specific genes in the early release chromosomal assembly of the P. vulgaris genome. Genes involved in multiple sulfur metabolic processes were expressed in both species. Expression of Sultr3 members was predominant in P. vulgaris, whereas expression of Sultr5 members predominated in V. mungo. Expression of the cytosolic SERAT1;1 and -1;2 was approximately fourfold higher in P. vulgaris while expression of the plastidic SERAT2;1 was twofold higher in V. mungo. Among BSAS family members, BSAS4;1, encoding a cytosolic cysteine desulfhydrase, and BSAS1;1, encoding a cytosolic O-acetylserine sulphydrylase were most highly expressed in both species. This was followed by BSAS3;1 encoding a plastidic ?-cyanoalanine synthase which was more highly expressed by 10-fold in P. vulgaris. The data identify BSAS3;1 as a candidate enzyme for the biosynthesis of S-methylcysteine through the use of methanethiol as substrate instead of cyanide. Expression of GLC1 would provide a complete sequence leading to the biosynthesis of ?-Glutamyl-S-methylcysteine in plastids. The detection of S-methylhomoglutathione in P. vulgaris suggested that homoglutathione synthetase may accept, to some extent, ?-Glutamyl-S-methylcysteine as substrate, which might lead to the formation of S-methylated phytochelatins. In conclusion, 454 sequencing was effective at revealing differences in the expression of sulfur metabolic genes, providing information on candidate genes for the biosynthesis of distinct sulfur amino acid ?-Glutamyl dipeptides between P. vulgaris and V. mungo. PMID:23532826

  15. Distinctions between Bovine Herpesvirus 1 and Herpes Simplex Virus Type 1 VP22 Tegument Protein Subcellular Associations

    PubMed Central

    Harms, Jerome S.; Ren, Xiaodi; Oliveira, Sergio C.; Splitter, Gary A.

    2000-01-01

    The alphaherpesvirus tegument protein VP22 has been characterized with multiple traits including microtubule reorganization, nuclear localization, and nonclassical intercellular trafficking. However, all these data were derived from studies using herpes simplex virus type 1 (HSV-1) and may not apply to VP22 homologs of other alphaherpesviruses. We compared subcellular attributes of HSV-1 VP22 (HVP22) with bovine herpesvirus 1 (BHV-1) VP22 (BVP22) using green fluorescent protein (GFP)-fused VP22 expression vectors. Fluorescence microscopy of cell lines transfected with these constructs revealed differences as well as similarities between the two VP22 homologs. Compared to that of HVP22, the BVP22 microtubule interaction was much less pronounced. The VP22 nuclear interaction varied, with a marbled or halo appearance for BVP22 and a speckled or nucleolus-bound appearance for HVP22. Both VP22 homologs associated with chromatin at various stages of mitosis and could traffic from expressing cells to the nuclei of nonexpressing cells. However, distinct qualitative differences in microtubule, nuclear, and chromatin association as well as trafficking were observed. The differences in VP22 homolog characteristics revealed in this study will help define VP22 function within HSV-1 and BHV-1 infection. PMID:10708447

  16. Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations

    NSDL National Science Digital Library

    Karen M Eny (University of Toronto Nutritional Sciences)

    2008-03-18

    Glucose sensing in the brain has been proposed to be involved in regulating food intake, but the mechanism is not known. Glucose transporter type 2 (GLUT2)-null mice fail to control their food intake in response to glucose, suggesting a potential role for this transporter as a glucose sensor in the brain. Here we show that individuals with a genetic variation in GLUT2 (Thr110Ile) have a higher daily intake of sugars in two distinct populations. In the first population, compared with individuals with the Thr/Thr genotype, carriers of the Ile allele had a significantly higher intake of sugars as assessed from 3-day food records administered on two separate visits (visit 1: 112 ± 9 vs. 86 ± 4 g/day, P = 0.01; visit 2: 111 ± 8 vs. 82 ± 4 g/day, P = 0.003), demonstrating within-population reproducibility. In a second population, carriers of the Ile allele also reported consuming a significantly greater intake of sugars (131 ± 5 vs. 115 ± 3 g/day, P = 0.007) over a 1-mo period as measured from a food frequency questionnaire. GLUT2 genotypes were not associated with fat, protein, or alcohol intake in either population. These observations were consistent across older and younger adults as well as among subjects with early Type 2 diabetes and healthy individuals. Taken together, our findings show that a genetic variation in GLUT2 is associated with habitual consumption of sugars, suggesting an underlying glucose-sensing mechanism that regulates food intake.

  17. Distinct transcriptome profiles identified in normal human bronchial epithelial cells after exposure to ?-rays and different elemental particles of high Z and energy

    PubMed Central

    2013-01-01

    Background Ionizing radiation composed of accelerated ions of high atomic number (Z) and energy (HZE) deposits energy and creates damage in cells in a discrete manner as compared to the random deposition of energy and damage seen with low energy radiations such as ?- or x-rays. Such radiations can be highly effective at cell killing, transformation, and oncogenesis, all of which are concerns for the manned space program and for the burgeoning field of HZE particle radiotherapy for cancer. Furthermore, there are differences in the extent to which cells or tissues respond to such exposures that may be unrelated to absorbed dose. Therefore, we asked whether the energy deposition patterns produced by different radiation types would cause different molecular responses. We performed transcriptome profiling using human bronchial epithelial cells (HBECs) after exposure to ?-rays and to two different HZE particles (28Si and 56Fe) with different energy transfer properties to characterize the molecular response to HZE particles and ?-rays as a function of dose, energy deposition pattern, and time post-irradiation. Results Clonogenic assay indicated that the relative biological effectiveness (RBE) for 56Fe was 3.91 and for 28Si was 1.38 at 34% cell survival. Unsupervised clustering analysis of gene expression segregated samples according to the radiation species followed by the time after irradiation, whereas dose was not a significant parameter for segregation of radiation response. While a subset of genes associated with p53-signaling, such as CDKN1A, TRIM22 and BTG2 showed very similar responses to all radiation qualities, distinct expression changes were associated with the different radiation species. Gene enrichment analysis categorized the differentially expressed genes into functional groups related to cell death and cell cycle regulation for all radiation types, while gene pathway analysis revealed that the pro-inflammatory Acute Phase Response Signaling was specifically induced after HZE particle irradiation. A 73 gene signature capable of predicting with 96% accuracy the radiation species to which cells were exposed, was developed. Conclusions These data suggest that the molecular response to the radiation species used here is a function of the energy deposition characteristics of the radiation species. This novel molecular response to HZE particles may have implications for radiotherapy including particle selection for therapy and risk for second cancers, risk for cancers from diagnostic radiation exposures, as well as NASA’s efforts to develop more accurate lung cancer risk estimates for astronaut safety. Lastly, irrespective of the source of radiation, the gene expression changes observed set the stage for functional studies of initiation or progression of radiation-induced lung carcinogenesis. PMID:23724988

  18. Cell-Type–Specific Transcriptional Profiles of the Dimorphic Pathogen Penicillium marneffei Reflect Distinct Reproductive, Morphological, and Environmental Demands

    PubMed Central

    Pasricha, Shivani; Payne, Michael; Canovas, David; Pase, Luke; Ngaosuwankul, Nathamon; Beard, Sally; Oshlack, Alicia; Smyth, Gordon K.; Chaiyaroj, Sansanee C.; Boyce, Kylie J.; Andrianopoulos, Alex

    2013-01-01

    Penicillium marneffei is an opportunistic human pathogen endemic to Southeast Asia. At 25° P. marneffei grows in a filamentous hyphal form and can undergo asexual development (conidiation) to produce spores (conidia), the infectious agent. At 37° P. marneffei grows in the pathogenic yeast cell form that replicates by fission. Switching between these growth forms, known as dimorphic switching, is dependent on temperature. To understand the process of dimorphic switching and the physiological capacity of the different cell types, two microarray-based profiling experiments covering approximately 42% of the genome were performed. The first experiment compared cells from the hyphal, yeast, and conidiation phases to identify “phase or cell-state–specific” gene expression. The second experiment examined gene expression during the dimorphic switch from one morphological state to another. The data identified a variety of differentially expressed genes that have been organized into metabolic clusters based on predicted function and expression patterns. In particular, C-14 sterol reductase–encoding gene ergM of the ergosterol biosynthesis pathway showed high-level expression throughout yeast morphogenesis compared to hyphal. Deletion of ergM resulted in severe growth defects with increased sensitivity to azole-type antifungal agents but not amphotericin B. The data defined gene classes based on spatio-temporal expression such as those expressed early in the dimorphic switch but not in the terminal cell types and those expressed late. Such classifications have been helpful in linking a given gene of interest to its expression pattern throughout the P. marneffei dimorphic life cycle and its likely role in pathogenicity. PMID:24062530

  19. SNPsea: an algorithm to identify cell types, tissues and pathways affected by risk loci

    PubMed Central

    Slowikowski, Kamil; Hu, Xinli; Raychaudhuri, Soumya

    2014-01-01

    Summary: We created a fast, robust and general C++ implementation of a single-nucleotide polymorphism (SNP) set enrichment algorithm to identify cell types, tissues and pathways affected by risk loci. It tests trait-associated genomic loci for enrichment of specificity to conditions (cell types, tissues and pathways). We use a non-parametric statistical approach to compute empirical P-values by comparison with null SNP sets. As a proof of concept, we present novel applications of our method to four sets of genome-wide significant SNPs associated with red blood cell count, multiple sclerosis, celiac disease and HDL cholesterol. Availability and implementation: http://broadinstitute.org/mpg/snpsea Contact: soumya@broadinstitute.org Supplementary information: Supplementary data are available at Bioinformatics online. PMID:24813542

  20. IDENTIFYING NEARBY, YOUNG, LATE-TYPE STARS BY MEANS OF THEIR CIRCUMSTELLAR DISKS

    SciTech Connect

    Schneider, Adam; Song, Inseok [Department of Physics and Astronomy, University of Georgia, Athens, GA 30602 (United States); Melis, Carl [Center for Astrophysics and Space Sciences, University of California, San Diego, CA 92093 (United States); Zuckerman, B. [Department of Physics and Astronomy, University of California, Los Angeles, CA, 90095 (United States); Bessell, Mike, E-mail: aschneid@physast.uga.edu, E-mail: song@physast.uga.edu, E-mail: cmelis@ucsd.edu, E-mail: ben@astro.ucla.edu, E-mail: bessell@mso.anu.edu.au [Research School of Astronomy and Astrophysics, The Australian National University, Weston Creek, ACT 2611 (Australia)

    2012-10-01

    It has recently been shown that a significant fraction of late-type members of nearby, very young associations (age {approx}<10 Myr) display excess emission at mid-IR wavelengths indicative of dusty circumstellar disks. We demonstrate that the detection of mid-IR excess emission can be utilized to identify new nearby, young, late-type stars including two definite new members ('TWA 33' and 'TWA 34') of the TW Hydrae Association (TWA). Both new TWA members display mid-IR excess emission in the Wide-field Infrared Survey Explorer catalog and they show proper motion and youthful spectroscopic characteristics-namely, H{alpha} emission, strong lithium absorption, and low surface gravity features consistent with known TWA members. We also detect mid-IR excess-the first unambiguous evidence of a dusty circumstellar disk-around a previously identified UV-bright, young, accreting star (2M1337) that is a likely member of the Lower-Centaurus Crux region of the Scorpius-Centaurus Complex.

  1. Identifying the potential extracellular electron transfer pathways from a c-type cytochrome network.

    PubMed

    Ding, De-Wu; Xu, Jun; Li, Ling; Xie, Jian-Ming; Sun, Xiao

    2014-12-01

    Extracellular electron transfer (EET) is the key feature of some bacteria, such as Geobacter sulfurreducens and Shewanella oneidensis. Via EET processes, these bacteria can grow on electrode surfaces and make current output of microbial fuel cells. c-Type cytochromes can be used as carriers to transfer electrons, which play an important role in EET processes. Typically, from the inner (cytoplasmic) membrane through the periplasm to the outer membrane, they could form EET pathways. Recent studies suggest that a group of c-type cytochromes could form a network which extended the well-known EET pathways. We obtained the protein interaction information for all 41 c-type cytochromes in Shewanella oneidensis MR-1, constructed a large-scale protein interaction network, and studied its structural characteristics and functional significance. Centrality analysis has identified the top 10 key proteins of the network, and 7 of them are associated with electricity production in the bacteria, which suggests that the ability of Shewanella oneidensis MR-1 to produce electricity might be derived from the unique structure of the c-type cytochrome network. By modularity analysis, we obtained 5 modules from the network. The subcellular localization study has shown that the proteins in these modules all have diversiform cellular compartments, which reflects their potential to form EET pathways. In particular, combination of protein subcellular localization and operon analysis, the well-known and new candidate EET pathways are obtained from the Mtr-like module, indicating that potential EET pathways could be obtained from such a c-type cytochrome network. PMID:25227320

  2. Two novel mast cell phenotypic markers, monoclonal antibodies Ki-MC1 and Ki-M1P, identify distinct mast cell subtypes.

    PubMed

    Hamann, K; Haas, N; Grabbe, J; Welker, P; Czarnetzki, B M

    1995-10-01

    In order to identify more specific or selective mast cell markers, the reactivity of two monoclonal antibodies, Ki-MC1 and Ki-M1P, was studied by immunohistochemistry in two human cell lines (mast cell line HMC-1, basophilic cell line KU812), in mast cells cultured from blood precursors, in adherent mononuclear cells from peripheral blood, and in mast cells of tissue sections from 13 urticaria pigmentosa lesions, five mastocytomas and five normal skin specimens. Toluidine blue staining, fluorescence staining with FITC-conjugated avidin, and immunohistochemical staining (APAAP) with other mast cell reactive monoclonal antibodies, was performed for comparison. Double staining with the APAAP method, using the Ki-antibodies and toluidine blue, was also carried out. Both Ki-antibodies showed reactivity for skin mast cells, but with a different staining pattern. In addition, the Ki-MC1 antibody did not react with the cell lines, and reacted only with a few peripheral blood mononuclear cells and cultured mast cells. In contrast, the Ki-M1P antibody reacted with almost all cultured mast cells and blood mononuclear cells, but stained only about one-half of lesional and one-fifth of normal skin mast cells. Ki-M1P also reacted with many toluidine blue-negative dermal cells, particularly in urticaria pigmentosa. Ki-MC1 antibody can thus be considered as a useful additional marker for normal skin mast cells. In contrast, the Ki-M1P antibody primarily identifies immature mast cells and monocytes/macrophages, suggesting that these cell types probably originate from the same bone marrow precursor. PMID:7577581

  3. Introduction to the Special Issue on Hybrid Systems Hybrid systems contain two distinct types of components, subsystems with continuous dynamics and subsystems

    E-print Network

    Antsaklis, Panos

    Introduction to the Special Issue on Hybrid Systems Hybrid systems contain two distinct types. In this special issue the emphasis is on approaches that combine concepts from continuous control systems and synthesis results for hybrid systems. This special issue consists of four papers that describe different

  4. 2000 Macmillan Magazines LtdNATURE |VOL 403 |3 FEBRUARY 2000 |www.nature.com 503 Distinct types of diffuse large

    E-print Network

    Ford, James

    ............................................................................................................................................................................................................................................................................ Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically Distinct types of diffuse large B-cell lymphoma identi®ed by gene expression pro®ling Ash A. Alizadeh1

  5. Why HalleyTypes Resonate but LongPeriod Comets Don't: A Dynamical Distinction between Short and LongPeriod Comets

    E-print Network

    Chambers, John

    Why Halley­Types Resonate but Long­Period Comets Don't: A Dynamical Distinction between Short and Long­Period Comets J. E. Chambers Department of Terrestrial Magnetism, Carnegie Institution 02138. Abstract Several recent studies have noted that the orbital evolution of many comets

  6. Identifiers Identifiers

    E-print Network

    Brass, Stefan

    , July 1998. . Tim Berners­Lee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] Stefan://archive.ncsa.uiuc.edu/demoweb/url­primer.html] . T. Berners­Lee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. Berners­Lee, L. Masinter, M. McCahill: Uniform Resource

  7. Identifiers Identifiers

    E-print Network

    Brass, Stefan

    , July 1998. . Tim Berners­Lee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] . Uniform://archive.ncsa.uiuc.edu/demoweb/url­primer.html] . T. Berners­Lee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. Berners­Lee, L. Masinter, M. McCahill: Uniform Resource

  8. Isolation and characterization of epithelial and myogenic cells by "fishing" for the morphologically distinct cell types in rat primary periodontal ligament cultures.

    PubMed

    Tominaga, Noriko; Nakahara, Taka; Nasu, Masanori; Satoh, Tazuko

    2013-02-01

    The periodontal ligament (PDL) contains various cell populations and plays a central role in the maintenance, repair, and regeneration of the periodontium, i.e., tooth-supporting structures. Because primary cells isolated from PDL tissue are heterogeneous, the establishment of an effective isolation method for cells of interest is desired. In the present study, two morphologically distinct cell types were identified in confluent primary cultures derived from rat PDL. To isolate these cell populations, a small piece of filter paper soaked with trypsin-EDTA was placed directly onto the target cell population, enabling the cells to detach from the culture dish. The filter papers were then transferred into fresh culture dishes to establish outgrowth cultures; these two steps constitute the "cell fishing" method. The "fished" cell types were propagated and subcultured for further analyses. In morphological evaluation, immunocytochemical analyses, and reverse transcription-polymerase chain reaction, the isolated cells exhibited a polygonal appearance or a mono- or multinucleated appearance, with a high cytoplasm-to-nucleus ratio, leading to their being characterized as epithelial or myogenic cell populations, respectively. Surprisingly, a notable proportion of the multinuclear cells in the primary and subsequent isolated cultures demonstrated dramatic, spontaneous contractions, a feature typical of skeletal muscle cells. Finally, the isolated cell populations maintained a normal karyotype with a diploid chromosomal number. These results demonstrated that physiological epithelial and skeletal muscle cells can be obtained from primary PDL cultures without artificial induction using growth factors or chemicals, and can be propagated as individual lineage-committed cell populations; the populations consisted of differentiated and progenitor cells that maintained chromosomal stability. This simple, classical culture procedure provides new insights into the biological properties of PDL cells, which are potentially important for the differentiation of tissue or somatic stem cells and for the development of future cell-based therapies for dental and muscular diseases. PMID:23649106

  9. Detection of a Distinct Metal-poor Stellar Halo in the Early-type Galaxy NGC 3115†

    NASA Astrophysics Data System (ADS)

    Peacock, Mark B.; Strader, Jay; Romanowsky, Aaron J.; Brodie, Jean P.

    2015-02-01

    We present the resolved stellar populations in the inner and outer halo of the nearby lenticular galaxy NGC 3115. Using deep Hubble Space Telescope observations, we analyze stars 2 mag fainter than the tip of the red giant branch (TRGB). We study three fields along the minor axis of this galaxy, 19, 37, and 54 kpc from its center—corresponding to 7, 14, and 21 effective radii (re ). Even at these large galactocentric distances, all of the fields are dominated by a relatively enriched population, with the main peak in the metallicity distribution decreasing with radius from [Z/H] ~ –0.5 to –0.65. The fraction of metal-poor stars ([Z/H] < –0.95) increases from 17% at 16-37 kpc to 28% at ~54 kpc. We observe a distinct low-metallicity population (peaked at [Z/H] ~ –1.3 and with total mass 2 × 1010 M ? ~ 14% of the galaxy's stellar mass) and argue that this represents the detection of an underlying low-metallicity stellar halo. Such halos are generally predicted by galaxy formation theories and have been observed in several late-type galaxies, including the Milky Way and M31. The metallicity and spatial distribution of the stellar halo of NGC 3115 are consistent with the galaxy's globular cluster system, which has a similar low-metallicity population that becomes dominant at these large radii. This finding supports the use of globular clusters as bright chemodynamical tracers of galaxy halos. These data also allow us to make a precise measurement of the magnitude of the TRGB, from which we derive a distance modulus of NGC 3115 of 30.05 ± 0.05 ± 0.10sys (10.2 ± 0.2 ± 0.5sys Mpc). Based on observations made with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. These observations are associated with program #13048.

  10. Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology.

    PubMed Central

    Gao, F; Yue, L; Robertson, D L; Hill, S C; Hui, H; Biggar, R J; Neequaye, A E; Whelan, T M; Ho, D D; Shaw, G M

    1994-01-01

    The virulence properties of human immunodeficiency virus type 2 (HIV-2) are known to vary significantly and to range from relative attenuation in certain individuals to high-level pathogenicity in others. These differences in clinical manifestations may, at least in part, be determined by genetic differences among infecting virus strains. Evaluation of the full spectrum of HIV-2 genetic diversity is thus a necessary first step towards understanding its molecular epidemiology, natural history of infection, and biological diversity. In this study, we have used nested PCR techniques to amplify viral sequences from the DNA of uncultured peripheral blood mononuclear cells from 12 patients with HIV-2 seroreactivity. Sequence analysis of four nonoverlapping genomic regions allowed a comprehensive analysis of HIV-2 phylogeny. The results revealed (i) the existence of five distinct and roughly equidistant evolutionary lineages of HIV-2 which, by analogy with HIV-1, have been termed sequence subtypes A to E; (ii) evidence for a mosaic HIV-2 genome, indicating that coinfection with genetically divergent strains and recombination can occur in HIV-2-infected individuals; and (iii) evidence supporting the conclusion that some of the HIV-2 subtypes may have arisen from independent introductions of genetically diverse sooty mangabey viruses into the human population. Importantly, only a subset of HIV-2 strains replicated in culture: all subtype A viruses grew to high titers, but attempts to isolate representatives of subtypes C, D, and E, as well as the majority of subtype B viruses, remained unsuccessful. Infection with all five viral subtypes was detectable by commercially available serological (Western immunoblot) assays, despite intersubtype sequence differences of up to 25% in the gag, pol, and env regions. These results indicate that the genetic and biological diversity of HIV-2 is far greater than previously appreciated and suggest that there may be subtype-specific differences in virus biology. Systematic natural history studies are needed to determine whether this heterogeneity has clinical relevance and whether the various HIV-2 subtypes differ in their in vivo pathogenicity. Images PMID:7933127

  11. Multimodal functional and anatomic imaging identifies preclinical microvascular abnormalities in type 1 diabetes mellitus.

    PubMed

    Lockhart, C J; McCann, A J; Pinnock, R A; Hamilton, P K; Harbinson, M T; McVeigh, G E

    2014-12-15

    Structural and functional changes in the microcirculation in type 1 diabetes mellitus predict future end-organ damage and macrovascular events. We explored the utility of novel signal processing techniques to detect and track changes in ocular hemodynamics in patients with this disease. Twenty-four patients with uncomplicated type 1 diabetes mellitus and eighteen age- and sex-matched control subjects were studied. Doppler ultrasound was used to interrogate the carotid and ophthalmic arteries, and digital photography was used to image the retinal vasculature. Frequency analysis algorithms were applied to quantify velocity waveform structure and retinal photographic data at baseline and after inhalation of 100% O2. Frequency data were compared between groups. No significant differences were found in the resistive index between groups at baseline or after inhaled O2. Frequency analysis of Doppler flow velocity waveforms identified significant differences in bands 3-7 between patients and control subjects in data captured from the ophthalmic artery (P < 0.01 for each band). In response to inhaled O2, changes in frequency band amplitudes were significantly greater in control subjects compared with patients (P < 0.05). Only control subjects demonstrated a positive correlation (R = 0.61) between changes in retinal vessel diameter and frequency band amplitudes derived from ophthalmic artery waveform data. The use of multimodal signal processing techniques applied to Doppler flow velocity waveforms and retinal photographic data identified preclinical changes in the ocular microcirculation in patients with uncomplicated diabetes mellitus. An impaired autoregulatory response of the retinal microvasculature may contribute to the future development of retinopathy in such patients. PMID:25281566

  12. Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility

    PubMed Central

    Das, Swapan Kumar; Sharma, Neeraj Kumar

    2014-01-01

    Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for “missing heritability” may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D. PMID:24748924

  13. Significant Deregulated Pathways in Diabetes Type II Complications Identified through Expression Based Network Biology

    NASA Astrophysics Data System (ADS)

    Ukil, Sanchaita; Sinha, Meenakshee; Varshney, Lavneesh; Agrawal, Shipra

    Type 2 Diabetes is a complex multifactorial disease, which alters several signaling cascades giving rise to serious complications. It is one of the major risk factors for cardiovascular diseases. The present research work describes an integrated functional network biology approach to identify pathways that get transcriptionally altered and lead to complex complications thereby amplifying the phenotypic effect of the impaired disease state. We have identified two sub-network modules, which could be activated under abnormal circumstances in diabetes. Present work describes key proteins such as P85A and SRC serving as important nodes to mediate alternate signaling routes during diseased condition. P85A has been shown to be an important link between stress responsive MAPK and CVD markers involved in fibrosis. MAPK8 has been shown to interact with P85A and further activate CTGF through VEGF signaling. We have traced a novel and unique route correlating inflammation and fibrosis by considering P85A as a key mediator of signals. The next sub-network module shows SRC as a junction for various signaling processes, which results in interaction between NF-kB and beta catenin to cause cell death. The powerful interaction between these important genes in response to transcriptionally altered lipid metabolism and impaired inflammatory response via SRC causes apoptosis of cells. The crosstalk between inflammation, lipid homeostasis and stress, and their serious effects downstream have been explained in the present analyses.

  14. Genome-wide association study identifies three novel loci for type 2 diabetes.

    PubMed

    Hara, Kazuo; Fujita, Hayato; Johnson, Todd A; Yamauchi, Toshimasa; Yasuda, Kazuki; Horikoshi, Momoko; Peng, Chen; Hu, Cheng; Ma, Ronald C W; Imamura, Minako; Iwata, Minoru; Tsunoda, Tatsuhiko; Morizono, Takashi; Shojima, Nobuhiro; So, Wing Yee; Leung, Ting Fan; Kwan, Patrick; Zhang, Rong; Wang, Jie; Yu, Weihui; Maegawa, Hiroshi; Hirose, Hiroshi; Kaku, Kohei; Ito, Chikako; Watada, Hirotaka; Tanaka, Yasushi; Tobe, Kazuyuki; Kashiwagi, Atsunori; Kawamori, Ryuzo; Jia, Weiping; Chan, Juliana C N; Teo, Yik Ying; Shyong, Tai E; Kamatani, Naoyuki; Kubo, Michiaki; Maeda, Shiro; Kadowaki, Takashi

    2014-01-01

    Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases. PMID:23945395

  15. Spectroscopic characterization of a newly-identified substellar companion to an early-type star

    NASA Astrophysics Data System (ADS)

    De Rosa, Robert; Patience, Jenny; Vigan, Arthur; Young, Patrick; Rajan, Abhi; Ward-Duong, Kim; Bulger, Joanna; Truitt, Amanda

    2014-02-01

    With the cross-dispersed spectroscopy mode of the GNIRS instrument, we propose to obtain YJHK spectra of a newly identified co-moving companion to a nearby A-type star. The co-moving object resolved in previous Gemini/NIRI observations has a K-band magnitude consistent with a 40-50 Mj companion, if physically associated. Based on the position of the early A-type primary on the colour-magnitude diagram, the age of the system is intermediate to known brown dwarfs within young moving groups (<100 Myrs), and within the field (>1 Gyrs) - occupying an age range for which very few brown dwarfs are currently known. We also propose to obtain higher-resolution NIFS K-band spectra in order to measure the C/O ratio of the companion, thought to be diagnostic of the mechanism through which the object formed, providing important context to the recent C/O measurement of the HR 8799 c exoplanet. The proposed observations will confirm the substellar nature of this object, as well as provide a useful empirical benchmark for the development of theoretical evolutionary models of these cool, low-mass objects.

  16. Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes.

    PubMed

    Yip, Linda; Fuhlbrigge, Rebecca; Taylor, Cariel; Creusot, Remi J; Nishikawa-Matsumura, Teppei; Whiting, Chan C; Schartner, Jill M; Akter, Rahima; von Herrath, Matthias; Fathman, C Garrison

    2015-02-01

    Peripheral tolerance is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph node stromal cells (LNSCs). We previously identified a transcriptional regulator, deformed epidermal autoregulatory factor 1 (Deaf1), that can regulate PTA expression in LNSCs of the pancreatic lymph nodes (PLNs). During the pathogenesis of type 1 diabetes (T1D), Deaf1 is spliced to form the dominant-negative isoform Deaf1-Var1. Here we show that Deaf1-Var1 expression correlates with the severity of disease in NOD mice and is reduced in the PLNs of mice that do not develop hyperglycemia. Inflammation and hyperglycemia independently drive Deaf1 splicing through activation of the splicing factors Srsf10 and Ptbp2, respectively. Inflammation induced by injection of activated splenocytes increased Deaf1-Var1 and Srsf10, but not Ptbp2, in the PLNs of NOD.SCID mice. Hyperglycemia induced by treatment with the insulin receptor agonist S961 increased Deaf1-Var1 and Ptbp2, but not Srsf10, in the PLNs of NOD.B10 and NOD mice. Overexpression of PTBP2 and/or SRSF10 also increased human DEAF1-VAR1 and reduced PTA expression in HEK293T cells. These data suggest that during the progression of T1D, inflammation and hyperglycemia mediate the splicing of DEAF1 and loss of PTA expression in LNSCs by regulating the expression of SRSF10 and PTBP2. PMID:25187368

  17. Targeted Allelic Expression Profiling in Human Islets Identifies cis-Regulatory Effects for Multiple Variants Identified by Type 2 Diabetes Genome-Wide Association Studies.

    PubMed

    Locke, Jonathan M; Hysenaj, Gerald; Wood, Andrew R; Weedon, Michael N; Harries, Lorna W

    2015-04-01

    Genome-wide association studies (GWAS) have identified variation at >65 genomic loci associated with susceptibility to type 2 diabetes, but little progress has been made in elucidating the molecular mechanisms behind most of these associations. Using samples heterozygous for transcribed single nucleotide polymorphisms (SNPs), allelic expression profiling is a powerful technique for identifying cis-regulatory variants controlling gene expression. In this study, exonic SNPs, suitable for measuring mature mRNA levels and in high linkage disequilibrium with 65 lead type 2 diabetes GWAS SNPs, were identified and allelic expression determined by real-time PCR using RNA and DNA isolated from islets of 36 white nondiabetic donors. A significant allelic expression imbalance (AEI) was identified for 7/14 (50%) genes tested (ANPEP, CAMK2B, HMG20A, KCNJ11, NOTCH2, SLC30A8, and WFS1), with significant AEI confirmed for five of these genes using other linked exonic SNPs. Lastly, results of a targeted islet expression quantitative trait loci experiment support the AEI findings for ANPEP, further implicating ANPEP as the causative gene at its locus. The results of this study support the hypothesis that changes to cis-regulation of gene expression are involved in a large proportion of SNP associations with type 2 diabetes susceptibility. PMID:25392243

  18. Identifying low-dimensional dynamics in type-I edge-localised-mode processes in JET plasmas

    SciTech Connect

    Calderon, F. A.; Chapman, S. C.; Nicol, R. M. [Department of Physics, Centre for Fusion, Space and Astrophysics, University of Warwick, Coventry CV4 7AL (United Kingdom); Dendy, R. O. [EURATOM/CCFE Fusion Association, Culham Science Centre, Abingdon, Oxfordshire OX14 3DB (United Kingdom); Department of Physics, Centre for Fusion, Space and Astrophysics, University of Warwick, Coventry CV4 7AL (United Kingdom); Webster, A. J.; Alper, B. [EURATOM/CCFE Fusion Association, Culham Science Centre, Abingdon, Oxfordshire OX14 3DB (United Kingdom); Collaboration: JET EFDA Contributors

    2013-04-15

    Edge localised mode (ELM) measurements from reproducibly similar plasmas in the Joint European Torus (JET) tokamak, which differ only in their gas puffing rate, are analysed in terms of the pattern in the sequence of inter-ELM time intervals. It is found that the category of ELM defined empirically as type I-typically more regular, less frequent, and having larger amplitude than other ELM types-embraces substantially different ELMing processes. By quantifying the structure in the sequence of inter-ELM time intervals using delay time plots, we reveal transitions between distinct phase space dynamics, implying transitions between distinct underlying physical processes. The control parameter for these transitions between these different ELMing processes is the gas puffing rate.

  19. Two Types of Functionally Distinct Fiber Containing Structural Protein Complexes Are Produced during Infection of Adenovirus Serotype 5

    PubMed Central

    Zhang, Bo; Yan, Yuhua; Jin, Jie; Lin, Hongyu; Li, Zongyi; Zhang, Xiaoyan; Liu, Jin; Xi, Chao; Lieber, Andre; Fan, Xiaolong; Ran, Liang

    2015-01-01

    Adenoviruses are common pathogens. The localization of their receptors coxsackievirus and adenovirus receptor, and desmoglein-2 in cell-cell junction complexes between polarized epithelial cells represents a major challenge for adenovirus infection from the apical surface. Structural proteins including hexon, penton base and fiber are excessively produced in serotype 5 adenovirus (Ad5)-infected cells. We have characterized the composition of structural protein complexes released from Ad5 infected cells and their capacity in remodeling cell-cell junction complexes. Using T84 cells as a model for polarized epithelium, we have studied the effect of Ad5 structural protein complexes in remodeling cell-cell junctions in polarized epithelium. The initial Ad5 infection in T84 cell culture was inefficient. However, progressive distortion of cell-cell junction in association with fiber release was evident during progression of Ad5 infection. Incubation of T84 cell cultures with virion-free supernatant from Ad5 infected culture resulted in distortion of cell-cell junctions and decreased infectivity of Ad5-GFP vector. We used gel filtration chromatography to fractionate fiber containing virion–free supernatant from Ad5 infected culture supernatant. Fiber containing fractions were further characterized for their capacity to inhibit the infection of Ad5-GFP vector, their composition in adenovirus structural proteins using western blot and LC-MS/MS and their capacity in remolding cell-cell junctions. Fiber molecules in complexes containing penton base and hexon, or mainly hexon were identified. Only the fiber complexes with relatively high content of penton base, but not the fiber-hexon complexes with low penton base, were able to penetrate into T84 cells and cause distortion of cell-cell junctions. Our findings suggest that these two types of fiber complexes may play different roles in adenoviral infection. PMID:25723153

  20. Two distinct endogenous type C viruses isolated from the asian rodent Mus cervicolor: conservation of virogene sequences in related rodent species.

    PubMed Central

    Benveniste, R E; Callahan, R; Sherr, C J; Chapman, V; Todaro, G J

    1977-01-01

    The cocultivation of a lung cell line from the Southeast Asian mouse Mus cervicolor with cells from heterologous species has resulted in the isolation of two new distinct type C viruses. Both viruses are endogenous to M. cervicolor and are present in multiple copies in the cellular DNA of these mice. One of the viruses, designated M. cervicolor type CI, replicates readily in the SIRC rabbit cell line and is antigenically related to the infectious primate type C viruses isolated from a woolly monkey (simian sarcoma-associated virus) and gibbon apes (gibbon ape leukemia virus). This virus is also closely related by both immunological and nucleic acid hybridization criteria to a type C virus previously isolated from a second Asian murine species, Mus caroli. The isolation of the M. cervicolor type C I virus thus provides further evidence that the infectious primate type C viruses originated by trans-species infection of primates by an endogenous virus of mice. The second virus, designated M. cervicolor type C II, replicates well in various cell lines derived from the laboratory mouse Mus musculus. While antigenically related to type C viruses derived from M. musculus, the M. cervicolor type C II virus isolate can be readily distinguished from standard murine leukemia viruses. Both new type C viruses from M. cervicolor are unrelated to the previously described retrovirus (M432) isolated from the same Mus species. The DNA of M. cervicolor therefore contains multiple copies of at least three distinct classes of endogenous viral genes. An examination of the cellular DNA of other rodent species for nucleic acid sequences related to the genomes of both M. cervicolor type C I and II reveals that both viruses have been highly conserved evolutionarily, and that other species of rodents, such as laboratory mice and rats, contain endogenous virogenes related to those in the DNA of M. cervicolor. PMID:66330

  1. Multiple structurally distinct ER? mRNA variants in zebrafish are differentially expressed by tissue type, stage of development and estrogen exposure.

    PubMed

    Cotter, Kellie A; Yershov, Anya; Novillo, Apolonia; Callard, Gloria V

    2013-12-01

    It is well established that estrogen-like environmental chemicals interact with the ligand-binding site of estrogen receptors (ERs) to disrupt transcriptional control of estrogen responsive targets. Here we investigate the possibility that estrogens also impact splicing decisions on estrogen responsive genes, such as that encoding ER? itself. Targeted PCR cloning was applied to identify six ER? mRNA variants in zebrafish. Sequencing revealed alternate use of transcription and translation start sites, multiple exon deletions, intron retention and alternate polyadenylation. As determined by quantitative (q)PCR, N-terminal mRNA variants predicting long (ER?A(L)) and short (ER?(S)) isoforms were differentially expressed by tissue-type, sex, stage of development and estrogen exposure. Whereas ER?(L) mRNA was diffusely distributed in liver, brain, heart, eye, and gonads, ER?(S) mRNA was preferentially expressed in liver (female>male) and ovary. Neither ER?(L) nor ER?(S) transcripts varied significantly during development, but 17?-estradiol selectively increased accumulation of ER?(S) mRNA (?170-fold by 120 hpf), an effect mimicked by bisphenol-A and diethylstilbestrol. Significantly, a C-truncated variant (ER?(S)-Cx) lacking most of the ligand binding and AF-2 domains was transcribed exclusively from the short isoform promoter and was similar to ER?(S) in its tissue-, stage- and estrogen inducible expression. These results support the idea that promoter choice and alternative splicing of the esr1 gene of zebrafish are part of the autoregulatory mechanism by which estrogen modulates subsequent ER? expression, and further suggest that environmental estrogens could exert some of their toxic effects by altering the relative abundance of structurally and functionally distinct ER? isoforms. PMID:24090614

  2. Multiple Structurally Distinct ER? mRNA Variants in Zebrafish are Differentially Expressed by Tissue Type, Stage of Development and Estrogen Exposure

    PubMed Central

    Cotter, Kellie A.; Yershov, Anya; Novillo, Apolonia; Callard, Gloria V.

    2013-01-01

    It is well established that estrogen-like environmental chemicals interact with the ligand-binding site of estrogen receptors (ER) to disrupt transcriptional control of estrogen responsive targets. Here we investigate the possibility that estrogens also impact splicing decisions on estrogen responsive genes, such as that encoding ER? itself. Targeted PCR cloning was applied to identify six ER? mRNA variants in zebrafish. Sequencing revealed alternate use of transcription and translation start sites, multiple exon deletions, intron retention and alternate polyadenylation. As determined by quantitative (q)PCR, N-terminal mRNA variants predicting long (ER?L) and short (ER?S) isoforms were differentially expressed by tissue-type, sex, stage of development and estrogen exposure. Whereas ER?L mRNA was diffusely distributed in liver, brain, heart, eye, and gonads, ER?S mRNA was preferentially expressed in liver (female > male) and ovary. Neither ER?L nor ER?S transcripts varied significantly during development, but 17?-estradiol selectively increased accumulation of ER?S mRNA (~170-fold by 120 hpf), an effect mimicked by bisphenol-A and diethylstilbestrol. Significantly, a C-truncated variant (ER?S-Cx) lacking most of the ligand binding and AF-2 domains was transcribed exclusively from the short isoform promoter and was similar to ER?S in its tissue-, stage- and estrogen inducible expression. These results support the idea that promoter choice and alternative splicing of the esr1 gene of zebrafish are part of the autoregulatory mechanism by which estrogen modulates subsequent ER? expression, and further suggest that environmental estrogens could exert some of their toxic effects by altering the relative abundance of structurally and functionally distinct ER? isoforms. PMID:24090614

  3. GAD65 Autoantibodies Detected by Electrochemiluminescence Assay Identify High Risk for Type 1 Diabetes

    PubMed Central

    Miao, Dongmei; Guyer, K. Michelle; Dong, Fran; Jiang, Ling; Steck, Andrea K.; Rewers, Marian; Eisenbarth, George S.; Yu, Liping

    2013-01-01

    The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.7 years; and 181 age-matched, healthy, antibody-negative children. The ECL-GADA assay had a sensitivity similar to that of the standard GADA radioassay in children newly diagnosed with T1D, prediabetic children, and high-risk children with multiple positive islet autoantibodies. On the other hand, only 9 of 39 nondiabetic children with only a single islet autoantibody (GADA only) by radioassay were positive for ECL-GADA. GADA not detectable by ECL assay is shown to be of low affinity and likely not predictive of future diabetes. In conclusion, the new ECL assay identifies disease-relevant GADA by radioassay. It may help to improve the prediction and correct diagnosis of T1D among subjects positive only for GADA and no other islet autoantibodies. PMID:23974918

  4. GAD65 autoantibodies detected by electrochemiluminescence assay identify high risk for type 1 diabetes.

    PubMed

    Miao, Dongmei; Guyer, K Michelle; Dong, Fran; Jiang, Ling; Steck, Andrea K; Rewers, Marian; Eisenbarth, George S; Yu, Liping

    2013-12-01

    The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.7 years; and 181 age-matched, healthy, antibody-negative children. The ECL-GADA assay had a sensitivity similar to that of the standard GADA radioassay in children newly diagnosed with T1D, prediabetic children, and high-risk children with multiple positive islet autoantibodies. On the other hand, only 9 of 39 nondiabetic children with only a single islet autoantibody (GADA only) by radioassay were positive for ECL-GADA. GADA not detectable by ECL assay is shown to be of low affinity and likely not predictive of future diabetes. In conclusion, the new ECL assay identifies disease-relevant GADA by radioassay. It may help to improve the prediction and correct diagnosis of T1D among subjects positive only for GADA and no other islet autoantibodies. PMID:23974918

  5. A widespread bacterial type VI secretion effector superfamily identified using a heuristic approach

    PubMed Central

    Russell, Alistair B.; Singh, Pragya; Brittnacher, Mitchell; Bui, Nhat Khai; Hood, Rachel D.; Carl, Mike A.; Agnello, Danielle M.; Schwarz, Sandra; Goodlett, David R.; Vollmer, Waldemar; Mougous, Joseph D.

    2012-01-01

    Summary Sophisticated mechanisms are employed to facilitate information exchange between interfacing bacteria. A type VI secretion system (T6SS) of Pseudomonas aeruginosa was shown to deliver cell wall-targeting effectors to neighboring cells. However, the generality of bacteriolytic effectors, and moreover, of antibacterial T6S, remained unknown. Using parameters derived from experimentally validated bacterial T6SS effectors and informatics, we identified a phylogenetically disperse superfamily of T6SS-associated peptidoglycan-degrading effectors. The effectors separate into four families composed of peptidoglycan amidase enzymes of differing specificities. Effectors strictly co-occur with cognate immunity proteins, indicating that self-intoxication is a general property of antibacterial T6SSs and effector delivery by the system exerts a strong selective pressure in nature. The presence of antibacterial effectors in a plethora of organisms, including many that inhabit or infect polymicrobial niches in the human body, suggests that the system could mediate interbacterial interactions of both environmental and clinical significance. PMID:22607806

  6. A widespread bacterial type VI secretion effector superfamily identified using a heuristic approach.

    PubMed

    Russell, Alistair B; Singh, Pragya; Brittnacher, Mitchell; Bui, Nhat Khai; Hood, Rachel D; Carl, Mike A; Agnello, Danielle M; Schwarz, Sandra; Goodlett, David R; Vollmer, Waldemar; Mougous, Joseph D

    2012-05-17

    Sophisticated mechanisms are employed to facilitate information exchange between interfacing bacteria. A type VI secretion system (T6SS) of Pseudomonas aeruginosa was shown to deliver cell wall-targeting effectors to neighboring cells. However, the generality of bacteriolytic effectors and, moreover, of antibacterial T6S remained unknown. Using parameters derived from experimentally validated bacterial T6SS effectors we identified a phylogenetically disperse superfamily of T6SS-associated peptidoglycan-degrading effectors. The effectors separate into four families composed of peptidoglycan amidase enzymes of differing specificities. Effectors strictly co-occur with cognate immunity proteins, indicating that self-intoxication is a general property of antibacterial T6SSs and effector delivery by the system exerts a strong selective pressure in nature. The presence of antibacterial effectors in a plethora of organisms, including many that inhabit or infect polymicrobial niches in the human body, suggests that the system could mediate interbacterial interactions of both environmental and clinical significance. PMID:22607806

  7. Expression and Clinical Significance of Focal Adhesion Kinase in the Two Distinct Histological Types, Intestinal and Diffuse, of Human Gastric Adenocarcinoma

    Microsoft Academic Search

    Constantinos T. Giaginis; Stephanie Vgenopoulou; Gerasimos S. Tsourouflis; Ekaterini N. Politi; Gregorios P. Kouraklis; Stamatios E. Theocharis

    2009-01-01

    Focal adhesion kinase (FAK), a non-receptor tyrosine kinase protein, acts as an early modulator of integrin signaling cascade,\\u000a regulating basic cellular functions. In transformed cells, unopposed FAK signaling has been considered to promote tumor growth,\\u000a progression and metastasis. The aim of this study was to assess the clinical significance of FAK expression in the two distinct\\u000a histological types of human

  8. New Gastric Epithelial Cell Lines from Mice Transgenic for Temperature-Sensitive Simian Virus 40 Large T Antigen Show Distinct Types of Cell Differentiation

    Microsoft Academic Search

    Yoshiaki Tabuchi; Yuko Arai; Hiroki Shioya; Ryosuke Kuribayashi; Kotaro Ishibashi; Norifumi Sugiyama; Masuo Obinata; Noriaki Takeguchi; Shinji Asano

    2003-01-01

    Aim: To develop conditionally immortalized gastric mucosal cell lines that show distinct types of cell differentiation from transgenic mice harboring temperature-sensitive simian virus 40 (tsSV40) large T antigen. Methods: Gastric mucosal cells from the transgenic mice were cultured at a permissive temperature (33°C), and proliferative cells were then cloned by colony formation. Results: Eight gastric cell lines showed epithelial-like morphology

  9. ‘Snake River (SR)-type’ volcanism at the Yellowstone hotspot track: distinctive products from unusual, high-temperature silicic super-eruptions

    Microsoft Academic Search

    M. J. Branney; B. Bonnichsen; G. D. M. Andrews; B. Ellis; T. L. Barry; M. McCurry

    2008-01-01

    A new category of large-scale volcanism, here termed Snake River (SR)-type volcanism, is defined with reference to a distinctive\\u000a volcanic facies association displayed by Miocene rocks in the central Snake River Plain area of southern Idaho and northern\\u000a Nevada, USA. The facies association contrasts with those typical of silicic volcanism elsewhere and records unusual, voluminous\\u000a and particularly environmentally devastating styles

  10. Genealogical concordance between the mating type locus and seven other nuclear genes supports formal recognition of nine phylogenetically distinct species within the Fusarium graminearum cladeq

    Microsoft Academic Search

    Kerry ODonnell; Todd J. Ward; David M. Geiser; H. Corby Kistler; Takayuki Aokid

    Species limits were investigated within the Fusarium graminearum clade (Fg clade) through phylogenetic analyses of DNA sequences from portions of 11 nuclear genes including the mating-type (MAT) locus. Nine phylogenetically distinct species were resolved within the Fg clade, and they all possess contiguous MAT1-1 and MAT1-2 idiomorphs consistent with a homothallic reproductive mode. In contrast, only one of the two

  11. Clinical, pathological and antigenic aspects of bovine viral diarrhea virus (BVDV) type 2 isolates identified in Brazil

    Microsoft Academic Search

    E. F Flores; L. H. G. V Gil; S. A Botton; R Weiblen; J. F Ridpath; L. C Kreutz; C Pilati; D Driemeyer; V Moojen; A. C Wendelstein

    2000-01-01

    Nucleotide sequencing and phylogenetic analysis of Brazilian bovine viral diarrhea virus (BVDV) field isolates identified four viruses belonging to the genotype 2. Comparison of 5? UTR sequences from these isolates to those of North American BVDV type 2 revealed genomic variations that correlated with the geographic origins of the isolates. Two of the Brazilian type 2 viruses were isolated from

  12. Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus

    PubMed Central

    Pipi, Elena; Marketou, Marietta; Tsirogianni, Alexandra

    2014-01-01

    Ever since its first appearance among the multiple forms of diabetes, latent autoimmune diabetes in adults (LADA), has been the focus of endless discussions concerning mainly its existence as a special type of diabetes. In this mini-review, through browsing important peer-reviewed publications, (original articles and reviews), we will attempt to refresh our knowledge regarding LADA hoping to enhance our understanding of this controversial diabetes entity. A unique combination of immunological, clinical and metabolic characteristics has been identified in this group of patients, namely persistent islet cell antibodies, high frequency of thyroid and gastric autoimmunity, DR3 and DR4 human leukocyte antigen haplotypes, progressive loss of beta cells, adult disease onset, normal weight, defective glycaemic control, and without tendency to ketoacidosis. Although anthropomorphic measurements are useful as a first line screening, the detection of C-peptide levels and the presence of glutamic acid decarboxylase (GAD) autoantibodies is undoubtedly the sine qua non condition for a confirmatory LADA diagnosis. In point of fact, GAD autoantibodies are far from being solely a biomarker and the specific role of these autoantibodies in disease pathogenesis is still to be thoroughly studied. Nevertheless, the lack of diagnostic criteria and guidelines still puzzle the physicians, who struggle between early diagnosis and correct timing for insulin treatment. PMID:25126396

  13. The 'blue-on' opponent pathway in primate retina originates from a distinct bistratified ganglion cell type

    Microsoft Academic Search

    Dennis M. Dacey; Barry B. Lee

    1994-01-01

    COLOUR vision in humans and Old World monkeys begins with the differential activation of three types of cone photoreceptor which are maximally sensitive to short (S), medium (M) and long (L) wavelengths. Signals from the three cone types are relayed to the retinal ganglion cells via cone-specific bipolar cell types1-4. Colour-coding ganglion cells fall into two major physiological classes: the

  14. Wild type RTA and less toxic variants have distinct requirements for Png1 for their depurination activity and toxicity in Saccharomyces cerevisiae.

    PubMed

    Yan, Qing; Li, Xiao-Ping; Tumer, Nilgun E

    2014-01-01

    Ricin A chain (RTA) undergoes retrograde trafficking and is postulated to use components of the endoplasmic reticulum (ER) associated degradation (ERAD) pathway to enter the cytosol to depurinate ribosomes. However, it is not known how RTA evades degradation by the proteasome after entry into the cytosol. We observed two distinct trafficking patterns among the precursor forms of wild type RTA and nontoxic variants tagged with enhanced green fluorescent protein (EGFP) at their C-termini in yeast. One group, which included wild type RTA, underwent ER-to-vacuole transport, while another group, which included the G83D variant, formed aggregates in the ER and was not transported to the vacuole. Peptide: N-glycanase (Png1), which catalyzes degradation of unfolded glycoproteins in the ERAD pathway affected depurination activity and toxicity of wild type RTA and G83D variant differently. PreG83D variant was deglycosylated by Png1 on the ER membrane, which reduced its depurination activity and toxicity by promoting its degradation. In contrast, wild type preRTA was deglycosylated by the free pool of Png1 in the cytosol, which increased its depurination activity, possibly by preventing its degradation. These results indicate that wild type RTA has a distinct requirement for Png1 compared to the G83D variant and is deglycosylated by Png1 in the cytosol as a possible strategy to avoid degradation by the ERAD pathway to reach the ribosome. PMID:25436896

  15. Wild Type RTA and Less Toxic Variants Have Distinct Requirements for Png1 for Their Depurination Activity and Toxicity in Saccharomyces cerevisiae

    PubMed Central

    Yan, Qing; Li, Xiao-Ping; Tumer, Nilgun E.

    2014-01-01

    Ricin A chain (RTA) undergoes retrograde trafficking and is postulated to use components of the endoplasmic reticulum (ER) associated degradation (ERAD) pathway to enter the cytosol to depurinate ribosomes. However, it is not known how RTA evades degradation by the proteasome after entry into the cytosol. We observed two distinct trafficking patterns among the precursor forms of wild type RTA and nontoxic variants tagged with enhanced green fluorescent protein (EGFP) at their C-termini in yeast. One group, which included wild type RTA, underwent ER-to-vacuole transport, while another group, which included the G83D variant, formed aggregates in the ER and was not transported to the vacuole. Peptide: N-glycanase (Png1), which catalyzes degradation of unfolded glycoproteins in the ERAD pathway affected depurination activity and toxicity of wild type RTA and G83D variant differently. PreG83D variant was deglycosylated by Png1 on the ER membrane, which reduced its depurination activity and toxicity by promoting its degradation. In contrast, wild type preRTA was deglycosylated by the free pool of Png1 in the cytosol, which increased its depurination activity, possibly by preventing its degradation. These results indicate that wild type RTA has a distinct requirement for Png1 compared to the G83D variant and is deglycosylated by Png1 in the cytosol as a possible strategy to avoid degradation by the ERAD pathway to reach the ribosome. PMID:25436896

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

    Microsoft Academic Search

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

    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

  17. Identifying Faculty Types Using Peer Ratings of Teaching, Research, and Service.

    ERIC Educational Resources Information Center

    Kremer, John

    1991-01-01

    A study classified 90 full-time tenure-track faculty in 1 university into 5 discrete types based on teaching, research, and service. Types include all-stars, teachers and good citizens, researchers, teachers, and uninvolved. This mix of types is seen as resulting from past administrative decisions and helps shape future decisions. (Author/MSE)

  18. NEW POLLEN-SPECIFIC RECEPTOR KINASES IDENTIFIED IN TOMATO, MAIZE AND ARABIDOPSIS: THE TOMATO KINASES SHOW OVERLAPPING BUT DISTINCT LOCALIZATOIN PATTERNS ON POLLEN TUBES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We previously characterized LePRKl and LePRK2, pollen-specific receptor kinases from tomato (Mushietti et al., 1998). Here we identify a similar receptor kinase from maize, ZmPRKl, that is also specifically expressed late in pollen development, and a third pollen receptor kinase from tomato, LePRK3...

  19. KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype

    E-print Network

    Clipson, Alexandra; Wang, Ming; de Leval, Laurence; Ashton-Key, Margaret; Wotherspoon, Andrew; Vassiliou, George; Bolli, Niccolo; Grove, Carolyn; Moody, Sarah; Ibarz, Leire Escudero; Gundem, Gunes; Brugger, Kim; Xue, Xuemin; Mi, Ella; Bench, Anthony; Scott, Mike; Liu, Hongxiang; Follows, George; Robles, Eloy F.; Climent, Jose Angel Martinez; Oscier, David; Watkins, A. James; Du, Ming-Qing

    2014-11-27

    sequencing identifies 488 frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 2011; 469: 489 539-542. 490 22 Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC et al. The landscape of 491 cancer genes...

  20. Two novel mutations identified in a type 3 von Willebrand disease patient.

    PubMed

    Ouyang, Wanyan; Yu, Ziqiang; Yin, Jie; Su, Jian; Yang, Chunchen; Ruan, Changgeng

    2014-12-01

    von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans. Caused by mutations in the von Willebrand factor (VWF) gene, these defects result in qualitatively abnormal variants of VWF (classified as type 2 VWD) or a decrease in VWF levels (types 1 and 3 VWD). Type 3 VWD is the most severe type and usually presented with undetectable VWF level. In this report, we describe a type 3 VWD patient. Molecular analysis of the whole VWF gene reveals two novel mutations, c.2480G>A (p.C827Y) in exon 19 and c.3897delT in exon 28. PMID:24914743

  1. Gene Expression Profile of Adult T Cell Acute Lymphocytic Leukemia Identifies Distinct Subsets of Patients with Different Response to Therapy and Survival

    Microsoft Academic Search

    Sabina Chiaretti; Xiaochun Li; Robert Gentleman; Antonella Vitale; Marco Vignetti; Franco Mandelli; Jerome Ritz; Robin Foa

    2010-01-01

    Gene expression profiles were examined in 33 adult patients with T-cell acute lym- phocytic leukemia (T-ALL). Nonspecific filtering criteria identified 313 genes differ- entially expressed in the leukemic cells. Hierarchical clustering of samples identi- fied 2 groups that reflected the degree of T-cell differentiation but was not associ- ated with clinical outcome. Comparison between refractory patients and those who responded

  2. Spatial Relationships between GABAergic and Glutamatergic Synapses on the Dendrites of Distinct Types of Mouse Retinal Ganglion Cells across Development

    PubMed Central

    Bleckert, Adam; Parker, Edward D.; Kang, YunHee; Pancaroglu, Raika; Soto, Florentina; Lewis, Renate; Craig, Ann Marie; Wong, Rachel O. L.

    2013-01-01

    Neuronal output requires a concerted balance between excitatory and inhibitory (I/E) input. Like other circuits, inhibitory synaptogenesis in the retina precedes excitatory synaptogenesis. How then do neurons attain their mature balance of I/E ratios despite temporal offset in synaptogenesis? To directly compare the development of glutamatergic and GABAergic synapses onto the same cell, we biolistically transfected retinal ganglion cells (RGCs) with PSD95CFP, a marker of glutamatergic postsynaptic sites, in transgenic Thy1­YFP?2 mice in which GABAA receptors are fluorescently tagged. We mapped YFP?2 and PSD95CFP puncta distributions on three RGC types at postnatal day P12, shortly before eye opening, and at P21 when robust light responses in RGCs are present. The mature IGABA/E ratios varied among ON-Sustained (S) A-type, OFF-S A-type, and bistratified direction selective (DS) RGCs. These ratios were attained at different rates, before eye-opening for ON-S and OFF-S A-type, and after eye-opening for DS RGCs. At both ages examined, the IGABA/E ratio was uniform across the arbors of the three RGC types. Furthermore, measurements of the distances between neighboring PSD95CFP and YFP?2 puncta on RGC dendrites indicate that their local relationship is established early in development, and cannot be predicted by random organization. These close spatial associations between glutamatergic and GABAergic postsynaptic sites appear to represent local synaptic arrangements revealed by correlative light and EM reconstructions of a single RGC's dendrites. Thus, although RGC types have different IGABA/E ratios and establish these ratios at separate rates, the local relationship between excitatory and inhibitory inputs appear similarly constrained across the RGC types studied. PMID:23922756

  3. A Systems Biology Approach Identifies a R2R3 MYB Gene Subfamily with Distinct and Overlapping Functions in Regulation of Aliphatic Glucosinolates

    PubMed Central

    Bjarnholt, Nanna; Ticconi, Carla; Halkier, Barbara Ann; Kliebenstein, Daniel J.

    2007-01-01

    Background Glucosinolates are natural metabolites in the order Brassicales that defend plants against both herbivores and pathogens and can attract specialized insects. Knowledge about the genes controlling glucosinolate regulation is limited. Here, we identify three R2R3 MYB transcription factors regulating aliphatic glucosinolate biosynthesis in Arabidopsis by combining several systems biology tools. Methodology/Principal Findings MYB28 was identified as a candidate regulator of aliphatic glucosinolates based on its co-localization within a genomic region controlling variation both in aliphatic glucosinolate content (metabolite QTL) and in transcript level for genes involved in the biosynthesis of aliphatic glucosinolates (expression QTL), as well as its co-expression with genes in aliphatic glucosinolate biosynthesis. A phylogenetic analysis with the R2R3 motif of MYB28 showed that it and two homologues, MYB29 and MYB76, were members of an Arabidopsis-specific clade that included three characterized regulators of indole glucosinolates. Over-expression of the individual MYB genes showed that they all had the capacity to increase the production of aliphatic glucosinolates in leaves and seeds and induce gene expression of aliphatic biosynthetic genes within leaves. Analysis of leaves and seeds of single knockout mutants showed that mutants of MYB29 and MYB76 have reductions in only short-chained aliphatic glucosinolates whereas a mutant in MYB28 has reductions in both short- and long-chained aliphatic glucosinolates. Furthermore, analysis of a double knockout in MYB28 and MYB29 identified an emergent property of the system since the absence of aliphatic glucosinolates in these plants could not be predicted by the chemotype of the single knockouts. Conclusions/Significance It seems that these cruciferous-specific MYB regulatory genes have evolved both overlapping and specific regulatory capacities. This provides a unique system within which to study the evolution of MYB regulatory factors and their downstream targets. PMID:18094747

  4. Two phenotypically distinct T cells are involved in ultraviolet-irradiated urocanic acid-induced suppression of the efferent delayed-type hypersensitivity response to herpes simplex virus, type 1 in vivo

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.

    1987-09-01

    When UVB-irradiated urocanic acid, the putative photoreceptor/mediator for UVB suppression, is administered to mice it induces a dose-dependent suppression of the delayed-type hypersensitivity response to herpes simplex virus, type 1 (HSV-1), of similar magnitude to that induced by UV irradiation of mice. In this study, the efferent suppression of delayed-type hypersensitivity by UV-irradiated urocanic acid is demonstrated to be due to 2 phenotypically distinct T cells, (Thy1+, L3T4-, Ly2+) and (Thy1+, L3T4+, Ly2-). The suppression is specific for HSV-1. This situation parallels the generation of 2 distinct T-suppressor cells for HSV-1 by UV irradiation of mice and provides further evidence for the involvement of urocanic acid in the generation of UVB suppression.

  5. Investigation of the population structure of Mycobacterium abscessus complex strains using 17-locus variable number tandem repeat typing and the further distinction of Mycobacterium massiliense hsp65 genotypes.

    PubMed

    Yoshida, Shiomi; Arikawa, Kentaro; Tsuyuguchi, Kazunari; Kurashima, Atsuyuki; Harada, Toshiyuki; Nagai, Hideaki; Suzuki, Katsuhiro; Iwamoto, Tomotada; Hayashi, Seiji

    2015-03-01

    Mycobacterium abscessus complex is a significant pathogen in patients with non-cystic fibrosis (non-CF). Nevertheless, there is little description of the genetic diversity of this species. The aims of this study were to investigate the distribution of M. abscessus complex isolated from respiratory specimens by variable number tandem repeat (VNTR) typing. The results of 104 clinical isolates from 104 non-CF patients were compared using PFGE, hsp65 genotypes and clarithromycin susceptibility. The allelic diversity (Hunter-Gaston Discriminatory Index) of the 17 loci examined by VNTR typing was high (0.977). We determined that C28 sequevar erm(41) genotypes and clarithromycin-acquired resistance isolates were scattered in the minimum spanning tree. Intriguingly, VNTR typing and PFGE were highly congruent and revealed that there were clear examples of grouping of isolates from different individuals amongst both M. abscessus and M. massiliense, and showed five clusters of distinct identical isolates. Within these clusters, M. massiliense hsp65 type I formed three different clusters. Although the distribution of M. massiliense hsp65 type II-1 was low (9.3?%), M. massiliense hsp65 type II-1 isolates separated from clusters contained hsp65 type I isolates. Thus, M. massiliense hsp65 genotypes could be discriminated by analysing VNTRs with sufficient genetic distance for intra-species-level discrimination. PMID:25596119

  6. The type of species of Apiognomonia, Apiognomonia veneta, with its Discula anamorph is distinct from Apiognomonia errabunda

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Species of Apiognomonia and their Discula anamorphic states in the Gnomoniaceae, Diaporthales, are known throughout the temperate northern hemisphere and cause diseases such as sycamore anthracnose. The genus Apiognomonia was described based on A. veneta as the type species; however, there has been...

  7. Distinct axonal projections from two types of olfactory receptor neurons in the middle chamber epithelium of Xenopus laevis.

    PubMed

    Nakamuta, Shoko; Nakamuta, Nobuaki; Taniguchi, Kazuyuki

    2011-10-01

    Most vertebrates have two olfactory organs, the olfactory epithelium (OE) and the vomeronasal organ. African clawed frog, Xenopus laevis, which spends their entire life in water, have three types of olfactory sensory epithelia: the OE, the middle chamber epithelium (MCE) and the vomeronasal epithelium (VNE). The axons from these epithelia project to the dorsal part of the main olfactory bulb (d-MOB), the ventral part of the MOB (v-MOB) and the accessory olfactory bulb, respectively. In the MCE, which is thought to function in water, two types of receptor neurons (RNs) are intermingled and express one of two types of G-proteins, Golf and Go, respectively. However, axonal projections from these RNs to the v-MOB are not fully understood. In this study, we examined the expression of G-proteins by immunohistochemistry to reveal the projection pattern of olfactory RNs of Xenopus laevis, especially those in the MCE. The somata of Golf- and Go-positive RNs were separately situated in the upper and lower layers of the MCE. The former were equipped with cilia and the latter with microvilli on their apical surface. These RNs are suggested to project to the rostromedial and the caudolateral regions of the v-MOB, respectively. Such segregation patterns observed in the MCE and v-MOB are also present in the OE and olfactory bulbs of most bony fish. Thus, Xenopus laevis is a very interesting model to understand the evolution of vertebrate olfactory systems because they have a primitive, fish-type olfactory system in addition to the mammalian-type olfactory system. PMID:21938396

  8. An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features of tamoxifen resistant breast tumors.

    PubMed

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers. PMID:21789246

  9. PKscan: a program to identify H-type RNA pseudoknots in any RNA sequence with unlimited length

    PubMed Central

    Huang, Xiaolan; Du, Zhihua; Cheng, Jie; Cheng, Qiang

    2013-01-01

    A computer program written in C++ has been developed which can detect all potential H-type RNA pseudoknots within any given RNA sequence. There is no limit on the length of the input sequence. A validation run of the program using the full-length (8173 nt) genomic mRNA of simian retrovirus type-1 (SRV-1) identifies the established -1 frameshift stimulating pseudokont at the gagpro junction as the most stable pseudoknot within the genomic mRNA. PMID:23847396

  10. Identifying and mapping cell-type-specific chromatin programming of gene expression

    PubMed Central

    Marstrand, Troels T.; Storey, John D.

    2014-01-01

    A problem of substantial interest is to systematically map variation in chromatin structure to gene-expression regulation across conditions, environments, or differentiated cell types. We developed and applied a quantitative framework for determining the existence, strength, and type of relationship between high-resolution chromatin structure in terms of DNaseI hypersensitivity and genome-wide gene-expression levels in 20 diverse human cell types. We show that ?25% of genes show cell-type-specific expression explained by alterations in chromatin structure. We find that distal regions of chromatin structure (e.g., ±200 kb) capture more genes with this relationship than local regions (e.g., ±2.5 kb), yet the local regions show a more pronounced effect. By exploiting variation across cell types, we were capable of pinpointing the most likely hypersensitive sites related to cell-type-specific expression, which we show have a range of contextual uses. This quantitative framework is likely applicable to other settings aimed at relating continuous genomic measurements to gene-expression variation. PMID:24469817

  11. Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection

    PubMed Central

    Elsner, Rebecca A.; Ernst, David N.

    2012-01-01

    Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (TFH) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of TFH subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (TGC) as lymph node-resident CD4+ ICOS+ CXCR4+ CXCR5+ PSGL-1lo PD-1hi cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only TFH subsets missing in influenza virus-infected, germinal center-deficient SAP?/? mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as “extrafollicular” helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS+ subsets induced similar antibody levels in vitro, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of TFH function. PMID:22532671

  12. Proteome and metabolome profiling of cytokinin action in Arabidopsis identifying both distinct and similar responses to cytokinin down- and up-regulation

    PubMed Central

    Hoehenwarter, Wolfgang; Brzobohatý, B?etislav

    2013-01-01

    In plants, numerous developmental processes are controlled by cytokinin (CK) levels and their ratios to levels of other hormones. While molecular mechanisms underlying the regulatory roles of CKs have been intensely researched, proteomic and metabolomic responses to CK deficiency are unknown. Transgenic Arabidopsis seedlings carrying inducible barley cytokinin oxidase/dehydrogenase (CaMV35S>GR>HvCKX2) and agrobacterial isopentenyl transferase (CaMV35S>GR>ipt) constructs were profiled to elucidate proteome- and metabolome-wide responses to down- and up-regulation of CK levels, respectively. Proteome profiling identified >1100 proteins, 155 of which responded to HvCKX2 and/or ipt activation, mostly involved in growth, development, and/or hormone and light signalling. The metabolome profiling covered 79 metabolites, 33 of which responded to HvCKX2 and/or ipt activation, mostly amino acids, carbohydrates, and organic acids. Comparison of the data sets obtained from activated CaMV35S>GR>HvCKX2 and CaMV35S>GR>ipt plants revealed unexpectedly extensive overlaps. Integration of the proteomic and metabolomic data sets revealed: (i) novel components of molecular circuits involved in CK action (e.g. ribosomal proteins); (ii) previously unrecognized links to redox regulation and stress hormone signalling networks; and (iii) CK content markers. The striking overlaps in profiles observed in CK-deficient and CK-overproducing seedlings might explain surprising previously reported similarities between plants with down- and up-regulated CK levels. PMID:24064926

  13. Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors

    PubMed Central

    Cho, Kyoung-in; Yu, Minzhong; Hao, Ying; Qiu, Sunny; Pillai, Indulekha C. L.; Peachey, Neal S.; Ferreira, Paulo A.

    2013-01-01

    Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+-apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders. PMID:23818861

  14. Differential Expression Profiling of Spleen MicroRNAs in Response to Two Distinct Type II Interferons in Tetraodon nigroviridis

    PubMed Central

    Peng, Wan; Wang, Ting; Zhang, Yong; Lin, Haoran

    2014-01-01

    MicroRNAs are endogenous, small non-coding RNAs approximately 18–26 nucleotides in length that regulate target gene expression at the post-transcription level. Interferon-? (IFN-?) is a Th1 cytokine that is involved in both the innate and adaptive immune responses. We previously identified two IFN-? genes in green-spotted puffer fish (Tetraodon nigroviridis). To determine whether miRNAs participate in IFN-?-related immune responses, T. nigroviridis spleen cells were treated with recombinant IFN-? isoforms, and a Solexa high-throughput sequencing method was used to identify miRNAs. In total, 1,556, 1,538 and 1,573 miRNAs were found in the three samples, and differentially expressed miRNAs were determined. In total, 398 miRNAs were differentially expressed after rIFN-?1 treatment, and 438 miRNAs were differentially expressed after rIFN-?2 treatment; additionally, 403 miRNAs were differentially expressed between the treatment groups. Ten differentially expressed miRNAs were chosen for validation using qRT-PCR. Target genes for the differentially expressed miRNAs were predicted, and GO and KEGG analyses were performed. This study provides basic knowledge regarding fish IFN-?-induced miRNAs and offers clues for further studies into the mechanisms underlying fish IFN-?-mediated immune responses. PMID:24800866

  15. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes.

    PubMed

    Zoja, Carla; Cattaneo, Sara; Fiordaliso, Fabio; Lionetti, Vincenzo; Zambelli, Vanessa; Salio, Monica; Corna, Daniela; Pagani, Chiara; Rottoli, Daniela; Bisighini, Cinzia; Remuzzi, Giuseppe; Benigni, Ariela

    2011-11-01

    Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF. PMID:21816757

  16. Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers

    PubMed Central

    Fadare, Oluwole; Zheng, Wenxin

    2008-01-01

    In this article, the authors briefly review the historical evolution of the various putative precursor lesions for Type II endometrial cancers, with an emphasis on the newly defined "Endometrial Glandular Dysplasia (EmGD)". The evidentiary basis for delineating serous EmGD as the most probable precursor lesions to endometrial serous carcinoma is reviewed in detail. An argument is advanced for the discontinuation of the term serous "endometrial intraepithelial carcinoma (EIC)" as a descriptor for a supposedly intraepithelial, precancerous lesion. Preliminary evidence is also presented that suggests that there is a morphologically recognizable "clear cell EmGD" that probably represents a precancerous lesion to endometrial clear cell carcinomas. PMID:18261213

  17. A GIS APPROACH TO IDENTIFY AND CLASSIFY HYDROGEOMORPHIC TYPES OF COASTAL WETLANDS

    EPA Science Inventory

    Description of the georeferenced digital database produced by the U.S. EPA/MED along with the U.S. FWS for a R-EMAP project funded by EPA/ORD for Region 5 that produced an inventory of the coastal wetlands of the Great Lakes was described. The process used to identify and classif...

  18. Galleria mellonella Model Identifies Highly Virulent Strains among All Major Molecular Types of Cryptococcus gattii

    PubMed Central

    Firacative, Carolina; Duan, Shuyao; Meyer, Wieland

    2014-01-01

    Cryptococcosis is mainly caused by Cryptococcus neoformans. However, the number of cases due to C. gattii is increasing, affecting mainly immunocompetent hosts. C. gattii is divided into four major molecular types, VGI to VGIV, which differ in their host range, epidemiology, antifungal susceptibility and geographic distribution. Besides studies on the Vancouver Island outbreak strains, which showed that the subtype VGIIa is highly virulent compared to the subtype VGIIb, little is known about the virulence of the other major molecular types. To elucidate the virulence potential of the major molecular types of C. gattii, Galleria mellonella larvae were inoculated with ten globally selected strains per molecular type. Survival rates were recorded and known virulence factors were studied. One VGII, one VGIII and one VGIV strain were more virulent (p <0.05) than the highly virulent Vancouver Island outbreak strain VGIIa (CDCR265), 11 (four VGI, two VGII, four VGIII and one VGIV) had similar virulence (p >0.05), 21 (five VGI, five VGII, four VGIII and seven VGIV) were less virulent (p <0.05) while one strain of each molecular type were avirulent. Cell and capsule size of all strains increased markedly during larvae infection (p <0.001). No differences in growth rate at 37°C were observed. Melanin synthesis was directly related with the level of virulence: more virulent strains produced more melanin than less virulent strains (p <0.05). The results indicate that all C. gattii major molecular types exhibit a range of virulence, with some strains having the potential to be more virulent. The study highlights the necessity to further investigate the genetic background of more and less virulent strains in order to recognize critical features, other than the known virulence factors (capsule, melanin and growth at mammalian body temperature), that maybe crucial for the development and progression of cryptococcosis. PMID:25133687

  19. Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A.

    PubMed

    Serrill, Jeffrey D; Tan, Michelle; Fotso, Serge; Sikorska, Justyna; Kasanah, Noer; Hau, Andrew M; McPhail, Kerry L; Santosa, Dwi Andreas; Zabriskie, T Mark; Mahmud, Taifo; Viollet, Benoit; Proteau, Philip J; Ishmael, Jane E

    2015-02-01

    Apoptolidin A was first isolated as a secondary metabolite of a Nocardiopsis sp. and is the founding member of a family of potential selective cancer cell toxins. We now report the isolation, production and pharmacological characterization of apoptolidins A and C from an alternate actinomycete producer, an Amycolatopsis sp. from soil samples collected in Indonesia. We investigated the action of apoptolidins A and C in representative human glioblastoma cells, lung cancer cells and mouse embryonic fibroblasts (MEFs) to better understand the mechanism of action of the known apoptolidins. Shifts in cellular metabolism in intact cells and the status of the AMP-activated protein kinase (AMPK) stress pathway in response to apoptolidin A were entirely consistent with the actions of an ATP synthase inhibitor. We find the metabolic phenotype of the cell to be a critical determinant of apoptolidin sensitivity and the likely basis for cancer cell selectivity. The apoptolidins induce indirect activation of AMPK and trigger autophagy in sensitive cell types without significant inhibition of mTORC1. Human U87-MG glioblastoma cells and wild type MEFs showed increased phosphorylation of AMPK (Thr172), ACC (Ser79) and ULK1 (Ser555), whereas AMPK?-null MEFs and more glycolytic SF-295 glioblastoma cells lacked this response. Although both are reported to be selective inhibitors of mitochondrial ATP synthase, differences between apoptolidin- and oligomycin A-induced responses in cells indicate that the action of these macrolides is not identical. PMID:25511868

  20. A new point mutation in the ND1 mitochondrial gene identified in a type II diabetic patient

    SciTech Connect

    Kalinin, V.N. [Research Center of Medical Genetics, Moscow (Russian Federation); Schmidt, W.; Olek, K. [Institut fuer Molekularbiologische Diagnostik, Bonn (Germany)] [and others

    1995-08-01

    A novel mutation in a mitochondrial gene was identified in a patient with type II diabetes mellitus. G-to-A transition was localized at the nt3316 position of gene ND1 and resulted in alanine threonine replacement at position 4 of mitochondrial NAD-H-dehydrogenase. 6 refs., 2 figs.

  1. A-type and B-type lamins initiate layer assembly at distinct areas of the nuclear envelope in living cells

    SciTech Connect

    Furukawa, Kazuhiro, E-mail: furukawa@chem.sc.niigata-u.ac.jp [Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181 (Japan)] [Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181 (Japan); Ishida, Kazuya; Tsunoyama, Taka-aki; Toda, Suguru; Osoda, Shinichi; Horigome, Tsuneyoshi [Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181 (Japan)] [Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181 (Japan); Fisher, Paul A. [Department of Pharmacological Sciences, School of Medicine, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651 (United States)] [Department of Pharmacological Sciences, School of Medicine, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651 (United States); Sugiyama, Shin [Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602 (Japan)] [Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602 (Japan)

    2009-04-15

    To investigate nuclear lamina re-assembly in vivo, Drosophila A-type and B-type lamins were artificially expressed in Drosophila lamin Dm{sub 0}null mutant brain cells. Both exogenous lamin C (A-type) and Dm{sub 0} (B-type) formed sub-layers at the nuclear periphery, and efficiently reverted the abnormal clustering of the NPC. Lamin C initially appeared where NPCs were clustered, and subsequently extended along the nuclear periphery accompanied by the recovery of the regular distribution of NPCs. In contrast, lamin Dm{sub 0} did not show association with the clustered NPCs during lamina formation and NPC spacing recovered only after completion of a closed lamin Dm{sub 0} layer. Further, when lamin Dm{sub 0} and C were both expressed, they did not co-polymerize, initiating layer formation in separate regions. Thus, A and B-type lamins reveal differing properties during lamina assembly, with A-type having the primary role in organizing NPC distribution. This previously unknown complexity in the assembly of the nuclear lamina could be the basis for intricate nuclear envelope functions.

  2. A support vector machine to identify irrigated crop types using time-series Landsat NDVI data

    NASA Astrophysics Data System (ADS)

    Zheng, Baojuan; Myint, Soe W.; Thenkabail, Prasad S.; Aggarwal, Rimjhim M.

    2015-02-01

    Site-specific information of crop types is required for many agro-environmental assessments. The study investigated the potential of support vector machines (SVMs) in discriminating various crop types in a complex cropping system in the Phoenix Active Management Area. We applied SVMs to Landsat time-series Normalized Difference Vegetation Index (NDVI) data using training datasets selected by two different approaches: stratified random approach and intelligent selection approach using local knowledge. The SVM models effectively classified nine major crop types with overall accuracies of >86% for both training datasets. Our results showed that the intelligent selection approach was able to reduce the training set size and achieved higher overall classification accuracy than the stratified random approach. The intelligent selection approach is particularly useful when the availability of reference data is limited and unbalanced among different classes. The study demonstrated the potential of utilizing multi-temporal Landsat imagery to systematically monitor crop types and cropping patterns over time in arid and semi-arid regions.

  3. Single nucleotide polymorphisms in the interferon gamma gene are associated with distinct types of retinochoroidal scar lesions presumably caused by Toxoplasma gondii infection

    PubMed Central

    Peixe, Ricardo Guerra; Boechat, Marcela Santana Bastos; Rangel, Alba Lucinia Peixoto; Rosa, Rhônia França Gomes; Petzl-Erler, Maria Luiza; Bahia-Oliveira, Lilian MG

    2013-01-01

    The association of single nucleotide polymorphisms (SNPs) in the interferon (IFN)-? gene ( IFNG ) with different types of retinal scar lesions presumably caused by toxoplasmosis were investigated in a cross-sectional population-based genetic study. Ten SNPs were investigated and after Bonferroni correction, only the associations between SNPs rs2069718 and rs3181035 with retinal/retinochoroidal scar lesions type A (most severe scar lesions) and C (least severe scar lesions), respectively, remained significant. The associations of two different IFNG SNPs with two different types of retinal lesions attributable to toxoplasmosis support the hypothesis that different inflammatory mechanisms underlie the development of these lesions. The in vitro analysis of IFN-? secretion by peripheral blood mononuclear cells stimulated with Toxoplasma gondii antigens was also investigated. The association between SNP rs2069718 and type A scar lesions revealed that differential IFN-? levels are correlated with distinct genotypes. However, no correlation was observed with IFN-? secretion levels and the SNP rs3181035 , which was significantly associated with type C scar lesions. Our findings strongly suggest that immunogenetic studies of individuals with congenital or postnatally acquired infection are needed to better understand the role of IFN-? and its polymorphisms in the pathogenesis of ocular toxoplasmosis. PMID:24626309

  4. Distinct Hydration Properties of Wild-Type and Familial Point Mutant A53T of ?-Synuclein Associated with Parkinson's Disease

    PubMed Central

    Hazy, E.; Bokor, M.; Kalmar, L.; Gelencser, A.; Kamasa, P.; Han, K.-H.; Tompa, K.; Tompa, P.

    2011-01-01

    The propensity of ?-synuclein to form amyloid plays an important role in Parkinson's disease. Three familial mutations, A30P, E46K, and A53T, correlate with Parkinson's disease. Therefore, unraveling the structural effects of these mutations has basic implications in understanding the molecular basis of the disease. Here, we address this issue through comparing details of the hydration of wild-type ?-synuclein and its A53T mutant by a combination of wide-line NMR, differential scanning calorimetry, and molecular dynamics simulations. All three approaches suggest a hydrate shell compatible with a largely disordered state of both proteins. Its fine details, however, are different, with the mutant displaying a somewhat higher level of hydration, suggesting a bias to more open structures, favorable for protein-protein interactions leading to amyloid formation. These differences disappear in the amyloid state, suggesting basically the same surface topology, irrespective of the initial monomeric state. PMID:22067166

  5. Clinical next generation sequencing of pediatric-type malignancies in adult patients identifies novel somatic aberrations

    PubMed Central

    Silva, Jorge Galvez; Corrales-Medina, Fernando F.; Maher, Ossama M.; Tannir, Nizar; Huh, Winston W.; Rytting, Michael E.; Subbiah, Vivek

    2015-01-01

    Pediatric malignancies in adults, in contrast to the same diseases in children are clinically more aggressive, resistant to chemotherapeutics, and carry a higher risk of relapse. Molecular profiling of tumor sample using next generation sequencing (NGS) has recently become clinically available. We report the results of targeted exome sequencing of six adult patients with pediatric-type malignancies : Wilms tumor(n=2), medulloblastoma(n=2), Ewing's sarcoma( n=1) and desmoplastic small round cell tumor (n=1) with a median age of 28.8 years. Detection of druggable somatic aberrations in tumors is feasible. However, identification of actionable target therapies in these rare adult patients with pediatric-type malignancies is challenging. Continuous efforts to establish a rare disease registry are warranted.

  6. Variants of Human Papillomavirus Types 53, 58 and 66 Identified in Central Brazil

    Microsoft Academic Search

    Daniela Marreco Cerqueira; GeniNoceti de Lima Camara; Márcio Rojas da Cruz; Evandro Oliveira Silva; Marcelo de Macedo BrÍgido; LucianoGonçalves de Souza Carvalho; Cláudia Renata Fernandes Martins

    2003-01-01

    The present study on molecular characterization of human papillomaviruses occurring in Central Brazil, describes two variants each of HPV-53 and HPV-58 and one variant of HPV-66 detected in samples from smears of women showing cervical intraepithelial neoplasia grade II (CIN II). Samples were assayed by PCR using MY09\\/MY11 consensus primers, followed by restriction fragment length polymorphism typing. The five isolates

  7. A genome-wide association study identifies novel risk loci for type 2 diabetes

    Microsoft Academic Search

    Robert Sladek; Ghislain Rocheleau; Johan Rung; Christian Dina; Lishuang Shen; David Serre; Philippe Boutin; Daniel Vincent; Alexandre Belisle; Samy Hadjadj; Beverley Balkau; Barbara Heude; Guillaume Charpentier; Thomas J. Hudson; Alexandre Montpetit; Alexey V. Pshezhetsky; Marc Prentki; Barry I. Posner; David J. Balding; David Meyre; Constantin Polychronakos; Philippe Froguel

    2007-01-01

    Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers

  8. Identifying the types of waves: A value adding study on the ocean observing data buoy system

    NASA Astrophysics Data System (ADS)

    Ramakrishnan, B.; Sannasiraj, S.; Sundar, V.

    2007-05-01

    Understanding of the wave climate in a particular place of interest is one of the primary aspects of any ocean observing system. Engineers and scientists working in the area of coastal or offshore engineering require to have knowledge on the types of waves that predominantly prevailing not only for the design of the ocean structures but also to understand the physical behavior of ocean surface. For example, identification of breaking waves is given prime importance as it has potential to answer for many of the water-air interaction or turbulence mixing problems. On the other hand, group of waves in which successive wave heights exceed the significant value could exert tremendous forces on the ocean structures and may lead catastrophic damage to it. Apart from deriving the conventional information such as the significant wave periods, heights and the predominant direction of prevailing, knowledge on the existence of type of waves would certainly help the designers, engineers and researchers. In an attempt to classify the types of waves from the buoy measurements, a detailed experimental program was conducted in the Department of Ocean Engineering, Indian Institute of Technology Madras. The buoy model was subjected to variety of waves such as group and breaking waves. The challenging task of the study is to simulate the group and breaking waves in the controlled laboratory environment. For which, initially, these waves are simulated theoretically, which intern converted into first order wave paddle signals to simulate the waves in the flume. The buoy heave, surge and pitch motions were measured by using potentiometers and the non-contact motion capturing cameras. The experimentally obtained wave elevation and the buoy motions time histories were analyzed by statistical, continuous wavelet transformation and phase-time methods to find the traces of wave types. A careful step by step analysis of the buoy motions yields presence of wave groupiness and breaking events. The details of the model, instrumentation, testing conditions and the analysis are presented and discussed in this paper.

  9. Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior

    PubMed Central

    Nakamura, Toru; Sato, Asako; Kitsukawa, Takashi; Momiyama, Toshihiko; Yamamori, Tetsuo; Sasaoka, Toshikuni

    2014-01-01

    Both D1R and D2R knock out (KO) mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT) mice. First, we examined spontaneous motor activity in the home cage environment for consecutive 5 days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT and mutant mice. PMID:25076876

  10. Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients.

    PubMed

    Nitta, Hirohisa; Unoki, Motoko; Ichiyanagi, Kenji; Kosho, Tomoki; Shigemura, Tomonari; Takahashi, Hiroshi; Velasco, Guillaume; Francastel, Claire; Picard, Capucine; Kubota, Takeo; Sasaki, Hiroyuki

    2013-07-01

    Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that shows DNA hypomethylation at pericentromeric satellite-2 and -3 repeats in chromosomes 1, 9 and 16. ICF syndrome is classified into two groups: type 1 (ICF1) patients have mutations in the DNMT3B gene and about half of type 2 (ICF2) patients have mutations in the ZBTB24 gene. Besides satellite-2 and -3 repeats, ?-satellite repeats are also hypomethylated in ICF2. In this study, we report three novel ZBTB24 mutations in ICF2. A Japanese patient was homozygous for a missense mutation (C383Y), and a Cape Verdean patient was compound heterozygous for a nonsense mutation (K263X) and a frame-shift mutation (C327W fsX54). In addition, the second Japanese patient was homozygous for a previously reported nonsense mutation (R320X). The C383Y mutation abolished a C2H2 motif in one of the eight zinc-finger domains, and the other three mutations caused a complete or large loss of the zinc-finger domains. Our immunofluorescence analysis revealed that mouse Zbtb24 proteins possessing a mutation corresponding to either C383Y or R320X are mislocalized from pericentrometic heterochromatin, suggesting the importance of the zinc-finger domains in proper intranuclear localization of this protein. We further revealed that the proper localization of wild-type Zbtb24 protein does not require DNA methylation. PMID:23739126

  11. Human antibodies react with an epitope of the human papillomavirus type 6b L1 open reading frame which is distinct from the type-common epitope.

    PubMed Central

    Jenison, S A; Yu, X P; Valentine, J M; Galloway, D A

    1989-01-01

    Recombinant proteins encoded by the human papillomavirus type 6b (HPV6b) L1 open reading frame react with sera from patients with condylomata acuminata and also react with rabbit antiserum raised against sodium dodecyl sulfate-disrupted bovine papillomavirus type 1 (BPV1) virions. To map the immunoreactive epitopes, a series of procaryotic expression plasmids was made which contained a nested set of 3' to 5' deletions in the HPV6b L1 open reading frame. The deleted plasmids expressed a set of carboxy to amino terminus truncated fusion proteins. Regions containing the immunoreactive epitopes were mapped by determining which of the deleted fusion proteins retained reactivity with sera in Western immunoblot assays. The coding sequence for a human antibody-reactive linear epitope mapped between HPV6b nucleotide coordinates 7045 and 7087, and the rabbit anti-BPV1-reactive epitope coding sequence mapped between coordinates 6377 and 6454. Synthetic peptides derived from the epitope mapping were reacted with sera in enzyme-linked immunosorbent assay. Human sera reacted with synthetic peptide QSQAITCQKPTPEKEKPDPYK (HPV6b L1 amino acids 417 through 437). Rabbit anti-BPV1 and rabbit antisera raised against HPV16 L1 recombinant proteins reacted with the synthetic peptide DGDMVDTGFGAMNFADLQTNKSDVPIDI (HPV6b L1 amino acids 193 through 220). Human sera which reacted with HPV6b L1 fusion proteins cross-reacted with an HPV11 L1 fusion protein but did not react with fusion proteins encoded by HPV1a, HPV16, or HPV18. Rabbit anti-BPV1 reacted with L1 fusion proteins encoded by all of these HPV types. In contrast to the type-common (rabbit anti-BPV1-reactive) epitope, the human antibody-reactive epitope appears to be relatively HPV type specific. Images PMID:2463384

  12. Study identifies potential therapeutic target for incurable, rare type of soft-tissue cancer

    Cancer.gov

    In a study published online in Cell Reports, scientists from the UT Southwestern Medical Center (home of the Harold C. Simmons Cancer Center) found that inhibiting the action of a protein called BRD4 caused cancer cells to die in a mouse model of malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly aggressive sarcomas that form around nerves. These tumors can develop sporadically, but about half of cases are in patients with a genetic disorder called neurofibromatosis type 1 (NF1) that affects 1 in 3,500 people.

  13. Complete Genome Sequence of a Duck Hepatitis A Virus Type 3 Identified in Eastern China

    PubMed Central

    Xu, Qian; Zhang, Ruihua; Chen, Linlin; Yang, Lei; Li, Jingxin; Dou, Pengfei; Wang, Hui; Xie, Zhijing; Wang, Yu

    2012-01-01

    We report here the complete genome sequence of a novel duck hepatitis A virus type 3 (DHAV-3) isolated from a dead Cherry Valley duckling in eastern China. The whole genomic nucleotide sequence and polyprotein amino acid sequence of the virus had higher homology with those of Chinese DHAV-3 isolates, medium homology with those of Korean DHAV-3 isolates, and the lowest homology with those of Vietnamese isolate DN2. The result indicated that the genetic evolution of DHAV-3 isolates had obvious geographical features. PMID:23166253

  14. Two mechanistically distinct effects of dihydropyridine nifedipine on CaV1.2 L-type Ca²? channels revealed by Timothy syndrome mutation.

    PubMed

    Sheng, Xiaona; Nakada, Tsutomu; Kobayashi, Motohiro; Kashihara, Toshihide; Shibazaki, Toshihide; Horiuchi-Hirose, Miwa; Gomi, Simmon; Hirose, Masamichi; Aoyama, Toshifumi; Yamada, Mitsuhiko

    2012-06-15

    Dihydropyridine Ca(2+) channel antagonists (DHPs) block Ca(V)1.2 L-type Ca(2+) channels (LTCCs) by stabilizing their voltage-dependent inactivation (VDI); however, it is still not clear how DHPs allosterically interact with the kinetically distinct (fast and slow) VDI. Thus, we analyzed the effect of a prototypical DHP, nifedipine on LTCCs with or without the Timothy syndrome mutation that resides in the I-II linker (L(I)-(II)) of Ca(V)1.2 subunits and impairs VDI. Whole-cell Ba(2+) currents mediated by rabbit Ca(V)1.2 with or without the Timothy mutation (G436R) (analogous to the human G406R mutation) were analyzed in the presence and absence of nifedipine. In the absence of nifedipine, the mutation significantly impaired fast closed- and open-state VDI (CSI and OSI) at -40 and 0 mV, respectively, but did not affect channels' kinetics at -100 mV. Nifedipine equipotently blocked these channels at -80 mV. In wild-type LTCCs, nifedipine promoted fast CSI and OSI at -40 and 0 mV and promoted or stabilized slow CSI at -40 and -100 mV, respectively. In LTCCs with the mutation, nifedipine resumed the impaired fast CSI and OSI at -40 and 0 mV, respectively, and had the same effect on slow CSI as in wild-type LTCCs. Therefore, nifedipine has two mechanistically distinct effects on LTCCs: the promotion of fast CSI/OSI caused by L(I-II) at potentials positive to the sub-threshold potential and the promotion or stabilization of slow CSI caused by different mechanisms at potentials negative to the sub-threshold potential. PMID:22554770

  15. Automated computation of arbor densities: a step toward identifying neuronal cell types

    PubMed Central

    Sümbül, Uygar; Zlateski, Aleksandar; Vishwanathan, Ashwin; Masland, Richard H.; Seung, H. Sebastian

    2014-01-01

    The shape and position of a neuron convey information regarding its molecular and functional identity. The identification of cell types from structure, a classic method, relies on the time-consuming step of arbor tracing. However, as genetic tools and imaging methods make data-driven approaches to neuronal circuit analysis feasible, the need for automated processing increases. Here, we first establish that mouse retinal ganglion cell types can be as precise about distributing their arbor volumes across the inner plexiform layer as they are about distributing the skeletons of the arbors. Then, we describe an automated approach to computing the spatial distribution of the dendritic arbors, or arbor density, with respect to a global depth coordinate based on this observation. Our method involves three-dimensional reconstruction of neuronal arbors by a supervised machine learning algorithm, post-processing of the enhanced stacks to remove somata and isolate the neuron of interest, and registration of neurons to each other using automatically detected arbors of the starburst amacrine interneurons as fiducial markers. In principle, this method could be generalizable to other structures of the CNS, provided that they allow sparse labeling of the cells and contain a reliable axis of spatial reference. PMID:25505389

  16. Picosecond-resolved FRET on non-amplified DNA for identifying individuals genetically susceptible to type-1 diabetes

    NASA Astrophysics Data System (ADS)

    Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra

    2012-06-01

    By tens-of-picosecond resolved fluorescence detection we study Förster resonance energy transfer between a donor and a black-hole-quencher bound at the 5'- and 3'-positions of an oligonucleotide probe matching the highly polymorphic region between codons 51 and 58 of the human leukocyte antigen DQB1 0201 allele, conferring susceptibility to type-1 diabetes. The probe is annealed with non-amplified genomic DNAs carrying either the 0201 sequence or other DQB1 allelic variants. We detect the longest-lived donor fluorescence in the case of hybridization with the 0201 allele and definitely faster and distinct decays for the other allelic variants, some of which are single-nucleotide polymorphic.

  17. Environmental Trigger(s) of Type 1 Diabetes: Why So Difficult to Identify?

    PubMed Central

    2015-01-01

    Type 1 diabetes (T1D) is one of the most common chronic diseases with childhood onset, and the disease has increased two- to fivefold over the past half century by as yet unknown means. T1D occurs when the body's immune system turns against itself so that, in a very specific and targeted way, it destroys the pancreatic ?-cells. T1D results from poorly defined interactions between susceptibility genes and environmental determinants. In contrast to the rapid progress in finding T1D genes, identification and confirmation of environmental determinants remain a formidable challenge. This review article will focus on factors which have to be evaluated and decision to take before starting a new prospective cohort study. Considering all the large ongoing prospective studies, new and more conclusive data than that obtained so far should instead come from international collaboration on the ongoing cohort studies.

  18. Ticking Stellar Time Bomb Identified - Astronomers find prime suspect for a Type Ia supernova

    NASA Astrophysics Data System (ADS)

    2009-11-01

    Using ESO's Very Large Telescope and its ability to obtain images as sharp as if taken from space, astronomers have made the first time-lapse movie of a rather unusual shell ejected by a "vampire star", which in November 2000 underwent an outburst after gulping down part of its companion's matter. This enabled astronomers to determine the distance and intrinsic brightness of the outbursting object. It appears that this double star system is a prime candidate to be one of the long-sought progenitors of the exploding stars known as Type Ia supernovae, critical for studies of dark energy. "One of the major problems in modern astrophysics is the fact that we still do not know exactly what kinds of stellar system explode as a Type Ia supernova," says Patrick Woudt, from the University of Cape Town and lead author of the paper reporting the results. "As these supernovae play a crucial role in showing that the Universe's expansion is currently accelerating, pushed by a mysterious dark energy, it is rather embarrassing." The astronomers studied the object known as V445 in the constellation of Puppis ("the Stern") in great detail. V445 Puppis is the first, and so far only, nova showing no evidence at all for hydrogen. It provides the first evidence for an outburst on the surface of a white dwarf [1] dominated by helium. "This is critical, as we know that Type Ia supernovae lack hydrogen," says co-author Danny Steeghs, from the University of Warwick, UK, "and the companion star in V445 Pup fits this nicely by also lacking hydrogen, instead dumping mainly helium gas onto the white dwarf." In November 2000, this system underwent a nova outburst, becoming 250 times brighter than before and ejecting a large quantity of matter into space. The team of astronomers used the NACO adaptive optics instrument [2] on ESO's Very Large Telescope (VLT) to obtain very sharp images of V445 Puppis over a time span of two years. The images show a bipolar shell, initially with a very narrow waist, with lobes on each side. Two knots are also seen at both the extreme ends of the shell, which appear to move at about 30 million kilometres per hour. The shell - unlike any previously observed for a nova - is itself moving at about 24 million kilometres per hour. A thick disc of dust, which must have been produced during the last outburst, obscures the two central stars. "The incredible detail that we can see on such small scales - about hundred milliarcseconds, which is the apparent size of a one euro coin seen from about forty kilometres - is only possible thanks to the adaptive optics technology available on large ground-based telescopes such as ESO's VLT," says Steeghs. A supernova is one way that a star can end its life, exploding in a display of grandiose fireworks. One family of supernovae, called Type Ia supernovae, are of particular interest in cosmology as they can be used as "standard candles" to measure distances in the Universe [3] and so can be used to calibrate the accelerating expansion that is driven by dark energy. One defining characteristic of Type Ia supernovae is the lack of hydrogen in their spectrum. Yet hydrogen is the most common chemical element in the Universe. Such supernovae most likely arise in systems composed of two stars, one of them being the end product of the life of sun-like stars, or white dwarfs. When such white dwarfs, acting as stellar vampires that suck matter from their companion, become heavier than a given limit, they become unstable and explode [4]. The build-up is not a simple process. As the white dwarf cannibalises its prey, matter accumulates on its surface. If this layer becomes too dense, it becomes unstable and erupts as a nova. These controlled, mini-explosions eject part of the accumulated matter back into space. The crucial question is thus to know whether the white dwarf can manage to gain weight despite the outburst, that is, if some of the matter taken from the companion stays on the white dwarf, so that it will eventual

  19. A sodium channel mutation identified in Aedes aegypti selectively reduces cockroach sodium channel sensitivity to type I, but not type II pyrethroids.

    PubMed

    Hu, Zhaonong; Du, Yuzhe; Nomura, Yoshiko; Dong, Ke

    2011-01-01

    Voltage-gated sodium channels are the primary target of pyrethroid insecticides. Numerous point mutations in sodium channel genes have been identified in pyrethroid-resistant insect species, and many have been confirmed to reduce or abolish sensitivity of channels expressed in Xenopus oocytes to pyrethroids. Recently, several novel mutations were reported in sodium channel genes of pyrethroid-resistant Aedes mosquito populations. One of the mutations is a phenylalanine (F) to cysteine (C) change in segment 6 of domain III (IIIS6) of the Aedes mosquito sodium channel. Curiously, a previous study showed that alanine substitution of this F did not alter the action of deltamethrin, a type II pyrethroid, on a cockroach sodium channel. In this study, we changed this F to C in a pyrethroid-sensitive cockroach sodium channel and examined mutant channel sensitivity to permethrin as well as five other type I or type II pyrethroids in Xenopus oocytes. Interestingly, the F to C mutation drastically reduced channel sensitivity to three type I pyrethroids, permethrin, NRDC 157 (a deltamethrin analogue lacking the ?-cyano group) and bioresemthrin, but not to three type II pyrethroids, cypermethrin, deltamethrin and cyhalothrin. These results confirm the involvement of the F to C mutation in permethrin resistance, and raise the possibility that rotation of type I and type II pyrethroids might be considered in the control of insect pest populations where this particular mutation is present. PMID:20869441

  20. Multi-Virulence-Locus Sequence Typing Identifies Single Nucleotide Polymorphisms Which Differentiate Epidemic Clones and Outbreak Strains of Listeria monocytogenes

    Microsoft Academic Search

    Yi Chen; Wei Zhang; Stephen J. Knabel

    2007-01-01

    A recently developed multi-virulence-locus sequence typing (MVLST) method showed improved discrimi- natory power for subtyping genetically diverse Listeria monocytogenes isolates and identified epidemic clone II isolates associated with two recent U.S. multistate listeriosis outbreaks. To evaluate the ability of MVLST to distinguish other epidemic clones and outbreak strains of L. monocytogenes, 58 outbreak-related isolates from 14 outbreaks and 49 unrelated

  1. The Potential Use of DNA Methylation Biomarkers to Identify Risk and Progression of Type 2 Diabetes

    PubMed Central

    Gillberg, Linn; Ling, Charlotte

    2015-01-01

    Type 2 diabetes mellitus (T2D) is a slowly progressive disease that can be postponed or even avoided through lifestyle changes. Recent data demonstrate highly significant correlations between DNA methylation and the most important risk factors of T2D, including age and body mass index, in blood and human tissues relevant to insulin resistance and T2D. Also, T2D patients and individuals with increased risk of the disease display differential DNA methylation profiles and plasticity compared to controls. Accordingly, the novel clues to DNA methylation fingerprints in blood and tissues with deteriorated metabolic capacity indicate that blood-borne epigenetic biomarkers of T2D progression might become a reality. This Review will address the most recent associations between DNA methylation and diabetes-related traits in human tissues and blood. The overall focus is on the potential of future epigenome-wide studies, carried out across tissues and populations with correlations to pre-diabetes and T2D risk factors, to build up a library of epigenetic markers of risk and early progression of T2D. These markers may, tentatively in combination with other predictors of T2D development, increase the possibility of individual-based lifestyle prevention of T2D and associated metabolic diseases. PMID:25870586

  2. Gene expression profiling identifies molecular subtypes of gliomas

    Microsoft Academic Search

    Ruty Shai; Tao Shi; Thomas J Kremen; Steve Horvath; Linda M Liau; Timothy F Cloughesy; Paul S Mischel; Stanley F Nelson

    2003-01-01

    Identification of distinct molecular subtypes is a critical challenge for cancer biology. In this study, we used Affymetrix high-density oligonucleotide arrays to identify the global gene expression signatures associated with gliomas of different types and grades. Here, we show that the global transcriptional profiles of gliomas of different types and grades are distinct from each other and from the normal

  3. Bone mineralization in young patients with type 1 diabetes mellitus and screening-identified evidence of celiac disease.

    PubMed

    Diniz-Santos, Daniel R; Brandão, Flávia; Adan, Luis; Moreira, Agnaluce; Vicente, Eliézer J; Silva, Luciana R

    2008-05-01

    The aims of this study were to evaluate bone mineral density (BMD) and bone turnover markers in patients with type 1 diabetes and screening-identified evidence of celiac disease, i.e., celiac autoimmunity. We screened 50 consecutive type 1 diabetic patients for IgA antitissue transglutaminase to identify those with celiac autoimmunity. Eight seropositive patients were identified on this screening, and 12 patients matched for gender and age range were selected as a control group from among the type 1 diabetic patients without celiac autoimmunity. Patients and controls underwent dual-energy X-ray absorptiometry (DEXA) for measurement of bone mineral status and had their blood levels of osteocalcin, carboxy-terminal telopeptide of type I collagen (CTX), calcium, and phosphorus determined. BMD was further adjusted for height, weight, and pubertal stage. Radiographic and blood markers of bone mineralization were compared between patients and controls. BMD (Z-score) at the lumbar spine was -1.44 +/- 0.5 SD for patients and 0.04 +/- 0.2 SD for controls (P = 0.02). Bone mineral content was 37.9 +/- 4.5 g for patients and 49.4 +/- 2.6 g for controls (P = 0.049). Adjusted BMD was -0.62 +/- 0.5 SD for patients and 0.81 +/- 0.09 SD for controls (P = 0.04). After adjustment, four patients and none of the controls presented BMD < -1 SD (P = 0.01). Osteocalcin, CTX, calcium, and phosphorus blood levels were not significantly different between patients and controls. Celiac autoimmunity is associated with reduced bone mineralization in type 1 diabetic patients. The pathophysiological mechanisms and clinical relevance of this finding remain to be further investigated. PMID:17939041

  4. An Optimized Histochemical Method to Assess Skeletal Muscle Glycogen and Lipid Stores Reveals Two Metabolically Distinct Populations of Type I Muscle Fibers

    PubMed Central

    Prats, Clara; Gomez-Cabello, Alba; Nordby, Pernille; Andersen, Jesper L.; Helge, Jørn W.; Dela, Flemming; Baba, Otto; Ploug, Thorkil

    2013-01-01

    Skeletal muscle energy metabolism has been a research focus of physiologists for more than a century. Yet, how the use of intramuscular carbohydrate and lipid energy stores are coordinated during different types of exercise remains a subject of debate. Controversy arises from contradicting data from numerous studies, which used different methodological approaches. Here we review the “pros and cons” of previously used histochemical methods and describe an optimized method to ensure the preservation and specificity of detection of both intramyocellular carbohydrate and lipid stores. For optimal preservation of muscle energy stores, air drying cryosections or cycles of freezing-thawing need to be avoided. Furthermore, optimization of the imaging settings in order to specifically image intracellular lipid droplets stained with oil red O or Bodipy-493/503 is shown. When co-staining lipid droplets with associated proteins, Bodipy-493/503 should be the dye of choice, since oil red O creates precipitates on the lipid droplets blocking the light. In order to increase the specificity of glycogen stain, an antibody against glycogen is used. The resulting method reveals the existence of two metabolically distinct myosin heavy chain I expressing fibers: I-1 fibers have a smaller crossectional area, a higher density of lipid droplets, and a tendency to lower glycogen content compared to I-2 fibers. Type I-2 fibers have similar lipid content than IIA. Exhaustive exercise lead to glycogen depletion in type IIA and IIX fibers, a reduction in lipid droplets density in both type I-1 and I-2 fibers, and a decrease in the size of lipid droplets exclusively in type I-1 fibers. PMID:24204959

  5. Identifying and meeting the challenges of insulin therapy in type 2 diabetes

    PubMed Central

    Sorli, Christopher; Heile, Michael K

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is a chronic illness that requires clinical recognition and treatment of the dual pathophysiologic entities of altered glycemic control and insulin resistance to reduce the risk of long-term micro- and macrovascular complications. Although insulin is one of the most effective and widely used therapeutic options in the management of diabetes, it is used by less than one-half of patients for whom it is recommended. Clinician-, patient-, and health care system-related challenges present numerous obstacles to insulin use in T2DM. Clinicians must remain informed about new insulin products, emerging technologies, and treatment options that have the potential to improve adherence to insulin therapy while optimizing glycemic control and mitigating the risks of therapy. Patient-related challenges may be overcome by actively listening to the patient’s fears and concerns regarding insulin therapy and by educating patients about the importance, rationale, and evolving role of insulin in individualized self-treatment regimens. Enlisting the services of Certified Diabetes Educators and office personnel can help in addressing patient-related challenges. Self-management of diabetes requires improved patient awareness regarding the importance of lifestyle modifications, self-monitoring, and/or continuous glucose monitoring, improved methods of insulin delivery (eg, insulin pens), and the enhanced convenience and safety provided by insulin analogs. Health care system-related challenges may be improved through control of the rising cost of insulin therapy while making it available to patients. To increase the success rate of treatment of T2DM, the 2012 position statement from the American Diabetes Association and the European Association for the Study of Diabetes focused on individualized patient care and provided clinicians with general treatment goals, implementation strategies, and tools to evaluate the quality of care. PMID:25061317

  6. Identifying clinical criteria to predict Type 1 diabetes, as defined by absolute insulin deficiency: a systematic review protocol

    PubMed Central

    Shields, Beverley M; Peters, Jaime L; Cooper, Chris; Powell, Roy J; Knight, Bridget A; Hyde, Christopher; Hattersley, Andrew T

    2012-01-01

    Introduction Management of a patient's diabetes is entirely dependent upon the type of diabetes they are deemed to have. Patients with Type 1 diabetes are insulin deficient so require multiple daily insulin injections, whereas patients with Type 2 diabetes still have some endogenous insulin production so insulin treatment is only required when diet and tablets do not establish good glycaemic control. Despite the importance of a correct diagnosis, classification of diabetes is based on aetiology and relies on clinical judgement. There are no clinical guidelines on how to determine whether a patient has Type 1 or Type 2 diabetes. We aim to systematically review the literature to derive evidence-based clinical criteria for the classification of the major subtypes of diabetes. Methods and analysis We will perform a systematic review of diagnostic accuracy studies to establish clinical criteria that predict the subsequent development of absolute insulin deficiency seen in Type 1 diabetes. Insulin deficiency will be determined by reference standard C-peptide concentrations. Synthesis of criteria identified will be undertaken using hierarchical summary receiver operating characteristic curves. Ethics and dissemination As this is a systematic review, there will be no ethical issues. We will disseminate results by writing up the final systematic review and synthesis for publication in a peer-reviewed journal and will present at national and international diabetes-related meetings. PMID:23274675

  7. Genome wide DNA copy number analysis of serous type ovarian carcinomas identifies genetic markers predictive of clinical outcome.

    PubMed

    Engler, David A; Gupta, Sumeet; Growdon, Whitfield B; Drapkin, Ronny I; Nitta, Mai; Sergent, Petra A; Allred, Serena F; Gross, Jenny; Deavers, Michael T; Kuo, Wen-Lin; Karlan, Beth Y; Rueda, Bo R; Orsulic, Sandra; Gershenson, David M; Birrer, Michael J; Gray, Joe W; Mohapatra, Gayatry

    2012-01-01

    Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups. PMID:22355333

  8. Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells.

    PubMed

    van Vliet, Sandra J; van Liempt, Ellis; Saeland, Eirikur; Aarnoudse, Corlien A; Appelmelk, Ben; Irimura, Tatsuro; Geijtenbeek, Teunis B H; Blixt, Ola; Alvarez, Richard; van Die, Irma; van Kooyk, Yvette

    2005-05-01

    Dendritic cells (DCs) are key to the maintenance of peripheral tolerance to self-antigens and the orchestration of an immune reaction to foreign antigens. C-type lectins, expressed by DCs, recognize carbohydrate moieties on antigens that can be internalized for processing and presentation. Little is known about the exact glycan structures on self-antigens and pathogens that are specifically recognized by the different C-type lectins and how this interaction influences DC function. We have analyzed the carbohydrate specificity of the human C-type lectin macrophage galactose-type lectin (MGL) using glycan microarray profiling and identified an exclusive specificity for terminal alpha- and beta-linked GalNAc residues that naturally occur as parts of glycoproteins or glycosphingolipids. Specific glycan structures containing terminal GalNAc moieties, expressed by the human helminth parasite Schistosoma mansoni as well as tumor antigens and a subset of gangliosides, were identified as ligands for MGL. Our results indicate an endogenous function for DC-expressed MGL in the clearance and tolerance to self-gangliosides, and in the pattern recognition of tumor antigens and foreign glycoproteins derived from helminth parasites. PMID:15802303

  9. A Rule-Based Prognostic Model for Type 1 Diabetes by Identifying and Synthesizing Baseline Profile Patterns

    PubMed Central

    Lin, Ying; Qian, Xiaoning; Krischer, Jeffrey; Vehik, Kendra; Lee, Hye-Seung; Huang, Shuai

    2014-01-01

    Objective To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, and metabolic markers and synthesize these patterns for risk prediction. Research Design and Methods RuleFit is used to identify the risk-predictive baseline profile patterns of demographic, immunologic, and metabolic markers, using 356 subjects who were randomized into the control arm of the prospective Diabetes Prevention Trial-Type 1 (DPT-1) study. A novel latent trait model is developed to synthesize these baseline profile patterns for disease risk prediction. The primary outcome was Type 1 Diabetes (T1D) onset. Results We identified ten baseline profile patterns that were significantly predictive to the disease onset. Using these ten baseline profile patterns, a risk prediction model was built based on the latent trait model, which produced superior prediction performance over existing risk score models for T1D. Conclusion Our results demonstrated that the underlying disease progression process of T1D can be detected through some risk-predictive patterns of demographic, immunologic, and metabolic markers. A synthesis of these patterns provided accurate prediction of disease onset, leading to more cost-effective design of prevention trials of T1D in the future. PMID:24926781

  10. Analysis of chromatin-state plasticity identifies cell-type–specific regulators of H3K27me3 patterns

    PubMed Central

    Pinello, Luca; Xu, Jian; Orkin, Stuart H.; Yuan, Guo-Cheng

    2014-01-01

    Chromatin states are highly cell-type–specific, but the underlying mechanisms for the establishment and maintenance of their genome-wide patterns remain poorly understood. Here we present a computational approach for investigation of chromatin-state plasticity. We applied this approach to investigate an ENCODE ChIP-seq dataset profiling the genome-wide distributions of the H3K27me3 mark in 19 human cell lines. We found that the high plasticity regions (HPRs) can be divided into two functionally and mechanistically distinct subsets, which correspond to CpG island (CGI) proximal or distal regions, respectively. Although the CGI proximal HPRs are typically associated with continuous variation across different cell-types, the distal HPRs are associated with binary-like variations. We developed a computational approach to predict putative cell-type–specific modulators of H3K27me3 patterns and validated the predictions by comparing with public ChIP-seq data. Furthermore, we applied this approach to investigate mechanisms for poised enhancer establishment in primary human erythroid precursors. Importantly, we predicted and experimentally validated that the principal hematopoietic regulator T-cell acute lymphocytic leukemia-1 (TAL1) is involved in regulating H3K27me3 variations in collaboration with the transcription factor growth factor independent 1B (GFI1B), providing fresh insights into the context-specific role of TAL1 in erythropoiesis. Our approach is generally applicable to investigate the regulatory mechanisms of epigenetic pathways in establishing cellular identity. PMID:24395799

  11. A set-based association test identifies sex-specific gene sets associated with type 2 diabetes

    PubMed Central

    He, Tao; Zhong, Ping-Shou; Cui, Yuehua

    2014-01-01

    Single variant analysis in genome-wide association studies (GWAS) has been proven to be successful in identifying thousands of genetic variants associated with hundreds of complex diseases. However, these identified variants only explain a small fraction of inheritable variability in many diseases, suggesting that other resources, such as multilevel genetic variations, may contribute to disease susceptibility. In this work, we proposed to combine genetic variants that belong to a gene set, such as at gene- and pathway-level to form an integrated signal aimed to identify major players that function in a coordinated manner conferring disease risk. The integrated analysis provides novel insight into disease etiology while individual signals could be easily missed by single variant analysis. We applied our approach to a genome-wide association study of type 2 diabetes (T2D) with male and female data analyzed separately. Novel sex-specific genes and pathways were identified to increase the risk of T2D. We also demonstrated the performance of signal integration through simulation studies. PMID:25429300

  12. Distinct Cell Clusters Touching Islet Cells Induce Islet Cell Replication in Association with Over-Expression of Regenerating Gene (REG) Protein in Fulminant Type 1 Diabetes

    PubMed Central

    Aida, Kaoru; Saitoh, Sei; Nishida, Yoriko; Yokota, Sadanori; Ohno, Shinichi; Mao, Xiayang; Akiyama, Daiichiro; Tanaka, Shoichiro; Awata, Takuya; Shimada, Akira; Oikawa, Youichi; Shimura, Hiroki; Furuya, Fumihiko; Takizawa, Soichi; Ichijo, Masashi; Ichijo, Sayaka; Itakura, Jun; Fujii, Hideki; Hashiguchi, Akinori; Takasawa, Shin; Endo, Toyoshi; Kobayashi, Tetsuro

    2014-01-01

    Background Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear. Procedures The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. Result Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) I? protein. The vesicles containing REG I? protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG I? protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. Conclusion The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG I? protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG I? in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells. PMID:24759849

  13. On Identifiability of Bias-Type Actuator-Sensor Faults in Multiple-Model-Based Fault Detection and Identification

    NASA Technical Reports Server (NTRS)

    Joshi, Suresh M.

    2012-01-01

    This paper explores a class of multiple-model-based fault detection and identification (FDI) methods for bias-type faults in actuators and sensors. These methods employ banks of Kalman-Bucy filters to detect the faults, determine the fault pattern, and estimate the fault values, wherein each Kalman-Bucy filter is tuned to a different failure pattern. Necessary and sufficient conditions are presented for identifiability of actuator faults, sensor faults, and simultaneous actuator and sensor faults. It is shown that FDI of simultaneous actuator and sensor faults is not possible using these methods when all sensors have biases.

  14. Cell-type specificity of regulatory elements identified by linker scanning mutagenesis in the promoter of the chicken lysozyme gene.

    PubMed Central

    Luckow, B; Schütz, G

    1989-01-01

    The chicken lysozyme gene is constitutively expressed in macrophages, in oviduct cells its expression is controlled by steroid hormones, and in fibroblasts the gene is not expressed. A fusion gene consisting of promoter sequences of the lysozyme gene from -208 to +15 in front of the chloramphenicol acetyltransferase (CAT) coding region was more than 50 times less active in non-expressing cells as compared to expressing cells. In order to identify the element(s) responsible for this cell-type specificity 31 different linker scanning mutations were generated within this promoter fragment and analyzed by transient transfections in the three types of chicken cells mentioned above. Three mutation sensitive regions located around position -25, -100 and between -158 and -208 were detected in each cell type, however, several LS mutations displayed clear cell-type specific differences in their phenotypic effects. Interestingly, a few LS mutations led to an increase in promoter activity in fibroblasts suggesting that the corresponding wildtype sequences represent binding sites for negatively acting transcription factors. PMID:2511554

  15. Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

    PubMed

    Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ismeet; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay K; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K; Saxena, Madhukar; Banerjee, Monisha; Mathur, Sandeep; Bhansali, Anil; Shah, Viral N; Madhu, Sri Venkata; Marwaha, Raman K; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I; Venkatesan, Radha; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan

    2013-03-01

    Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10??). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10?¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. PMID:23209189

  16. Multiple types of data are required to identify the mechanisms influencing the spatial expansion of melanoma cell colonies

    PubMed Central

    2013-01-01

    Background The expansion of cell colonies is driven by a delicate balance of several mechanisms including cell motility, cell–to–cell adhesion and cell proliferation. New approaches that can be used to independently identify and quantify the role of each mechanism will help us understand how each mechanism contributes to the expansion process. Standard mathematical modelling approaches to describe such cell colony expansion typically neglect cell–to–cell adhesion, despite the fact that cell–to-cell adhesion is thought to play an important role. Results We use a combined experimental and mathematical modelling approach to determine the cell diffusivity, D, cell–to–cell adhesion strength, q, and cell proliferation rate, ?, in an expanding colony of MM127 melanoma cells. Using a circular barrier assay, we extract several types of experimental data and use a mathematical model to independently estimate D, q and ?. In our first set of experiments, we suppress cell proliferation and analyse three different types of data to estimate D and q. We find that standard types of data, such as the area enclosed by the leading edge of the expanding colony and more detailed cell density profiles throughout the expanding colony, does not provide sufficient information to uniquely identify D and q. We find that additional data relating to the degree of cell–to–cell clustering is required to provide independent estimates of q, and in turn D. In our second set of experiments, where proliferation is not suppressed, we use data describing temporal changes in cell density to determine the cell proliferation rate. In summary, we find that our experiments are best described using the range D=161?243?m2hour?1, q=0.3?0.5 (low to moderate strength) and ?=0.0305?0.0398hour?1, and with these parameters we can accurately predict the temporal variations in the spatial extent and cell density profile throughout the expanding melanoma cell colony. Conclusions Our systematic approach to identify the cell diffusivity, cell–to–cell adhesion strength and cell proliferation rate highlights the importance of integrating multiple types of data to accurately quantify the factors influencing the spatial expansion of melanoma cell colonies. PMID:24330479

  17. Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin Microarray

    PubMed Central

    Inoue, Kentaro; Wada, Jun; Eguchi, Jun; Nakatsuka, Atsuko; Teshigawara, Sanae; Murakami, Kazutoshi; Ogawa, Daisuke; Terami, Takahiro; Katayama, Akihiro; Tone, Atsuhito; Iseda, Izumi; Hida, Kazuyuki; Yamada, Masao; Ogawa, Tomohisa; Makino, Hirofumi

    2013-01-01

    We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n?=?17) and measured urinary excretion of fetuin-A (n?=?85). The increased signals of urine samples were observed in Sia?2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography–tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40±0.43; A2, 0.60±0.53; A3 1.57±1.13 ng/gCr; p?=?7.29×10?8) and of GFR stages (G1, 0.39±0.39; G2, 0.49±0.45; G3, 1.25±1.18; G4, 1.34±0.80 ng/gCr; p?=?3.89×10?4). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR<60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881–11.844) and 3.739 (1.785–7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy. PMID:24143207

  18. A genome-wide screen identifies a Bordetella type III secretion effector and candidate effectors in other species.

    PubMed

    Panina, Ekaterina M; Mattoo, Seema; Griffith, Natasha; Kozak, Natalia A; Yuk, Ming H; Miller, Jeff F

    2005-10-01

    Bordetella bronchiseptica utilizes a type III secretion system (TTSS) for induction of non-apoptotic cytotoxicity in host cells and modulation of host immunity. The identity of Bordetella TTSS effectors, however, has remained elusive. Here we report a genome-wide screen for TTSS effectors based on shared biophysical and functional characteristics of class I chaperones and their frequent colocalization with TTSS effectors. When applied to B. bronchiseptica, the screen identified the first TTSS chaperone-effector locus, btcA-bteA, and we experimentally confirmed its function. Expression of bteA is co-ordinated with expression of TTSS apparatus genes, BteA is secreted through the TTSS of B. bronchiseptica, it is required for cytotoxicity towards mammalian cells, and it is highly conserved in the human-adapted subspecies B. pertussis and B. parapertussis. Transfection of bteA into epithlieal cells results in rapid cell death, indicating that BteA alone is sufficient to induce potent cytotoxicity. Finally, an in vitro interaction between BteA and BtcA was demonstrated. The search for TTSS chaperones and effectors was then expanded to other bacterial genomes, including mammalian and insect pathogens, where we identified a large number of novel candidate chaperones and effectors. Although the majority of putative effectors are proteins of unknown function, several have similarities to eukaryotic protein domains or previously identified effectors from other species. PMID:16164564

  19. Discrete typing units of Trypanosoma cruzi identified in rural dogs and cats in the humid Argentinean Chaco

    PubMed Central

    ENRIQUEZ, G.F.; CARDINAL, M.V.; OROZCO, M.M.; LANATI, L.; SCHIJMAN, A.G.; GÜRTLER, R.E.

    2013-01-01

    SUMMARY The discrete typing units (DTUs) of Trypanosoma cruzi that infect domestic dogs and cats have rarely been studied. With this purpose we conducted a cross-sectional xenodiagnostic survey of dog and cat populations residing in two infested rural villages in Pampa del Indio, in the humid Argentine Chaco. Parasites were isolated by culture from 44 dogs and 12 cats with a positive xenodiagnosis. DTUs were identified from parasite culture samples using a strategy based on multiple polymerase-chain reactions. TcVI was identified in 37 of 44 dogs and in 10 of 12 cats, whereas TcV was identified in five dogs and in two cats –a new finding for cats. No mixed infections were detected. The occurrence of two dogs infected with TcIII –classically found in armadillos– suggests a probable link with the local sylvatic transmission cycle involving Dasypus novemcinctus armadillos and a potential risk of human infection with TcIII. Our study reinforces the importance of dogs and cats as domestic reservoir hosts and sources of various DTUs infecting humans, and suggests a link between dogs and the sylvatic transmission cycle of TcIII. PMID:23058180

  20. Identifying Candidate Genes for Type 2 Diabetes Mellitus and Obesity through Gene Expression Profiling in Multiple Tissues or Cells

    PubMed Central

    Meng, Yuhuan; Zhou, Jinghui; Zhuo, Min; Ling, Fei; Zhang, Yu; Du, Hongli; Wang, Xiaoning

    2013-01-01

    Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity. PMID:24455749

  1. Suzaku Studies of the Central Engine in the Typical Type I Seyfert NGC 3227: Detection of Multiple Primary X-ray Continua with Distinct Properties

    E-print Network

    Noda, Hirofumi; Yamada, Shin'ya; Nakazawa, Kazuhiro; Sakurai, Soki; Miyake, Katsuma

    2014-01-01

    The type I Seyfert galaxy NGC 3227 was observed by \\textit{Suzaku} six times in 2008, with intervals of $\\sim1$ week and net exposures of $\\sim50$~ksec each. Among the six observations, the source varied by nearly an order of magnitude, being brightest in the 1st observation with a 2--10~keV luminosity of $1.2\\times10^{42}$~erg~s$^{-1}$, while faintest in the 4th with $2.9\\times10^{41}$~erg~s$^{-1}$. As it became fainter, the continuum in a 2--45~keV band became harder, while a narrow Fe-K$\\alpha$ emission line, detected on all occasions at 6.4~keV of the source rest frame, remained approximately constant in the photon flux. Through a method of variability-assisted broad-band spectroscopy (e.g., Noda et al. 2013), the 2--45~keV spectrum of NGC 3227 was decomposed into three distinct components. One is a relatively soft power-law continuum with a photon index of $\\sim 2.3$, weakly absorbed and highly variable on time scales of $\\sim5$~ksec; it was observed only when the source was above a threshold luminosity ...

  2. Eliminating unwanted far-field excitation in objective-type TIRF. Part I. identifying sources of nonevanescent excitation light.

    PubMed

    Brunstein, Maia; Teremetz, Maxime; Hérault, Karine; Tourain, Christophe; Oheim, Martin

    2014-03-01

    Total internal reflection fluorescence microscopy (TIRFM) achieves subdiffraction axial sectioning by confining fluorophore excitation to a thin layer close to the cell/substrate boundary. However, it is often unknown how thin this light sheet actually is. Particularly in objective-type TIRFM, large deviations from the exponential intensity decay expected for pure evanescence have been reported. Nonevanescent excitation light diminishes the optical sectioning effect, reduces contrast, and renders TIRFM-image quantification uncertain. To identify the sources of this unwanted fluorescence excitation in deeper sample layers, we here combine azimuthal and polar beam scanning (spinning TIRF), atomic force microscopy, and wavefront analysis of beams passing through the objective periphery. Using a variety of intracellular fluorescent labels as well as negative staining experiments to measure cell-induced scattering, we find that azimuthal beam spinning produces TIRFM images that more accurately portray the real fluorophore distribution, but these images are still hampered by far-field excitation. Furthermore, although clearly measureable, cell-induced scattering is not the dominant source of far-field excitation light in objective-type TIRF, at least for most types of weakly scattering cells. It is the microscope illumination optical path that produces a large cell- and beam-angle invariant stray excitation that is insensitive to beam scanning. This instrument-induced glare is produced far from the sample plane, inside the microscope illumination optical path. We identify stray reflections and high-numerical aperture aberrations of the TIRF objective as one important source. This work is accompanied by a companion paper (Pt.2/2). PMID:24606927

  3. Eliminating Unwanted Far-Field Excitation in Objective-Type TIRF. Part I. Identifying Sources of Nonevanescent Excitation Light

    PubMed Central

    Brunstein, Maia; Teremetz, Maxime; Hérault, Karine; Tourain, Christophe; Oheim, Martin

    2014-01-01

    Total internal reflection fluorescence microscopy (TIRFM) achieves subdiffraction axial sectioning by confining fluorophore excitation to a thin layer close to the cell/substrate boundary. However, it is often unknown how thin this light sheet actually is. Particularly in objective-type TIRFM, large deviations from the exponential intensity decay expected for pure evanescence have been reported. Nonevanescent excitation light diminishes the optical sectioning effect, reduces contrast, and renders TIRFM-image quantification uncertain. To identify the sources of this unwanted fluorescence excitation in deeper sample layers, we here combine azimuthal and polar beam scanning (spinning TIRF), atomic force microscopy, and wavefront analysis of beams passing through the objective periphery. Using a variety of intracellular fluorescent labels as well as negative staining experiments to measure cell-induced scattering, we find that azimuthal beam spinning produces TIRFM images that more accurately portray the real fluorophore distribution, but these images are still hampered by far-field excitation. Furthermore, although clearly measureable, cell-induced scattering is not the dominant source of far-field excitation light in objective-type TIRF, at least for most types of weakly scattering cells. It is the microscope illumination optical path that produces a large cell- and beam-angle invariant stray excitation that is insensitive to beam scanning. This instrument-induced glare is produced far from the sample plane, inside the microscope illumination optical path. We identify stray reflections and high-numerical aperture aberrations of the TIRF objective as one important source. This work is accompanied by a companion paper (Pt.2/2). PMID:24606927

  4. Purification and characterization of three distinct types of phospholipase A2 inhibitors from the blood plasma of the Chinese mamushi, Agkistrodon blomhoffii siniticus.

    PubMed Central

    Ohkura, N; Okuhara, H; Inoue, S; Ikeda, K; Hayashi, K

    1997-01-01

    Three distinct types of phospholipase A2 (PLA2) inhibitory proteins (PLIalpha, PLIbeta, and PLIgamma) were isolated from the blood plasma of the Chinese mamushi, Agkistrodon blomhoffii siniticus. PLIalpha is an inhibitor that we have already purified and whose amino acid sequence we have already determined [Ohkura, Inoue, Ikeda and Hayashi (1993) J. Biochem. (Tokyo) 113, 413-419]. It inhibited selectively the group-II acidic PLA2s from Crotalidae venom. PLIbeta was a 160-kDa glycoprotein having a trimeric structure composed of 50-kDa subunits. The amino acid sequence of the first 30 amino acids of the N-terminal part of the 50-kDa subunit was determined and found to have no significant homology to that of known proteins. PLIbeta was a selective inhibitor against the group-II basic PLA2s from Crotalidae venom. Some amino acid residues located in or close to the interfacial binding surface of the group-II basic PLA2s were suggested to be involved in selective binding to PLIbeta. PLIgamma was a 100-kDa glycoprotein containing 25-kDa and 20-kDa subunits and inhibited all of the PLA2s investigated equally, including Elapidae venom PLA2s (group I), Crotalidae and Viperidae venom PLA2s (group II) and honey-bee PLA2 (group III). From the N-terminal sequences of the two subunits, PLIgamma was found to be the same type of PLI that had been purified from Thailand cobra plasma. PMID:9230137

  5. 'Snake River (SR)-type' volcanism at the Yellowstone hotspot track: Distinctive products from unusual, high-temperature silicic super-eruptions

    USGS Publications Warehouse

    Branney, M.J.; Bonnichsen, B.; Andrews, G.D.M.; Ellis, B.; Barry, T.L.; McCurry, M.

    2008-01-01

    A new category of large-scale volcanism, here termed Snake River (SR)-type volcanism, is defined with reference to a distinctive volcanic facies association displayed by Miocene rocks in the central Snake River Plain area of southern Idaho and northern Nevada, USA. The facies association contrasts with those typical of silicic volcanism elsewhere and records unusual, voluminous and particularly environmentally devastating styles of eruption that remain poorly understood. It includes: (1) large-volume, lithic-poor rhyolitic ignimbrites with scarce pumice lapilli; (2) extensive, parallel-laminated, medium to coarse-grained ashfall deposits with large cuspate shards, crystals and a paucity of pumice lapilli; many are fused to black vitrophyre; (3) unusually extensive, large-volume rhyolite lavas; (4) unusually intense welding, rheomorphism, and widespread development of lava-like facies in the ignimbrites; (5) extensive, fines-rich ash deposits with abundant ash aggregates (pellets and accretionary lapilli); (6) the ashfall layers and ignimbrites contain abundant clasts of dense obsidian and vitrophyre; (7) a bimodal association between the rhyolitic rocks and numerous, coalescing low-profile basalt lava shields; and (8) widespread evidence of emplacement in lacustrine-alluvial environments, as revealed by intercalated lake sediments, ignimbrite peperites, rhyolitic and basaltic hyaloclastites, basalt pillow-lava deltas, rhyolitic and basaltic phreatomagmatic tuffs, alluvial sands and palaeosols. Many rhyolitic eruptions were high mass-flux, large volume and explosive (VEI 6-8), and involved H2O-poor, low-??18O, metaluminous rhyolite magmas with unusually low viscosities, partly due to high magmatic temperatures (900-1,050??C). SR-type volcanism contrasts with silicic volcanism at many other volcanic fields, where the fall deposits are typically Plinian with pumice lapilli, the ignimbrites are low to medium grade (non-welded to eutaxitic) with abundant pumice lapilli or fiamme, and the rhyolite extrusions are small volume silicic domes and coule??es. SR-type volcanism seems to have occurred at numerous times in Earth history, because elements of the facies association occur within some other volcanic fields, including Trans-Pecos Texas, Etendeka-Paran, Lebombo, the English Lake District, the Proterozoic Keewanawan volcanics of Minnesota and the Yardea Dacite of Australia. ?? Springer-Verlag 2007.

  6. ZnT8-Specific CD4+ T cells display distinct cytokine expression profiles between type 1 diabetes patients and healthy adults.

    PubMed

    Chujo, Daisuke; Foucat, Emile; Nguyen, Thien-Son; Chaussabel, Damien; Banchereau, Jacques; Ueno, Hideki

    2013-01-01

    Determination of antigen-specific T cell repertoires in human blood has been a challenge. Here, we show a novel integrated approach that permits determination of multiple parameters of antigen-specific T cell repertoires. The approach consists of two assays: the Direct assay and the Cytokine-driven assay. Briefly, human PBMCs are first stimulated with overlapping peptides encoding a given antigen for 48 hours to measure cytokine secretion (Direct assay). Peptide-reactive T cells are further expanded by IL-2 for 5 days; and after overnight starvation, expanded cells are stimulated with the same peptides from the initial culture to analyze cytokine secretion (Cytokine-driven assay). We first applied this integrated approach to determine the type of islet-antigen-specific T cells in healthy adults. Out of ten donors, the Direct assay identified GAD65-specific CD4(+) T cells in three adults and zinc transporter 8 (ZnT8)-specific CD4(+) T cells in five adults. The intracytoplasmic cytokine staining assay showed that these islet-antigen-specific CD4(+) T cells belonged to the CD45RO(+) memory compartment. The Cytokine-driven assay further revealed that islet-antigen-specific CD4(+) T cells in healthy adults were capable of secreting various types of cytokines including type 1 and type 2 cytokines as well as IL-10. We next applied our integrated assay to determine whether the type of ZnT8-specific CD4(+) T cells is different between Type 1 diabetes patients and age/gender/HLA-matched healthy adults. We found that ZnT8-specific CD4(+) T cells were skewed towards Th1 cells in T1D patients, while Th2 and IL-10-producing cells were prevalent in healthy adults. In conclusion, the Direct assay and the Cytokine-driven assay complement each other, and the combination of the two assays provides information of antigen-specific T cell repertoires on the breadth, type, and avidity. This strategy is applicable to determine the differences in the quality of antigen-specific T cells between health and disease. PMID:23390544

  7. Distinctive plasma aldosterone, 18-hydroxycorticosterone, and 18-hydroxydeoxycorticosterone profile in the 21-, 17 alpha-, and 11 beta-hydroxylase deficiency types of congenital adrenal hyperplasia.

    PubMed

    Kater, C E; Biglieri, E G

    1983-07-01

    Forms of congenital adrenal hyperplasia resulting from deficient steroid hydroxylation at positions 21, 17 alpha, and 11 beta have several similar clinical and biochemical characteristics. Biochemical diagnosis has been dependent on the demonstration of elevated plasma or urinary concentrations of metabolites of the immediate biosynthetic precursor before the enzymatic block, especially after stimulation with adrenocorticotropin. Aldosterone, 18-hydroxycorticosterone, and 18-hydroxydeoxycorticosterone are not closely involved nor are they immediate precursors of any of these enzymatic defects. However, simultaneous determination of the baseline plasma levels of these steroids in patients with nonsodium-losing 21-hydroxylase deficiency (n = 12), 17 alpha-hydroxylase deficiency (n = 6), and 11 beta-hydroxylase deficiency (n = 2) revealed a consistent and distinct pattern (mean +/- SEM in nanograms per deciliter): aldosterone (28.1 +/- 2.8) and 18-hydroxycorticosterone (84.5 +/- 9.2) levels were elevated and 18-hydroxydeoxycorticosterone (8.0 +/- 0.8) levels were within normal limits in 21-hydroxylase deficiency; 18-hydroxycorticosterone (327.2 +/- 73.9) and 18-hydroxydeoxycorticosterone (236.0 +/- 33.8) levels were elevated and aldosterone (3.5 +/- 0.6) levels were reduced in 17 alpha-hydroxylase deficiency; levels of all three steroids (aldosterone 2.6 +/- 0.4, 18-hydroxycorticosterone 5.1 +/- 3.1, 18-hydroxydeoxycorticosterone 0.9 +/- 0.1) were reduced in 11 beta-hydroxylase deficiency. It is suggested that simultaneous measurement of these three steroids can be useful in identifying and further characterizing each of these forms of congenital adrenal hyperplasia. PMID:6602548

  8. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

    PubMed

    Kooner, Jaspal S; Saleheen, Danish; Sim, Xueling; Sehmi, Joban; Zhang, Weihua; Frossard, Philippe; Been, Latonya F; Chia, Kee-Seng; Dimas, Antigone S; Hassanali, Neelam; Jafar, Tazeen; Jowett, Jeremy B M; Li, Xinzhong; Radha, Venkatesan; Rees, Simon D; Takeuchi, Fumihiko; Young, Robin; Aung, Tin; Basit, Abdul; Chidambaram, Manickam; Das, Debashish; Grundberg, Elin; Hedman, Asa K; Hydrie, Zafar I; Islam, Muhammed; Khor, Chiea-Chuen; Kowlessur, Sudhir; Kristensen, Malene M; Liju, Samuel; Lim, Wei-Yen; Matthews, David R; Liu, Jianjun; Morris, Andrew P; Nica, Alexandra C; Pinidiyapathirage, Janani M; Prokopenko, Inga; Rasheed, Asif; Samuel, Maria; Shah, Nabi; Shera, A Samad; Small, Kerrin S; Suo, Chen; Wickremasinghe, Ananda R; Wong, Tien Yin; Yang, Mingyu; Zhang, Fan; Abecasis, Goncalo R; Barnett, Anthony H; Caulfield, Mark; Deloukas, Panos; Frayling, Timothy M; Froguel, Philippe; Kato, Norihiro; Katulanda, Prasad; Kelly, M Ann; Liang, Junbin; Mohan, Viswanathan; Sanghera, Dharambir K; Scott, James; Seielstad, Mark; Zimmet, Paul Z; Elliott, Paul; Teo, Yik Ying; McCarthy, Mark I; Danesh, John; Tai, E Shyong; Chambers, John C

    2011-10-01

    We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D. PMID:21874001

  9. Multi-virulence-locus sequence typing identifies single nucleotide polymorphisms which differentiate epidemic clones and outbreak strains of Listeria monocytogenes.

    PubMed

    Chen, Yi; Zhang, Wei; Knabel, Stephen J

    2007-03-01

    A recently developed multi-virulence-locus sequence typing (MVLST) method showed improved discriminatory power for subtyping genetically diverse Listeria monocytogenes isolates and identified epidemic clone II isolates associated with two recent U.S. multistate listeriosis outbreaks. To evaluate the ability of MVLST to distinguish other epidemic clones and outbreak strains of L. monocytogenes, 58 outbreak-related isolates from 14 outbreaks and 49 unrelated isolates were analyzed. Results showed that MVLST provided very high discriminatory power (0.99), epidemiological concordance (1.0), stability, and typeability. MVLST accurately identified three previously known epidemic clones (epidemic clones I, II, and III) and redefined another epidemic clone (epidemic clone IV) in serotype 4b of L. monocytogenes. A set of 28 single nucleotide polymorphisms (SNPs) differentiated all epidemiologically unrelated isolates. A subset of 16 SNPs differentiated all epidemic clones and outbreak strains. Phylogenetic analysis showed congruence between MVLST clusters, serotypes, and previously defined genetic lineages of L. monocytogenes. SNPs in virulence genes appear to be excellent molecular markers for the epidemiological investigation of epidemics and outbreaks caused by L. monocytogenes. PMID:17215339

  10. Multi-Virulence-Locus Sequence Typing Identifies Single Nucleotide Polymorphisms Which Differentiate Epidemic Clones and Outbreak Strains of Listeria monocytogenes?

    PubMed Central

    Chen, Yi; Zhang, Wei; Knabel, Stephen J.

    2007-01-01

    A recently developed multi-virulence-locus sequence typing (MVLST) method showed improved discriminatory power for subtyping genetically diverse Listeria monocytogenes isolates and identified epidemic clone II isolates associated with two recent U.S. multistate listeriosis outbreaks. To evaluate the ability of MVLST to distinguish other epidemic clones and outbreak strains of L. monocytogenes, 58 outbreak-related isolates from 14 outbreaks and 49 unrelated isolates were analyzed. Results showed that MVLST provided very high discriminatory power (0.99), epidemiological concordance (1.0), stability, and typeability. MVLST accurately identified three previously known epidemic clones (epidemic clones I, II, and III) and redefined another epidemic clone (epidemic clone IV) in serotype 4b of L. monocytogenes. A set of 28 single nucleotide polymorphisms (SNPs) differentiated all epidemiologically unrelated isolates. A subset of 16 SNPs differentiated all epidemic clones and outbreak strains. Phylogenetic analysis showed congruence between MVLST clusters, serotypes, and previously defined genetic lineages of L. monocytogenes. SNPs in virulence genes appear to be excellent molecular markers for the epidemiological investigation of epidemics and outbreaks caused by L. monocytogenes. PMID:17215339

  11. A chemical biology approach identified PI3K as a potential therapeutic target for neurofibromatosis type 2

    PubMed Central

    Petrilli, Alejandra M; Fuse, Marisa A; Donnan, Mathew S; Bott, Marga; Sparrow, Nicklaus A; Tondera, Daniel; Huffziger, Julia; Frenzel, Corina; Malany, C Siobhan; Echeverri, Christophe J; Smith, Layton; Fernández-Valle, Cristina

    2014-01-01

    Mutations in the merlin tumor suppressor gene cause Neurofibromatosis type 2 (NF2), which is a disease characterized by development of multiple benign tumors in the nervous system. The current standard of care for NF2 calls for surgical resection of the characteristic tumors, often with devastating neurological consequences. There are currently no approved non-surgical therapies for NF2. In an attempt to identify much needed targets and therapeutically active compounds for NF2 treatment, we employed a chemical biology approach using ultra-high-throughput screening. To support this goal, we created a merlin-null mouse Schwann cell (MSC) line to screen for compounds that selectively decrease their viability and proliferation. We optimized conditions for 384-well plate assays and executed a proof-of-concept screen of the Library of Pharmacologically Active Compounds. Further confirmatory and selectivity assays identified phosphatidylinositol 3-kinase (PI3K) as a potential NF2 drug target. Notably, loss of merlin function is associated with activation of the PI3K/Akt pathway in human schwannomas. We report that AS605240, a PI3K inhibitor, decreased merlin-null MSC viability in a dose-dependent manner without significantly decreasing viability of control Schwann cells. AS605240 exerted its action on merlin-null MSCs by promoting caspase-dependent apoptosis and inducing autophagy. Additional PI3K inhibitors tested also decreased viability of merlin-null MSCs in a dose-dependent manner. In summary, our chemical genomic screen and subsequent hit validation studies have identified PI3K as potential target for NF2 therapy. PMID:25360213

  12. The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color

    PubMed Central

    2013-01-01

    Background Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. Results We describe the sequencing and assembly of the genome of Theobroma cacao L. cultivar Matina 1-6. The genome of the Matina 1-6 cultivar is 445 Mbp, which is significantly larger than a sequenced Criollo cultivar, and more typical of other cultivars. The chromosome-scale assembly, version 1.1, contains 711 scaffolds covering 346.0 Mbp, with a contig N50 of 84.4 kbp, a scaffold N50 of 34.4 Mbp, and an evidence-based gene set of 29,408 loci. Version 1.1 has 10x the scaffold N50 and 4x the contig N50 as Criollo, and includes 111 Mb more anchored sequence. The version 1.1 assembly has 4.4% gap sequence, while Criollo has 10.9%. Through a combination of haplotype, association mapping and gene expression analyses, we leverage this robust reference genome to identify a promising candidate gene responsible for pod color variation. We demonstrate that green/red pod color in cacao is likely regulated by the R2R3 MYB transcription factor TcMYB113, homologs of which determine pigmentation in Rosaceae, Solanaceae, and Brassicaceae. One SNP within the target site for a highly conserved trans-acting siRNA in dicots, found within TcMYB113, seems to affect transcript levels of this gene and therefore pod color variation. Conclusions We report a high-quality sequence and annotation of Theobroma cacao L. and demonstrate its utility in identifying candidate genes regulating traits. PMID:23731509

  13. Mathematical Modeling and Experimental Validation of the Spatial Distribution of Boron in the Root of Arabidopsis thaliana Identify High Boron Accumulation in the Tip and Predict a Distinct Root Tip Uptake Function

    PubMed Central

    Shimotohno, Akie; Sotta, Naoyuki; Sato, Takafumi; De Ruvo, Micol; Marée, Athanasius F.M.; Grieneisen, Verônica A.; Fujiwara, Toru

    2015-01-01

    Boron, an essential micronutrient, is transported in roots of Arabidopsis thaliana mainly by two different types of transporters, BORs and NIPs (nodulin26-like intrinsic proteins). Both are plasma membrane localized, but have distinct transport properties and patterns of cell type-specific accumulation with different polar localizations, which are likely to affect boron distribution. Here, we used mathematical modeling and an experimental determination to address boron distributions in the root. A computational model of the root is created at the cellular level, describing the boron transporters as observed experimentally. Boron is allowed to diffuse into roots, in cells and cell walls, and to be transported over plasma membranes, reflecting the properties of the different transporters. The model predicts that a region around the quiescent center has a higher concentration of soluble boron than other portions. To evaluate this prediction experimentally, we determined the boron distribution in roots using laser ablation-inductivity coupled plasma-mass spectrometry. The analysis indicated that the boron concentration is highest near the tip and is lower in the more proximal region of the meristem zone, similar to the pattern of soluble boron distribution predicted by the model. Our model also predicts that upward boron flux does not continuously increase from the root tip toward the mature region, indicating that boron taken up in the root tip is not efficiently transported to shoots. This suggests that root tip-absorbed boron is probably used for local root growth, and that instead it is the more mature root regions which have a greater role in transporting boron toward the shoots. PMID:25670713

  14. Mathematical Modeling and Experimental Validation of the Spatial Distribution of Boron in the Root of Arabidopsis thaliana Identify High Boron Accumulation in the Tip and Predict a Distinct Root Tip Uptake Function.

    PubMed

    Shimotohno, Akie; Sotta, Naoyuki; Sato, Takafumi; De Ruvo, Micol; Marée, Athanasius F M; Grieneisen, Verônica A; Fujiwara, Toru

    2015-04-01

    Boron, an essential micronutrient, is transported in roots of Arabidopsis thaliana mainly by two different types of transporters, BORs and NIPs (nodulin26-like intrinsic proteins). Both are plasma membrane localized, but have distinct transport properties and patterns of cell type-specific accumulation with different polar localizations, which are likely to affect boron distribution. Here, we used mathematical modeling and an experimental determination to address boron distributions in the root. A computational model of the root is created at the cellular level, describing the boron transporters as observed experimentally. Boron is allowed to diffuse into roots, in cells and cell walls, and to be transported over plasma membranes, reflecting the properties of the different transporters. The model predicts that a region around the quiescent center has a higher concentration of soluble boron than other portions. To evaluate this prediction experimentally, we determined the boron distribution in roots using laser ablation-inductivity coupled plasma-mass spectrometry. The analysis indicated that the boron concentration is highest near the tip and is lower in the more proximal region of the meristem zone, similar to the pattern of soluble boron distribution predicted by the model. Our model also predicts that upward boron flux does not continuously increase from the root tip toward the mature region, indicating that boron taken up in the root tip is not efficiently transported to shoots. This suggests that root tip-absorbed boron is probably used for local root growth, and that instead it is the more mature root regions which have a greater role in transporting boron toward the shoots. PMID:25670713

  15. Global Biochemical Profiling Identifies ?-Hydroxypyruvate as a Potential Mediator of Type 2 Diabetes in Mice and Humans.

    PubMed

    Zhang, Sheng; Wang, Songyan; Puhl, Matthew D; Jiang, Xuntian; Hyrc, Krzysztof L; Laciny, Erin; Wallendorf, Michael J; Pappan, Kirk L; Coyle, Joseph T; Wice, Burton M

    2015-04-01

    Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the "incretin response." To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin-expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. ?-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting ?-hydroxypyruvate production from d-serine. In vitro, ?-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. ?-Hydroxypyruvate-to-d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to ?-hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and ?-cells by regulating ?-hydroxypyruvate levels. PMID:25368100

  16. Suzaku Studies of the Central Engine in the Typical Type I Seyfert NGC 3227: Detection of Multiple Primary X-Ray Continua with Distinct Properties

    NASA Astrophysics Data System (ADS)

    Noda, Hirofumi; Makishima, Kazuo; Yamada, Shin'ya; Nakazawa, Kazuhiro; Sakurai, Soki; Miyake, Katsuma

    2014-10-01

    The type I Seyfert galaxy NGC 3227 was observed by Suzaku six times in 2008, with intervals of ~1 week and net exposures of ~50 ks each. Among the six observations, the source varied by nearly an order of magnitude; it was brightest in the first observation with a 2-10 keV luminosity of 1.2 × 1042 erg s-1, while faintest in the fourth observation with 2.9 × 1041 erg s-1. As it became fainter, the continuum in the 2-45 keV band became harder, while the narrow Fe-K? emission line, detected on all occasions at 6.4 keV of the source rest frame, remained approximately constant in the photon flux. Through a method of variability-assisted broadband spectroscopy, the 2-45 keV spectrum of NGC 3227 was decomposed into three distinct components. One is a relatively soft power-law continuum with a photon index of ~2.3, weakly absorbed and highly variable on timescales of ~5 ks it was observed only when the source was above a threshold luminosity of ~6.6 × 1041 erg s-1 (in 2-10 keV), and was responsible for further source brightening beyond. Another is a harder and more absorbed continuum with a photon index of ~1.6, which persisted through the six observations and varied slowly on timescales of a few weeks by a factor of ~2. This component, carrying a major fraction of the broadband emission when the source is below the threshold luminosity, is considered as an additional primary emission. The last one is a reflection component with the narrow iron line, produced at large distances from the central black hole.

  17. Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis

    PubMed Central

    Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.

    2014-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count. PMID:25329635

  18. Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

    PubMed

    Pemov, Alexander; Sung, Heejong; Hyland, Paula L; Sloan, Jennifer L; Ruppert, Sarah L; Baldwin, Andrea M; Boland, Joseph F; Bass, Sara E; Lee, Hyo Jung; Jones, Kristine M; Zhang, Xijun; Mullikin, James C; Widemann, Brigitte C; Wilson, Alexander F; Stewart, Douglas R

    2014-10-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count. PMID:25329635

  19. Modified Needle-Tip PcrV Proteins Reveal Distinct Phenotypes Relevant to the Control of Type III Secretion and Intoxication by Pseudomonas aeruginosa

    PubMed Central

    Sato, Hiromi; Hunt, Meredith L.; Weiner, Joshua J.; Hansen, Andrew T.; Frank, Dara W.

    2011-01-01

    The type III secretion system (T3SS) is employed to deliver effector proteins to the cytosol of eukaryotic hosts by multiple species of Gram-negative bacteria, including Pseudomonas aeruginosa. Translocation of effectors is dependent on the proteins encoded by the pcrGVHpopBD operon. These proteins form a T3S translocator complex, composed of a needle-tip complex (PcrV), translocons (PopB and PopD), and chaperones (PcrG and PcrH). PcrV mediates the folding and insertion of PopB/PopD in host plasmic membranes, where assembled translocons form a translocation channel. Assembly of this complex and delivery of effectors through this machinery is tightly controlled by PcrV, yet the multifunctional aspects of this molecule have not been defined. In addition, PcrV is a protective antigen for P. aeruginosa infection as is the ortholog, LcrV, for Yersinia. We constructed PcrV derivatives containing in-frame linker insertions and site-specific mutations. The expression of these derivatives was regulated by a T3S-specific promoter in a pcrV-null mutant of PA103. Nine derivatives disrupted the regulation of effector secretion and constitutively released an effector protein into growth medium. Three of these regulatory mutants, in which the linker was inserted in the N-terminal globular domain, were competent for the translocation of a cytotoxin, ExoU, into eukaryotic host cells. We also isolated strains expressing a delayed-toxicity phenotype, which secrete translocators slowly despite the normal level of effector secretion. Most of the cytotoxic translocation-competent strains retained the protective epitope of PcrV derivatives, and Mab166 was able to protect erythrocytes during infection with these strains. The use of defined PcrV derivatives possessing distinct phenotypes may lead to a better understanding of the functional aspects of T3 needle-tip proteins and the development of therapeutic agents or vaccines targeting T3SS-mediated intoxication. PMID:21479247

  20. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal-type

    E-print Network

    Paris-Sud XI, Université de

    1 Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies

  1. Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes

    PubMed Central

    2010-01-01

    Background Skeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers. Methods We profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes. Results The muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 × 10-8), post-translational modification (P < 9.7 × 10-5) and developmental (P < 1.3 × 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation. Conclusions We provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions. PMID:20353613

  2. Genetic disassembly and combinatorial reassembly identify a minimal functional repertoire of type III effectors in Pseudomonas syringae

    PubMed Central

    Cunnac, Sébastien; Chakravarthy, Suma; Kvitko, Brian H.; Russell, Alistair B.; Martin, Gregory B.; Collmer, Alan

    2011-01-01

    The virulence of Pseudomonas syringae and many other proteobacterial pathogens is dependent on complex repertoires of effector proteins injected into host cells by type III secretion systems. The 28 well-expressed effector genes in the repertoire of the model pathogen P. syringae pv. tomato DC3000 were deleted to produce polymutant DC3000D28E. Growth of DC3000D28E in Nicotiana benthamiana was symptomless and 4 logs lower than that of DC3000?hopQ1-1, which causes disease in this model plant. DC3000D28E seemed functionally effectorless but otherwise WT in diagnostic phenotypes relevant to plant interactions (for example, ability to inject the AvrPto-Cya reporter into N. benthamiana). Various effector genes were integrated by homologous recombination into native loci or by a programmable or random in vivo assembly shuttle (PRIVAS) system into the exchangeable effector locus in the Hrp pathogenicity island of DC3000D28E. The latter method exploited dual adapters and recombination in yeast for efficient assembly of PCR products into programmed or random combinations of multiple effector genes. Native and PRIVAS-mediated integrations were combined to identify a minimal functional repertoire of eight effector genes that restored much of the virulence of DC3000?hopQ1-1 in N. benthamiana, revealing a hierarchy in effector function: AvrPtoB acts with priority in suppressing immunity, enabling other effectors to promote further growth (HopM1 and HopE1), chlorosis (HopG1), lesion formation (HopAM1-1), and near full growth and symptom production (AvrE, HopAA1-1, and/or HopN1 functioning synergistically with the previous effectors). DC3000D28E, the PRIVAS method, and minimal functional repertoires provide new resources for probing the plant immune system. PMID:21282655

  3. A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans.

    PubMed

    Li, Huaixing; Gan, Wei; Lu, Ling; Dong, Xiao; Han, Xueyao; Hu, Cheng; Yang, Zhen; Sun, Liang; Bao, Wei; Li, Pengtao; He, Meian; Sun, Liangdan; Wang, Yiqin; Zhu, Jingwen; Ning, Qianqian; Tang, Yong; Zhang, Rong; Wen, Jie; Wang, Di; Zhu, Xilin; Guo, Kunquan; Zuo, Xianbo; Guo, Xiaohui; Yang, Handong; Zhou, Xianghai; Zhang, Xuejun; Qi, Lu; Loos, Ruth J F; Hu, Frank B; Wu, Tangchun; Liu, Ying; Liu, Liegang; Yang, Ze; Hu, Renming; Jia, Weiping; Ji, Linong; Li, Yixue; Lin, Xu

    2013-01-01

    Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of ?-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility. PMID:22961080

  4. The Cribriform Pattern Identifies a Subset of Acinar Predominant Tumors with Poor Prognosis in Patients with Stage I Lung Adenocarcinoma: A Conceptual Proposal to Classify Cribriform Predominant Tumors as a Distinct Histologic Subtype

    PubMed Central

    Kadota, Kyuichi; Yeh, Yi-Chen; Sima, Camelia S.; Rusch, Valerie W.; Moreira, Andre L.; Adusumilli, Prasad S.; Travis, William D.

    2015-01-01

    The 2011 IASLC/ATS/ERS lung adenocarcinoma classification emphasizes the prognostic significance of histologic subtypes. However, one limitation of this classification is that the highest percentage of patients (~40%) is classified as acinar predominant tumors, and these patients display a spectrum of favorable and unfavorable clinical behaviors. We investigated whether the cribriform pattern can further stratify prognosis by histologic subtype. Tumor slides from 1038 patients with stage I lung adenocarcinoma (1995–2009) were reviewed. Tumors were classified according to the IASLC/ATS/ERS classification. The percentage of cribriform pattern was recorded, and the cribriform predominant subtype was considered as a subtype for analysis. The log-rank test was used to analyze the association between histologic variables and recurrence-free probability. The 5-year recurrence-free probability for patients with cribriform predominant tumors (n=46) wasa 70%. The recurrence-free probability for patients with cribriform predominant tumors was significantly lower than that for patients with acinar (5-year recurrence-free probability, 87%; P=0.002) or papillary predominant tumors (83%; P=0.020) but was comparable to that for patients with micropapillary (P=0.34) or solid predominant tumors (P=0.56). The recurrence-free probability for patients with ?10% cribriform pattern tumors (n=214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with <10% cribriform pattern tumors (n=824; 84%; P<0.001). In multivariate analysis, patients with acinar predominant tumors with ?10% cribriform pattern remained at significantly increased risk of recurrence, compared with those with <10% cribriform pattern (P=0.042). Cribriform predominant tumors should be considered a distinct subtype with a high risk of recurrence, and presence (?10%) of the cribriform pattern is an independent predictor of recurrence, identifying a poor prognostic subset of acinar predominant tumors. Our findings highlight the important prognostic value of comprehensive histologic subtyping and recording the percentage of each histologic pattern, according to the IASLC/ATS/ERS classification with the addition of the cribriform subtype. PMID:24186133

  5. Genomes of Ashbya Fungi Isolated from Insects Reveal Four Mating-Type Loci, Numerous Translocations, Lack of Transposons, and Distinct Gene Duplications

    PubMed Central

    Dietrich, Fred S.; Voegeli, Sylvia; Kuo, Sidney; Philippsen, Peter

    2013-01-01

    The filamentous fungus Ashbya gossypii is a cotton pathogen transmitted by insects. It is readily grown and manipulated in the laboratory and is commercially exploited as a natural overproducer of vitamin B2. Our previous genome analysis of A. gossypii isolate ATCC10895, collected in Trinidad nearly 100 years ago, revealed extensive synteny with the Saccharomyces cerevisiae genome, leading us to use it as a model organism to understand the evolution of filamentous growth. To further develop Ashbya as a model system, we have investigated the ecological niche of A. gossypii and isolated additional strains and a sibling species, both useful in comparative analysis. We isolated fungi morphologically similar to A. gossypii from different plant-feeding insects of the suborder Heteroptera, generated a phylogenetic tree based on rDNA-ITS sequences, and performed high coverage short read sequencing with one A. gossypii isolate from Florida, a new species, Ashbya aceri, isolated in North Carolina, and a genetically marked derivative of ATCC10895 intensively used for functional studies. In contrast to S. cerevisiae, all strains carry four not three mating type loci, adding a new puzzle in the evolution of Ashbya species. Another surprise was the genome identity of 99.9% between the Florida strain and ATCC10895, isolated in Trinidad. The A. aceri and A. gossypii genomes show conserved gene orders rearranged by eight translocations, 90% overall sequence identity, and fewer tandem duplications in the A. aceri genome. Both species lack transposable elements. Finally, our work identifies plant-feeding insects of the suborder Heteroptera as the most likely natural reservoir of Ashbya, and that infection of cotton and other plants may be incidental to the growth of the fungus in its insect host. PMID:23749448

  6. Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Breast Cancer Latency and Affect Tumor Type

    PubMed Central

    Nguyen, David H.; Oketch-Rabah, Hellen A.; Illa-Bochaca, Irineu; Geyer, Felipe C.; Reis-Filho, Jorge S.; Mao, Jian-Hua; Ravani, Shraddha A.; Zavadil, Jiri; Borowsky, Alexander D.; Jerry, D. Joseph; Dunphy, Karen A.; Seo, Jae Hong; Haslam, Sandra; Medina, Daniel; Barcellos-Hoff, Mary Helen

    2011-01-01

    SUMMARY Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from non-irradiated hosts. Molecular and genetic approaches show that TGF? mediated tumor acceleration; molecular signatures implicated TGF? and genetically reducing TGF? abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGF? independent and linked to mammary stem cell activity. Thus the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms. PMID:21575864

  7. Complexes between tissue-type plasminogen activator and proteinase inhibitors in human plasma, identified with an immunoradiometric assay

    SciTech Connect

    Rijken, D.C. (Univ. of Leuven, Belgium); Juhan-Vague, I.; Collen, D.

    1983-02-01

    Extrinsic (tissue-type) plasminogen activator antigen in human plasma, as measured by a two-site immunoradiometric assay, is composed of a fibrin-adsorbable and a nonadsorbable fraction. Gel filtration on Ultrogel AcA 44 in 1.6M KSCN of the fibrin-adsorbable fraction showed a peak with M/sub r/ approx. =70,000, which contained plasminogen activator activity and was assumed to represent free extrinsic plasminogen activator. The nonadsorbable fraction showed a broad peak with M/sub r/ approx. =140,000 without plasminogen activator activity. Overnight incubation at 37/sup 0/C of postexercise plasma revealed a shift of the M/sub r/ approx. =70,000 peak to the M/sub r/ approx. =140,000 position, suggesting that the M/sub r/ approx. =140,000 peak consists of extrinsic plasminogen activator-protease inhibitor complex(es). ..cap alpha../sub 2/-Antiplasmin is the main inhibitor of extrinsic plasminogen activator in plasma and is probably responsible for the generation of the M/sub r/ approx. =140,000 component. A possible involvement of other plasma proteinase inhibitors was explored by incubation of /sup 125/I-labeled extrinsic plasminogen activator in ..cap alpha../sub 2/-antiplasmin-depleted plasma. A complex was formed with a t1/2 of about 1 hr, which was identified by immunoprecipitation as extrinsic plasminogen activator-..cap alpha../sub 2/-antiplasmin complex. Additional evidence for the presence of extrinsic plasminogen activator complexes with ..cap alpha../sub 2/-antiplasmin and ..cap alpha../sub 1/-antitrypsin in plasma was obtained from two-site immunoradiometric assays. It was concluded that plasma contains both free extrinsic plasminogen activator and plasminogen activator complexes with ..cap alpha../sub 2/-antiplasmin and ..cap alpha../sub 1/-antitrypsin. These complexes are also present in plasma collected on the active site inhibitor, D-Phe-Pro-Arg-CH/sub 2/Cl, at rest and after exercise and are therefore assumed to circulate in vivo. (JMT)

  8. In vivo and in vitro studies of GAD-antibody positive subjects with Type 2 diabetes: A distinct sub-phenotype

    Microsoft Academic Search

    Donal J. O’Gorman; Obada Yousif; Gordon Dixon; Siobhan McQuaid; Elaine Murphy; Yousif Rahman; Declan Gasparro; Giovanni Pacini; Philip Newsholme; John J. Nolan

    2008-01-01

    The purpose of this study was to determine if immune mechanisms in GAD positive patients’ contribute to the pathogenesis of a specific sub-type of Type 2 diabetes. GAD positive (n=8) and GAD negative (n=8) subjects diagnosed with Type 2 diabetes were matched for age, gender, body mass index, duration of diabetes and glycaemic control. All subjects underwent an insulin-modified frequently

  9. Identifying the progenitor set of present-day early-type galaxies: a view from the standard model

    NASA Astrophysics Data System (ADS)

    Kaviraj, S.; Devriendt, J. E. G.; Ferreras, I.; Yi, S. K.; Silk, J.

    2009-08-01

    We present a comprehensive theoretical study, using a semi-analytical model within the standard LCDM framework, of the photometric properties of the progenitors of present-day early-type galaxies in the redshift range 0 < z < 1. We explore progenitors of all morphologies and study their characteristics as a function of the luminosity and local environment of the early-type remnant at z = 0. In agreement with previous studies, we find that, while larger early-types are generally assembled later, their luminosity-weighted stellar ages are typically older. In dense cluster-like environments, ~70 percent of early-type systems are “in place” by z = 1 and evolve without interactions thereafter, while in the field the corresponding value is ~30 percent. Averaging across all environments at z ~ 1, less than 50 percent of the stellar mass which ends up in early-types today is actually in early-type progenitors at this redshift, in agreement with recent observational work. The corresponding value is ~65 percent in clusters, due to faster morphological evolution in such dense environments. We develop probabilistic prescriptions which provide a means of including spiral (i.e. non early-type) progenitors at intermediate and high redshifts, based on their luminosity and optical colours. For example, we find that, at intermediate redshifts (z ~ 0.5), large (MV < -21.5), red (B-V > 0.7) spirals have ~75-95 percent chance of being an early-type progenitor, while the corresponding probability for large blue spirals (MB < -21.5, B-V < 0.7) is ~50-75 percent. The prescriptions developed here can be used to address, from the perspective of the standard model, the issue of “progenitor bias”, whereby the exclusion of late-type progenitors in observational studies can lead to inaccurate conclusions regarding the evolution of the early-type population over cosmic time. Finally, we explore the correspondence between the true “progenitor set” of the present-day early-type population - defined as the set of all galaxies that are progenitors of present-day early-types regardless of their morphologies - and the frequently used “red-sequence”, defined as the set of galaxies within the part of the colour-magnitude space which is dominated by early-type objects. We find that, while more massive members (MV ? -21) of the “red sequence” trace the progenitor set reasonably well, the relationship breaks down at fainter luminosities (MV ? -21). Thus, while the results of recent observational studies which exploit the red sequence are valid (since they are largely restricted to massive galaxies), more care should be taken when deeper observations (which will probe fainter luminosities) become available in the future.

  10. Genotypic characterization of Toxoplasma gondii in sheep from Brazilian slaughterhouses: New atypical genotypes and the clonal type II strain identified

    Microsoft Academic Search

    Rodrigo Costa da Silva; Helio Langoni; Chunlei Su; Aristeu Vieira da Silva

    2011-01-01

    Toxoplasma gondii strains are genetically diverse in South America. To date, hundreds of T. gondii isolates from different animal hosts were genotyped in Brazil, most of them are different from those identified around the world. This study aimed to determine T. gondii infection rate in sheep from Brazilian slaughterhouses, as well as the genotype of these isolates. T. gondii antibodies

  11. In vivo and in vitro studies of GAD-antibody positive subjects with Type 2 diabetes: A distinct sub-phenotype.

    PubMed

    O'Gorman, Donal J; Yousif, Obada; Dixon, Gordon; McQuaid, Siobhan; Murphy, Elaine; Rahman, Yousif; Gasparro, Declan; Pacini, Giovanni; Newsholme, Philip; Nolan, John J

    2008-06-01

    The purpose of this study was to determine if immune mechanisms in GAD positive patients' contribute to the pathogenesis of a specific sub-type of Type 2 diabetes. GAD positive (n=8) and GAD negative (n=8) subjects diagnosed with Type 2 diabetes were matched for age, gender, body mass index, duration of diabetes and glycaemic control. All subjects underwent an insulin-modified frequently sampled intravenous glucose tolerance test to measure insulin sensitivity and insulin secretory function with minimal model analysis. In addition, BRIN-BD11 clonal beta-cells were supplemented with patients' sera to determine basal and alanine-stimulated insulin secretion and terminal complement complex (TCC) formation. Both groups were severely insulin resistant (0.56+/-0.17 vs. 0.99+/-0.3310(-4)min(-1)/(microUml(-1)) for GADneg and GADpos, respectively) but the GAD negative subjects had a higher basal (87+/-11 vs. 58+/-14pmoll(-1), p<0.05) and glucose-stimulated insulin secretion (DeltaAUCins 0.96+/-0.12 vs. 0.60+/-0.12pmol/(l(-1)min), p<0.05). In vivo measures of insulin secretion were negatively correlated with TCC formation, independent of antibody status. In conclusion, GAD positive subjects initially diagnosed with Type 2 diabetes are unable to compensate for insulin resistance due to more pronounced beta-cell impairment. TCC formation may be partly responsible for the insulin secretory dysfunction associated with this specific sub-type of Type 2 diabetes. PMID:18405999

  12. A sodium channel mutation identified in Aedes aegypti selectively reduces cockroach sodium channel sensitivity to type I, but not type II pyrethroids

    Microsoft Academic Search

    Zhaonong Hu; Yuzhe Du; Yoshiko Nomura; Ke Dong

    2011-01-01

    Voltage-gated sodium channels are the primary target of pyrethroid insecticides. Numerous point mutations in sodium channel genes have been identified in pyrethroid-resistant insect species, and many have been confirmed to reduce or abolish sensitivity of channels expressed in Xenopus oocytes to pyrethroids. Recently, several novel mutations were reported in sodium channel genes of pyrethroid-resistant Aedes mosquito populations. One of the

  13. Phylogenetic Analysis of Clinical Herpes Simplex Virus Type 1 Isolates Identified Three Genetic Groups and Recombinant Viruses

    Microsoft Academic Search

    Peter Norberg; Tomas Bergstrom; Elham Rekabdar; Magnus Lindh; J.-A. Liljeqvist

    2004-01-01

    Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen which establishes lifelong infections. In the present study, we determined the sequence diversity of the complete genes coding for glycoproteins G (gG), I (gI), and E (gE), comprising 2.3% of the HSV-1 genome and located within the unique short (US) region, for 28 clinical HSV-1 isolates inducing oral lesions,

  14. Distinct HIV Type 1 Strains in Different Risk Groups and the Absence of New Infections by Drug-Resistant Strains in Lithuania

    PubMed Central

    Caplinskas, Saulius; Loukachov, Vladimir V.; Gasich, Elena L.; Gilyazova, Alla V.; Caplinskiene, Irma

    2013-01-01

    Abstract To analyze HIV-1 genotypes in Lithuania and the transmission of drug-resistant viruses, HIV-1 sequences were obtained from 138 individuals, who were diagnosed as HIV-1 infected in 1990–2008 and represented all major risk groups. Subtype A strains, dominating in the former Soviet Union (90% of cases), were found in 60% of individuals, followed by subtype B (22%) and CRF03_AB (12%) strains. The remaining 7% of the strains included variants belonging to subtype C, CRF01_AE, CRF02_AG, more complex recombinant forms, and strains that could not be reliably genotyped. Analysis of virus genotypes per risk group revealed the circulation of distinct HIV-1 strains in different risk groups: subtype A viruses were present in 82% of injecting drug users (IDUs), but less than a half of heterosexually infected individuals and cases with unknown transmission route, and none of men having sex with men (MSM). We observed no mutations causing drug resistance among 27 newly diagnosed HIV-1 cases. PMID:23186249

  15. Sarco/endoplasmic reticulum Ca2+ATPase type 3 isoforms (SERCA3b and SERCA3f): distinct roles in cell adhesion and ER stress.

    PubMed

    Chaâbane, Chiraz; Corvazier, Elisabeth; Bredoux, Raymonde; Dally, Saoussen; Raïes, Aly; Villemain, Aude; Dupuy, Evelyne; Enouf, Jocelyne; Bobe, Régis

    2006-07-14

    Sarco/endoplasmic reticulum Ca(2+)ATPases (SERCAs) pump free Ca(2+) from the cytosol into the endoplasmic reticulum. The human SERCA3 family counts six members named SERCA3a to 3f. However, the exact role of these different isoforms in cellular physiology remains undetermined. In this study, we compared some physiological consequences of SERCA3b and SERCA3f overexpression in HEK-293 cells. We observed that overexpression of SERCA3b affected cell adhesion capacity associated with a major disorganization of F-actin and a decrease in focal adhesion. Furthermore, we found that SERCA3f overexpression resulted in an increase in endoplasmic reticulum stress markers (including processing of X-box-binding protein-1 (XBP-1) mRNA and expression of chaperone glucose-regulated protein 78 (GRP78)). This was associated with the activation of caspase cascade and a higher spontaneous cell death. In conclusion, these data point for the first time to distinct physiological roles of SERCA3 isoforms in cell functions. PMID:16725111

  16. On the distinction of the mechanisms of DNA cleavage by restriction enzymes—The I-, II-, and III-type molecular motors

    NASA Astrophysics Data System (ADS)

    Pikin, S. A.

    2008-09-01

    A comparative physical description is given for the functioning of various restriction enzymes and for their processes of DNA cleavage. The previously proposed model system of kinetic equations is applied to the I-and III-type enzymes, which use ATP molecules as an energy source, while the II-type enzymes work thanks to catalytic reactions with participation of an electric field. All the enzymes achieved bending and twisting DNA, providing for either the linear motion of the II-type enzyme along the DNA chain or the DNA translocation by the I-and III-type enzymes due to moving chiral kinks. A comparative estimation of the considered linear and angular velocities is performed. The role of stalling forces for enzyme-DNA complexes, which induce the observed cutting of the DNA either inside the enzyme (II) or in some “weak” places outside enzymes I and III, which results in the supercoiling of the DNA, is shown. The role of ionic screening for the described processes is discussed.

  17. Clear Cell Carcinoma of the Ovary: A Distinct Histologic Type with Poor Prognosis and Resistance to Platinum-Based Chemotherapy in Stage III Disease

    Microsoft Academic Search

    Barbara A. Goff; Ricardo Sainz de la Cuesta; Howard G. Muntz; Deborah Fleischhacker; Marit Ek; Laurel W. Rice; Najmosama Nikrui; Hisham K. Tamimi; Joanna M. Cain; Benjamin E. Greer; Arlan F. Fuller Jr.

    1996-01-01

    Between 1982 and 1992, 24 women with Stage III clear cell ovarian cancer were identified from the tumor registry. Thirty-four women with Stage III papillary serous tumors treated between 1987 and 1989 were used as a comparison. All patients underwent cytoreductive surgery followed by conventional platinum-based chemotherapy. In the women with clear cell histology, nine (37.5%) had endometriosis in the

  18. Challenges for using quantitative PCR test batteries as a TIE-type approach to identify metal exposure in benthic invertebrates.

    PubMed

    Hook, Sharon E; Osborn, Hannah L; Spadaro, David A; Simpson, Stuart L

    2014-07-01

    The epibenthic amphipod Melita plumulosa shows unique gene expression profiles when exposed to different contaminants. We hypothesized that specific changes in transcript abundance could be used in a battery of quantitative polymerase chain reaction (qPCR) assays as a toxicity identification evaluation (TIE)-like approach to identify the most relevant stressor in field-contaminated sediments. To test this hypothesis, seven candidate transcriptomic markers were selected, and their specificity following metal exposure was confirmed. The performance of these markers across different levels of added metals was verified. The ability of these transcripts to act as markers was tested by exposing amphipods to metal-contaminated field-collected sediments and measuring changes in transcript abundance via qPCR. For two of the three sediments tested, at least some of the transcriptomic patterns matched our predictions, suggesting that they would be effective in helping to identify metal exposure in field sediments. However, following exposure to the third sediment, transcriptomic patterns were unlike our predictions. These results suggest that the seven transcripts may be insufficient to discern individual contaminants from complex mixtures and that microarray or RNA-Seq global gene expression profiles may be more effective for TIE. Changes in transcriptomics based on laboratory exposures to single compounds should be carefully validated before the results are used to analyze mixtures. PMID:24994105

  19. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci

    Microsoft Academic Search

    Deborah J Smyth; Adam M Smiles; Vincent Plagnol; Neil M Walker; James E Allen; Kate Downes; Jeffrey C Barrett; Barry C Healy; Josyf C Mychaleckyj; James H Warram; John A Todd; Jason D Cooper

    2008-01-01

    We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 × 10?8) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously

  20. Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes

    Microsoft Academic Search

    Iain J Gallagher; Camilla Scheele; Pernille Keller; Anders R Nielsen; Judit Remenyi; Christian P Fischer; Karim Roder; John Babraj; Claes Wahlestedt; Gyorgy Hutvagner; Bente K Pedersen; James A Timmons

    2010-01-01

    Background  Skeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded\\u000a characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of\\u000a protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains\\u000a to be fully elucidated. We produce

  1. A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series

    PubMed Central

    Rousseau-Nepton, Isabelle; Okubo, Minoru; Grabs, Rosemarie; Mitchell, John; Polychronakos, Constantin; Rodd, Celia

    2015-01-01

    Background: Glycogen storage disease type III is caused by mutations in both alleles of the AGL gene, which leads to reduced activity of glycogen-debranching enzyme. The clinical picture encompasses hypoglycemia, with glycogen accumulation leading to hepatomegaly and muscle involvement (skeletal and cardiac). We sought to identify the genetic cause of this disease within the Inuit community of Nunavik, in whom previous DNA sequencing had not identified such mutations. Methods: Five Inuit children with a clinical and biochemical diagnosis of glycogen storage disease type IIIa were recruited to undergo genetic testing: 2 underwent whole-exome sequencing and all 5 underwent Sanger sequencing to confirm the identified mutation. Selected DNA regions near the AGL gene were also sequenced to identify a potential founder effect in the community. In addition, control samples from 4 adults of European descent and 7 family members of the affected children were analyzed for the specific mutation by Sanger sequencing. Results: We identified a homozygous frame-shift deletion, c.4456delT, in exon 33 of the AGL gene in 2 children by whole-exome sequencing. Confirmation by Sanger sequencing showed the same mutation in all 5 patients, and 5 family members were found to be carriers. With the identification of this mutation in 5 probands, the estimated prevalence of genetically confirmed glycogen storage disease type IIIa in this region is among the highest worldwide (1:2500). Despite identical mutations, we saw variations in clinical features of the disease. Interpretation: Our detection of a homozygous frameshift mutation in 5 Inuit children determines the cause of glycogen storage disease type IIIa and confirms a founder effect. PMID:25602008

  2. Comparative genomics of the white-rot fungi, Phanerochaete carnosa and P. chrysosporium, to elucidate the genetic basis of the distinct wood types they colonize

    SciTech Connect

    Suzuki, Hitoshi; MacDonald, Jacqueline; Syed, Khajamohiddin; Salamov, Asaf; Hori, Chiaki; Aerts, Andrea; Henrissat, Bernard; Wiebenga, Ad; vanKuyk, Patricia A.; Barry, Kerrie; Lindquist, Erika; LaButti, Kurt; Lapidus, Alla; Lucas, Susan; Coutinho, Pedro; Gong, Yunchen; Samejima, Masahiro; Mahadevan, Radhakrishnan; Abou-Zaid, Mamdouh; de Vries, Ronald P.; Igarashi, Kiyohiko; Yadav, Jagit S.; Grigoriev, Igor V.; Master, Emma R.

    2012-02-17

    Background Softwood is the predominant form of land plant biomass in the Northern hemisphere, and is among the most recalcitrant biomass resources to bioprocess technologies. The white rot fungus, Phanerochaete carnosa, has been isolated almost exclusively from softwoods, while most other known white-rot species, including Phanerochaete chrysosporium, were mainly isolated from hardwoods. Accordingly, it is anticipated that P. carnosa encodes a distinct set of enzymes and proteins that promote softwood decomposition. To elucidate the genetic basis of softwood bioconversion by a white-rot fungus, the present study reports the P. carnosa genome sequence and its comparative analysis with the previously reported P. chrysosporium genome. Results P. carnosa encodes a complete set of lignocellulose-active enzymes. Comparative genomic analysis revealed that P. carnosa is enriched with genes encoding manganese peroxidase, and that the most divergent glycoside hydrolase families were predicted to encode hemicellulases and glycoprotein degrading enzymes. Most remarkably, P. carnosa possesses one of the largest P450 contingents (266 P450s) among the sequenced and annotated wood-rotting basidiomycetes, nearly double that of P. chrysosporium. Along with metabolic pathway modeling, comparative growth studies on model compounds and chemical analyses of decomposed wood components showed greater tolerance of P. carnosa to various substrates including coniferous heartwood. Conclusions The P. carnosa genome is enriched with genes that encode P450 monooxygenases that can participate in extractives degradation, and manganese peroxidases involved in lignin degradation. The significant expansion of P450s in P. carnosa, along with differences in carbohydrate- and lignin-degrading enzymes, could be correlated to the utilization of heartwood and sapwood preparations from both coniferous and hardwood species.

  3. Comparative genomics of the white-rot fungi, Phanerochaete carnosa and P. chrysosporium, to elucidate the genetic basis of the distinct wood types they colonize

    PubMed Central

    2012-01-01

    Background Softwood is the predominant form of land plant biomass in the Northern hemisphere, and is among the most recalcitrant biomass resources to bioprocess technologies. The white rot fungus, Phanerochaete carnosa, has been isolated almost exclusively from softwoods, while most other known white-rot species, including Phanerochaete chrysosporium, were mainly isolated from hardwoods. Accordingly, it is anticipated that P. carnosa encodes a distinct set of enzymes and proteins that promote softwood decomposition. To elucidate the genetic basis of softwood bioconversion by a white-rot fungus, the present study reports the P. carnosa genome sequence and its comparative analysis with the previously reported P. chrysosporium genome. Results P. carnosa encodes a complete set of lignocellulose-active enzymes. Comparative genomic analysis revealed that P. carnosa is enriched with genes encoding manganese peroxidase, and that the most divergent glycoside hydrolase families were predicted to encode hemicellulases and glycoprotein degrading enzymes. Most remarkably, P. carnosa possesses one of the largest P450 contingents (266 P450s) among the sequenced and annotated wood-rotting basidiomycetes, nearly double that of P. chrysosporium. Along with metabolic pathway modeling, comparative growth studies on model compounds and chemical analyses of decomposed wood components showed greater tolerance of P. carnosa to various substrates including coniferous heartwood. Conclusions The P. carnosa genome is enriched with genes that encode P450 monooxygenases that can participate in extractives degradation, and manganese peroxidases involved in lignin degradation. The significant expansion of P450s in P. carnosa, along with differences in carbohydrate- and lignin-degrading enzymes, could be correlated to the utilization of heartwood and sapwood preparations from both coniferous and hardwood species. PMID:22937793

  4. Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos.

    PubMed Central

    Du, S J; Purcell, S M; Christian, J L; McGrew, L L; Moon, R T

    1995-01-01

    Wnts are secreted signaling factors which influence cell fate and cell behavior in developing embryos. Overexpression in Xenopus laevis embryos of a Xenopus Wnt, Xwnt-8, leads to a duplication of the embryonic axis. In embryos ventralized by UV irradiation, Xwnt-8 restores expression of the putative transcription factor goosecoid, and rescues normal axis formation. In contrast, overexpression of Xwnt-5A in normal embryos generates defects in dorsoanterior structures, without inducing goosecoid or a secondary axis. To determine whether Xwnt-4 and Xwnt-11 fall into one of these two previously described classes of activity, synthetic mRNAs were introduced into animal caps, normal embryos, and UV-treated embryos. The results indicate that Xwnt-4, Xwnt-5A, and Xwnt-11 are members of a single functional class with activities that are indistinguishable in these assays. To investigate whether distinct regions of Xwnt-8 and Xwnt-5A were sufficient for eliciting the observed effects of overexpression, we generated a series of chimeric Xwnts. RNAs encoding the chimeras were injected into normal and UV-irradiated Xenopus embryos. Analysis of the embryonic phenotypes and goosecoid levels reveals that chimeras composed of carboxy-terminal regions of Xwnt-8 and amino-terminal regions of Xwnt-5A are indistinguishable from the activities of native Xwnt-8 and that are the reciprocal chimeras elicit effects indistinguishable from overexpression of native Xwnt-5A. We conclude that the carboxy-terminal halves of these Xwnts are candidate domains for specifying responses to Xwnt signals. PMID:7739543

  5. Predictive Validity of Personality Types Versus Personality Dimensions From Early Childhood to Adulthood: Implications for the Distinction Between Core and Surface Traits

    Microsoft Academic Search

    Jens B. Asendorpf; Jaap J. A. Denissen

    2006-01-01

    This study compared the long-term predictive validity of person-centered personality types and variable-centered personality dimensions assessed between ages 4–6 years in a population sample of 154 children. Results indicated that the predictive power of both approaches was remarkably robust between age 17 and 22, and even increased in the case of aggressiveness. At age 22 the long-term predictive ability of

  6. Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells

    Microsoft Academic Search

    Sandra J. van Vliet; Ellis van Liempt; Eirikur Saeland; Corlien A. Aarnoudse; Ben Appelmelk; Tatsuro Irimura; Teunis B. H. Geijtenbeek; Ola Blixt; Richard Alvarez; Die van I. M; Kooijk van Y

    2005-01-01

    Dendritic cells (DCs) are key to the maintenance of peripheral tolerance to self-antigens and the orchestration of an immune reaction to foreign antigens. C-type lectins, expressed by DCs, recognize carbohydrate moieties on antigens that can be internalized for processing and presentation. Little is known about the exact glycan structures on self-antigens and pathogens that are specifically recognized by the different

  7. Distinct functions and requirements for the Cys-His boxes of the human immunodeficiency virus type 1 nucleocapsid protein during RNA encapsidation and replication.

    PubMed Central

    Schwartz, M D; Fiore, D; Panganiban, A T

    1997-01-01

    The process of retroviral RNA encapsidation involves interaction between trans-acting viral proteins and cis-acting RNA elements. The encapsidation signal on human immunodeficiency virus type 1 (HIV-1) RNA is a multipartite structure composed of functional stem-loop structures. The nucleocapsid (NC) domain of the Gag polyprotein precursor contains two copies of a Cys-His box motif that have been demonstrated to be important in RNA encapsidation. To further characterize the role of the Cys-His boxes of the HIV-1 NC protein in RNA encapsidation, the relative efficiency of RNA encapsidation for virus particles that contained mutations within the Cys-His boxes was measured. Mutations that disrupted the first Cys-His box of the NC protein resulted in virus particles that encapsidated genomic RNA less efficiently and subgenomic RNA more efficiently than did wild-type virus. Mutations within the second Cys-His box did not significantly affect RNA encapsidation. In addition, a full complement of wild-type NC protein in virus particles is not required for efficient RNA encapsidation or virus replication. Finally, both Cys-His boxes of the NC protein play additional roles in virus replication. PMID:9371588

  8. A distinct congenital motor and sensory neuropathy (neuronal type) with dysmorphic features in a father and two sons. A variant of Charcot-Marie-Tooth disease.

    PubMed

    Ruiz, C; Rivas, F; Ramírez-Casillas, G; Vázquez-Santana, R; Mendoza-Chalita, B; Feria-Velasco, A; Tapia-Arizmendi, G; Cantú, J M

    1987-02-01

    A 37-year-old male had clinical and electrophysiological features of hereditary motor and sensory neuropathy (neuronal type) with onset in infancy, as well as histological picture of neurogenic myopathy. Two sons, aged 2 and 3 4/12 years, showed congenital contraction deformities of feet, delayed motor development, and electrophysiological features similar to those of the father. All three also presented laryngeal abnormalities, peculiar facies, short neck, narrow shoulders and protruding chest. The authors conclude that this aggregate of anomalies constitutes a "new" syndrome probably due to an autosomal dominant gene. PMID:3470161

  9. Evolution of type 2 vaccine derived poliovirus lineages. Evidence for codon-specific positive selection at three distinct locations on capsid wall.

    PubMed

    Hovi, Tapani; Savolainen-Kopra, Carita; Smura, Teemu; Blomqvist, Soile; Al-Hello, Haider; Roivainen, Merja

    2013-01-01

    Partial sequences of 110 type 2 poliovirus strains isolated from sewage in Slovakia in 2003-2005, and most probably originating from a single dose of oral poliovirus vaccine, were subjected to a detailed genetic analysis. Evolutionary patterns of these vaccine derived poliovirus strains (SVK-aVDPV2) were compared to those of type 1 and type 3 wild poliovirus (WPV) lineages considered to have a single seed strain origin, respectively. The 102 unique SVK-aVDPV VP1 sequences were monophyletic differing from that of the most likely parental poliovirus type 2/Sabin (PV2 Sabin) by 12.5-15.6%. Judging from this difference and from the rate of accumulation of synonymous transversions during the 22 month observation period, the relevant oral poliovirus vaccine dose had been administered to an unknown recipient more than 12 years earlier. The patterns of nucleotide substitution during the observation period differed from those found in the studied lineages of WPV1 or 3, including a lower transition/transversion (Ts/Tv) bias and strikingly lower Ts/Tv rate ratios at the 2(nd) codon position for both purines and pyrimidines. A relatively low preference of transitions at the 2(nd) codon position was also found in the large set of VP1 sequences of Nigerian circulating (c)VDPV2, as well as in the smaller sets from the Hispaniola cVDPV1 and Egypt cVDPV2 outbreaks, and among aVDPV1and aVDPV2 strains recently isolated from sewage in Finland. Codon-wise analysis of synonymous versus non-synonymous substitution rates in the VP1 sequences suggested that in five codons, those coding for amino acids at sites 24, 144, 147, 221 and 222, there may have been positive selection during the observation period. We conclude that pattern of poliovirus VP1 evolution in prolonged infection may differ from that found in WPV epidemics. Further studies on sufficiently large independent datasets are needed to confirm this suggestion and to reveal its potential significance. PMID:23840537

  10. Two distinct types of cellular mechanisms in the development of delayed hypersensitivity in mice: requirement of either mast cells or macrophages for elicitation of the response.

    PubMed

    Torii, I; Morikawa, S; Harada, T; Kitamura, Y

    1993-03-01

    Using mast cell-deficient mutant W/Wv mice and their normal counterpart we re-evaluated the significance of participation of mast cells in allergic inflammatory response. W/Wv mice developed immediate hypersensitivity (IH) footpad reaction (FPR) to a somewhat lesser degree than the normal mice, suggesting that the mast cell might amplify the response. To exert classical tuberculin (tbc) delayed-type hypersensitivity (DTH) mast cells were not an essential cellular component. Vasoactive amines were essential to develop the response, but it did not necessarily originate from mast cells. When mice were immunized with methylated human serum albumin (MHSA) emulsified in incomplete Freund's adjuvant (IFA), mast cells were required to elicit DTH FPR. This was confirmed by the lack of the response in W/Wv mice, and the restoration of FPR by local transplantation of mature mast cells into mutant mice. This mast cell-dependent (MD) DTH was different from tbc DTH as follows: mast cell dependency, macrophage dependency as revealed by ferritin sensitivity, kinetics of sensitization, effect of host's age and histopathology. Thus we concluded that there are two types of DTH in mice; one is macrophage-dependent tbc and the other is mast cell-dependent DTH. The correspondence of the DTH to the Jones-Mote (JM) DTH is discussed, although the dominance of mast cells in MD DTH lesion was not observed. PMID:8478030

  11. The effect of tissue expansion on the expression of collagen type I and type III mRNA in distinct areas of skin in the dog as an animal model

    Microsoft Academic Search

    G. Plenz; A. Löffler; R. Siegert; H. Weerda; P. K. Müller

    1998-01-01

    To evaluate the transcriptional response of skin to tissue expansion in the dog, the expression of procollagen ?1(I) mRNA\\u000a and procollagen ?1(III) mRNA were analyzed by in situ hybridization. This expression was evaluated in distinct skin areas\\u000a (subepidermal zone, dermis, capsular zone) after 4–85 days of expansion. Within the first 4 days of expansion expression of\\u000a procollagen ?1(I) and ?1(III)

  12. Genome-wide methylation analyses of primary human leukocyte subsets identifies functionally important cell-type–specific hypomethylated regions

    PubMed Central

    Zilbauer, Matthias; Rayner, Tim F.; Clark, Christine; Coffey, Alison J.; Joyce, Chris J.; Palta, Priit; Palotie, Aarno; Smith, Kenneth G. C.

    2013-01-01

    DNA methylation is an important mechanism by which gene transcription and hence cellular function are regulated. Here, we provide detailed functional genome-wide methylome maps of 5 primary peripheral blood leukocyte subsets including T cells, B cells, monocytes/macrophages, and neutrophils obtained from healthy individuals. A comparison of these methylomes revealed highly specific cell-lineage and cell-subset methylation profiles. DNA hypomethylation is known to be permissive for gene expression and we identified cell-subset–specific hypomethylated regions (HMRs) that strongly correlate with gene transcription levels suggesting these HMRs may regulate corresponding cell functions. Single-nucleotide polymorphisms associated with immune-mediated disease in genome-wide association studies preferentially localized to these cell-specific regulatory HMRs, offering insight into pathogenesis by highlighting cell subsets in which specific epigenetic changes may drive disease. Our data provide a valuable reference tool for researchers aiming to investigate the role of DNA methylation in regulating primary leukocyte function in health and immune-mediated disease. PMID:24159175

  13. DNA typing of ancient parasite eggs from environmental samples identifies human and animal worm infections in viking-age settlement.

    PubMed

    Søe, Martin Jensen; Nejsum, Peter; Fredensborg, Brian Lund; Kapel, Christian Moliin Outzen

    2015-02-01

    Ancient parasite eggs were recovered from environmental samples collected at a Viking-age settlement in Viborg, Denmark, dated 1018-1030 A.D. Morphological examination identified Ascaris sp., Trichuris sp., and Fasciola sp. eggs, but size and shape did not allow species identification. By carefully selecting genetic markers, PCR amplification and sequencing of ancient DNA (aDNA) isolates resulted in identification of: the human whipworm, Trichuris trichiura , using SSUrRNA sequence homology; Ascaris sp. with 100% homology to cox1 haplotype 07; and Fasciola hepatica using ITS1 sequence homology. The identification of T. trichiura eggs indicates that human fecal material is present and, hence, that the Ascaris sp. haplotype 07 was most likely a human variant in Viking-age Denmark. The location of the F. hepatica finding suggests that sheep or cattle are the most likely hosts. Further, we sequenced the Ascaris sp. 18S rRNA gene in recent isolates from humans and pigs of global distribution and show that this is not a suited marker for species-specific identification. Finally, we discuss ancient parasitism in Denmark and the implementation of aDNA analysis methods in paleoparasitological studies. We argue that when employing species-specific identification, soil samples offer excellent opportunities for studies of human parasite infections and of human and animal interactions of the past. PMID:25357228

  14. Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein.

    PubMed Central

    Shipp, M A; Richardson, N E; Sayre, P H; Brown, N R; Masteller, E L; Clayton, L K; Ritz, J; Reinherz, E L

    1988-01-01

    Common acute lymphoblastic leukemia antigen (CALLA) is a 100-kDa cell-surface glycoprotein expressed on most acute lymphoblastic leukemias and certain other immature lymphoid malignancies and on normal lymphoid progenitors. The latter are either uncommitted to B- or T-cell lineage or committed to only the earliest stages of B- or T-lymphocyte maturation. To elucidate to homogeneity, obtained the NH2-terminal sequence from both the intact protein and derived tryptic and V8 protease peptides and isolated CALLA cDNAs from a Nalm-6 cell line lambda gt10 library using redundant oligonucleotide probes. The CALLA cDNA sequence predicts a 750-amino acid integral membrane protein with a single 24-amino acid hydrophobic segment that could function as both a transmembrane region and a signal peptide. The COOH-terminal 700 amino acids, including six potential N-linked glycosylation sites compose the extracellular protein segment, whereas the 25 NH2-terminal amino acids remaining after cleavage of the initiation methionine form the cytoplasmic tail. CALLA+ cells contain CALLA transcripts of 2.7 to 5.7 kilobases with the major 5.7- and 3.7-kilobase mRNAs being preferentially expressed in specific cell types. Images PMID:2968607

  15. Joint and distinct risk factors associated with micro- and macrovascular complications in a cohort of type 2 diabetic patients cared through disease management

    Microsoft Academic Search

    Anna V. CiardulloM; M. Monica Daghio; Massimo Bevini; Gaetano Feltri; Doriano Novi; Giuseppe Fattori; Silvana Borsari; Carlo Di Donato

    2010-01-01

    We analysed the risk factors associated with diabetic complications in the cohort of patients assisted by a type 2 diabetes\\u000a mellitus (T2DM) shared-care program. We analysed registry data from 16,136 T2DM patients. Of them, 4,781 had microangiopathy,\\u000a 3,469 CV events. They were 70.5 ± 17.1 years old, 50% were male, disease duration 13.3 ± 7.8 years, BMI 28.7 ± 4.9 kg\\/m2, HbA1c 7.08 ± 1.23%, FBG 134.7 ± 35.7 mg\\/dl, 2hPPBG 163.9 ± 47.8 mg\\/dl, 12.5% smokers.

  16. DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles?

    PubMed Central

    Cox, Kara S.; Clair, James H.; Prokop, Michael T.; Sykes, Kara J.; Dubey, Sheri A.; Shiver, John W.; Robertson, Michael N.; Casimiro, Danilo R.

    2008-01-01

    Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1?, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed. PMID:18524823

  17. Expression-based network biology identifies alteration in key regulatory pathways of type 2 diabetes and associated risk/complications.

    PubMed

    Sengupta, Urmi; Ukil, Sanchaita; Dimitrova, Nevenka; Agrawal, Shipra

    2009-01-01

    Type 2 diabetes mellitus (T2D) is a multifactorial and genetically heterogeneous disease which leads to impaired glucose homeostasis and insulin resistance. The advanced form of disease causes acute cardiovascular, renal, neurological and microvascular complications. Thus there is a constant need to discover new and efficient treatment against the disease by seeking to uncover various novel alternate signalling mechanisms that can lead to diabetes and its associated complications. The present study allows detection of molecular targets by unravelling their role in altered biological pathways during diabetes and its associated risk factors and complications. We have used an integrated functional networks concept by merging co-expression network and interaction network to detect the transcriptionally altered pathways and regulations involved in the disease. Our analysis reports four novel significant networks which could lead to the development of diabetes and other associated dysfunctions. (a) The first network illustrates the up regulation of TGFBRII facilitating oxidative stress and causing the expression of early transcription genes via MAPK pathway leading to cardiovascular and kidney related complications. (b) The second network demonstrates novel interactions between GAPDH and inflammatory and proliferation candidate genes i.e., SUMO4 and EGFR indicating a new link between obesity and diabetes. (c) The third network portrays unique interactions PTPN1 with EGFR and CAV1 which could lead to an impaired vascular function in diabetic nephropathy condition. (d) Lastly, from our fourth network we have inferred that the interaction of beta-catenin with CDH5 and TGFBR1 through Smad molecules could contribute to endothelial dysfunction. A probability of emergence of kidney complication might be suggested in T2D condition. An experimental investigation on this aspect may further provide more decisive observation in drug target identification and better understanding of the pathophysiology of T2D and its complications. PMID:19997558

  18. Multiscale Complexity Analysis of the Cardiac Control Identifies Asymptomatic and Symptomatic Patients in Long QT Syndrome Type 1

    PubMed Central

    Bari, Vlasta; Valencia, José F.; Vallverdú, Montserrat; Girardengo, Giulia; Marchi, Andrea; Bassani, Tito; Caminal, Pere; Cerutti, Sergio; George, Alfred L.; Brink, Paul A.; Crotti, Lia; Schwartz, Peter J.; Porta, Alberto

    2014-01-01

    The study assesses complexity of the cardiac control directed to the sinus node and to ventricles in long QT syndrome type 1 (LQT1) patients with KCNQ1-A341V mutation. Complexity was assessed via refined multiscale entropy (RMSE) computed over the beat-to-beat variability series of heart period (HP) and QT interval. HP and QT interval were approximated respectively as the temporal distance between two consecutive R-wave peaks and between the R-wave apex and T-wave end. Both measures were automatically taken from 24-hour electrocardiographic Holter traces recorded during daily activities in non mutation carriers (NMCs, n?=?14) and mutation carriers (MCs, n?=?34) belonging to a South African LQT1 founder population. The MC group was divided into asymptomatic (ASYMP, n?=?11) and symptomatic (SYMP, n?=?23) patients according to the symptom severity. Analyses were carried out during daytime (DAY, from 2PM to 6PM) and nighttime (NIGHT, from 12PM to 4AM) off and on beta-adrenergic blockade (BBoff and BBon). We found that the complexity of the HP variability at short time scale was under vagal control, being significantly increased during NIGHT and BBon both in ASYMP and SYMP groups, while the complexity of both HP and QT variability at long time scales was under sympathetic control, being smaller during NIGHT and BBon in SYMP subjects. Complexity indexes at long time scales in ASYMP individuals were smaller than those in SYMP ones regardless of therapy (i.e. BBoff or BBon), thus suggesting that a reduced complexity of the sympathetic regulation is protective in ASYMP individuals. RMSE analysis of HP and QT interval variability derived from routine 24-hour electrocardiographic Holter recordings might provide additional insights into the physiology of the cardiac control and might be fruitfully exploited to improve risk stratification in LQT1 population. PMID:24705789

  19. Biochemical and Localization Analyses of Putative Type III Secretion Translocator Proteins CopB and CopB2 of Chlamydia trachomatis Reveal Significant Distinctions ?

    PubMed Central

    Chellas-Géry, B.; Wolf, K.; Tisoncik, J.; Hackstadt, T.; Fields, K. A.

    2011-01-01

    Chlamydia spp. are among the many pathogenic Gram-negative bacteria that employ a type III secretion system (T3SS) to overcome host defenses and exploit available resources. Significant progress has been made in elucidating contributions of T3S to the pathogenesis of these medically important, obligate intracellular parasites, yet important questions remain. Chief among these is how secreted effector proteins traverse eukaryotic membranes to gain access to the host cytosol. Due to a complex developmental cycle, it is possible that chlamydiae utilize a different complement of proteins to accomplish translocation at different stages of development. We investigated this possibility by extending the characterization of C. trachomatis CopB and CopB2. CopB is detected early during infection but is depleted and not detected again until about 20 h postinfection. In contrast, CopB2 was detectible throughout development. CopB is associated with the inclusion membrane. Biochemical and ectopic expression analyses were consistent with peripheral association of CopB2 with inclusion membranes. This interaction correlated with development and required both chlamydial de novo protein synthesis and T3SS activity. Collectively, our data indicate that it is unlikely that CopB serves as the sole chlamydial translocation pore and that CopB2 is capable of association with the inclusion membrane. PMID:21606186

  20. Fine mapping of the latency-related gene of herpes simplex virus type 1: alternative splicing produces distinct latency-related RNAs containing open reading frames

    SciTech Connect

    Wechsler, S.L.; Nesburn, A.B.; Watson, R.; Slanina, S.M.; Ghiasi, H.

    1988-11-01

    The latency-related (LR) gene of herpes simplex virus type 1 (HSV-1) is transcriptionally active during HSV-1 latency, producing at least two LR-RNAs. The LR gene partially overlaps the immediate-early gene ICP0 and is transcribed in the opposite direction from ICP0, producing LR-RNAs that are complementary (antisense) to ICP0 mRNA. The LR gene is thought to be involved in HSV-1 latency. The authors report here the time mapping and partial sequence analysis of this HSV-1 LR gene. /sup 32/P-labeled genomic DNA restriction fragments and synthetic oligonucleotides were used as probes for in situ hybridizations and Northern (RNA) blot hybridizations of RNA from trigeminal ganglia of rabbits latently infected with HSV-1. The two most abundant LR-RNAs appeared to share their 5' and 3' ends and to be produced by alternative splicing. These LR-RNAs were approximately 2 and 1.3 to 1.5 kilobases in length and were designated LR-RNA 1 and LF-RNA 2, respectively. LR-RNA 1 appeared to have at least one intron removed, while LR-RNA 2 appeared to have at least two introns removed. The LR-RNAs contained two potential long open reading frames, suggesting the possibility that one or more of the LR-RNAs may be a functional mRNA.

  1. Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling

    PubMed Central

    Röring, Michael; Herr, Ricarda; Fiala, Gina J; Heilmann, Katharina; Braun, Sandra; Eisenhardt, Anja E; Halbach, Sebastian; Capper, David; von Deimling, Andreas; Schamel, Wolfgang W; Saunders, Darren N; Brummer, Tilman

    2012-01-01

    The dimerisation of Raf kinases involves a central cluster within the kinase domain, the dimer interface (DIF). Yet, the importance of the DIF for the signalling potential of wild-type B-Raf (B-Raf wt) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf wt and several of its gain-of-function (g-o-f) mutants. In contrast, the B-Raf V600E, B-Raf insT and B-Raf G469A oncoproteins are remarkably resistant to mutations in the DIF. However, compared with B-Raf wt, B-Raf V600E displays extended protomer contacts, increased homodimerisation and incorporation into larger protein complexes. In contrast, B-Raf wt and Raf-1wt mediated signalling triggered by oncogenic Ras as well as the paradoxical activation of Raf-1 by kinase-inactivated B-Raf require an intact DIF. Surprisingly, the B-Raf DIF is not required for dimerisation between Raf-1 and B-Raf, which was inactivated by the D594A mutation, sorafenib or PLX4720. This suggests that paradoxical MEK/ERK activation represents a two-step mechanism consisting of dimerisation and DIF-dependent transactivation. Our data further implicate the Raf DIF as a potential target against Ras-driven Raf-mediated (paradoxical) ERK activation. PMID:22510884

  2. Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling.

    PubMed

    Röring, Michael; Herr, Ricarda; Fiala, Gina J; Heilmann, Katharina; Braun, Sandra; Eisenhardt, Anja E; Halbach, Sebastian; Capper, David; von Deimling, Andreas; Schamel, Wolfgang W; Saunders, Darren N; Brummer, Tilman

    2012-05-30

    The dimerisation of Raf kinases involves a central cluster within the kinase domain, the dimer interface (DIF). Yet, the importance of the DIF for the signalling potential of wild-type B-Raf (B-Raf(wt)) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf(wt) and several of its gain-of-function (g-o-f) mutants. In contrast, the B-Raf(V600E), B-Raf(insT) and B-Raf(G469A) oncoproteins are remarkably resistant to mutations in the DIF. However, compared with B-Raf(wt), B-Raf(V600E) displays extended protomer contacts, increased homodimerisation and incorporation into larger protein complexes. In contrast, B-Raf(wt) and Raf-1(wt) mediated signalling triggered by oncogenic Ras as well as the paradoxical activation of Raf-1 by kinase-inactivated B-Raf require an intact DIF. Surprisingly, the B-Raf DIF is not required for dimerisation between Raf-1 and B-Raf, which was inactivated by the D594A mutation, sorafenib or PLX4720. This suggests that paradoxical MEK/ERK activation represents a two-step mechanism consisting of dimerisation and DIF-dependent transactivation. Our data further implicate the Raf DIF as a potential target against Ras-driven Raf-mediated (paradoxical) ERK activation. PMID:22510884

  3. Triton College: One Institution's Search for Distinctiveness.

    ERIC Educational Resources Information Center

    Townsend, Barbara K.; Catanzaro, James L.

    1989-01-01

    Recounts Triton College's efforts to identify its distinctive elements. Reviews empirical evidence showing that Triton's school schedule, curricular offerings, and continuing education and support services are distinctive among local colleges. Discusses students' and staff members' perceptions of Triton. Considers the value of the research to the…

  4. Pseudomonas aeruginosa Possesses Two Putative Type I Signal Peptidases, LepB and PA1303, Each with Distinct Roles in Physiology and Virulence

    PubMed Central

    Rose, Ruth S.; Rangarajan, Minnie; Aduse-Opoku, Joseph; Hashim, Ahmed; Curtis, Michael A.

    2012-01-01

    Type I signal peptidases (SPases) cleave signal peptides from proteins during translocation across biological membranes and hence play a vital role in cellular physiology. SPase activity is also of fundamental importance to the pathogenesis of infection for many bacteria, including Pseudomonas aeruginosa, which utilizes a variety of secreted virulence factors, such as proteases and toxins. P. aeruginosa possesses two noncontiguous SPase homologues, LepB (PA0768) and PA1303, which share 43% amino acid identity. Reverse transcription (RT)-PCR showed that both proteases were expressed, while a FRET-based assay using a peptide based on the signal sequence cleavage region of the secreted LasB elastase showed that recombinant LepB and PA1303 enzymes were both active. LepB is positioned within a genetic locus that resembles the locus containing the extensively characterized SPase of E. coli and is of similar size and topology. It was also shown to be essential for viability and to have high sequence identity with SPases from other pseudomonads (?78%). In contrast, PA1303, which is small for a Gram-negative SPase (20 kDa), was found to be dispensable. Mutation of PA1303 resulted in an altered protein secretion profile and increased N-butanoyl homoserine lactone production and influenced several quorum-sensing-controlled phenotypic traits, including swarming motility and the production of rhamnolipid and elastinolytic activity. The data indicate different cellular roles for these P. aeruginosa SPase paralogues; the role of PA1303 is integrated with the quorum-sensing cascade and includes the suppression of virulence factor secretion and virulence-associated phenotypes, while LepB is the primary SPase. PMID:22730125

  5. Distinct Increased Metabotropic Glutamate Receptor Type 5 (mGluR5) in Temporal Lobe Epilepsy With and Without Hippocampal Sclerosis

    PubMed Central

    Kandratavicius, Ludmyla; Rosa-Neto, Pedro; Monteiro, Mariana Raquel; Guiot, Marie-Christine; Assirati, Joao Alberto; Carlotti, Carlos Gilberto; Kobayashi, Eliane; Leite, Joao Pereira

    2013-01-01

    Metabotropic glutamate receptor type 5 (mGluR5) upregulation in temporal lobe epilepsy (TLE) and the correlation of its expression with features of hippocampal sclerosis (HS) remains unclear. Here we characterized mGluR5 immunoreactivity in hippocampus, entorhinal cortex (EC), and subiculum of TLE specimens with confirmed HS, with neocortical TLE (non-HS) and necropsy controls. We correlated mGluR5 immunoreactivity with neuronal density, mossy fiber sprouting, astrogliosis (GFAP), and dendritic alterations (MAP2). TLE specimens showed increased mGluR5 expression, which was most pronounced in the EC, subiculum, CA2, and dentate gyrus outer molecular layer. Increased mGluR5 expression was seen in hippocampal head and body segments and was independent of neuronal density, astrogliosis, or dendritic alterations. Positive correlation between mGluR5 expression with mossy fiber sprouting and with MAP2 in CA3 and CA1 was found only in HS specimens. Negative correlation between mGluR5 expression with seizure frequency and epilepsy duration was found only in non-HS cases. Specimens from HS patients without previous history of febrile seizure (FS) showed higher mGluR5 and MAP2 expression in CA2. Our study suggests that mGluR5 upregulation is part of a repertoire of post-synaptic adaptations that might control overexcitation and excessive glutamate release rather than a dysfunction that leads to seizure facilitation. That would explain why non-HS cases, on which seizures are likely to originate outside the hippocampal formation, also exhibit upregulated mGluR5. On the other hand, lower mGluR5 expression was related to increased seizure frequency. In addition to its role in hyperexcitability, mGluR5 upregulation could play a role in counterbalance mechanisms along the hyperexcitable circuitry uniquely altered in sclerotic hippocampal formation. Inefficient post-synaptic compensatory morphological (dendritic branching) and glutamatergic (mGluR5 expression) mechanisms in CA2 subfield could potentially underlie the association of FS with HS and TLE. © 2013 Wiley Periodicals, Inc. PMID:23804486

  6. Two Distinct Channels Mediated by m2mAChR and ?9nAChR Co-Exist in Type II Vestibular Hair Cells of Guinea Pig

    PubMed Central

    Zhou, Tao; Wang, Yi; Guo, Chang-Kai; Zhang, Wen-Juan; Yu, Hong; Zhang, Kun; Kong, Wei-Jia

    2013-01-01

    Acetylcholine (ACh) is the principal vestibular efferent neurotransmitter among mammalians. Pharmacologic studies prove that ACh activates a small conductance Ca2+-activated K+ channels (KCa) current (SK2), mediated by ?9-containing nicotinic ACh receptor (?9nAChR) in mammalian type II vestibular hair cells (VHCs II). However, our studies demonstrate that the m2 muscarinic ACh receptor (m2mAChR) mediates a big conductance KCa current (BK) in VHCs II. To better elucidate the correlation between these two distinct channels in VHCs II of guinea pig, this study was designed to verify whether these two channels and their corresponding AChR subtypes co-exist in the same VHCs II by whole-cell patch clamp recordings. We found that m2mAChR sensitive BK currents were activated in VHCs II isolated by collagenase IA, while ?9nAChR sensitive SK2 currents were activated in VHCs II isolated by trypsin. Interestingly, after exposing the patched cells isolated by trypsin to collagenase IA for 3 min, the ?9nAChR sensitive SK2 current was abolished, while m2mAChR-sensitive BK current was activated. Therefore, our findings provide evidence that the two distinct channels and their corresponding AChR subtypes may co-exist in the same VHCs II, and the alternative presence of these two ACh receptors-sensitive currents depended on isolating preparation with different enzymes. PMID:23615472

  7. A 20-residue peptide of the inner membrane protein OutC mediates interaction with two distinct sites of the outer membrane secretin OutD and is essential for the functional type II secretion system in Erwinia chrysanthemi.

    PubMed

    Login, Frédéric H; Fries, Markus; Wang, Xiaohui; Pickersgill, Richard W; Shevchik, Vladimir E

    2010-05-01

    The type II secretion system (T2SS) is widely exploited by proteobacteria to secrete enzymes and toxins involved in bacterial survival and pathogenesis. The outer membrane pore formed by the secretin OutD and the inner membrane protein OutC are two key components of the secretion complex, involved in secretion specificity. Here, we show that the periplasmic regions of OutC and OutD interact directly and map the interaction site of OutC to a 20-residue peptide named OutCsip (secretin interacting peptide, residues 139-158). This peptide interacts in vitro with two distinct sites of the periplasmic region of OutD, one located on the N0 subdomain and another overlapping the N2-N3' subdomains. The two interaction sites of OutD have different modes of binding to OutCsip. A single substitution, V143S, located within OutCsip prevents its interaction with one of the two binding sites of OutD and fully inactivates the T2SS. We show that the N0 subdomain of OutD interacts also with a second binding site within OutC located in the region proximal to the transmembrane segment. We suggest that successive interactions between these distinct regions of OutC and OutD may have functional importance in switching the secretion machine. PMID:20444086

  8. Application of multiple-locus variable number tandem repeat analysis to identify outbreak-associated Neisseria meningitides serogroup C sequence type 4821 in China.

    PubMed

    Shan, Xiaoying; Zhou, Haijian; Zhang, Ji; Zhu, Bingqing; Xu, Li; Hu, Guangchun; Bai, Aiying; Shao, Zhujun; Jiang, Baofa

    2015-01-01

    Neisseria meningitidis (N. meningitidis) serogroup C sequence type (ST)-4821 caused an outbreak in 2010 in Shandong province of China. Twenty-one non-outbreak-associated strains were isolated, along with twenty-eight N. meningitides serogroup C ST-4821 isolates. Therefore, it's essential to identify and clarify characterization of the real outbreak-associated strains with a rapid method during an outbreak investigation. In this study, multiple-locus variable number tandem repeat analysis (MLVA) was applied to analyze 84 N. meningitidis strains, among which 58 were recovered from two outbreaks and 26 were sporadic isolates. Three MLVA schemes with different combination of VNTR loci were tested, and two of them were suitable for isolates from China: scheme 2 with six loci was found to separate ST into finer resolution, and scheme 3 with five loci can be used to identify outbreak-associated isolates from the same outbreak that caused by N. meningitidis serogroup C ST-4821. PMID:25603352

  9. Independent optical excitation of distinct neural populations

    E-print Network

    Klapoetke, Nathan Cao

    Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian ...

  10. Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis*

    PubMed Central

    Culver, Brady P.; Savas, Jeffrey N.; Park, Sung K.; Choi, Jeong H.; Zheng, Shuqiu; Zeitlin, Scott O.; Yates, John R.; Tanese, Naoko

    2012-01-01

    Huntington disease is a neurodegenerative disorder caused by a CAG repeat amplification in the gene huntingtin (HTT) that is reflected by a polyglutamine expansion in the Htt protein. Nearly 20 years of research have uncovered roles for Htt in a wide range of cellular processes, and many of these discoveries stemmed from the identification of Htt-interacting proteins. However, no study has employed an impartial and comprehensive strategy to identify proteins that differentially associate with full-length wild-type and mutant Htt in brain tissue, the most relevant sample source to the disease condition. We analyzed Htt affinity-purified complexes from wild-type and HTT mutant juvenile mouse brain from two different biochemical fractions by tandem mass spectrometry. We compared variations in protein spectral counts relative to Htt to identify those proteins that are the most significantly contrasted between wild-type and mutant Htt purifications. Previously unreported Htt interactions with Myo5a, Prkra (PACT), Gnb2l1 (RACK1), Rps6, and Syt2 were confirmed by Western blot analysis. Gene Ontology analysis of these and other Htt-associated proteins revealed a statistically significant enrichment for proteins involved in translation among other categories. Furthermore, Htt co-sedimentation with polysomes in cytoplasmic mouse brain extracts is dependent upon the presence of intact ribosomes. Finally, wild-type or mutant Htt overexpression inhibits cap-dependent translation of a reporter mRNA in an in vitro system. Cumulatively, these data support a new role for Htt in translation and provide impetus for further study into the link between protein synthesis and Huntington disease pathogenesis. PMID:22556411

  11. Population Genetics of Vibrio vulnificus: Identification of Two Divisions and a Distinct Eel-Pathogenic Clone

    Microsoft Academic Search

    Michaela Gutacker; Nadine Conza; Cinzia Benagli; Ambra Pedroli; Marco Valerio Bernasconi; Lise Permin; Rosa Aznar; Jean-Claude Piffaretti

    2003-01-01

    Genetic relationships among 62 Vibrio vulnificus strains of different geographical and host origins were analyzed by multilocus enzyme electrophoresis (MLEE), random amplification of polymorphic DNA (RAPD), and sequence analyses of the recA and glnA genes. Out of 15 genetic loci analyzed by MLEE, 11 were polymorphic. Cluster analysis identified 43 distinct electrophoretic types (ETs) separating the V. vulnificus population into

  12. Phase Distinctions In The Compilation Of Epigram

    Microsoft Academic Search

    James McKinna; Edwin Brady

    2005-01-01

    We describe the execution of Epigram on a stock architec- ture, compiling via a core type theory and a supercombinator language. We show, via optimising transformations on the core type theory, that unused or duplicated values can be erased at run-time. Thus there exists a phase distinction, not between types and values, but between values which are used at compile-time

  13. Identifying and Classifying Rocks

    NSDL National Science Digital Library

    Elisabeth Owen

    2010-11-03

    How do we identify and classify rocks? In this lesson, we are going to learn about different ways that we classify and identify rocks! There are three types of rocks. Sedimentary Metamorphic Igneous As we are learning about the three types of rocks, print out this chart and use it to write down what you learn about each type of ...

  14. Compounds with species and cell type specific toxicity identified in a 2000 compound drug screen of neural stem cells and rat mixed cortical neurons.

    PubMed

    Malik, Nasir; Efthymiou, Anastasia G; Mather, Karly; Chester, Nathaniel; Wang, Xiantao; Nath, Avindra; Rao, Mahendra S; Steiner, Joseph P

    2014-12-01

    Human primary neural tissue is a vital component for the quick and simple determination of chemical compound neurotoxicity in vitro. In particular, such tissue would be ideal for high-throughput screens that can be used to identify novel neurotoxic or neurotherapeutic compounds. We have previously established a high-throughput screening platform using human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) and neurons. In this study, we conducted a 2000 compound screen with human NSCs and rat cortical cells to identify compounds that are selectively toxic to each group. Approximately 100 of the tested compounds showed specific toxicity to human NSCs. A secondary screen of a small subset of compounds from the primary screen on human iPSCs, NSC-derived neurons, and fetal astrocytes validated the results from >80% of these compounds with some showing cell specific toxicity. Amongst those compounds were several cardiac glycosides, all of which were selectively toxic to the human cells. As the screen was able to reliably identify neurotoxicants, many with species and cell-type specificity, this study demonstrates the feasibility of this NSC-driven platform for higher-throughput neurotoxicity screens. PMID:25454721

  15. Use of whole-genus genome sequence data to develop a multilocus sequence typing tool that accurately identifies Yersinia isolates to the species and subspecies levels.

    PubMed

    Hall, Miquette; Chattaway, Marie A; Reuter, Sandra; Savin, Cyril; Strauch, Eckhard; Carniel, Elisabeth; Connor, Thomas; Van Damme, Inge; Rajakaruna, Lakshani; Rajendram, Dunstan; Jenkins, Claire; Thomson, Nicholas R; McNally, Alan

    2015-01-01

    The genus Yersinia is a large and diverse bacterial genus consisting of human-pathogenic species, a fish-pathogenic species, and a large number of environmental species. Recently, the phylogenetic and population structure of the entire genus was elucidated through the genome sequence data of 241 strains encompassing every known species in the genus. Here we report the mining of this enormous data set to create a multilocus sequence typing-based scheme that can identify Yersinia strains to the species level to a level of resolution equal to that for whole-genome sequencing. Our assay is designed to be able to accurately subtype the important human-pathogenic species Yersinia enterocolitica to whole-genome resolution levels. We also report the validation of the scheme on 386 strains from reference laboratory collections across Europe. We propose that the scheme is an important molecular typing system to allow accurate and reproducible identification of Yersinia isolates to the species level, a process often inconsistent in nonspecialist laboratories. Additionally, our assay is the most phylogenetically informative typing scheme available for Y. enterocolitica. PMID:25339391

  16. Proinflammatory secreted phospholipase A2 type IIA (sPLA-IIA) induces integrin activation through direct binding to a newly identified binding site (site 2) in integrins ?v?3, ?4?1, and ?5?1.

    PubMed

    Fujita, Masaaki; Zhu, Kan; Fujita, Chitose K; Zhao, Min; Lam, Kit S; Kurth, Mark J; Takada, Yoko K; Takada, Yoshikazu

    2015-01-01

    Integrins are activated by signaling from inside the cell (inside-out signaling) through global conformational changes of integrins. We recently discovered that fractalkine activates integrins in the absence of CX3CR1 through the direct binding of fractalkine to a ligand-binding site in the integrin headpiece (site 2) that is distinct from the classical RGD-binding site (site 1). We propose that fractalkine binding to the newly identified site 2 induces activation of site 1 though conformational changes (in an allosteric mechanism). We reasoned that site 2-mediated activation of integrins is not limited to fractalkine. Human secreted phospholipase A2 type IIA (sPLA2-IIA), a proinflammatory protein, binds to integrins ?v?3 and ?4?1 (site 1), and this interaction initiates a signaling pathway that leads to cell proliferation and inflammation. Human sPLA2-IIA does not bind to M-type receptor very well. Here we describe that sPLA2-IIA directly activated purified soluble integrin ?v?3 and transmembrane ?v?3 on the cell surface. This activation did not require catalytic activity or M-type receptor. Docking simulation predicted that sPLA2-IIA binds to site 2 in the closed-headpiece of ?v?3. A peptide from site 2 of integrin ?1 specifically bound to sPLA2-IIA and suppressed sPLA2-IIA-induced integrin activation. This suggests that sPLA2-IIA activates ?v?3 through binding to site 2. sPLA2-IIA also activated integrins ?4?1 and ?5?1 in a site 2-mediated manner. We recently identified small compounds that bind to sPLA2-IIA and suppress integrin-sPLA2-IIA interaction (e.g. compound 21 (Cmpd21)). Cmpd21 effectively suppressed sPLA2-IIA-induced integrin activation. These results define a novel mechanism of proinflammatory action of sPLA2-IIA through integrin activation. PMID:25398877

  17. Analysis of the Crystal Structure of the ExsC.ExsE Complex Reveals Distinctive Binding Interactions of the Pseudomonas aeruginosa Type III Secretion Chaperone ExsC with ExsE and ExsD

    SciTech Connect

    Vogelaar, N.J.; Robinson, H.; Jing, X.; Schubot, F. D.

    2010-07-20

    Pseudomonas aeruginosa, like many Gram-negative bacterial pathogens, requires its type III secretion system (T3SS) to facilitate acute infections. In P. aeruginosa, the expression of all T3SS-related genes is regulated by the transcriptional activator ExsA. A signaling cascade involving ExsA and three additional proteins, ExsC, ExsD, and ExsE, directly ties the upregulation of ExsA-mediated transcription to the activation of the type III secretion apparatus. In order to characterize the events underlying the signaling process, the crystal structure of the T3SS chaperone ExsC in complex with its cognate effector ExsE has been determined. The structure reveals critical contacts that mediate the interactions between these two proteins. Particularly striking is the presence of two Arg-X-Val-X-Arg motifs in ExsE that form identical interactions along opposite sides of an ExsC dimer. The structure also provides insights into the interactions of ExsC with the antiactivator protein ExsD. It was shown that the amino-terminal 46 residues of ExsD are sufficient for ExsC binding. On the basis of these findings, a new model for the ExsC {center_dot} ExsD complex is proposed to explain its distinctive 2:2 stoichiometry and why ExsC displays a weaker affinity for ExsD than for ExsE.

  18. Identifying the integrated neural networks involved in capsaicin-induced pain using fMRI in awake TRPV1 knockout and wild-type rats.

    PubMed

    Yee, Jason R; Kenkel, William; Caccaviello, John C; Gamber, Kevin; Simmons, Phil; Nedelman, Mark; Kulkarni, Praveen; Ferris, Craig F

    2015-01-01

    In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type vs. knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain. PMID:25745388

  19. Identifying the integrated neural networks involved in capsaicin-induced pain using fMRI in awake TRPV1 knockout and wild-type rats

    PubMed Central

    Yee, Jason R.; Kenkel, William; Caccaviello, John C.; Gamber, Kevin; Simmons, Phil; Nedelman, Mark; Kulkarni, Praveen; Ferris, Craig F.

    2015-01-01

    In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type vs. knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain.

  20. Herpes Simplex Virus Glycoproteins: Participation of Individual Herpes Simplex Virus Type 1 Glycoprotein Antigens in Immunocytolysis and Their Correlation with Previously Identified Glycopolypeptides

    PubMed Central

    Norrild, B.; Shore, S. L.; Nahmias, A. J.

    1979-01-01

    Tissue culture cells infected with herpes simplex type 1 virus express virus-specified glycoprotein antigens on the plasma membrane. Three of these have been previously identified and have been designated as Ag-11, Ag-8, and Ag-6. In the present study, immunoglobulins to each of the antigens were shown to be capable of mediating immunocytolysis in the presence of either complement (antibody-dependent complement-mediated cytotoxicity) or peripheral blood mononuclear cells (antibody-dependent cell-mediated cytotoxicity [ADCC]). Two herpes simplex virus type 1 strains, VR-3 and F, reacted similarly in the ADCC test in the presence of immunoglobulins to Ag-11, Ag-8, and Ag-6 in both infected Chang liver cells and HEp-2 cells. Anti-Ag-6, however, produced a lower ADCC reaction in HEp-2 cells than in Chang liver cells, suggesting differences in the Ag-6 surface expression in, or release from, these cells. Chang liver and HEp-2 cells infected with the MP mutant strain of herpes simplex virus type 1 showed reduced ADCC in the presence of anti-Ag-11 and anti-Ag-8, but no reactivity at all with anti-Ag-6. Crossed immunoelectrophoretic analysis showed that MP-infected cell extracts contain Ag-11 and Ag-8, but lack Ag-6. Polypeptide analysis of herpes simplex virus type 1 strains F, VR-3, and MP showed that Ag-11 consists of the glycoproteins gA and gB, that Ag-8 consists of gD, and that Ag-6 consists of gC. In conclusion, the present study demonstrates that either one of the glycoproteins (gC, gD, and a mixture of gA and gB) can function as a target for immunocytolysis and that the antibody preparation to gC (Ag-6) does not cross-react with any of the other glycoproteins. Images PMID:229263

  1. Infection of monocyte-derived macrophages with human immunodeficiency virus type 1 (HIV-1). Monocyte-tropic and lymphocyte-tropic strains of HIV-1 show distinctive patterns of replication in a panel of cell types

    PubMed Central

    1989-01-01

    To characterize the host range of different strains of HIV-1, we have used four types of cells, primary monocyte-derived macrophages (MDM), primary PBL, a promonocyte cell line (U937), and a CD4+ T cell line (SUP-T1). These cells were infected with three prototype strains of HIV- 1, a putative lymphocyte-tropic strain (IIIB), and two putative monocyte-tropic strains (SF162 and DV). Infections were monitored by assays for infectious virus, for cell-free and cell-associated viral antigen (p24), and for the proportion of cells infected by immunohistochemical staining. It was concluded that: (a) the use of four different cell types provides a useful biological matrix for distinguishing the tropism of different strains of HIV-1; this matrix yields more information than the infection of any single cell type. (b) A monocyte-tropic strain of HIV-1, such as strain SF162, shows a reciprocal host range when compared with a lymphocyte-tropic strain such as IIIB; strain SF162 replicates well in primary MDM but not in U937 or SUP-T1 cells, while strain IIIB replicates well in both U937 and SUP-T1 cells but not in MDM. (c) Both lymphocyte-tropic and monocyte-tropic strains of HIV-1 replicate well in PBL. (d) The promonocyte cell line, U937, and the T cell line, SUP-T1, differ markedly from primary cells, such as MDM and PBL, in their ability to support the replication of different strains of HIV-1; these cell lines cannot be used as surrogates for primary cells in host range studies of HIV-1 strains. PMID:2571666

  2. Identifying Market Segments.

    ERIC Educational Resources Information Center

    Wakstein, Julie

    1987-01-01

    A systematic exploratory technique used primarily in the commercial sector to successfully identify market segments can be applied by an educational institution to a group of inquirers to learn more about its image and distinguish between distinct market subgroups that merit differentiated communication and program development strategies. (MSE)

  3. Two Types of Type-2?

    NASA Astrophysics Data System (ADS)

    Martinez-Sansigre, Alejo; Fadda, Dario; Mark, Lacy; Marleau, Francine; Matt, Jarvis; Rawlings, Steve; Simpson, Chris; Willott, Chris

    2006-05-01

    We propose to use the Spitzer IRS instrument to test the hypothesis that there are two distinct types of Type-2 (obscured) QSO: the first in which the nucleus is obscured at optical wavelengths by an organized torus; and the second, in which the nucleus is obscured by more distributed dust in an associated starburst. We will target a complete sample of Type-2 QSOs at z = 1.4-2 from the Spitzer First-Look Survey which, from optical spectroscopy, split into objects with high excitation, narrow-emission lines (torus-obscured QSOs?) and objects with totally blank optical spectra (starburst-obscured QSOs?). The IRS spectra will be sensitive to the the `Silicate Break' (and PAH features) and therefore identify and provide redshifts for any starburst-obscured QSOs, whereas QSOs in which there is a clear view of hot dust in the torus, will have relatively featureless mid-IR spectra, except for the silicate absorption feature.

  4. Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual ?-cell function 1 year after diagnosis of type 1 diabetes.

    PubMed

    Andersen, Marie Louise Max; Rasmussen, Morten Arendt; Pörksen, Sven; Svensson, Jannet; Vikre-Jørgensen, Jennifer; Thomsen, Jane; Hertel, Niels Thomas; Johannesen, Jesper; Pociot, Flemming; Petersen, Jacob Sten; Hansen, Lars; Mortensen, Henrik Bindesbøl; Nielsen, Lotte Brøndum

    2013-01-01

    The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual ?-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P?=?0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P?=?0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P?=?0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data--future functional studies will be needed to clarify the relevance of these patterns. PMID:23755131

  5. Application of Multiple-Locus Variable Number Tandem Repeat Analysis to Identify Outbreak-Associated Neisseria meningitides Serogroup C Sequence Type 4821 in China

    PubMed Central

    Shan, Xiaoying; Zhou, Haijian; Zhang, Ji; Zhu, Bingqing; Xu, Li; Hu, Guangchun; Bai, Aiying; Shao, Zhujun; Jiang, Baofa

    2015-01-01

    Neisseria meningitidis (N. meningitidis) serogroup C sequence type (ST)-4821 caused an outbreak in 2010 in Shandong province of China. Twenty-one non-outbreak-associated strains were isolated, along with twenty-eight N. meningitides serogroup C ST-4821 isolates. Therefore, it’s essential to identify and clarify characterization of the real outbreak-associated strains with a rapid method during an outbreak investigation. In this study, multiple-locus variable number tandem repeat analysis (MLVA) was applied to analyze 84 N. meningitidis strains, among which 58 were recovered from two outbreaks and 26 were sporadic isolates. Three MLVA schemes with different combination of VNTR loci were tested, and two of them were suitable for isolates from China: scheme 2 with six loci was found to separate ST into finer resolution, and scheme 3 with five loci can be used to identify outbreak-associated isolates from the same outbreak that caused by N. meningitidis serogroup C ST-4821. PMID:25603352

  6. Cytometric profiling of CD133+ cells in human colon ?carcinoma cell lines identifies a common core phenotype ?and cell type-specific mosaics.

    PubMed

    Gemei, Marica; Di Noto, Rosa; Mirabelli, Peppino; Del Vecchio, Luigi

    2013-05-14

    In colorectal cancer, CD133+ cells from fresh biopsies proved to be more tumorigenic than their CD133- counterparts. Nevertheless, the function of CD133 protein in tumorigenic cells seems only marginal. Moreover, CD133 expression alone is insufficient to isolate true cancer stem cells, since only 1 out of 262 CD133+ cells actually displays stem-cell capacity. Thus, new markers for colorectal cancer stem cells are needed. Here, we show the extensive characterization of CD133+ cells in 5 different colon carcinoma continuous cell lines (HT29, HCT116, Caco2, GEO and LS174T), each representing a different maturation level of colorectal cancer cells. Markers associated with stemness, tumorigenesis and metastatic potential were selected. We identified 6 molecules consistently present on CD133+ cells: CD9, CD29, CD49b, CD59, CD151, and CD326. By contrast, CD24, CD26, CD54, CD66c, CD81, CD90, CD99, CD112, CD164, CD166, and CD200 showed a discontinuous behavior, which led us to identify cell type-specific surface antigen mosaics. Finally, some antigens, e.g. CD227, indicated the possibility of classifying the CD133+ cells into 2 subsets likely exhibiting specific features. This study reports, for the first time, an extended characterization of the CD133+ cells in colon carcinoma cell lines and provides a "dictionary" of antigens to be used in colorectal cancer research. PMID:23709346

  7. VSEAMS: a pipeline for variant set enrichment analysis using summary GWAS data identifies IKZF3, BATF and ESRRA as key transcription factors in type 1 diabetes

    PubMed Central

    Burren, Oliver S.; Guo, Hui; Wallace, Chris

    2014-01-01

    Motivation: Genome-wide association studies (GWAS) have identified many loci implicated in disease susceptibility. Integration of GWAS summary statistics (P-values) and functional genomic datasets should help to elucidate mechanisms. Results: We extended a non-parametric SNP set enrichment method to test for enrichment of GWAS signals in functionally defined loci to a situation where only GWAS P-values are available. The approach is implemented in VSEAMS, a freely available software pipeline. We use VSEAMS to identify enrichment of type 1 diabetes (T1D) GWAS associations near genes that are targets for the transcription factors IKZF3, BATF and ESRRA. IKZF3 lies in a known T1D susceptibility region, while BATF and ESRRA overlap other immune disease susceptibility regions, validating our approach and suggesting novel avenues of research for T1D. Availability and implementation: VSEAMS is available for download (http://github.com/ollyburren/vseams). Contact: chris.wallace@cimr.cam.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25170024

  8. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

    PubMed Central

    Zeggini, Eleftheria; Scott, Laura J.; Saxena, Richa; Voight, Benjamin F.; Marchini, Jonathan L; Hu, Tainle; de Bakker, Paul IW; Abecasis, Gonçalo R; Almgren, Peter; Andersen, Gitte; Ardlie, Kristin; Boström, Kristina Bengtsson; Bergman, Richard N; Bonnycastle, Lori L; Borch-Johnsen, Knut; Burtt, Noël P; Chen, Hong; Chines, Peter S; Daly, Mark J; Deodhar, Parimal; Ding, Charles; Doney, Alex S F; Duren, William L; Elliott, Katherine S; Erdos, Michael R; Frayling, Timothy M; Freathy, Rachel M; Gianniny, Lauren; Grallert, Harald; Grarup, Niels; Groves, Christopher J; Guiducci, Candace; Hansen, Torben; Herder, Christian; Hitman, Graham A; Hughes, Thomas E; Isomaa, Bo; Jackson, Anne U; Jørgensen, Torben; Kong, Augustine; Kubalanza, Kari; Kuruvilla, Finny G; Kuusisto, Johanna; Langenberg, Claudia; Lango, Hana; Lauritzen, Torsten; Li, Yun; Lindgren, Cecilia M; Lyssenko, Valeriya; Marvelle, Amanda F; Meisinger, Christa; Midthjell, Kristian; Mohlke, Karen L; Morken, Mario A; Morris, Andrew D; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Palmer, Colin NA; Payne, Felicity; Perry, John RB; Pettersen, Elin; Platou, Carl; Prokopenko, Inga; Qi, Lu; Qin, Li; Rayner, Nigel W; Rees, Matthew; Roix, Jeffrey J; Sandbæk, Anelli; Shields, Beverley; Sjögren, Marketa; Steinthorsdottir, Valgerdur; Stringham, Heather M; Swift, Amy J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Timpson, Nicholas J; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Walker, Mark; Watanabe, Richard M; Weedon, Michael N; Willer, Cristen J; Illig, Thomas; Hveem, Kristian; Hu, Frank B; Laakso, Markku; Stefansson, Kari; Pedersen, Oluf; Wareham, Nicholas J; Barroso, Inês; Hattersley, Andrew T; Collins, Francis S; Groop, Leif; McCarthy, Mark I; Boehnke, Michael; Altshuler, David

    2009-01-01

    Genome-wide association (GWA) studies have identified multiple new genomic loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1-11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to discover loci at which common alleles have modest effects, we performed meta-analysis of three T2D GWA scans encompassing 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed). Replication testing was performed in an independent sample with an effective sample size of up to 53,975. At least six new loci with robust evidence for association were detected, including the JAZF1 (p=5.0×10?14), CDC123/CAMK1D (p=1.2×10?10), TSPAN8/LGR5 (p=1.1×10?9), THADA (p=1.1×10?9), ADAMTS9 (p=1.2×10?8), and NOTCH2 (p=4.1×10?8) gene regions. The large number of loci with relatively small effects indicates the value of large discovery and follow-up samples in identifying additional clues about the inherited basis of T2D. PMID:18372903

  9. [MRSA clones identified in outpatient dermatology clinics].

    PubMed

    Hosoya, Shino; Ito, Teruyo; Misawa, Shigeki; Yoshiike, Takashi; Oguri, Toyoko; Hiramatsu, Keiichi

    2014-11-01

    To know the characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains disseminating through the Japanese community, we have determined types of Staphylococcal cassette chromosome mec (SCCmec) elements, Multi-Locus Sequence Typing (MLST), and carriages of four exotoxin genes (toxic-shock syndrome toxin, Panton-Valentine Leukocidine, and exfoliative toxins a and b) using 54 MRSA strains isolated from outpatients attending dermatology clinics at the four university hospitals of Juntendo University. Ten clonal complexes and 12 SCCmec types have been identified. As a result, more than 15 MRSA clones that were defined by the combination of genotype and SCCmec type, were identified. Among them, Clonal Complex (CC) 5-type IIa SCCmec strains were the most major (16 strains). In contrast to the fact that CC5- type IIa SCCmec strains known as a hospital-associated MRSA clone in Japan carried toxic-shock syndrome toxin gene (tst), only 2 of 16 strains have been shown to carry tst. Thirty-eight (70.4%) of isolates belonged to the clones distinct from the CC5-type IIa SCCmec strains. Among them, CC8 strains were major (12 strains), which contained 9 tst-positive CC8-type IVl SCCmec clones and a CC8-type IVa SCCmec strain carrying the Panton Valentine Leukocidin gene (lukS, F-PV). Clones related to impetigo were also identified: 7 exfoliative toxin b (etb) -positive clones, CC89-type IIa SCCmec and CC89-type V SCCmec strains; and 2 exfoliative toxin a (eta) -positive CC121-type V SCCmec strains. Other clones were as follows: CC1-type IVa SCCmec, CC8-type I SCCmec, CC81-type IVg SCCmec, CC97-type IVc SCCmec, CC91-type IVa SCCmec, CC59-type IVg SCCmec, CC45-type IIn SCCmec, CC89-SCCmec nontypeable, and CC8-type IVm, novel subtype of type IV SCCmec were identified in this study. Our data showed that many novel MRSA clones have emerged in the community. PMID:25764806

  10. Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population

    PubMed Central

    Go, Min Jin; Hwang, Joo-Yeon; Park, Tae-Joon; Kim, Young Jin; Oh, Ji Hee; Kim, Yeon-Jung; Han, Bok-Ghee

    2014-01-01

    Background Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. Methods We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. Results A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of ?-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. Conclusion Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population. PMID:25349825

  11. Two novel mutations in glucocerebrosidase, C23W and IVS7-1 G>A, identified in Type 1 Gaucher patients heterozygous for N370S.

    PubMed

    Jack, Alexandria; Amato, Dominick; Morris, Geoffrey; Choy, Francis Y M

    2014-03-15

    Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from deficient glucocerebrosidase activity. There have been nearly 300 mutations described to date. Novel mutations can potentially provide insight into the biochemical basis of the disease. Two novel mutations are described in two Type 1 Gaucher patients with N370S compound heterozygosity; a point mutation that causes an amino acid substitution at cysteine residue 23 for tryptophan, and a second point mutation within the splicing element at the 3' end of intron 7. Both mutations were identified by PCR amplification and sequence analysis of patient glucocerebrosidase genomic DNA. Restriction fragment length polymorphism analysis was established for both novel mutations for efficient identification in future patients. Past literature suggests that mutations affecting cysteine residues involved in disulfide bridges, as well as mutations affecting splicing patterns of the glucocerebrosidase transcript, are detrimental to enzyme activity. However, compound heterozygosity with N370S, a mild mutation, will lead to a mild phenotype. The cases reported here support these past findings. PMID:24434810

  12. Screening for type 2 diabetes in a multiethnic setting using known risk factors to identify those at high risk: a cross-sectional study

    PubMed Central

    Gray, Laura J; Tringham, Jennifer R; Davies, Melanie J; Webb, David R; Jarvis, Janet; Skinner, Timothy C; Farooqi, Azhar M; Khunti, Kamlesh

    2010-01-01

    Introduction Screening enables the identification of type 2 diabetes mellitus (T2DM) during its asymptomatic stage and therefore allows early intervention which may lead to fewer complications and improve outcomes. A targeted screening program was carried out in a United Kingdom (UK) multiethnic population to identify those with abnormal glucose tolerance. Methods A sample of individuals aged 25–75 years (40–75 white European) with at least one risk factor for T2DM were invited for screening from 17 Leicestershire (UK) general practices or through a health awareness campaign. All participants received a 75 g oral glucose tolerance test, cardiovascular risk assessment, detailed medical and family histories and anthropometric measurements. Results In the 3,225 participants who were screened. 640 (20%) were found to have some form of abnormal glucose tolerance of whom 4% had T2DM, 3% impaired fasting glucose (IFG), 10% impaired glucose tolerance (IGT) and 3% both IFG and IGT. The odds of detecting IGT was approximately 60% greater (confounder-adjusted odds ratios [OR] 1.67 [1.22–2.29]) in the South Asian population. Conclusions Around one in five people who had targeted screening have IGT, IFG or T2DM, with a higher prevalence in those of South Asian origin. The prevalence of undetected T2DM is lower in South Asians compared to previously published studies and maybe due to increased awareness of this group being at high risk. PMID:20957129

  13. SPC3, a synthetic peptide derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120, inhibits HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms.

    PubMed

    Yahi, N; Fantini, J; Baghdiguian, S; Mabrouk, K; Tamalet, C; Rochat, H; Van Rietschoten, J; Sabatier, J M

    1995-05-23

    The third variable region (V3 loop) of gp120, the HIV-1 surface envelope glycoprotein, plays a key role in HIV-1 infection and pathogenesis. Recently, we reported that a synthetic multibranched peptide (SPC3) containing eight V3-loop consensus motifs (GPGRAF) inhibited HIV-1 infection in both CD4+ and CD4- susceptible cells. In the present study, we investigated the mechanisms of action of SPC3 in these cell types--i.e., CD4+ lymphocytes and CD4- epithelial cells expressing galactosylceramide (GalCer), an alternative receptor for HIV-1 gp120. We found that SPC3 was a potent inhibitor of HIV-1 infection in CD4+ lymphocytes when added 1 h after initial exposure of the cells to HIV-1, whereas it had no inhibitory effect when present only before and/or during the incubation with HIV-1. These data suggested that SPC3 did not inhibit the binding of HIV-1 to CD4+ lymphocytes but interfered with a post-binding step necessary for virus entry. In agreement with this hypothesis, SPC3 treatment after HIV-1 exposure dramatically reduced the number of infected cells without altering gp120-CD4 interaction or viral gene expression. In contrast, SPC3 blocked HIV-1 entry into CD4-/GalCer+ human colon epithelial cells when present in competition with HIV-1 but had no effect when added after infection. Accordingly, SPC3 was found to inhibit the binding of gp120 to the GalCer receptor. Thus, the data suggest that SPC3 affects HIV-1 infection by two distinct mechanisms: (i) prevention of GalCer-mediated HIV-1 attachment to the surface of CD4-/GalCer+ cells and (ii) post-binding inhibition of HIV-1 entry into CD4+ lymphocytes. PMID:7761414

  14. SPC3, a synthetic peptide derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120, inhibits HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms.

    PubMed Central

    Yahi, N; Fantini, J; Baghdiguian, S; Mabrouk, K; Tamalet, C; Rochat, H; Van Rietschoten, J; Sabatier, J M

    1995-01-01

    The third variable region (V3 loop) of gp120, the HIV-1 surface envelope glycoprotein, plays a key role in HIV-1 infection and pathogenesis. Recently, we reported that a synthetic multibranched peptide (SPC3) containing eight V3-loop consensus motifs (GPGRAF) inhibited HIV-1 infection in both CD4+ and CD4- susceptible cells. In the present study, we investigated the mechanisms of action of SPC3 in these cell types--i.e., CD4+ lymphocytes and CD4- epithelial cells expressing galactosylceramide (GalCer), an alternative receptor for HIV-1 gp120. We found that SPC3 was a potent inhibitor of HIV-1 infection in CD4+ lymphocytes when added 1 h after initial exposure of the cells to HIV-1, whereas it had no inhibitory effect when present only before and/or during the incubation with HIV-1. These data suggested that SPC3 did not inhibit the binding of HIV-1 to CD4+ lymphocytes but interfered with a post-binding step necessary for virus entry. In agreement with this hypothesis, SPC3 treatment after HIV-1 exposure dramatically reduced the number of infected cells without altering gp120-CD4 interaction or viral gene expression. In contrast, SPC3 blocked HIV-1 entry into CD4-/GalCer+ human colon epithelial cells when present in competition with HIV-1 but had no effect when added after infection. Accordingly, SPC3 was found to inhibit the binding of gp120 to the GalCer receptor. Thus, the data suggest that SPC3 affects HIV-1 infection by two distinct mechanisms: (i) prevention of GalCer-mediated HIV-1 attachment to the surface of CD4-/GalCer+ cells and (ii) post-binding inhibition of HIV-1 entry into CD4+ lymphocytes. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7761414

  15. The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders.

    PubMed

    Naluai, A T; Nilsson, S; Samuelsson, L; Gudjónsdóttir, A H; Ascher, H; Ek, J; Hallberg, B; Kristiansson, B; Martinsson, T; Nerman, O; Sollid, L M; Wahlström, J

    2000-10-01

    The effect of the gene region on chromosome 2q33 containing the CD28 and the cytotoxic T-lymphocyte associated (CTLA4) genes has been investigated in several diseases with chronic inflammatory nature. In addition to celiac disease (CD), type I diabetes, Grave's disease, rheumatoid arthritis and multiple sclerosis have all demonstrated associations to the A/G single nucleotide polymorphism (SNP) in exon 1, position +49 of the CTLA4 gene. The purpose of this study was to investigate this gene region in a genetically homogeneous population consisting of 107 Swedish and Norwegian families with CD using genetic association and linkage methods. We found a significant association with preferential transmission of the A-allele of the exon 1 +49 polymorphism by using the transmission disequilibrium test (TDT). Suggestive linkage of this region to CD was moreover demonstrated by non-parametric linkage (NPL) analysis giving a NPL-score of 2.1. These data strongly indicates that the CTLA4 region is a susceptibility region in CD. Interestingly, of the several chronic inflammatory diseases that exhibit associations to the CTLA4 +49 A/G dimorphism, CD appears to be the only disease associated to the A allele. This suggests that the +49 alleles of the CTLA4 gene are in linkage disequilibrium with two distinct disease predisposing alleles with separate effects. The peculiar association found in the gut disorder CD may possibly relate to the fact that the gastrointestinal immune system, in contrast to the rest of the immune system, aims to establish tolerance to foreign proteins. PMID:11098935

  16. Protein ligands of the human adenovirus type 2 outer capsid identified by biopanning of a phage-displayed peptide library on separate domains of wild-type and mutant penton capsomers.

    PubMed Central

    Hong, S S; Boulanger, P

    1995-01-01

    A filamentous phage-displayed random hexapeptide library was screened on the adenovirus type 2 (Ad2) penton capsomer and its separate domains, penton base, full-length fiber, fiber shaft and fiber knob. Affinity supports were designed to immobilize the penton ligate with a preferred orientation, via immuno-adsorption to pre-coated antibody. Three classes of phagotopes were distinguished in the eluates from the penton and fiber domains. (i) The first class represented peptide sequences identified in certain Ad2 capsid proteins, protein IIIa, protein pVIII, penton base and penton fiber. Data from specific ligand elution of phages bound to fiber and penton base wild-types and mutants suggested that the region overlapping the RLSNLLG motif at residues 254-260 in the penton base and the FNPVYP motif at residues 11-16 in the fiber tail formed mutual interacting sites in the penton capsomer. (ii) The second class consisted of phagotopes homologous to peptide sequences found in host cell membrane proteins involved in receptor or adhesion functions. One of the most abundant species corresponded to a conserved motif present in the beta-strand B of type III modules of human fibronectin. In addition, phages which were screened for their failure to bind to penton base RGD mutants were found to carry consensus motifs to peptide sequences present in the RGD recognition site of human integrin beta subunits. (iii) The third class comprised peptide motifs common to both viral and cellular proteins, suggesting that a mechanism of ligand exchange could occur during virus entry and uncoating, and virus assembly and release. Images PMID:7588601

  17. Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Han Chinese Population: A Replication Study and Meta-Analysis

    PubMed Central

    Yu, Yu-Hsiang; Kuo, Shan-Shan; Chang, Tien-Jyun; Jiang, Yi-Der; Nong, Jiun-Yi; Hwang, Juey-Jen; Chuang, Lee-Ming

    2014-01-01

    Background Several genome-wide association studies (GWAS) involving European populations have successfully identified risk genetic variants associated with type 2 diabetes mellitus (T2DM). However, the effects conferred by these variants in Han Chinese population have not yet been fully elucidated. Methods We analyzed the effects of 24 risk genetic variants with reported associations from European GWAS in 3,040 Han Chinese subjects in Taiwan (including 1,520 T2DM cases and 1,520 controls). The discriminative power of the prediction models with and without genotype scores was compared. We further meta-analyzed the association of these variants with T2DM by pooling all candidate-gene association studies conducted in Han Chinese. Results Five risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples. The odds ratio was 2.22 (95% confidence interval, 1.81-2.73, P<0.0001) for subjects with the highest genetic score quartile (score>34) as compared with subjects with the lowest quartile (score<29). The incoporation of genotype score into the predictive model increased the C-statistics from 0.627 to 0.657 (P<0.0001). These estimates are very close to those observed in European populations. Gene-environment interaction analysis showed a significant interaction between rs13266634 in SLC30A8 gene and age on T2DM risk (P<0.0001). Further meta-analysis pooling 20 studies in Han Chinese confirmed the association of 10 genetic variants in IGF2BP2, CDKAL1, JAZF1, SCL30A8, HHEX, TCF7L2, EXT2, and FTO genes with T2DM. The effect sizes conferred by these risk variants in Han Chinese were similar to those observed in Europeans but the allele frequencies differ substantially between two populations. Conclusion We confirmed the association of 10 variants identified by European GWAS with T2DM in Han Chinese population. The incorporation of genotype scores into the prediction model led to a small but significant improvement in T2DM prediction. PMID:24736664

  18. Genome-Wide DNA Methylation Analysis of Human Pancreatic Islets from Type 2 Diabetic and Non-Diabetic Donors Identifies Candidate Genes That Influence Insulin Secretion

    PubMed Central

    Dayeh, Tasnim; Volkov, Petr; Salö, Sofia; Hall, Elin; Nilsson, Emma; Olsson, Anders H.; Kirkpatrick, Clare L.; Wollheim, Claes B.; Eliasson, Lena; Rönn, Tina; Bacos, Karl; Ling, Charlotte

    2014-01-01

    Impaired insulin secretion is a hallmark of type 2 diabetes (T2D). Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, ?- and ?-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3?UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea) were hypermethylated in human islets, ?- and ?-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (?7%) and overrepresented in the open sea (?60%). 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic ?- and ?-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal ?- and ?-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These results highlight the importance of epigenetics in the pathogenesis of T2D. PMID:24603685

  19. Genome-Wide Linkage Scan to Identify Loci Associated with Type 2 Diabetes and Blood Lipid Phenotypes in the Sikh Diabetes Study

    PubMed Central

    Sanghera, Dharambir K.; Been, Latonya F.; Ralhan, Sarju; Wander, Gurpreet S.; Mehra, Narinder K.; Singh, Jai Rup; Ferrell, Robert E.; Kamboh, Mohammed I.; Aston, Christopher E.

    2011-01-01

    In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using Sall statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p?0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p?=?0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p?=?0.0016) and 5p15.33 (p?=?0.0031) and for LDL cholesterol at 10p11.23 (p?=?0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance. PMID:21698157

  20. Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study.

    PubMed

    Sanghera, Dharambir K; Been, Latonya F; Ralhan, Sarju; Wander, Gurpreet S; Mehra, Narinder K; Singh, Jai Rup; Ferrell, Robert E; Kamboh, Mohammed I; Aston, Christopher E

    2011-01-01

    In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S(all) statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p?0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p?=?0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p?=?0.0016) and 5p15.33 (p?=?0.0031) and for LDL cholesterol at 10p11.23 (p?=?0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance. PMID:21698157

  1. Genetic Screen of a Mutant Poxvirus Library Identifies an Ankyrin Repeat Protein Involved in Blocking Induction of Avian Type I Interferon

    PubMed Central

    Laidlaw, Stephen M.; Robey, Rebecca; Davies, Marc; Giotis, Efstathios S.; Ross, Craig; Buttigieg, Karen; Goodbourn, Stephen

    2013-01-01

    Mammalian poxviruses, including vaccinia virus (VACV), have evolved multiple mechanisms to evade the host type I interferon (IFN) responses at different levels, with viral proteins targeting IFN induction, signaling, and antiviral effector functions. Avian poxviruses (avipoxviruses), which have been developed as recombinant vaccine vectors for permissive (i.e., poultry) and nonpermissive (i.e., mammals, including humans) species, encode no obvious equivalents of any of these proteins. We show that fowlpox virus (FWPV) fails to induce chicken beta IFN (ChIFN2) and is able to block its induction by transfected poly(I·C), an analog of cytoplasmic double-stranded RNA (dsRNA). A broad-scale loss-of-function genetic screen was used to find FWPV-encoded modulators of poly(I·C)-mediated ChIFN2 induction. It identified fpv012, a member of a family of poxvirus genes highly expanded in the avipoxviruses (31 in FWPV; 51 in canarypox virus [CNPV], representing 15% of the total gene complement), encoding proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. Under ectopic expression, the first ANK of fpv012 is dispensable for inhibitory activity and the CNPV ortholog is also able to inhibit induction of ChIFN2. FWPV defective in fpv012 replicates well in culture and barely induces ChIFN2 during infection, suggesting that other factors are involved in blocking IFN induction and resisting the antiviral effectors. Nevertheless, unlike parental and revertant viruses, the mutants induce moderate levels of expression of interferon-stimulated genes (ISGs), suggesting either that there is sufficient ChIFN2 expression to partially induce the ISGs or the involvement of alternative, IFN-independent pathways that are also normally blocked by fpv012. PMID:23427153

  2. Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India.

    PubMed

    Saxena, Richa; Saleheen, Danish; Been, Latonya F; Garavito, Martha L; Braun, Timothy; Bjonnes, Andrew; Young, Robin; Ho, Weang Kee; Rasheed, Asif; Frossard, Philippe; Sim, Xueling; Hassanali, Neelam; Radha, Venkatesan; Chidambaram, Manickam; Liju, Samuel; Rees, Simon D; Ng, Daniel Peng-Keat; Wong, Tien-Yin; Yamauchi, Toshimasa; Hara, Kazuo; Tanaka, Yasushi; Hirose, Hiroshi; McCarthy, Mark I; Morris, Andrew P; Basit, Abdul; Barnett, Anthony H; Katulanda, Prasad; Matthews, David; Mohan, Viswanathan; Wander, Gurpreet S; Singh, Jai Rup; Mehra, Narinder K; Ralhan, Sarju; Kamboh, M Ilyas; Mulvihill, John J; Maegawa, Hiroshi; Tobe, Kazuyuki; Maeda, Shiro; Cho, Yoon S; Tai, E Shyong; Kelly, M Ann; Chambers, John C; Kooner, Jaspal S; Kadowaki, Takashi; Deloukas, Panos; Rader, Daniel J; Danesh, John; Sanghera, Dharambir K

    2013-05-01

    We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10?³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10??) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10??) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10?³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10??) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10?? to < 10??), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. PMID:23300278

  3. A GT box element is essential for basal and cyclic adenosine 3',5'-monophosphate regulation of the human surfactant protein A2 gene in alveolar type II cells: evidence for the binding of lung nuclear factors distinct from Sp1.

    PubMed

    Young, P P; Mendelson, C R

    1997-07-01

    The gene encoding surfactant protein-A (SP-A) is developmentally regulated in type II cells of the fetal lung. In humans there are two SP-A genes, SP-A1 and SP-A2. The SP-A2 gene is more highly regulated by cAMP and during fetal development than SP-A1. In earlier studies we determined that 296 bp of sequence flanking the 5'-end of the SP-A2 gene is sufficient to mediate high basal and cAMP-inducible reporter gene expression in primary cultures of transfected type II cells, suggesting that this region contains important cis-acting elements involved in tissue-specific and hormonal regulation of SP-A2 promoter activity. We also observed that mutagenesis of a cAMP response element (CRE)-like sequence at -242 bp (CRE(SP-A2)) greatly reduced basal and cAMP-stimulated expression in transfected type II cells. In the present study, we identified a GT box (GGGGTGGGG) at -61 bp of SP-A2 5'-flanking sequence that is highly conserved among the SP-A genes of different species. In type II cell transfection studies, we found that mutagenesis of the GT box of SP-A2 markedly reduced basal and abolished cAMP-induced reporter gene expression. Thus, CRE(SP-A2) and the GT box cooperatively interact to mediate basal and cAMP induction of SP-A2 promoter activity in type II cells. By electrophoretic mobility shift assays (EMSA), it was observed that nuclear proteins isolated from primary cultures of type II cells bound the GT box as five specific complexes. By contrast, nuclear proteins isolated from lung fibroblasts displayed notably reduced binding activity. Competition and supershift EMSA indicate that the ubiquitously expressed transcription factor Sp1, a GC box-binding protein of approximately 100 kDa, is a component of the complex of proteins that bind the GT box of SP-A2. The finding that only two of the five GT box-binding complexes were supershifted by incubation with Sp1 antibody suggests that a factor(s) in type II cell nuclear extracts that is distinct from Sp1 also interacts with the GT box. By UV cross-linking and SDS-PAGE/EMSA analysis, we have identified a approximately 55-kDa GT box-binding factor in type II cell nuclear proteins that preferentially binds the GT box of SP-A2 over the consensus Sp1 GC box sequence. This 55-kDa factor was able to bind the GT box independently of Sp1. PMID:9212056

  4. Distinct Sets of Genetic Alterations in Melanoma

    Microsoft Academic Search

    John A. Curtin; Jane Fridlyand; Toshiro Kageshita; Hetal N. Patel; Klaus J. Busam; Heinz Kutzner; Kwang-Hyun Cho; Setsuya Aiba; Eva-Bettina Bröcker; Philip E. LeBoit; Dan Pinkel; Boris C. Bastian

    2010-01-01

    background Exposure to ultraviolet light is a major causative factor in melanoma, although the re- lationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different sus- ceptibility to ultraviolet light. methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF

  5. Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells*

    PubMed Central

    Hirayama, Mio; Kobayashi, Daiki; Mizuguchi, Souhei; Morikawa, Takashi; Nagayama, Megumi; Midorikawa, Uichi; Wilson, Masayo M.; Nambu, Akiko N.; Yoshizawa, Akiyasu C.; Kawano, Shin; Araki, Norie

    2013-01-01

    Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, “dynein IC2-GR-COX-1 signaling,” was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural abnormalities are, in part, caused by up-regulation of dynein IC2-GR-COX-1 signaling, which may be a novel therapeutic target for NF1. PMID:23358504

  6. Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

    PubMed Central

    Saxena, Richa; Saleheen, Danish; Been, Latonya F.; Garavito, Martha L.; Braun, Timothy; Bjonnes, Andrew; Young, Robin; Ho, Weang Kee; Rasheed, Asif; Frossard, Philippe; Sim, Xueling; Hassanali, Neelam; Radha, Venkatesan; Chidambaram, Manickam; Liju, Samuel; Rees, Simon D.; Ng, Daniel Peng-Keat; Wong, Tien-Yin; Yamauchi, Toshimasa; Hara, Kazuo; Tanaka, Yasushi; Hirose, Hiroshi; McCarthy, Mark I.; Morris, Andrew P.; Basit, Abdul; Barnett, Anthony H.; Katulanda, Prasad; Matthews, David; Mohan, Viswanathan; Wander, Gurpreet S.; Singh, Jai Rup; Mehra, Narinder K.; Ralhan, Sarju; Kamboh, M. Ilyas; Mulvihill, John J.; Maegawa, Hiroshi; Tobe, Kazuyuki; Maeda, Shiro; Cho, Yoon S.; Tai, E. Shyong; Kelly, M. Ann; Chambers, John C.; Kooner, Jaspal S.; Kadowaki, Takashi; Deloukas, Panos; Rader, Daniel J.; Danesh, John; Sanghera, Dharambir K.

    2013-01-01

    We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10?3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10?4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10?8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10?3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10?4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10?5 to < 10?7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. PMID:23300278

  7. Regulation of beta-cell viability and gene expression by distinct agonist fragments of adiponectin

    Microsoft Academic Search

    James E. P. Brown; Alex C. Conner; Janet E. Digby; Manjunath Ramanjaneya; Harpal S. Randeva; Simon J. Dunmore

    2010-01-01

    Obesity is an established risk factor for type 2 diabetes. Activation of the adiponectin receptors has a clear role in improving insulin resistance although conflicting evidence exists for its effects on pancreatic beta-cells. Previous reports have identified both adiponectin receptors (ADR-1 and ADR-2) in the beta-cell. Recent evidence has suggested that two distinct regions of the adiponectin molecule, the globular

  8. Types, numbers and distribution of synapses on the dendritic tree of an identified visual interneuron in the brain of the locust

    Microsoft Academic Search

    F. Killmann; H. Gras; F.-W. Schürmann

    1999-01-01

    The descending contralateral movement detector (DCMD), an identified descending interneuron in the brain of the locust Schistocerca gregaria has been investigated by using light and electron microscopy. We describe the fine structure, distribution and numbers of synapes that it receives from another identified brain neuron, the lobular giant movement detector (LGMD), and from unidentified neurons. The DCMD dendrites emerging from

  9. 1 07/01/2013 The Account chartfield is a 5-character numeric value which identifies the nature or type of the

    E-print Network

    Derisi, Joseph

    the nature or type of the transaction by classifying them into Assets, Liabilities, Equity (net position of measure used to track the statistical amounts. Account Type AN 1 A ­ Asset E ­ Expense L ­ Liability Q to facilitate reporting, management decisions, and timely reconciliations · No existing account describes

  10. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: Where are the insulin resistance genes?

    Microsoft Academic Search

    J. C. Florez

    2008-01-01

    Although type 2 diabetes has been traditionally understood as a metabolic disorder initiated by insulin resistance, it has\\u000a recently become apparent that an impairment in insulin secretion contributes to its manifestation and may play a prominent\\u000a role in its early pathophysiology. The genetic dissection of Mendelian and, more recently, polygenic types of diabetes confirms\\u000a the notion that primary defects in

  11. Ability of the MicroScan Rapid Gram-Negative ID Type 3 Panel To Identify Nonenteric Glucose-Fermenting and Nonfermenting Gram-Negative Bacilli

    PubMed Central

    O'Hara, Caroline M.; Miller, J. Michael

    2002-01-01

    The MicroScan Rapid Neg ID3 panel is designed for the identification of Enterobacteriaceae and nonenteric glucose-fermenting and nonfermenting gram-negative bacilli. We evaluated this panel for its ability to identify gram-negative non-Enterobacteriaceae bacteria. A total of 134 strains, representing 26 genera and 42 species, were taken from storage at ?70oC, passaged three times before testing, and inoculated into the panels according to the manufacturer's directions before being inserted into a Walk/Away 96 instrument loaded with version 22.28 software. At the end of the initial 2.5-h incubation period, 89 isolates (66.4%) were correctly identified at a probability level of ?85%. After additional testing recommended by the manufacturer was completed, another 11 isolates (8.2%) were correctly identified at probability levels of ?85%. Twenty-five (18.7%) isolates were correctly identified after additional testing, but the probability levels were less than 85%. Two isolates were unidentified, and seven (5.2%) were incorrectly identified. The seven misidentified strains were not concentrated in any one genus. With an accuracy approaching 75%, this product may be used for the identification of the commonly isolated non-Enterobacteriaceae bacteria but may present problems in identification of other non-glucose-fermenting gram-negative bacilli. PMID:12354875

  12. Identifying Galaxies

    NSDL National Science Digital Library

    In this activity, students describe the characteristics of different types of galaxies (spiral, elliptical, barred spiral, peculiar, or irregular) in their own words. They also classify galaxies seen in the Hubble Deep Field. This activity includes a student worksheet and background information for the teacher. This is activity two in "The Hidden Lives of Galaxies" information and activity booklet.

  13. Tumor Types

    MedlinePLUS

    ... and how the cells behave, from the least aggressive (benign) to the most aggressive (malignant). Some tumor types are assigned a grade, ... four distinct genetic subtypes that respond differently to aggressive therapies, making treatment extremely difficult and challenging. Parallel ...

  14. Identifying Erosion

    NSDL National Science Digital Library

    COSI

    2009-01-01

    In this environmental science activity (page 3 of the PDF), leaners will identify and explain the causes of erosion. They will observe the effects of erosion on the surrounding area and further explore examples of erosion online. An extension activity allows learners to make a hands-on model of soil erosion. Though this was created as a pre-visit activity for a workshop about water flow and erosion, it makes a great stand-alone activity as well!

  15. A 1-year lifestyle intervention for weight loss in individuals with type 2 diabetes reduces high C-reactive protein levels and identifies metabolic predictors of change

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE: We examined whether a 1-year intensive lifestyle intervention (ILI) for weight loss reduced elevated high-sensitivity C-reactive protein (hs-CRP) levels in obese individuals with diabetes and identified metabolic and fitness predictors of hs-CRP change. RESEARCH DESIGN AND METHODS: Look A...

  16. Positive Selection Detection in 40,000 Human Immunodeficiency Virus (HIV) Type 1 Sequences Automatically Identifies Drug Resistance and Positive Fitness Mutations in HIV Protease and Reverse Transcriptase

    Microsoft Academic Search

    Lamei Chen; Alla Perlina; Christopher J. Lee

    2004-01-01

    Drug resistance is a major problem in the treatment of AIDS, due to the very high mutation rate of human immunodeficiency virus (HIV) and subsequent rapid development of resistance to new drugs. Identification of mutations associated with drug resistance is critical for both individualized treatment selection and new drug design. We have performed an automated mutation analysis of HIV Type

  17. SHIGA TOXIN BACTERIOPHAGE INSERTION SITES IDENTIFY DIVERSE ESCHERIHICA COLI O157:H7 STRAIN TYPES WITH DISTRIBUTIONS BIASED TO THE BOVINE HOST RESERVOIR

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: The incidence of human disease caused by E. coli O157:H7 is surprisingly low considering its ubiquitous distribution (and frequently, high prevalence) in the bovine reservoir and its low infectious dose for humans. The purpose of this study was to detect E. coli O157:H7 strain types in t...

  18. Keyword Thesaurus. A List of Terms and Codes to Identify Areas of Interest for Research and Other Types of Sponsored Programs. Keyword Thesaurus Project Update for New Participants.

    ERIC Educational Resources Information Center

    Rodman, John A.

    This list of program types and keywords (with codes) was prepared for program officers at the National Endowment for the Humanities, the National Institute of Education, and the National Science Foundation to use when preparing program announcements and requests for proposals. Staff persons responsible for screening such documents at colleges and…

  19. The Prevalence of Human Papillomavirus Genotypes in Nonmelanoma Skin Cancers of Nonimmunosuppressed Individuals Identifies High-Risk Genital Types as Possible Risk Factors1

    Microsoft Academic Search

    Angelika Iftner; Stefanie J. Klug; Claus Garbe; Andreas Blum; Alice Stancu; Sharon P. Wilczynski; Thomas Iftner

    2003-01-01

    Nonmelanoma skin cancer is the most commonly diagnosed malignant disease in Caucasians. Known risk factors include fair skin, sun exposure, male gender, advancing age, and the presence of solar keratosis. No viral risk factors have been established thus far. To examine the association between nonmelanoma skin cancer and infection with human papilloma virus (HPV) types, we performed a retrospective study

  20. Emergence of a New Lineage of Dengue Virus Type 2 Identified in Travelers Entering Western Australia from Indonesia, 2010-2012

    PubMed Central

    Ernst, Timo; McCarthy, Suzi; Chidlow, Glenys; Luang-Suarkia, Dagwin; Holmes, Edward C.; Smith, David W.; Imrie, Allison

    2015-01-01

    Dengue virus (DENV) transmission is ubiquitous throughout the tropics. More than 70% of the current global dengue disease burden is borne by people who live in the Asia-Pacific region. We sequenced the E gene of DENV isolated from travellers entering Western Australia between 2010–2012, most of whom visited Indonesia, and identified a diverse array of DENV1-4, including multiple co-circulating viral lineages. Most viruses were closely related to lineages known to have circulated in Indonesia for some time, indicating that this geographic region serves as a major hub for dengue genetic diversity. Most notably, we identified a new lineage of DENV-2 (Cosmopolitan genotype) that emerged in Bali in 2011–2012. The spread of this lineage should clearly be monitored. Surveillance of symptomatic returned travellers provides important and timely information on circulating DENV serotypes and genotypes, and can reveal the herald wave of dengue and other emerging infectious diseases. PMID:25635775

  1. Listening and Questioning: The "Apophatic/Cataphatic" Distinction Revisited

    ERIC Educational Resources Information Center

    Waks, Leonard

    2007-01-01

    In an earlier article I drew a distinction between two general types of listening. In one the listener brings pre-determined categories to bear in extracting useful information from the speaker's utterance. In the other the listener suspends such categories to hear as much as possible in the utterance. This distinction has been challenged by…

  2. Is Face Distinctiveness Gender Based?

    ERIC Educational Resources Information Center

    Baudouin, Jean-Yves; Gallay, Mathieu

    2006-01-01

    Two experiments were carried out to study the role of gender category in evaluations of face distinctiveness. In Experiment 1, participants had to evaluate the distinctiveness and the femininity-masculinity of real or artificial composite faces. The composite faces were created by blending either faces of the same gender (sexed composite faces,…

  3. Severe hypoglycemia identifies vulnerable patients with type 2 diabetes at risk for premature death and all-site cancer: the Hong Kong diabetes registry.

    PubMed

    Kong, Alice P S; Yang, Xilin; Luk, Andrea; Ma, Ronald C W; So, Wing Yee; Ozaki, Risa; Ting, Rose; Cheung, Kitty; Ho, Chung Shun; Chan, Michael H M; Chow, Chun Chung; Chan, Juliana C N

    2014-04-01

    OBJECTIVE We examined the associations of clinical profiles in type 2 diabetic patients who developed severe hypoglycemia and their clinical outcomes, including death and all-site cancer. RESEARCH DESIGN AND METHODS A consecutive cohort of 8,767 type 2 diabetic patients with and without severe hypoglycemia in the 12 months before enrollment were recruited between 1995 and 2007, with follow-up until 2009. Severe hypoglycemia was defined by ICD-9 codes as hospitalizations resulting from hypoglycemia. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% CIs of clinical factors collected at enrollment for severe hypoglycemia. RESULTS In this cohort, mean age was 57.4 (SD 13.2) years and median disease duration of diabetes was 5 (interquartile range [IQR] 1-11) years. During a median follow-up of 6.71 (IQR 3.47-10.38) years, 235 patients had severe hypoglycemia (incidence 3.96 [95% CI 3.45-4.46] per 1,000 patient-years). At enrollment, patients with and without severe hypoglycemia had similar cancer rates. During follow-up, patients with severe hypoglycemia had a higher incidence of all-site cancer (13.4 vs. 6.4%, P < 0.0001) and mortality (32.8 vs. 11.2%, P < 0.0001) than those without severe hypoglycemia. After adjusting for confounders, old age, low BMI, high glycated hemoglobin, low triglyceride (TG), low LDL cholesterol (LDL-C), albuminuria, and chronic kidney disease were independent predictors for severe hypoglycemia. CONCLUSIONS In type 2 diabetes, severe hypoglycemia is associated with advanced age, renal dysfunction, poor glycemic control, and cancer subphenotypes (low BMI, low LDL-C, and low TG). PMID:24513587

  4. Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT Syndrome

    PubMed Central

    Boczek, Nicole J.; Best, Jabe M.; Tester, David J.; Giudicessi, John R.; Middha, Sumit; Evans, Jared M.; Kamp, Timothy J.; Ackerman, Michael J.

    2013-01-01

    Background Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results We combined whole exome sequencing (WES) and bioinformatic/systems biology to identify the pathogenic substrate responsible for non-syndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree and established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with “genotype-negative/phenotype-positive” LQTS. WES was utilized on three members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, co-segregated with the disease within the pedigree, was ranked by three disease-network algorithms as the most probable LQTS-susceptibility gene, and involves a conserved residue localizing to the PEST domain in the II–III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain-of-function with increased ICa,L and increased surface membrane expression of the channel compared to wildtype. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2’s PEST domain. Conclusions This study provides evidence that coupling WES and bioinformatic/systems biology is an effective strategy for the identification of potential disease causing genes/mutations. The identification of a functional CACNA1C mutation co-segregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome. PMID:23677916

  5. Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals

    Microsoft Academic Search

    E. R. Gamazon; J. V. Morrison; A. Konkashbaev; A. Pluzhnikov; P. M. McKeigue; E. J. Parra; S. C. Elbein; D. M. Hallman; D. L. Nicolae; G. I. Bell; M. Cruz; N. J. Cox; C. L. Hanis

    2011-01-01

    Aims\\/hypothesis  We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and\\u000a characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA.\\u000a \\u000a \\u000a \\u000a \\u000a Method  Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic\\u000a controls, we conducted Armitage trend tests. To improve power in this population

  6. An NF-?B-Based High-Throughput Screen Identifies Piericidins as Inhibitors of the Yersinia pseudotuberculosis Type III Secretion System

    PubMed Central

    Duncan, Miles C.; Wong, Weng Ruh; Dupzyk, Allison J.; Bray, Walter M.; Linington, Roger G.

    2014-01-01

    The type III secretion system (T3SS) is a bacterial appendage used by dozens of Gram-negative pathogens to subvert host defenses and cause disease, making it an ideal target for pathogen-specific antimicrobials. Here, we report the discovery and initial characterization of two related natural products with T3SS-inhibitory activity that were derived from a marine actinobacterium. Bacterial extracts containing piericidin A1 and the piericidin derivative Mer-A 2026B inhibited Yersinia pseudotuberculosis from triggering T3SS-dependent activation of the host transcription factor NF-?B in HEK293T cells but were not toxic to mammalian cells. As the Yersinia T3SS must be functional in order to trigger NF-?B activation, these data indicate that piericidin A1 and Mer-A 2026B block T3SS function. Consistent with this, purified piericidin A1 and Mer-A 2026B dose-dependently inhibited translocation of the Y. pseudotuberculosis T3SS effector protein YopM inside CHO cells. In contrast, neither compound perturbed bacterial growth in vitro, indicating that piericidin A1 and Mer-A 2026B do not function as general antibiotics in Yersinia. In addition, when Yersinia was incubated under T3SS-inducing culture conditions in the absence of host cells, Mer-A 2026B and piericidin A1 inhibited secretion of T3SS cargo as effectively as or better than several previously described T3SS inhibitors, such as MBX-1641 and aurodox. This suggests that Mer-A 2026B and piericidin A1 do not block type III secretion by blocking the bacterium-host cell interaction, but rather inhibit an earlier stage, such as T3SS needle assembly. In summary, the marine-derived natural products Mer-A 2026B and piericidin A1 possess previously uncharacterized activity against the bacterial T3SS. PMID:24295981

  7. Analysis of the 5' portion of the type 19A capsule locus identifies two classes of cpsC, cpsD, and cpsE genes in Streptococcus pneumoniae.

    PubMed

    Morona, J K; Morona, R; Paton, J C

    1999-06-01

    Analysis of the sequence data obtained from the 5' portion of the Streptococcus pneumoniae type 19A capsular polysaccharide biosynthesis locus (cps19a) revealed that the first seven genes are homologous to the first seven genes in the type 19F (cps19f) locus. The former genes were designated cps19aA to -G and were 70 to 90% identical to their cps19f counterparts. Southern hybridization analysis of the cps loci from various S. pneumoniae serotypes with probes specific for the cps19aC, cps19aD, and cps19aE genes indicated a hybridization pattern complementary to that previously reported for cps19fC, cps19fD, and cps19fE. That is, all serotypes tested contained high-stringency homologues of either the cps19aC to -E genes or the cps19fC to -E genes, but not both. On this basis S. pneumoniae cps loci can be divided into two distinct classes. Long-range PCR was used to amplify the cps regions between cpsB and aliA from a variety of pneumococcal serotypes. Direct sequencing of the 5' end of these PCR products, and phylogenetic analysis of the sequence data, confirmed the presence of the two distinct classes of cpsC. Whereas members within one class are greater than 95% identical to each other, the DNA sequence identity between the two classes is only approximately 70%. PMID:10348877

  8. Development of a phenotypic high-content assay to identify pharmacoperone drugs for the treatment of primary hyperoxaluria type 1 by high-throughput screening.

    PubMed

    Madoux, Franck; Janovick, Jo Ann; Smithson, David; Fargue, Sonia; Danpure, Christopher J; Scampavia, Louis; Chen, Yih-Tai; Spicer, Timothy P; Conn, P Michael

    2015-01-01

    Primary hyperoxaluria is a severe disease for which the best current therapy is dialysis or organ transplantation. These are risky, inconvenient, and costly procedures. In some patients, pyridoxine treatment can delay the need for these surgical procedures. The underlying cause of particular forms of this disease is the misrouting of a specific enzyme, alanine:glyoxylate aminotransferase (AGT), to the mitochondria instead of the peroxisomes. Pharmacoperones are small molecules that can rescue misfolded proteins and redirect them to their correct location, thereby restoring their function and potentially curing disease. In the present study, we miniaturized a cell-based assay to identify pharmacoperone drugs present in large chemical libraries to selectively correct AGT misrouting. This assay employs AGT-170, a mutant form of AGT that predominantly resides in the mitochondria, which we monitor for its relocation to the peroxisomes through automated image acquisition and analysis. Over the course of a pilot screen of 1,280 test compounds, we achieved an average Z'-factor of 0.72±0.02, demonstrating the suitability of this assay for HTS. PMID:25710543

  9. Magnetic ejection of diamagnetic sub-millimeter grains observed by a chamber-type ?G generator orientated to identify material of a single particle

    NASA Astrophysics Data System (ADS)

    Hisayoshi, K.; Uyeda, C.; Kuwada, K.; Mamiya, M.; Nagai, H.

    2013-03-01

    A principle to identify the material of a single particle without destroying the sample is examined by an experiment in microgravity ( ?G). Such an identification is important as a first stage of analyzing various grains of primitive materials. The identification was based on diamagnetic susceptibility ? DIA obtained from translation of the grain induced by a magnetic field. When a grain is released in an area of a monotonously decreasing field under ?G conditions, it will be ejected in the direction of the field reduction; here, the area is occupied with diffused gas medium. The material identification of a primitive grain is possible by comparing the measured ? DIA with published values; an intrinsic ? DIA value is assigned to a material according to a molecular orbital model. We report here that the ejection is realized for sub-mm-sized crystals of various organic and inorganic materials. By developing a short drop shaft ( ?G duration ~0.5 s), the proposed material identification can be easily performed in an ordinary chamber. Using conventional methods, ? DIA cannot be detected for a small sample of diameter below the level of a millimetre. The achieved result is a step to realize the identification of micron-sized grains that compose primitive materials.

  10. A Drosophila functional evaluation of candidates from human genome-wide association studies of type?2?diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

    PubMed Central

    2013-01-01

    Background Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type?2?diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits. Results Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity. Conclusion Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system. PMID:23445342

  11. Transcriptome Analysis of Arabidopsis Wild-Type and gl3–sst sim Trichomes Identifies Four Additional Genes Required for Trichome Development

    PubMed Central

    Marks, M. David; Wenger, Jonathan P.; Gilding, Edward; Jilk, Ross; Dixon, Richard A.

    2009-01-01

    Transcriptome analyses have been performed on mature trichomes isolated from wild-type Arabidopsis leaves and on leaf trichomes isolated from the gl3–sst sim double mutant, which exhibit many attributes of immature trichomes. The mature trichome profile contained many highly expressed genes involved in cell wall synthesis, protein turnover, and abiotic stress response. The most highly expressed genes in the gl3–sst sim profile encoded ribosomal proteins and other proteins involved in translation. Comparative analyses showed that all but one of the genes encoding transcription factors previously found to be important for trichome formation, and many other trichome-important genes, were preferentially expressed in gl3–sst sim trichomes. The analysis of genes preferentially expressed in gl3–sst sim led to the identification of four additional genes required for normal trichome development. One of these was the HDG2 gene, which is a member of the HD–ZIP IV transcription factor gene family. Mutations in this gene did not alter trichome expansion, but did alter mature trichome cell walls. Mutations in BLT resulted in a loss of trichome branch formation. The relationship between blt and the phenotypically identical mutant, sti, was explored. Mutations in PEL3, which was previously shown to be required for development of the leaf cuticle, resulted in the occasional tangling of expanding trichomes. Mutations in another gene encoding a protein with an unknown function altered trichome branch formation. PMID:19626137

  12. Transcriptome analysis of Arabidopsis wild-type and gl3-sst sim trichomes identifies four additional genes required for trichome development.

    PubMed

    Marks, M David; Wenger, Jonathan P; Gilding, Edward; Jilk, Ross; Dixon, Richard A

    2009-07-01

    Transcriptome analyses have been performed on mature trichomes isolated from wild-type Arabidopsis leaves and on leaf trichomes isolated from the gl3-sst sim double mutant, which exhibit many attributes of immature trichomes. The mature trichome profile contained many highly expressed genes involved in cell wall synthesis, protein turnover, and abiotic stress response. The most highly expressed genes in the gl3-sst sim profile encoded ribosomal proteins and other proteins involved in translation. Comparative analyses showed that all but one of the genes encoding transcription factors previously found to be important for trichome formation, and many other trichome-important genes, were preferentially expressed in gl3-sst sim trichomes. The analysis of genes preferentially expressed in gl3-sst sim led to the identification of four additional genes required for normal trichome development. One of these was the HDG2 gene, which is a member of the HD-ZIP IV transcription factor gene family. Mutations in this gene did not alter trichome expansion, but did alter mature trichome cell walls. Mutations in BLT resulted in a loss of trichome branch formation. The relationship between blt and the phenotypically identical mutant, sti, was explored. Mutations in PEL3, which was previously shown to be required for development of the leaf cuticle, resulted in the occasional tangling of expanding trichomes. Mutations in another gene encoding a protein with an unknown function altered trichome branch formation. PMID:19626137

  13. A Multi-Omics Approach Identifies Key Hubs Associated with Cell Type-Specific Responses of Airway Epithelial Cells to Staphylococcal Alpha-Toxin

    PubMed Central

    Richter, Erik; Harms, Manuela; Ventz, Katharina; Gierok, Philipp; Chilukoti, Ravi Kumar; Hildebrandt, Jan-Peter; Mostertz, Jörg; Hochgräfe, Falko

    2015-01-01

    Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla-treatment including activation of the epidermal growth factor receptor EGFR and mitogen-activated protein kinases MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects. PMID:25816343

  14. Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study)

    Microsoft Academic Search

    J. K. Hertel; S. Johansson; H. Ræder; K. Midthjell; V. Lyssenko; L. Groop; A. Molven; P. R. Njølstad

    2008-01-01

    Aims\\/hypothesis  Recent genome-wide association studies performed in selected patients and control participants have provided strong support\\u000a for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel\\u000a loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study).\\u000a \\u000a \\u000a \\u000a Methods  We genotyped single nucleotide

  15. Identifying challenges in humanitarian logistics

    Microsoft Academic Search

    Gyöngyi Kovács; Karen Spens

    2009-01-01

    Purpose – The purpose of this paper is to identify the challenges of humanitarian logisticians with respect to different types of disasters, phases of disaster relief and the type of humanitarian organization. A conceptual model is constructed that serves as a basis to identify these challenges. Design\\/methodology\\/approach – The paper is based on a country as a case, namely Ghana.

  16. Islet Autoimmunity Identifies a Unique Pattern of Impaired Pancreatic Beta-Cell Function, Markedly Reduced Pancreatic Beta Cell Mass and Insulin Resistance in Clinically Diagnosed Type 2 Diabetes

    PubMed Central

    Subauste, Angela; Gianani, Roberto; Chang, Annette M.; Plunkett, Cynthia; Pietropaolo, Susan L.; Zhang, Ying-Jian; Barinas-Mitchell, Emma; Kuller, Lewis H.; Galecki, Andrzej; Halter, Jeffrey B.; Pietropaolo, Massimo

    2014-01-01

    There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired ?-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic ?-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage. PMID:25226365

  17. Pathogenic and Antigenic Properties of Phylogenetically Distinct Reassortant H3N2 Swine Influenza Viruses Cocirculating in the United States

    Microsoft Academic Search

    Jurgen A. Richt; Kelly M. Lager; Bruce H. Janke; Roger D. Woods; Robert G. Webster; Richard J. Webby

    2003-01-01

    Swine influenza is an acute respiratory disease caused by type A influenza viruses. Before 1998, swine influenza virus isolates in the United States were mainly of the classical H1N1 lineage. Since then, phyloge- netically distinct reassortant H3N2 viruses have been identified as respiratory pathogens in pigs on U.S. farms. The H3N2 viruses presently circulating in the U.S. swine population are

  18. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

    PubMed

    Wang, Zhaoming; Zhu, Bin; Zhang, Mingfeng; Parikh, Hemang; Jia, Jinping; Chung, Charles C; Sampson, Joshua N; Hoskins, Jason W; Hutchinson, Amy; Burdette, Laurie; Ibrahim, Abdisamad; Hautman, Christopher; Raj, Preethi S; Abnet, Christian C; Adjei, Andrew A; Ahlbom, Anders; Albanes, Demetrius; Allen, Naomi E; Ambrosone, Christine B; Aldrich, Melinda; Amiano, Pilar; Amos, Christopher; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L; Arici, Cecilia; Arslan, Alan A; Austin, Melissa A; Baris, Dalsu; Barkauskas, Donald A; Bassig, Bryan A; Beane Freeman, Laura E; Berg, Christine D; Berndt, Sonja I; Bertazzi, Pier Alberto; Biritwum, Richard B; Black, Amanda; Blot, William; Boeing, Heiner; Boffetta, Paolo; Bolton, Kelly; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Brennan, Paul; Brinton, Louise A; Brotzman, Michelle; Bueno-de-Mesquita, H Bas; Buring, Julie E; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Cao, Guangwen; Caporaso, Neil E; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chang, Gee-Chen; Chang, I-Shou; Chang-Claude, Jenny; Che, Xu; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chung-Hsing; Chen, Constance; Chen, Kuan-Yu; Chen, Yuh-Min; Chokkalingam, Anand P; Chu, Lisa W; Clavel-Chapelon, Francoise; Colditz, Graham A; Colt, Joanne S; Conti, David; Cook, Michael B; Cortessis, Victoria K; Crawford, E David; Cussenot, Olivier; Davis, Faith G; De Vivo, Immaculata; Deng, Xiang; Ding, Ti; Dinney, Colin P; Di Stefano, Anna Luisa; Diver, W Ryan; Duell, Eric J; Elena, Joanne W; Fan, Jin-Hu; Feigelson, Heather Spencer; Feychting, Maria; Figueroa, Jonine D; Flanagan, Adrienne M; Fraumeni, Joseph F; Freedman, Neal D; Fridley, Brooke L; Fuchs, Charles S; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M; Garcia-Closas, Montserrat; Garcia-Closas, Reina; Gastier-Foster, Julie M; Gaziano, J Michael; Gerhard, Daniela S; Giffen, Carol A; Giles, Graham G; Gillanders, Elizabeth M; Giovannucci, Edward L; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M; Gonzalez, Carlos; Gorlick, Richard; Greene, Mark H; Gross, Myron; Grossman, H Barton; Grubb, Robert; Gu, Jian; Guan, Peng; Haiman, Christopher A; Hallmans, Goran; Hankinson, Susan E; Harris, Curtis C; Hartge, Patricia; Hattinger, Claudia; Hayes, Richard B; He, Qincheng; Helman, Lee; Henderson, Brian E; Henriksson, Roger; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holly, Elizabeth A; Hong, Yun-Chul; Hoover, Robert N; Hosgood, H Dean; Hsiao, Chin-Fu; Hsing, Ann W; Hsiung, Chao Agnes; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Hunter, David J; Inskip, Peter D; Ito, Hidemi; Jacobs, Eric J; Jacobs, Kevin B; Jenab, Mazda; Ji, Bu-Tian; Johansen, Christoffer; Johansson, Mattias; Johnson, Alison; Kaaks, Rudolf; Kamat, Ashish M; Kamineni, Aruna; Karagas, Margaret; Khanna, Chand; Khaw, Kay-Tee; Kim, Christopher; Kim, In-Sam; Kim, Jin Hee; Kim, Yeul Hong; Kim, Young-Chul; Kim, Young Tae; Kang, Chang Hyun; Jung, Yoo Jin; Kitahara, Cari M; Klein, Alison P; Klein, Robert; Kogevinas, Manolis; Koh, Woon-Puay; Kohno, Takashi; Kolonel, Laurence N; Kooperberg, Charles; Kratz, Christian P; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C; Kurucu, Nilgun; Lan, Qing; Lathrop, Mark; Lau, Ching C; Lecanda, Fernando; Lee, Kyoung-Mu; Lee, Maxwell P; Le Marchand, Loic; Lerner, Seth P; Li, Donghui; Liao, Linda M; Lim, Wei-Yen; Lin, Dongxin; Lin, Jie; Lindstrom, Sara; Linet, Martha S; Lissowska, Jolanta; Liu, Jianjun; Ljungberg, Börje; Lloreta, Josep; Lu, Daru; Ma, Jing; Malats, Nuria; Mannisto, Satu; Marina, Neyssa; Mastrangelo, Giuseppe; Matsuo, Keitaro; McGlynn, Katherine A; McKean-Cowdin, Roberta; McNeill, Lorna H; McWilliams, Robert R; Melin, Beatrice S; Meltzer, Paul S; Mensah, James E; Miao, Xiaoping; Michaud, Dominique S; Mondul, Alison M; Moore, Lee E; Muir, Kenneth; Niwa, Shelley; Olson, Sara H; Orr, Nick; Panico, Salvatore; Park, Jae Yong; Patel, Alpa V; Patino-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H M; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M; Picci, Piero; Pike, Malcolm C; Porru, Stefano; Prescott, Jennifer; Pu, Xia; Purdue, Mark P; Qiao, You-Lin; Rajaraman, Preetha; Riboli, Elio; Risch, Harvey A; Rodabough, Rebecca J; Rothman, Nathaniel; Ruder, Avima M; Ryu, Jeong-Seon; Sanson, Marc; Schned, Alan; Schumacher, Fredrick R; Schwartz, Ann G; Schwartz, Kendra L; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D; Severi, Gianluca; Shen, Hongbing; Shen, Min; Shete, Sanjay; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesumaga, Luis; Sierri, Sabina; Loon Sihoe, Alan Dart

    2014-12-15

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. PMID:25027329

  19. Adenylyl cyclase isoform expression in non-diabetic and diabetic Goto-Kakizaki (GK) rat pancreas. Evidence for distinct overexpression of type-8 adenylyl cyclase in diabetic GK rat islets

    Microsoft Academic Search

    Amel Guenifi; Guida Maria Portela-Gomes; Lars Grimelius; S. Efendi?; Samy M. Abdel-Halim

    2000-01-01

    Glucose-induced insulin release is markedly decreased in the spontaneously diabetic Goto-Kakizaki (GK) rat pancreas. This\\u000a defect was recently shown to be reversed by forskolin which markedly enhances cAMP generation in GK islets. These effects\\u000a of forskolin were associated with overexpression of type-3 adenylyl cyclase (AC) mRNA due to the presence of two functional\\u000a point mutations in the promoter region of

  20. Two Distinct Pathways for Intronless mRNA Expression: One Related, the Other Unrelated to Human Immunodeficiency Virus Rev and Human T Cell Leukemia Virus Type I Rex Functions

    Microsoft Academic Search

    Takahiro Kiyokawa; Tomoe Umemoto; Yoshihiko Watanabe; Shuzo Matsushita; Hisatoshi Shida

    1997-01-01

    Intronless mRNAs were classified into two classes based on the sensitivities of their expression to the inhibitory effect of TAgRex, a dominant-negative mutant of the Rex protein of human T cell leukemia virus type I, and their abilities to express the genes encoded in the intron of the human immunodeficiency virus (HIV) genome. Interferon-? mRNA could not induce the expression

  1. Characterization of an antigenically distinct porcine rotavirus.

    PubMed Central

    Bridger, J C; Clarke, I N; McCrae, M A

    1982-01-01

    A porcine virus with rotavirus morphology, which was antigenically unrelated to previously described rotaviruses, is described. Particles with an outer capsid layer measured 75 nm and those lacking the outer layer were 63 nm in diameter. Particles which resembled cores were also identified. The virus was shown to be antigenically distinct from other rotaviruses as judged by immunofluorescence and immune electron microscopy, and it failed to protect piglets from challenge with porcine rotavirus. Analysis of the genome indicated that it was composed of 11 segments of double-stranded RNA with the same overall size range as other rotaviruses but with an unusual segment pattern. Images PMID:6175575

  2. Abstract types have existential type

    Microsoft Academic Search

    John C. Mitchell; Gordon D. Plotkin

    1988-01-01

    Abstract data type declarations appear in typed programming languages like Ada, Alphard, CLU and ML. This form of declaration binds a list of identifiers to a type with associated operations, a composite “value” we call a data algebra. We use a second-order typed lambda calculus SOL to show how data algebras may be given types, passed as parameters, and returned

  3. Identifying Harmful Marine Dinoflagellates

    NSDL National Science Digital Library

    Maria A. Faust

    This Smithsonian Institution website features the publication "Identifying Harmful Marine Dinoflagellates", a fully illustrated identification guide for harmful dinoflagellate taxa. The website reviews general information on dinoflagellate morphology and other criteria used in species identification. Each taxon is presented with a species overview, and a taxonomic description of cell and thecal plate morphology, reproduction, life cycle, ecology, toxicity, species comparison, habitat and locality, and etymology. This is supplemented with a number of high-resolution light and scanning electron photomicrographs and line drawings. Taxonomic treatment of harmful dinoflagellate taxa includes nomenclatural types, type locality, and common synonyms. An extensive glossary of terms and relevant literature citations are also provided.

  4. The operant-respondent distinction: Future directions

    PubMed Central

    Pear, Joseph J.; Eldridge, Gloria D.

    1984-01-01

    The operant-respondent distinction has provided a major organizing framework for the data generated through the experimental analysis of behavior. Problems have been encountered, however, in using it as an explanatory concept for such phenomena as avoidance and conditioned suppression. Data now exist that do not fit neatly into the framework. Moreover, the discovery of autoshaping has highlighted difficulties in isolating the two types of behavior and conditioning. Despite these problems, the operant-respondent framework remains the most successful paradigm currently available for organizing behavioral data. Research and theoretical efforts should therefore probably be directed to modifying the framework to account for disparate data. PMID:16812402

  5. Distinct dopamine neurons mediate reward signals for short- and long-term memories

    PubMed Central

    Yamagata, Nobuhiro; Ichinose, Toshiharu; Aso, Yoshinori; Plaçais, Pierre-Yves; Friedrich, Anja B.; Sima, Richard J.; Preat, Thomas; Rubin, Gerald M.; Tanimoto, Hiromu

    2015-01-01

    Drosophila melanogaster can acquire a stable appetitive olfactory memory when the presentation of a sugar reward and an odor are paired. However, the neuronal mechanisms by which a single training induces long-term memory are poorly understood. Here we show that two distinct subsets of dopamine neurons in the fly brain signal reward for short-term (STM) and long-term memories (LTM). One subset induces memory that decays within several hours, whereas the other induces memory that gradually develops after training. They convey reward signals to spatially segregated synaptic domains of the mushroom body (MB), a potential site for convergence. Furthermore, we identified a single type of dopamine neuron that conveys the reward signal to restricted subdomains of the mushroom body lobes and induces long-term memory. Constant appetitive memory retention after a single training session thus comprises two memory components triggered by distinct dopamine neurons. PMID:25548178

  6. Distinct dopamine neurons mediate reward signals for short- and long-term memories.

    PubMed

    Yamagata, Nobuhiro; Ichinose, Toshiharu; Aso, Yoshinori; Plaçais, Pierre-Yves; Friedrich, Anja B; Sima, Richard J; Preat, Thomas; Rubin, Gerald M; Tanimoto, Hiromu

    2015-01-13

    Drosophila melanogaster can acquire a stable appetitive olfactory memory when the presentation of a sugar reward and an odor are paired. However, the neuronal mechanisms by which a single training induces long-term memory are poorly understood. Here we show that two distinct subsets of dopamine neurons in the fly brain signal reward for short-term (STM) and long-term memories (LTM). One subset induces memory that decays within several hours, whereas the other induces memory that gradually develops after training. They convey reward signals to spatially segregated synaptic domains of the mushroom body (MB), a potential site for convergence. Furthermore, we identified a single type of dopamine neuron that conveys the reward signal to restricted subdomains of the mushroom body lobes and induces long-term memory. Constant appetitive memory retention after a single training session thus comprises two memory components triggered by distinct dopamine neurons. PMID:25548178

  7. Comparative Genomic Analysis Identifies Divergent Genomic Features of Pathogenic Enterococcus cecorum Including a Type IC CRISPR-Cas System, a Capsule Locus, an epa-Like Locus, and Putative Host Tissue Binding Proteins

    PubMed Central

    Borst, Luke B.; Suyemoto, M. Mitsu; Scholl, Elizabeth H.; Fuller, Fredrick J.; Barnes, H. John

    2015-01-01

    Enterococcus cecorum (EC) is the dominant enteric commensal of adult chickens and contributes to the gut consortia of many avian and mammalian species. While EC infection is an uncommon zoonosis, like other enterococcal species it can cause life-threating nosocomial infection in people. In contrast to other enterococci which are considered opportunistic pathogens, emerging pathogenic strains of EC cause outbreaks of musculoskeletal disease in broiler chickens. Typical morbidity and mortality is comparable to other important infectious diseases of poultry. In molecular epidemiologic studies, pathogenic EC strains were found to be genetically clonal. These findings suggested acquisition of specific virulence determinants by pathogenic EC. To identify divergent genomic features and acquired virulence determinants in pathogenic EC; comparative genomic analysis was performed on genomes of 3 pathogenic and 3 commensal strains of EC. Pathogenic isolates had smaller genomes with a higher GC content, and they demonstrated large regions of synteny compared to commensal isolates. A molecular phylogenetic analysis demonstrated sequence divergence in pathogenic EC genomes. At a threshold of 98% identity, 414 predicted proteins were identified that were highly conserved in pathogenic EC but not in commensal EC. Among these, divergent CRISPR-cas defense loci were observed. In commensal EC, the type IIA arrangement typical for enterococci was present; however, pathogenic EC had a type IC locus, which is novel in enterococci but commonly observed in streptococci. Potential mediators of virulence identified in this analysis included a polysaccharide capsular locus similar to that recently described for E. faecium, an epa-like locus, and cell wall associated proteins which may bind host extracellular matrix. This analysis identified specific genomic regions, coding sequences, and predicted proteins which may be related to the divergent evolution and increased virulence of emerging pathogenic strains of EC. PMID:25860249

  8. Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals

    PubMed Central

    Below, J. E.; Gamazon, E. R.; Morrison, J. V.; Konkashbaev, A.; Pluzhnikov, A.; McKeigue, P. M.; Parra, E. J.; Elbein, S. C.; Hallman, D. M.; Nicolae, D. L.; Bell, G. I.; Cruz, M.

    2013-01-01

    Aims/hypothesis We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. Method Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. Result The top signals (unadjusted p value <1×10?5) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52× 10?6) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. Conclusions/Interpretation In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues. PMID:21647700

  9. Human germline and pan-cancer variomes and their distinct functional profiles

    PubMed Central

    Pan, Yang; Karagiannis, Konstantinos; Zhang, Haichen; Dingerdissen, Hayley; Shamsaddini, Amirhossein; Wan, Quan; Simonyan, Vahan; Mazumder, Raja

    2014-01-01

    Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 549 variations that significantly affect 10 major functional sites. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across 12 different cancer types led to the identification of 51 genes with 106 nsSNV affected functional sites found in 3 or more cancer types. 13 of the 51 genes overlap with previously identified Significantly Mutated Genes (Nature. 2013 Oct 17;502(7471)). 62 mutations in these 13 genes affecting functional sites such as DNA, ATP binding and various PTM sites occur across several cancers and can be prioritized for additional validation and investigations. PMID:25232094

  10. Distinctiveness Maps for Image Matching

    NASA Technical Reports Server (NTRS)

    Manduchi, Roberto; Tomasi, Carlo

    2000-01-01

    Stereo correspondence is hard because different image features can look alike. We propose a measure for the ambiguity of image points that allows matching distinctive points first and breaks down the matching task into smaller and separate subproblems. Experiments with an algorithm based on this measure demonstrate the ensuing efficiency and low likelihood of incorrect matches.

  11. Two Thousand Fourteen Faculty Distinction

    E-print Network

    Qian, Ning

    . Our faculty also received nine honorary degrees, five Guggenheim fellowships, and one Tony AwardTwo Thousand Fourteen Faculty Distinction Celebrating the awards, honors and recognition awards and honors. Over the course of the last academic year, four faculty members were elected

  12. Nornicotine application on cockroach dorsal unpaired median neurons induces two distinct ionic currents: implications of different nicotinic acetylcholine receptors.

    PubMed

    Calas-List, Delphine; List, Olivier; Thany, Steeve H

    2012-06-14

    The goal of the present study is to examine the agonist action of nornicotine on insect nicotinic acetylcholine receptors. Using patch-clamp techniques on cockroach dorsal unpaired median neurons, we demonstrated that nornicotine induced two distinct ionic currents named types 1 and 2. We found that alpha-bungarotoxin induced a rapid desensitization of type 1 currents whereas type 2 was completely blocked. Interestingly, types 1 and 2 currents were not blocked by the muscarinic antagonist, pirenzepine but by co-application of 1 ?M pirenzepine and 0.5 ?M alpha-bungarotoxin, suggesting that muscarinic receptors modulated nornicotine-induced current amplitudes. In addition, type 1 current amplitudes were strongly reduced by 20 ?M d-tubocurarine and 5 ?M mecamylamine which blocked the previously identified alpha-bungarotoxin-insensitive nAChR1 and nAChR2 receptors. Co-application of alpha-bungarotoxin with d-tubocurarine or mecamylamine completely blocked all ionic currents. We propose that types 1 and 2 currents are associated to several nicotinic receptors subtypes, including nAChR1 and nAChR2 receptors. Finally, we conclude that nornicotine could be used as an agonist to identify distinct insect nicotinic receptors. PMID:22580207

  13. Distinct functions of calmodulin are required for the uptake step of receptor-mediated endocytosis in yeast: the type I myosin Myo5p is one of the calmodulin targets.

    PubMed Central

    Geli, M I; Wesp, A; Riezman, H

    1998-01-01

    The uptake step of receptor-mediated endocytosis in yeast is dependent on the calcium binding protein calmodulin (Cmd1p). In order to understand the role that Cmd1p plays, a search was carried out for possible targets among the genes required for the internalization process. Co-immunoprecipitation, two-hybrid and overlay assays demonstrated that Cmd1p interacts with Myo5p, a type I unconventional myosin. Analysis of the endocytic phenotype and the Cmd1p-Myo5p interaction in thermosensitive cmd1 mutants indicated that the Cmd1p-Myo5p interaction is required for endocytosis in vivo. However, the Cmd1p-Myo5p interaction requirement was partially overcome by deleting the calmodulin binding sites (IQ motifs) from Myo5p, suggesting that these motifs inhibit Myo5p function. Additionally, genetic and biochemical evidence obtained with a collection of cmd1 mutant alleles strongly suggests that Cmd1p plays an additional role in the internalization step of receptor-mediated endocytosis in yeast. PMID:9450989

  14. A six-month intervention with two different types of micronutrient-fortified complementary foods had distinct short- and long-term effects on linear and ponderal growth of Vietnamese infants.

    PubMed

    Pham, V Phu; Nguyen, V Hoan; Salvignol, Bertrand; Treche, Serge; Wieringa, Frank T; Dijkhuizen, Marjoleine A; Nguyen, C Khan; Pham, D Tuong; Schwartz, Helene; Berger, Jacques

    2012-09-01

    Traditional complementary foods (CF) with a low nutrient density have been implicated in growth faltering, stunting, and other adverse outcomes in children. The efficacy of 2 types of locally produced, micronutrient-fortified CF to prevent stunting of infants living in rural Vietnam was evaluated. In a village-randomized controlled study, 426 infants, 5 mo of age, received for 6 mo a fortified CF, either as an instant flour (FF) or a food complement (FC) in village canteens, or traditional CF at home (C). After 6 mo of intervention, weight, length, length-for-age Z-score (LAZ) and weight-for-age Z-score were greater in the 2 intervention groups compared with the C group, with an estimated effect of +0.22 LAZ for the FF group and +0.21 LAZ for the FC group. At the last follow-up, 18 mo after the intervention, there was no significant difference in height-for-age Z-score (HAZ) between the groups, even though the HAZ in the FF group was 0.17 greater than that in the C group (P = 0.18). In contrast, the weight-for-height Z-score and BMI Z-score, indices of ponderal growth, were greater in the FF group (-0.49 and -0.26, respectively) than in the FC group (-0.73 and -0.49, respectively), with Z-scores in the C group intermediate and not significantly different from the others. This study shows that regular provision of locally produced CF fortified with micronutrients partly stopped growth faltering in Vietnamese infants, with differential effects on long-term length and ponderal growth. Providing only micronutrients instead of a complete array of nutrients might result in only short-term length growth benefits. PMID:22810985

  15. A distinct dinosaur life history?

    Microsoft Academic Search

    David J. Varricchio

    2011-01-01

    Five factors, mobile terrestrial lifestyle, oviparity, parental care, multi-year maturation and juvenile sociality, contribute to a distinct life history for Mesozoic dinosaurs in comparison to extant archosaurs and mammals. Upright, para-sagittal gait reflects several synapomorphies of Dinosauria, and wide histological sampling suggests that multi-year maturation typified dinosaurs across a range of body sizes. Fossil support for juvenile sociality exceeds that

  16. Anticancer Properties of Distinct Antimalarial Drug Classes

    PubMed Central

    Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

    2013-01-01

    We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

  17. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

    PubMed Central

    Andrikovics, Hajnalka; Krahling, Tunde; Balassa, Katalin; Halm, Gabriella; Bors, Andras; Koszarska, Magdalena; Batai, Arpad; Dolgos, Janos; Csomor, Judit; Egyed, Miklos; Sipos, Andrea; Remenyi, Peter; Tordai, Attila; Masszi, Tamas

    2014-01-01

    Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were younger and had higher platelet counts compared to Janus kinase 2 mutation-positive counterparts. Calreticulin mutation-positive patients with essential thrombocythemia showed a lower risk of developing venous thrombosis, but no difference in overall survival. Calreticulin mutation-positive patients with primary myelofibrosis had a better overall survival compared to that of the Janus kinase 2 mutation-positive (P=0.04) or triple-negative cases (P=0.01). Type 2 calreticulin mutation occurred more frequently in essential thrombocythemia than in primary myelofibrosis (P=0.049). In essential thrombocythemia, the calreticulin mutational load was higher than the Janus kinase 2 mutational load (P<0.001), and increased gradually in advanced stages. Calreticulin mutational load influenced blood counts even at the time point of diagnosis in essential thrombocythemia. We confirm that calreticulin mutation is associated with distinct clinical characteristics and explored relationships between mutation type, load and clinical outcome. PMID:24895336

  18. Renal tumors associated with germline SDHB mutation show distinctive morphology.

    PubMed

    Gill, Anthony J; Pachter, Nicholas S; Chou, Angela; Young, Barbara; Clarkson, Adele; Tucker, Katherine M; Winship, Ingrid M; Earls, Peter; Benn, Diana E; Robinson, Bruce G; Fleming, Stewart; Clifton-Bligh, Roderick J

    2011-10-01

    Germline succinate dehydrogenase B (SDHB) mutation causes pheochromocytoma/paraganglioma syndrome type 4 (PGL4). PGL4 is characterized by pheochromocytoma and paraganglioma, type 2 (SDHB negative) gastrointestinal stromal tumors and renal tumors, which are usually classified as carcinoma. We report 4 kindreds with 5 PGL4-associated renal tumors. Four of the tumors occurred before the age of 30 years, 4 were in the left kidney, 3 were in female patients, and 4 demonstrated consistent but previously unrecognized morphology. The tumors were composed of cuboidal cells with bubbly eosinophilic cytoplasm and indistinct cell borders. Many of the cells displayed distinctive cytoplasmic inclusions, which were vacuolated or contained eosinophilic fluid-like material. The cells were arranged in solid nests or in tubules surrounding central spaces. The tumors were well circumscribed or lobulated and frequently showed cystic change. Benign tubules or glomeruli were often entrapped at the edges of the tumors. The fifth tumor lacked these features but displayed sarcomatoid dedifferentiation. Immunohistochemistry for SDHB was completely negative in all 4 available tumors. Death from metastatic disease occurred in the patient with dedifferentiated tumor 1 year after diagnosis, whereas the other 4 tumors were cured by local excision alone (mean follow-up, 11 y; range, 2 to 30 y). We conclude that morphology supported by negative immunohistochemistry for SDHB can be used to identify kindreds with germline SDHB mutations (PGL4 syndrome) presenting with this unique type of renal tumor. These renal tumors appear to have a good prognosis after complete excision unless there is sarcomatoid dedifferentiation. PMID:21934479

  19. Two Distinct Domains in Drosophila melanogaster Telomeres

    PubMed Central

    Biessmann, Harald; Prasad, Sudha; Semeshin, Valery F.; Andreyeva, Eugenia N.; Nguyen, Quang; Walter, Marika F.; Mason, James M.

    2005-01-01

    Telomeres are generally considered heterochromatic. On the basis of DNA composition, the telomeric region of Drosophila melanogaster contains two distinct subdomains: a subtelomeric region of repetitive DNA, termed TAS, and a terminal array of retrotransposons, which perform the elongation function instead of telomerase. We have identified several P-element insertions into this retrotransposon array and compared expression levels of transgenes with similar integrations into TAS and euchromatic regions. In contrast to insertions in TAS, which are silenced, reporter genes in the terminal HeT-A, TAHRE, or TART retroelements did not exhibit repressed expression in comparison with the same transgene construct in euchromatin. These data, in combination with cytological studies, provide evidence that the subtelomeric TAS region exhibits features resembling heterochromatin, while the terminal retrotransposon array exhibits euchromatic characteristics. PMID:16143601

  20. Distinctive Solvation Patterns Make Renal Osmolytes Diverse

    PubMed Central

    Jackson-Atogi, Ruby; Sinha, Prem Kumar; Rösgen, Jörg

    2013-01-01

    The kidney uses mixtures of five osmolytes to counter the stress induced by high urea and NaCl concentrations. The individual roles of most of the osmolytes are unclear, and three of the five have not yet been thermodynamically characterized. Here, we report partial molar volumes and activity coefficients of glycerophosphocholine (GPC), taurine, and myo-inositol. We derive their solvation behavior from the experimental data using Kirkwood-Buff theory. We also provide their solubility data, including solubility data for scyllo-inositol. It turns out that renal osmolytes fall into three distinct classes with respect to their solvation. Trimethyl-amines (GPC and glycine-betaine) are characterized by strong hard-sphere-like self-exclusion; urea, taurine, and myo-inositol have a tendency toward self-association; sorbitol and most other nonrenal osmolytes have a relatively constant, intermediate solvation that has components of both exclusion and association. The data presented here show that renal osmolytes are quite diverse with respect to their solvation patterns, and they can be further differentiated based on observations from experiments examining their effect on macromolecules. It is expected, based on the available surface groups, that each renal osmolyte has distinct effects on various classes of biomolecules. This likely allows the kidney to use specific combinations of osmolytes independently to fine-tune the chemical activities of several types of molecules. PMID:24209862

  1. Rescue of an in vitro neuron phenotype identified in Niemann-Pick disease, type C1 induced pluripotent stem cell-derived neurons by modulating the WNT pathway and calcium signaling.

    PubMed

    Efthymiou, Anastasia G; Steiner, Joe; Pavan, William J; Wincovitch, Stephen; Larson, Denise M; Porter, Forbes D; Rao, Mahendra S; Malik, Nasir

    2015-03-01

    Niemann-Pick disease, type C1 (NPC1) is a familial disorder that has devastating consequences on postnatal development with multisystem effects, including neurodegeneration. There is no Food and Drug Administration-approved treatment option for NPC1; however, several potentially therapeutic compounds have been identified in assays using yeast, rodent models, and NPC1 human fibroblasts. Although these discoveries were made in fibroblasts from NPC1 subjects and were in some instances validated in animal models of the disease, testing these drugs on a cell type more relevant for NPC1 neurological disease would greatly facilitate both study of the disease and identification of more relevant therapeutic compounds. Toward this goal, we have generated an induced pluripotent stem cell line from a subject homozygous for the most frequent NPC1 mutation (p.I1061T) and subsequently created a stable line of neural stem cells (NSCs). These NSCs were then used to create neurons as an appropriate disease model. NPC1 neurons display a premature cell death phenotype, and gene expression analysis of these cells suggests dysfunction of important signaling pathways, including calcium and WNT. The clear readout from these cells makes them ideal candidates for high-throughput screening and will be a valuable tool to better understand the development of NPC1 in neural cells, as well as to develop better therapeutic options for NPC1. PMID:25637190

  2. A distinct molecular profile associated with mucinous epithelial ovarian cancer

    Microsoft Academic Search

    V A Heinzelmann-Schwarz; M Gardiner-Garden; S M Henshall; J P Scurry; R A Scolyer; A N Smith; A Bali; P Vanden Bergh; S Baron-Hay; C Scott; D Fink; N F Hacker; R L Sutherland; P M O'Brien

    2006-01-01

    Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express

  3. Contributions of distinct interneuron types to neocortical dynamics

    E-print Network

    Knoblich, Ulf

    2011-01-01

    Inhibitory interneurons are thought to play a crucial role in several features of neocortical processing, including dynamics on the timescale of milliseconds. Their anatomical and physiological characteristics are diverse, ...

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

    Microsoft Academic Search

    E. Dowty; M. Prinz; K. Keil

    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,

  5. Measuring Distinct Types of Musical Self-Efficacy

    ERIC Educational Resources Information Center

    Ritchie, Laura; Williamon, Aaron

    2011-01-01

    This research examines the specific nature of self-efficacy beliefs within music. Separate questionnaires assessing self-efficacy for musical learning and self-efficacy for musical performing were developed and tested, and the reliability of the new questionnaires was demonstrated using internal reliability tests and exploratory factor analysis. A…

  6. Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients.

    PubMed

    Gorus, F K; Balti, E V; Vermeulen, I; Demeester, S; Van Dalem, A; Costa, O; Dorchy, H; Tenoutasse, S; Mouraux, T; De Block, C; Gillard, P; Decochez, K; Wenzlau, J M; Hutton, J C; Pipeleers, D G; Weets, I

    2013-01-01

    In first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0-39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA(+) , GADA(+) , IA-2A(+) and/or ZnT8A(+) relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0-9, 10-19