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1

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

Microsoft Academic Search

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

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

2001-01-01

2

Distinct epitopes of Ik gene products identified by monoclonal antibodies.  

PubMed

Analysis of reactivity of monoclonal anti-Iak alloantibodies, obtained by fusion between NS 1 myeloma and spleen cells from alloimmune A. TH mice, permitted the identification of 9 distinct determinants of the Ik gene products. Competitive binding experiments indicated that 2 private epitopes (defined by H8-109.13 and H8-138.4 antibodies) of the I-Ak product could be separated, thereby apparently splitting the Ia.2 specificity. A public determinant of the I-Ak molecule (identified by H8-15.9 antibody) was found expressed not only on the I-A products of the H-2b, H-2d, H-2ja, H-2p and H-2q murine haplotypes, but also on human HLA-DR antigens. Four determinants of the I-E/Ck antigen (defined by H7-8.26, H10-81.10, H10-93.2 and H8-86.2 antibodies) had a strain distribution analogues to the Ia.7 specificity. However, competitive binding experiments, and the cross-reactivity pattern with Ia-like antigens from other species (e.g. human HLA-DR antigens) indicated that these antibodies detected distinct determinants on the I-E/Ck molecule, thereby subdividing the broad Ia. 7 specificity. Two other determinants (defined by H9-14.8 and H9-15.4 antibodies) had a strain distribution that did not permit a precise assignment to a given Ia antigen, even though preliminary data suggested that they could detect separate determinants on the I-E/Ck product. All these monoclonal antibodies identified membrane antigens with the expected Ia tissue distribution pattern, and most of them could precipitate a molecule containing two chains of 28kD and 35kD, from mouse spleen cell lysates. PMID:6162651

Pierres, M; Kourilsky, F M; Rebouah, J P; Dosseto, M; Caillol, D

1980-12-01

3

Individual Distinctiveness in Call Types of Wild Western Female Gorillas  

PubMed Central

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

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

2014-01-01

4

Distinct melanoma types based on reflectance confocal microscopy.  

PubMed

Distinct melanoma types exist in relation to patient characteristics, tumor morphology, histopathologic aspects and genetic background. A new diagnostic imaging tool, reflectance confocal microscopy (RCM), allows in vivo analysis of a given lesion with nearly histologic resolution while offering a dynamic view of the tissue in its 'natural' environment. The aim of this study was to analyse cell morphology of consecutive melanomas as they appear on RCM and to correlate morphology with tumor and patient characteristics. One hundred melanomas were visualized by RCM before excision. Clinical data, confocal features and histologic criteria were analysed. Four types of melanomas were identified as follows: (i) Melanomas with a predominantly dendritic cell population ('dendritic-cell melanomas') typically were thin by Breslow index; (ii) Melanomas typified by roundish melanocytes were smaller in size than dendritic cell MMs, but thicker by Breslow index, and predominantly occurred in patients with a high nevus count; (iii) Melanomas characterized by dermal nesting proliferation usually were thick by Breslow index at the time of diagnosis, although frequently smaller in size compared with the other types; and (iv) combined type melanomas may represent an evolution of dendritic cell and/or round cell types. Integration of confocal microscopy with clinical and histologic aspects may help in identifying and managing distinct tumors. PMID:24750486

Pellacani, Giovanni; De Pace, Barbara; Reggiani, Camilla; Cesinaro, Anna Maria; Argenziano, Giuseppe; Zalaudek, Iris; Soyer, H Peter; Longo, Caterina

2014-06-01

5

Novel Subtype-specific Genes Identify Distinct Subpopulations of Callosal Projection Neurons  

PubMed Central

Little is known about the molecular development and heterogeneity of callosal projection neurons (CPN), cortical commissural neurons that connect homotopic regions of the two cerebral hemispheres via the corpus callosum, and that are critical for bilateral integration of cortical information. Here we report on the identification of a series of genes that individually and in combination define CPN and novel CPN subpopulations during embryonic and postnatal development. We used in situ hybridization analysis, immunocytochemistry, and retrograde labeling to define the layer- and neuron type-specific distribution of these newly identified CPN genes across different stages of maturation. We demonstrate that a subset of these genes (e.g. Hspb3 and Lpl), appear specific to all CPN (in layers II/III and V–VI), while others (e.g. Nectin-3, Plexin-D1 and Dkk3) discriminate between CPN of the deep layers and those of the upper layers. Further, the data show that several genes finely subdivide CPN within individual layers and appear to label CPN subpopulations that have not been previously described using anatomical or morphological criteria. The genes identified here likely reflect the existence of distinct programs of gene expression governing the development, maturation, and function of the newly identified subpopulations of CPN. Together, these data define the first set of genes that identify and molecularly subcategorize distinct populations of callosal projection neurons, often located in distinct subdivisions of the canonical cortical laminae. PMID:19793993

Molyneaux, Bradley J.; Arlotta, Paola; Fame, Ryann M.; MacDonald, Jessica L.; MacQuarrie, Kyle L.; Macklis, Jeffrey D.

2009-01-01

6

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

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

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

2014-01-01

7

INTRODUCTION Two distinct types of hydromedusan propulsion are well known  

E-print Network

2436 INTRODUCTION Two distinct types of hydromedusan propulsion are well known (Colin and Costello, 2002). Prolate species such as Sarsia tubulosa primarily use a jetting type of propulsion with large that rowing propulsion is a necessary adaptation for larger hydromedusae due to morphological constraints

Mohseni, Kamran

8

Identifying elemental genomic track types and representing them uniformly  

PubMed Central

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

2011-01-01

9

Recurrent mutations of NOTCH genes in follicular lymphoma identify a distinctive subset of tumours.  

PubMed

Follicular lymphoma (FL) is one of the most common malignant lymphomas. The t(14;18)(q32;q21) translocation is found in about 80% of cases and plays an important role in lymphomagenesis. However, the molecular mechanisms involved in the development and transformation of this lymphoma are not fully understood. Gain-of-function mutations of NOTCH1 or NOTCH2 have recently been reported in several B cell lymphoid neoplasms but the role of these mutations in FL is not known. In this study we investigated the mutational status of these genes in 112 FLs. NOTCH1 and NOTCH2 mutations were identified in five and two cases, respectively (total 7/112, 6.3%). All mutations predicted for truncated protein in the PEST domain and were identical to those identified in other B cell lymphoid neoplasms. NOTCH-mutated FL cases were characterized by lower frequency of t(14;18) (14% versus 69%, p = 0.01), higher incidence of splenic involvement (71% versus 25%, p = 0.02) and female predominance (100% versus 55%, p = 0.04). A diffuse large B cell lymphoma (DLBCL) component was more frequently identified in NOTCH-mutated FL than in wild-type cases (57% versus 18%, p = 0.03). These results indicate that NOTCH mutations are uncommon in FL but may occur in a subset of cases with distinctive, characteristic, clinicopathological features. PMID:25141821

Karube, Kennosuke; Martínez, Daniel; Royo, Cristina; Navarro, Alba; Pinyol, Magda; Cazorla, Maite; Castillo, Paola; Valera, Alexandra; Carrió, Anna; Costa, Dolors; Colomer, Dolors; Rosenwald, Andreas; Ott, German; Esteban, Daniel; Giné, Eva; López-Guillermo, Armando; Campo, Elias

2014-11-01

10

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

E-print Network

regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identifiedThe intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations adult stem cell populations residing in the crypt of the small intestine, capable of supporting

Capecchi, Mario R.

11

Ferroan anorthosite - A widespread and distinctive lunar rock type  

NASA Technical Reports Server (NTRS)

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.

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

1974-01-01

12

Identifying marker typing incompatibilities in linkage analysis  

SciTech Connect

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.

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

1996-10-01

13

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

E-print Network

401 863 9845. E-mail address: Bethany_Bradley@brown.edu (B.A. Bradley). Remote Sensing of EnvironmentIdentifying land cover variability distinct from land cover change: Cheatgrass in the Great Basin August 2004 Abstract An understanding of land use/land cover change at local, regional, and global scales

Bradley, Bethany

14

p53 Status Identifies Two Subgroups of Triple-negative Breast Cancers with Distinct Biological Features  

E-print Network

p53 Status Identifies Two Subgroups of Triple-negative Breast Cancers with Distinct Biological, 2011 Objective: Despite the clinical similarities triple-negative and basal-like breast cancer heterogeneously expressed in triple-negative breast cancers, suggesting that it may be associated with specific

Aickelin, Uwe

15

Fluids, fault zone permeability and two distinct types of pseudotachylyte  

NASA Astrophysics Data System (ADS)

The comparative rarity of pseudotachylyte in ancient fault zones is surprising in light of estimates that ca. 90% of the energy budget of an earthquake is expended in frictional heating. One explanation is that frictional melting (pseudotachylyte generation) is suppressed after the initial rupture on a fault zone because fluids infiltrate the zone and thermal pressurization of these fluids inhibits melting in subsequent seismic events. While this seems plausible for many of the iconic occurrences of pseudotachylyte in otherwise undamaged crystalline rocks, some pseudotachylytes clearly formed in host rocks in which permeability was apparently high and fluids were present at the time of frictional melting. In these fault zones, cataclasites and pseudotachylyte commonly have mutually cross cutting relationships, and both types of fault rock have been complexly intruded into the surrounding damage zone. In contrast, cataclasites associated with pseudotachylyte in pristine crystalline rocks occur in smaller volumes and have simpler geometries, typically limited to the margins of fault veins or in dilational jogs. These observations suggest that there may be two distinct physical circumstances under which frictional melting may occur and thus two distinct genetic types of pseudotachylyte. Classic “dry” pseudotachylytes (e.g., Holsnøy, Bergen Arcs, Norway; Gole Larghe Fault, Italy) probably represent the initial seismic rupture of intact, low-permeability rock at high effective stress in the absence of fluids. When fluids are present, however (e.g., central Otago, New Zealand; Nojima fault, Japan), the potential for frictional melting depends on the relative rates at which heat and fluids can escape from a fault zone. Geophysical models of dynamic weakening mechanisms during earthquakes (Rempel and Rice, JGR, 2006) show that thermal pressurization occurs when the hydraulic diffusivity is effectively less than thermal diffusivity, while melting occurs when thermal diffusivity is less than hydraulic diffusivity. Because the hydraulic diffusivity of a fault zone typically decreases over time owing to progressive comminution of grains, “wet” pseudotachylytes - i.e., those formed in hydrated rocks -- may represent an intermediate stage in the evolution of a fault, the period between the formation of a high-permeability damage zone and the development of a low-permeability fault core. Pseudotachylytes may therefore form in either of two distinct permeability ‘windows’, depending the nature of the host rock and its antecedent fluid history; for dry, intact rock, the pseudotachylyte window closes once fluids get in, while for hydrous and initially permeable rock, that window closes once fluids can no longer get out.

Bjornerud, M.

2010-12-01

16

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

ERIC Educational Resources Information Center

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

Ball, Samuel A.; And Others

1995-01-01

17

Whole-genome screening identifies proteins localized to distinct nuclear bodies.  

PubMed

The nucleus is a unique organelle that contains essential genetic materials in chromosome territories. The interchromatin space is composed of nuclear subcompartments, which are defined by several distinctive nuclear bodies believed to be factories of DNA or RNA processing and sites of transcriptional and/or posttranscriptional regulation. In this paper, we performed a genome-wide microscopy-based screening for proteins that form nuclear foci and characterized their localizations using markers of known nuclear bodies. In total, we identified 325 proteins localized to distinct nuclear bodies, including nucleoli (148), promyelocytic leukemia nuclear bodies (38), nuclear speckles (27), paraspeckles (24), Cajal bodies (17), Sam68 nuclear bodies (5), Polycomb bodies (2), and uncharacterized nuclear bodies (64). Functional validation revealed several proteins potentially involved in the assembly of Cajal bodies and paraspeckles. Together, these data establish the first atlas of human proteins in different nuclear bodies and provide key information for research on nuclear bodies. PMID:24127217

Fong, Ka-Wing; Li, Yujing; Wang, Wenqi; Ma, Wenbin; Li, Kunpeng; Qi, Robert Z; Liu, Dan; Songyang, Zhou; Chen, Junjie

2013-10-14

18

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

PubMed Central

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

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

2014-01-01

19

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

PubMed Central

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

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

20

Resting-state connectivity identifies distinct functional networks in macaque cingulate cortex.  

PubMed

Subregions of the cingulate cortex represent prominent intersections in the structural networks of the primate brain. The relevance of the cingulate to the structure and dynamics of large-scale networks ultimately requires a link to functional connectivity. Here, we map fine-grained functional connectivity across the complete extent of the macaque (Macaca fascicularis) cingulate cortex and delineate subdivisions pertaining to distinct identifiable networks. In particular, we identified 4 primary networks representing the functional spectrum of the cingulate: somatomotor, attention-orienting, executive, and limbic. The cingulate nodes of these networks originated from separable subfields along the rostral-to-caudal axis and were characterized by positive and negative correlations of spontaneous blood oxygen level-dependent activity. These findings represent a critical component for understanding how the anterior and midcingulate cortices integrate and shape information processing during task performance. The connectivity patterns also suggest future electrophysiological targets that may reveal new functional representations including those involved in conflict monitoring. PMID:21840845

Hutchison, R Matthew; Womelsdorf, Thilo; Gati, Joseph S; Leung, L Stan; Menon, Ravi S; Everling, Stefan

2012-06-01

21

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

PubMed Central

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

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

22

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

PubMed

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

Malcovati, Luca; 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

2014-08-28

23

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

PubMed Central

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

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

2013-01-01

24

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

PubMed

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

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

25

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

PubMed Central

Background Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in ?-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. Conclusions The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life. PMID:18769486

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

2008-01-01

26

Frequent atrophic groups with mixed-type myofibers is distinctive to motor neuron syndromes.  

PubMed

This study was performed to determine whether there are distinctive features to the pattern of muscle denervation in motor neuron disease. We first compared muscle biopsies from patients with amyotrophic lateral sclerosis (ALS) or Kennedy's disease with other causes of denervation. Groups of atrophic muscle fibers, with individual groups containing both fiber types I and II, occurred frequently in motor neuron disease but not other causes of denervation. We then identified 11 additional muscle biopsies with frequent atrophic groups containing mixed fiber types. Chart review revealed that 10 patients had a final diagnosis of motor neuron disease or ALS and one had multifocal motor neuropathy. We conclude that muscle biopsy may have diagnostic utility early in the course of motor neuron disease. The muscle biopsy pattern of frequent atrophic groups containing mixed fiber types should suggest a diagnosis of a motor neuron syndrome or motor neuropathy. PMID:17299742

Baloh, Robert H; Rakowicz, Wojtek; Gardner, Robert; Pestronk, Alan

2007-07-01

27

Distinct Stability States of Disease-Associated Human Prion Protein Identified by Conformation-Dependent Immunoassay?  

PubMed Central

The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrPSc), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann-Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrPres) in conjunction with the presence of mutations and polymorphisms in the prion protein gene (PRNP). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrPSc and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrPres type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP. These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrPSc in human prion diseases. PMID:20844046

Choi, Young Pyo; Peden, Alexander H.; Gröner, Albrecht; Ironside, James W.; Head, Mark W.

2010-01-01

28

Eight types of symmetrically distinct vectorlike physical quantities.  

PubMed

The Letter draws the attention to the spatiotemporal symmetry of various vectorlike physical quantities. The symmetry is specified by their invariance under the action of symmetry operations of the nonrelativistic space-time rotation group O(3)×(1,1') = O'(3), where 1' is a time-reversal operation, the symbol × stands for the group direct product, and O(3) is a group of proper and improper rotations. It is argued that along with the canonical polar vector, there are another seven symmetrically distinct classes of stationary physical quantities, which can be--and often are--denoted as standard three-component vectors, even though they do not transform as a static polar vector under all operations of O'(3). The octet of symmetrically distinct "directional quantities" can be exemplified by two kinds of polar vectors (electric dipole moment P and magnetic toroidal moment T), two kinds of axial vectors (magnetization M and electric toroidal moment G), two kinds of chiral "bidirectors" C and F (associated with the so-called true and false chirality, respectively) and still another two bidirectors N and L, achiral ones, transforming as the nematic liquid crystal order parameter and as the antiferromagnetic order parameter of the hematite crystal ?-Fe(2)O(3), respectively. PMID:25361266

Hlinka, J

2014-10-17

29

Eight Types of Symmetrically Distinct Vectorlike Physical Quantities  

NASA Astrophysics Data System (ADS)

The Letter draws the attention to the spatiotemporal symmetry of various vectorlike physical quantities. The symmetry is specified by their invariance under the action of symmetry operations of the nonrelativistic space-time rotation group O(3)×{1,1'}=O'(3), where 1' is a time-reversal operation, the symbol×stands for the group direct product, and O(3) is a group of proper and improper rotations. It is argued that along with the canonical polar vector, there are another seven symmetrically distinct classes of stationary physical quantities, which can be—and often are—denoted as standard three-component vectors, even though they do not transform as a static polar vector under all operations of O'(3). The octet of symmetrically distinct "directional quantities" can be exemplified by two kinds of polar vectors (electric dipole moment P and magnetic toroidal moment T), two kinds of axial vectors (magnetization M and electric toroidal moment G), two kinds of chiral "bidirectors" C and F (associated with the so-called true and false chirality, respectively) and still another two bidirectors N and L, achiral ones, transforming as the nematic liquid crystal order parameter and as the antiferromagnetic order parameter of the hematite crystal ?-Fe2O3, respectively.

Hlinka, J.

2014-10-01

30

Dome-Type: A Distinctive Variant of Colonic Adenocarcinoma  

PubMed Central

Introduction. Ten cases of dome-type adenocarcinoma of the colon have been reported so far. Most of them were presented as early lesions, with endoscopic and microscopic distinguishing features. Methods and Results. A raised plaque was removed from the right colon during colonoscopy in a 56-year-old man. Histopathological examination showed a cancerized adenoma invading the submucosa with several typical features of dome-type adenocarcinoma, in particular the associated prominent lymphoid tissue. Immunohistochemistry showed retention of the mismatch repair proteins MLH-1, MSH-2, MLH-6, and PMS-2. Conclusion. We report an additional case of dome-type adenocarcinoma of the colon as an early, low-risk, and microsatellite stable tumor, indicating that this particular histotype may deserve specific consideration for both classification and management. PMID:23213588

Puppa, Giacomo; Molaro, Mariella

2012-01-01

31

Evidence for two distinct populations of type Ia supernovae.  

PubMed

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

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

2013-04-12

32

Two distinct gait types in swimming frogs Sandra Nauwelaerts* and Peter Aerts  

E-print Network

of frogs to their position in the phylogenetic tree. They stated that primitive frog species useTwo distinct gait types in swimming frogs Sandra Nauwelaerts* and Peter Aerts Department of Biology 2001) Abstract During terrestrial locomotion, frogs use two distinct gaits: out-of-phase leg movements

Nauwelaerts, Sandra

33

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

PubMed Central

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

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

2010-01-01

34

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

NASA Technical Reports Server (NTRS)

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.

Lnenicka, G. A.; Keshishian, H.

2000-01-01

35

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

PubMed Central

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

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

2015-01-01

36

Calcium Channel Types with Distinct Presynaptic Localization Couple Differentially to Transmitter Release in Single  

E-print Network

Calcium Channel Types with Distinct Presynaptic Localization Couple Differentially to Transmitter, Washington 98195-7280 We studied how Ca2 influx through different subtypes of Ca2 channels couples to release-specific toxins showed that Ca2 channels of the P/Q-, N-, and R-type con- trolled glutamate release at a single

Alford, Simon

37

DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.  

PubMed

We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates). PMID:20060365

Figueroa, Maria E; Lugthart, Sanne; Li, Yushan; Erpelinck-Verschueren, Claudia; Deng, Xutao; Christos, Paul J; Schifano, Elizabeth; Booth, James; van Putten, Wim; Skrabanek, Lucy; Campagne, Fabien; Mazumdar, Madhu; Greally, John M; Valk, Peter J M; Löwenberg, Bob; Delwel, Ruud; Melnick, Ari

2010-01-19

38

Two Types of Alpha Satellite DNA in Distinct Chromosomal Locations in Azara's Owl Monkey  

PubMed Central

Alpha satellite DNA is a repetitive sequence known to be a major DNA component of centromeres in primates (order Primates). New World monkeys form one major taxon (parvorder Platyrrhini) of primates, and their alpha satellite DNA is known to comprise repeat units of around 340 bp. In one species (Azara's owl monkey Aotus azarae) of this taxon, we identified two types of alpha satellite DNA consisting of 185- and 344-bp repeat units that we designated as OwlAlp1 and OwlAlp2, respectively. OwlAlp2 exhibits similarity throughout its entire sequence to the alpha satellite DNA of other New World monkeys. The chromosomal locations of the two types of sequence are markedly distinct: OwlAlp1 was observed at the centromeric constrictions, whereas OwlAlp2 was found in the pericentric regions. From these results, we inferred that OwlAlp1 was derived from OwlAlp2 and rapidly replaced OwlAlp2 as the principal alpha satellite DNA on a short time scale at the speciation level. A less likely alternative explanation is also discussed. PMID:23477842

Prakhongcheep, Ornjira; Hirai, Yuriko; Hara, Toru; Srikulnath, Kornsorn; Hirai, Hirohisa; Koga, Akihiko

2013-01-01

39

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

PubMed Central

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

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

2014-01-01

40

Will Jets Identify the Progenitors of Type Ia Supernovae?  

E-print Network

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.

Mario Livio; Adam Riess; William Sparks

2002-04-26

41

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

PubMed Central

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

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

2013-01-01

42

Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites  

PubMed Central

Histone acetylation has long been determined as a highly dynamic modification associated with open chromatin and transcriptional activation. Here we develop a metabolic labeling scheme using stable isotopes to study the kinetics of acetylation turnover at 19 distinct lysines on histones H3, H4, and H2A. Using human HeLa S3 cells, the analysis reveals 12 sites of histone acetylation with fast turnover and 7 sites stable over a 30 hour experiment. The sites showing fast turnover (anticipated from classical radioactive measurements of whole histones) have half-lives between ~1–2 hours. To support this finding, we use a broad-spectrum deacetylase inhibitor to verify that only fast turnover sites display 2–10 fold increases in acetylation whereas long-lived sites clearly do not. Most of these stable sites lack extensive functional studies or localization within global chromatin, and their role in non-genetic mechanisms of inheritance is as yet unknown. PMID:23892279

Zheng, Yupeng; Thomas, Paul M.; Kelleher, Neil L.

2013-01-01

43

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

PubMed Central

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

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

2012-01-01

44

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

PubMed

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

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

2012-08-20

45

In Silico Molecular Comparisons of C. elegans and Mammalian Pharmacology Identify Distinct Targets That Regulate Feeding  

PubMed Central

Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs. PMID:24260022

Lemieux, George A.; Keiser, Michael J.; Sassano, Maria F.; Laggner, Christian; Mayer, Fahima; Bainton, Roland J.; Werb, Zena; Roth, Bryan L.; Shoichet, Brian K.; Ashrafi, Kaveh

2013-01-01

46

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

SciTech Connect

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

Irfan, Muhammad; Yim, Jong-Hyuk, E-mail: jho@gist.ac.kr; Jho, Young-Dahl, E-mail: jho@gist.ac.kr [School of Info. and Comm., Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of); Kim, Changyoung [Institute of Physics and Applied physics, Yonsei University, Seoul 120-749 (Korea, Republic of)

2013-12-04

47

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

PubMed

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

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

48

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

PubMed Central

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

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

49

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

PubMed Central

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

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

2011-01-01

50

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

PubMed

Molecular genetic studies on vascular tumors are rare. Recently, possible involvement of MYC and KDR has been documented in a subset of angiosarcomas of soft tissue. We performed a cytogenetic analysis of primary angiosarcomas of bone (n?=?13) and soft tissue (n?=?5) using high density array-comparative genomic hybridization (array-CGH). Regions of interest were validated by fluorescence in situ hybridization (FISH). Antibodies for candidate genes (SKI, MYC, KDR, and MAPK9) were selected and immunohistochemistry was performed. Six angiosarcomas of bone and four angiosarcomas of soft tissue showed chromosomal losses, gains, and high level amplifications. Cluster analysis identified two groups: a group with a complex genetic profile and a group with only few genetic aberrations. Five regions of interest were selected, which were located at chromosome bands 1p36.23, 2q32-34, 5q35, 8q24, and 17q21.32-24.2. Interphase FISH confirmed the high-level amplifications. Immunohistochemical analysis showed high expression of MYC (16/60), MAPK9 (63/69), and SKI (52/62). There were no differences between the two groups with regards to location, immunohistochemical expression nor survival. In summary, we identified two subgroups of angiosarcoma: those with few or no gross aberrations and those which show numerous genetic aberrations consisting of chromosomal losses, gains and high level amplifications or complex aberrations. The most common finding was amplification of 2q and 17q in both angiosarcoma of bone and soft tissue, suggesting overlap in tumorigenesis irrespective of their location. We show MYC amplification in primary angiosarcoma indicating this is not entirely specific for radiation-induced angiosarcoma. © 2014 Wiley Periodicals, Inc. PMID:25231439

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

2015-02-01

51

A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival  

PubMed Central

With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine–cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM. PMID:23796897

Zheng, Siyuan; Fu, Jun; Vegesna, Rahulsimham; Mao, Yong; Heathcock, Lindsey E.; Torres-Garcia, Wandaliz; Ezhilarasan, Ravesanker; Wang, Shuzhen; McKenna, Aaron; Chin, Lynda; Brennan, Cameron W.; Yung, W.K. Alfred; Weinstein, John N.; Aldape, Kenneth D.; Sulman, Erik P.; Chen, Ken; Koul, Dimpy; Verhaak, Roel G.W.

2013-01-01

52

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

Microsoft Academic Search

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

F. Battaglia; F. George

1988-01-01

53

Epitope Predictions Indicate the Presence of Two Distinct Types of Epitope-Antibody-Reactivities Determined by  

E-print Network

Epitope Predictions Indicate the Presence of Two Distinct Types of Epitope-Antibody-Reactivities Determined by Epitope Profiling of Intravenous Immunoglobulins Mitja Lustrek1,2 , Peter Lorenz3 , Michael Rostock, University of Rostock, Rostock, Germany Abstract Epitope-antibody-reactivities (EAR

LuÂ?trek, Mitja

54

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

Microsoft Academic Search

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

Kevin A. Keay; Richard Bandler

2001-01-01

55

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, ...

56

Squamoid cyst of pancreatic ducts: A distinct type of cystic lesion in the pancreas.  

PubMed

The clinicopathologic features of a hitherto unrecognized cystic tumor of the pancreas are documented, and its possible relationship to a more common incidental microscopic lesion is analyzed. Six patients (3 men and 3 women) had undergone resection specifically for this cyst type. The mean age of the patients was 63 years (range 52 to 79 y) and the mean size of the tumors was 2.6 cm (median 1.5, range 0.8 to 9 cm). The cysts had variable lining ranging from attenuated, flat squamoid cells to transitional, to stratified squamous without keratinization (no granular layer). The cells forming the basal/parabasal region expressed p63 (transitional/squamous cell marker, not detected in any normal pancreas or nonsquamous neoplasia) and the surface cells were positive for MUC 1 and MUC 6 (markers present in intercalated duct cells), and negative for GLUT-1 (consistent marker of serous adenomas). The lesions appeared to be unilocular cystic dilatation of the ducts that typically contained distinctive muco-proteinaceous acidophilic acinar secretions forming concretions, confirming their communication with the acinar system, and suggesting a localized obstruction in their pathogenesis (a form of "retention" cyst). A thin fibrous wall devoid of any lymphoid tissue separated the cysts from unremarkable parenchyma. There was no evidence of pancreatitis (fibrosis or inflammation). Separately, 110 pancreata resected for various reasons were analyzed, and what seems to be microscopic/incidental version of this process was identified in 10 examples (8%). These microcysts were found lying within compact acinar tissue, and appeared to be transforming from intercalated ducts, some focally connected to acinar elements, and they had abortive (nonbridging) septae with pseudo-loculated appearance, irregular contours and often showed tightly packed clusters of ducts with similar morphology described in the cases underwent resection specifically for this cyst type. In conclusion, the distinctive morphologic, immunophenotypic, and clinical characteristics of this cystic lesion warrant its classification as a separate entity. We propose to refer to it as squamoid cyst of pancreatic ducts. It seems to be a metaplastic cystic transformation beginning in the intercalated ducts. Although obstructive etiology is suspected, a specific factor or surrogate evidence of obstruction such as chronic pancreatitis is typically lacking. PMID:17255775

Othman, Mohammad; Basturk, Olca; Groisman, Gabe; Krasinskas, Alyssa; Adsay, N Volkan

2007-02-01

57

Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms.  

PubMed

Ciliopathies are genetic disorders that are caused by dysfunctional cilia and affect multiple organs. One type of ciliopathy, Bardet-Biedl syndrome, is a rare disorder characterized by obesity, retinitis pigmentosa, polydactyly, mental retardation and susceptibility to cardiovascular diseases. The Wnt/Planar cell polarity (PCP) has been associated with cilia function and ciliogenesis in directing the orientation of cilia and basal bodies. Yet the exact relationship between PCP and ciliopathy is not well understood. Here, we examine interactions between a core PCP component, Prickle2 (Pk2), and a central BBS gene, Bbs7, using gene knockdown in the zebrafish. pk2 and bbs7 knockdown both disrupt the formation of a ciliated organ, the Kupffer?s vesicle (KV), but do not display a synergistic interaction. By measuring cell polarity in the neural tube, we find that bbs7 activity is not required for Pk asymmetric localization. Moreover, BBS protein complex formation is preserved in the Pk2-deficient (Pk2(-/-)) mouse. Previously we reported an intracellular melanosome transport delay as a cardinal feature of reduced bbs gene activity. We find that pk2 knockdown suppresses bbs7-related retrograde transport delay. Similarly, knockdown of ift22, an anterograde intraflagellar transport component, also suppresses the bbs7-related retrograde delay. Notably, we find that pk2 knockdown larvae show a delay in anterograde transport. These data suggest a novel role for Pk2 in directional intracellular transport and our analyses show that PCP and BBS function independently, yet result in overlapping phenotypes when knocked down in zebrafish. PMID:24938409

Mei, Xue; Westfall, Trudi A; Zhang, Qihong; Sheffield, Val C; Bassuk, Alexander G; Slusarski, Diane C

2014-08-15

58

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

PubMed

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

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

2014-03-01

59

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

PubMed Central

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

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

2013-01-01

60

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.

61

ON IDENTIFYING THE PROGENITORS OF Type Ia SUPERNOVAE  

SciTech Connect

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.

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

2011-10-10

62

Identifying patients at risk of type 2 diabetes.  

PubMed

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

Savill, Peter

2012-01-01

63

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

PubMed Central

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

2014-01-01

64

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

PubMed Central

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

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

65

Neuronal growth factor regulation of two different sodium channel types through distinct signal transduction pathways  

PubMed Central

Neuronal growth factors regulate the expression of voltage-activated sodium current in differentiating sympathetic neurons and PC12 cells. We show that, in PC12 cells, the NGF- and FGF-induced sodium current results from increased expression of two distinct sodium channel types. Sodium current results from the rapid induction of a novel sodium channel transcript, also found in peripheral neurons, and from the long term induction of brain type II/IIA mRNA. Expression of the type II/IIA sodium channel requires activation of the cyclic AMP-dependent protein kinase (A-kinase), whereas induction of the peripheral neuron type sodium channel occurs through an A-kinase-independent signal transduction pathway. These findings suggest that the two sodium channel types act in concert to ensure the generation of action potentials during neuronal differentiation. PMID:8394370

1993-01-01

66

Three types of ependymal cells with intracellular calcium oscillation are characterized by distinct cilia beating properties.  

PubMed

Ependymal cells are multiciliated epithelial cells that line the ventricles in the adult brain. Abnormal function or structure of ependymal cilia has been associated with various neurological deficits. For the first time, we report three distinct ependymal cell types, I, II, and III, based on their unique ciliary beating frequency and beating angle. These ependymal cells have specific localizations within the third ventricle of the mouse brain. Furthermore, neither ependymal cell types nor their localizations are altered by aging. Our high-speed fluorescence imaging analysis reveals that these ependymal cells have an intracellular pacing calcium oscillation property. Our study further shows that alcohol can significantly repress the amplitude of calcium oscillation and the frequency of ciliary beating, resulting in an overall decrease in volume replacement by the cilia. Furthermore, the pharmacological agent cilostazol could differentially increase cilia beating frequency in type II, but not in type I or type III, ependymal cells. In summary, we provide the first evidence of three distinct types of ependymal cells with calcium oscillation properties. PMID:24811319

Liu, Tongyu; Jin, Xingjian; Prasad, Rahul M; Sari, Youssef; Nauli, Surya M

2014-09-01

67

Congenital fibrosis of the extraocular muscles type 1, distinctive conjunctival changes and intrapapillary disc colobomata.  

PubMed

A 6-month-old boy presented with a congenital eye movement disorder consistent with congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Mutational analysis confirmed the most common mutation in the CFEOM1 gene KIF21A. In addition to the typical findings in CFEOM1, distinctive conjunctival changes and small bilateral optic disc colobomata were also noted. It is suggested that optic disc colobomata represent a new association of CFEOM1. PMID:19373680

Flaherty, Maree P; Balachandran, Chandra; Jamieson, Robyn; Engle, Elizabeth C

2009-06-01

68

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

NASA Astrophysics Data System (ADS)

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.

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

2012-06-01

69

Anti-angiogenic peptides identified in thrombospondin type I domains  

SciTech Connect

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.

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

70

Identifying Fracture Types and Relative Ages Using Fluid Inclusion Stratigraphy  

SciTech Connect

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.

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

2008-06-30

71

Integrative analysis of Head and Neck Cancer identifies two biologically distinct HPV and three non-HPV subtypes.  

PubMed

Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. Experimental Design: Here we use gene expression based consensus clustering, copy number profiling, and HPV-status on a clinically homogenous cohort of 134 locoregionally-advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 931 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics. Results: We identified five subtypes of HNSCC including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8+ lymphocytes characterizes this inflamed/mesenchymal subtypes - independent of HPV status. Compared to other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER-ligands and absence of EGFR/HER-ligand expression. By contrast the Basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype driven by multiple HER ligands, as well as strong hypoxic differentiation not seen in other subtypes. Conclusion: Our five-subtype classification provides a comprehensive overview of HPV(+) as well as HPV(-) HNSCC biology with significant translational implications for biomarker development and personalized care for HNSCC patients. PMID:25492084

Keck, Michaela K; Zuo, Zhixiang; Khattri, Arun; Stricker, Thomas P; Brown, Christopher; Imanguli, Matin; Rieke, Damian; Endhardt, Katharina; Fang, Petra; Bragelmann, Johannes; DeBoer, Rebecca; El Dinali, Mohamed; Aktolga, Serdal; Lei, Zhengdeng; Tan, Patrick; Rozen, Steven G; Salgia, Ravi; Weichselbaum, Ralph R; Lingen, Mark W; Story, Michael D; Ang, Kie Kian; Cohen, Ezra Ew; White, Kevin P; Vokes, Everett E; Seiwert, Tanguy Y

2014-12-01

72

Biosensor-Based Approach Identifies Four Distinct Calmodulin-Binding Domains in the G Protein-Coupled Estrogen Receptor 1  

PubMed Central

The G protein-coupled estrogen receptor 1 (GPER) has been demonstrated to participate in many cellular functions, but its regulatory inputs are not clearly understood. Here we describe a new approach that identifies GPER as a calmodulin-binding protein, locates interaction sites, and characterizes their binding properties. GPER coimmunoprecipitates with calmodulin in primary vascular smooth muscle cells under resting conditions, which is enhanced upon acute treatment with either specific ligands or a Ca2+-elevating agent. To confirm direct interaction and locate the calmodulin-binding domain(s), we designed a series of FRET biosensors that consist of enhanced cyan and yellow fluorescent proteins flanking each of GPER’s submembrane domains (SMDs). Responses of these biosensors showed that all four submembrane domains directly bind calmodulin. Modifications of biosensor linker identified domains that display the strongest calmodulin-binding affinities and largest biosensor dynamics, including a.a. 83–93, 150–175, 242–259, 330–351, corresponding respectively to SMDs 1, 2, 3, and the juxta-membranous section of SMD4. These biosensors bind calmodulin in a strictly Ca2+-dependent fashion and with disparate affinities in the order SMD2>SMD4>SMD3>SMD1, apparent Kd values being 0.44±0.03, 1.40±0.16, 8.01±0.29, and 136.62±6.56 µM, respectively. Interestingly, simultaneous determinations of biosensor responses and suitable Ca2+ indicators identified separate Ca2+ sensitivities for their interactions with calmodulin. SMD1-CaM complexes display a biphasic Ca2+ response, representing two distinct species (SMD1 sp1 and SMD1 sp2) with drastically different Ca2+ sensitivities. The Ca2+ sensitivities of CaM-SMDs interactions follow the order SMD1sp1>SMD4>SMD2>SMD1sp2>SMD3, EC50(Ca2+) values being 0.13±0.02, 0.75±0.05, 2.38±0.13, 3.71±0.13, and 5.15±0.25 µM, respectively. These data indicate that calmodulin may regulate GPER-dependent signaling at the receptor level through multiple interaction sites. FRET biosensors represent a simple method to identify unknown calmodulin-binding domains in G protein-coupled receptors and to quantitatively assess binding properties. PMID:24586950

Tran, Quang-Kim; VerMeer, Mark

2014-01-01

73

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

PubMed Central

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

Gentzbittel, Laurent

2013-01-01

74

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

Microsoft Academic Search

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

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

75

Type XII collagen: distinct extracellular matrix component discovered by cDNA cloning.  

PubMed Central

We have screened a cDNA library constructed from tendon fibroblast mRNA for the presence of collagenous coding sequences. Nucleotide sequence analysis of one isolated clone, pMG377, reveals that the clone encodes a polypeptide that is homologous to, yet distinctly different from, type IX short-chain collagen polypeptides. The structure of the conceptual translation product of the cDNA is also different from that of all other collagen types. Therefore, we have given the type IX-like collagen chain encoded by pMG377 the designation alpha 1(XII). Ribonuclease protection assays with single-stranded cRNA probes demonstrate that alpha 1(XII) mRNA is present in several tissues such as calvaria, tendon, and sternal cartilage of 17-day-old chicken embryo and in cornea from 6-day-old embryos. Using pMG377 as the hybridization probe, we isolated a fragment of the corresponding gene from a chicken genomic library. Partial nucleotide sequence analysis of the genomic clone DG12 shows that the exon/intron structure of the alpha 1(XII) collagen gene appears to be homologous to that of the alpha 1(IX) and alpha 2(IX) collagen genes. Our data demonstrate that types IX and XII collagen are two homologous members of a family of unique collagenous proteins that show tissue-specific patterns of expression. Based on their structure and the properties of their genes, we conclude that this family of collagens is distinctly different from that of fibrillar collagens. Images PMID:3476925

Gordon, M K; Gerecke, D R; Olsen, B R

1987-01-01

76

Identifying Aerosol Type/Mixture from Aerosol Absorption Properties Using AERONET  

NASA Technical Reports Server (NTRS)

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.

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

77

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

PubMed

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

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

2013-10-30

78

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

PubMed Central

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

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

2013-01-01

79

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

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

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

2013-01-01

80

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

PubMed Central

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

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

2014-01-01

81

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

PubMed

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

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

2014-01-01

82

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

PubMed Central

Background Enteroaggregative Escherichia coli (EAEC) are important diarrhoeal pathogens that are defined by a HEp-2 adherence assay performed in specialist laboratories. Multilocus sequence typing (MLST) has revealed that aggregative adherence is convergent, providing an explanation for why not all EAEC hybridize with the plasmid-derived probe for this category, designated CVD432. Some EAEC lineages are globally disseminated or more closely associated with disease. Results To identify genetic loci conserved within significant EAEC lineages, but absent from non-EAEC, IS3-based PCR profiles were generated for 22 well-characterised EAEC strains. Six bands that were conserved among, or missing from, specific EAEC lineages were cloned and sequenced. One band corresponded to the aggR gene, a plasmid-encoded regulator that has been used as a diagnostic target but predominantly detects EAEC bearing the plasmid already marked by CVD432. The sequence from a second band was homologous to an open-reading frame within the cryptic enterohaemorrhagic E. coli (EHEC) O157 genomic island, designated O-island 62. Screening of an additional 46 EAEC strains revealed that the EHEC O-island 62 was only present in those EAEC strains belonging to the ECOR phylogenetic group D, largely comprised of sequence type (ST) complexes 31, 38 and 394. Conclusions The EAEC 042 gene orf1600, which lies within the EAEC equivalent of O-island 62 island, can be used as a marker for EAEC strains belonging to the ECOR phylogenetic group D. The discovery of EHEC O-island 62 in EAEC validates the genetic profiling approach for identifying conserved loci among phylogenetically related strains. PMID:21450104

2011-01-01

83

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

PubMed

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

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

2015-01-01

84

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

PubMed Central

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

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

2009-01-01

85

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

PubMed Central

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

Berthold, E; Maldarelli, F

1996-01-01

86

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

PubMed

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, as well as '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 DNA. We also comment on the prospect of growing macroscopic structures in this manner. PMID:25005537

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

2014-09-14

87

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

PubMed Central

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

Neunuebel, Joshua P.; Knierim, James J.

2012-01-01

88

Identifying Cell Types from Spatially Referenced Single-Cell Expression Datasets  

PubMed Central

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

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

2014-01-01

89

Four distinct types of dehydration stress memory genes in Arabidopsis thaliana  

PubMed Central

Background How plants respond to dehydration stress has been extensively researched. However, how plants respond to multiple consecutive stresses is virtually unknown. Pre-exposure to various abiotic stresses (including dehydration) may alter plants’ subsequent responses by improving resistance to future exposures. These observations have led to the concept of ‘stress memory’ implying that during subsequent exposures plants provide responses that are different from those during their first encounter with the stress. Genes that provide altered responses in a subsequent stress define the ‘memory genes’ category; genes responding similarly to each stress form the ‘non-memory’ category. Results Using a genome-wide RNA-Seq approach we determine the transcriptional responses of Arabidopsis plants that have experienced multiple exposures to dehydration stress and compare them with the transcriptional behavior of plants encountering the stress for the first time. The major contribution of this study is the revealed existence of four distinct, previously unknown, transcription memory response patterns of dehydration stress genes in A.thaliana. The biological relevance for each of the four memory types is considered in the context of four overlapping strategies employed by a plant to improve its stress tolerance and/or survival: 1) increased synthesis of protective, damage-repairing, and detoxifying functions; 2) coordinating photosynthesis and growth under repetitive stress; 3) re-adjusting osmotic and ionic equilibrium to maintain homeostasis; and 4) re-adjusting interactions between dehydration and other stress/hormone regulated pathways. Conclusions The results reveal the unknown, hitherto, existence of four distinct transcription memory response types in a plant and provide genome-wide characterization of memory and non-memory dehydration stress response genes in A.thaliana. The transcriptional responses during repeated exposures to stress are different from known responses occurring during a single exposure. GO analyses of encoded proteins suggested implications for the cellular/organismal protective, adaptive, and survival functions encoded by the memory genes. The results add a new dimension to our understanding of plants’ responses to dehydration stress and to current models for interactions between different signaling systems when adjusting to repeated spells of water deficits. PMID:24377444

2013-01-01

90

Digital morphometry of rat cerebellar climbing fibers reveals distinct branch and bouton types  

PubMed Central

Cerebellar climbing fibers provide powerful excitatory input to Purkinje cells, which represent the sole output of the cerebellar cortex. Recent discoveries suggest that climbing fibers have information-rich signaling properties important for cerebellar function, beyond eliciting the well-known all-or-none Purkinje cell complex spike. Climbing fiber morphology has not been quantitatively analyzed at the same level of detail as their biophysical properties. Because morphology can greatly influence function, including the capacity for information processing, it is important to understand climbing fiber branching structure in detail, as well as its variability across and within arbors. We have digitally reconstructed 68 rat climbing fibers labeled using biotinylated dextran amine (BDA) injected into the inferior olive and comprehensively quantified their morphology. Climbing fiber structure was considerably diverse even within the same anatomical regions. Distinctly identifiable primary, tendril, and distal branches could be operationally differentiated by the relative size of the subtrees at their initial bifurcations. Additionally, primary branches were more directed toward the cortical surface and had fewer and less pronounced synaptic boutons, suggesting they prioritize efficient and reliable signal propagation. Tendril and distal branches were spatially segregated and bouton dense, indicating specialization in signal transmission. Furthermore, climbing fibers systematically targeted molecular layer interneuron cell bodies, especially at terminal boutons, potentially instantiating feed-forward inhibition on Purkinje cells. This study offers the most detailed and comprehensive characterization of climbing fiber morphology to date. The reconstruction files and metadata are publicly distributed at NeuroMorpho.Org. PMID:23077053

Brown, Kerry M.; Sugihara, Izumi; Shinoda, Yoshikazu; Ascoli, Giorgio A.

2012-01-01

91

Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling  

PubMed Central

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

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

2012-01-01

92

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

PubMed

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

Kvitsiani, D; Ranade, S; Hangya, B; Taniguchi, H; Huang, J Z; Kepecs, A

2013-06-20

93

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

PubMed Central

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

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

2014-01-01

94

Pseudomonas chromosomal replication origins: a bacterial class distinct from Escherichia coli-type origins.  

PubMed Central

The bacterial origins of DNA replication have been isolated from Pseudomonas aeruginosa and Pseudomonas putida. These origins comprise a second class of bacterial origins distinct from enteric-type origins: both origins function in both Pseudomonas species, and neither functions in Escherichia coli; enteric origins do not function in either pseudomonad. Both cloned sequences hybridize to chromosomal fragments that show properties expected of replication origins. These origin plasmids are highly unstable, are present at low copy number, and show mutual incompatibility properties. DNA sequence analysis shows that both origins contain several 9-base-pair (bp) E. coli DnaA protein binding sites; four of these are conserved in position and orientation, two of which resemble the R1 and R4 sites of the E. coli origin. Conserved 13-bp direct repeats adjacent to the analogous R1 site are also found. No GATC sites are in the P. aeruginosa origin and only four are in the P. putida origin; no other 4-bp sequence is present in high abundance. Both origins are found between sequences similar to the E. coli and Bacillus subtilis dnaA, dnaN, rpmH, and rnpA genes, a gene organization identical to that for B. subtilis and unlike that of E. coli. A second autonomously replicating sequence was obtained from P. aeruginosa that has some properties of bacterial origins. Images PMID:2106132

Yee, T W; Smith, D W

1990-01-01

95

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

PubMed Central

Background Kuntiz-type toxins (KTTs) have been found in the venom of animals such as snake, cone snail and sea anemone. The main ancestral function of Kunitz-type proteins was the inhibition of a diverse array of serine proteases, while toxic activities (such as ion-channel blocking) were developed under a variety of Darwinian selection pressures. How new functions were grafted onto an old protein scaffold and what effect Darwinian selection pressures had on KTT evolution remains a puzzle. Principal Findings Here we report the presence of a new superfamily of KTTs in spiders (Tarantulas: Ornithoctonus huwena and Ornithoctonus hainana), which share low sequence similarity to known KTTs and is clustered in a distinct clade in the phylogenetic tree of KTT evolution. The representative molecule of spider KTTs, HWTX-XI, purified from the venom of O. huwena, is a bi-functional protein which is a very potent trypsin inhibitor (about 30-fold more strong than BPTI) as well as a weak Kv1.1 potassium channel blocker. Structural analysis of HWTX-XI in 3-D by NMR together with comparative function analysis of 18 expressed mutants of this toxin revealed two separate sites, corresponding to these two activities, located on the two ends of the cone-shape molecule of HWTX-XI. Comparison of non-synonymous/synonymous mutation ratios (?) for each site in spider and snake KTTs, as well as PBTI like body Kunitz proteins revealed high Darwinian selection pressure on the binding sites for Kv channels and serine proteases in snake, while only on the proteases in spider and none detected in body proteins, suggesting different rates and patterns of evolution among them. The results also revealed a series of key events in the history of spider KTT evolution, including the formation of a novel KTT family (named sub-Kuntiz-type toxins) derived from the ancestral native KTTs with the loss of the second disulfide bridge accompanied by several dramatic sequence modifications. Conclusions/Significance These finding illustrate that the two activity sites of Kunitz-type toxins are functionally and evolutionally independent and provide new insights into effects of Darwinian selection pressures on KTT evolution, and mechanisms by which new functions can be grafted onto old protein scaffolds. PMID:18923708

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

2008-01-01

96

Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor  

PubMed Central

Background Cytokine-induced killer (CIK) cells are an emerging approach of cancer treatment. Our previous study have shown that CIK cells stimulated with combination of IL-2 and IL-15 displayed improved proliferation capacity and tumor cytotoxicity. However, the mechanisms of CIK cell proliferation and acquisition of cytolytic function against tumor induced by IL-2 and IL-15 have not been well elucidated yet. Methods CIKIL-2 and CIKIL-15 were generated from peripheral blood mononuclear cells primed with IFN-?, and stimulated with IL-2 and IL-15 in combination with OKT3 respectively. RNA-seq was performed to identify differentially expressed genes, and gene ontology and pathways based analysis were used to identify the distinct roles of IL-2 and IL-15 in CIK preparation. Results The results indicated that CIKIL-15 showed improved cell proliferation capacity compared to CIKIL-2. However, CIKIL-2 has exhibited greater tumor cytotoxic effect than CIKIL-15. Employing deep sequencing, we sequenced mRNA transcripts in CIKIL-2 and CIKIL-15. A total of 374 differentially expressed genes (DEGs) were identified including 175 up-regulated genes in CIKIL-15 and 199 up-regulated genes in CIKIL-2. Among DEGs in CIKIL-15, Wnt signaling and cell adhesion were significant GO terms and pathways which related with their functions. In CIKIL-2, type I interferon signaling and cytokine-cytokine receptor interaction were significant GO terms and pathways. We found that the up-regulation of Wnt 4 and PDGFD may contribute to enhanced cell proliferation capacity of CIKIL-15, while inhibitory signal from interaction between CTLA4 and CD80 may be responsible for the weak proliferation capacity of CIKIL-2. Moreover, up-regulated expressions of CD40LG and IRF7 may make for improved tumor cytolytic function of CIKIL-2 through type I interferon signaling. Conclusions Through our findings, we have preliminarily elucidated the cells proliferation and acquisition of tumor cytotoxicity mechanism of CIKIL-15 and CIKIL-2. Better understanding of these mechanisms will help to generate novel CIK cells with greater proliferation potential and improved tumor cytolytic function. PMID:25108500

2014-01-01

97

Evolutionarily distinct versions of the multidomain enzyme ?-isopropylmalate synthase share discrete mechanisms of V-type allosteric regulation.  

PubMed

Understanding the evolution of allostery in multidomain enzymes remains an important step in improving our ability to identify and exploit structure-function relationships in allosteric mechanisms. A recent protein similarity network for the DRE-TIM metallolyase superfamily indicated there are two evolutionarily distinct forms of the enzyme ?-isopropylmalate synthase (IPMS) sharing approximately 20% sequence identity. IPMS from Mycobacterium tuberculosis has been extensively characterized with respect to catalysis and the mechanism of feedback regulation by l-leucine. Here, IPMS from Methanococcus jannaschii (MjIPMS) is used as a representative of the second form of the enzyme, and its catalytic and regulatory mechanism is compared with that of MtIPMS to identify any functional differences between the two forms. MjIPMS exhibits kinetic parameters similar to those of other reported IPMS enzymes and is partially inhibited by l-leucine in a V-type manner. Identical values of (D2O)kcat (3.1) were determined in the presence and absence of l-leucine, indicating the hydrolytic step is rate-determining in the absence of l-leucine and remains so in the inhibited form of the enzyme. This mechanism is identical to the mechanism identified for MtIPMS ((D2O)kcat = 3.3 ± 0.3 in the presence of l-leucine) despite product release being rate-determining in the uninhibited MtIPMS enzyme. The identification of identical regulatory mechanisms in enzymes with low sequence identity raises important evolutionary questions concerning the acquisition and divergence of multidomain allosteric enzymes and highlights the need for caution when comparing regulatory mechanisms for homologous enzymes. PMID:24991690

Kumar, Garima; Frantom, Patrick A

2014-07-29

98

Comparative Analysis of Type III Secreted Effector Genes Reflects Divergence of Acidovorax citrulli Strains into Three Distinct Lineages.  

PubMed

ABSTRACT Acidovorax citrulli causes bacterial fruit blotch of cucurbits, a serious economic threat to watermelon (Citrullus lanatus) and melon (Cucumis melo) production worldwide. Based on genetic and biochemical traits, A. citrulli strains have been divided into two distinct groups: group I strains have been mainly isolated from various non-watermelon hosts, while group II strains have been generally isolated from and are highly virulent on watermelon. The pathogen depends on a functional type III secretion system for pathogenicity. Annotation of the genome of the group II strain AAC00-1 revealed 11 genes encoding putative type III secreted (T3S) effectors. Due to the crucial role of type III secretion for A. citrulli pathogenicity, we hypothesized that group I and II strains differ in their T3S effector repertoire. Comparative analysis of the 11 effector genes from a collection of 22 A. citrulli strains confirmed this hypothesis. Moreover, this analysis led to the identification of a third A. citrulli group, which was supported by DNA:DNA hybridization, DNA fingerprinting, multilocus sequence analysis of conserved genes, and virulence assays. The effector genes assessed in this study are homologous to effectors from other plant-pathogenic bacteria, mainly belonging to Xanthomonas spp. and Ralstonia solanacearum. Analyses of the effective number of codons and gas chromatography content of effector genes relative to a representative set of housekeeping genes support the idea that these effector genes were acquired by lateral gene transfer. Further investigation is required to identify new T3S effectors of A. citrulli and to determine their contribution to virulence and host preferential association. PMID:24848275

Eckshtain-Levi, Noam; Munitz, Tamar; Zivanovi?, Marija; Traore, Sy M; Spröer, Cathrin; Zhao, Bingyu; Welbaum, Gregory; Walcott, Ron; Sikorski, Johannes; Burdman, Saul

2014-11-01

99

Sources and Types of Confidence Identified by World Class Sport Performers  

Microsoft Academic Search

This study identified the sources and types of confidence salient to 14 (7 male, 7 female) successful World Class athletes. Nine sources of confidence were identified: Preparation, performance accomplishments, coaching, innate factors, social support, experience, competitive advantage, self-awareness, and trust. A testament to the multi-dimensional nature of sport confidence, six types of sport confidence were also identified: skill execution, achievement,

Kate Hays; Ian Maynard; Owen Thomas; Mark Bawden

2007-01-01

100

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

PubMed

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

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

2015-01-01

101

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

PubMed Central

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

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

2015-01-01

102

The influence of distinct types of aquatic vegetation on the flow field  

NASA Astrophysics Data System (ADS)

The Sustainable management of fluvial systems dealing with flood prevention, erosion protection and restoration of rivers and estuaries requires implementation of soft/green-engineering methods. In-stream aquatic vegetation can be regarded as one of these as it plays an important role for both river ecology (function) and geomorphology (form). The goal of this research is to offer insight gained from pilot experimental studies on the effects of a number of different elements modeling instream, aquatic vegetation on the local flow field. It is hypothesized that elements of the same effective "blockage" area but of distinct characteristics (structure, porosity and flexibility), will affect both the mean and fluctuating levels of the turbulent flow to a different degree. The above hypothesis is investigated through a set of rigorous set of experimental runs which are appropriately designed to assess the variability between the interaction of aquatic elements and flow, both quantitatively and qualitatively. In this investigation three elements are employed to model aquatic vegetation, namely a rigid cylinder, a porous but rigid structure and a flexible live plant (Cupressus Macrocarpa). Firstly, the flow field downstream each of the mentioned elements was measured under steady uniform flow conditions employing acoustic Doppler velocimetry. Three-dimensional flow velocities downstream the vegetation element are acquired along a measurement grid extending about five-fold the element's diameter. These measurements are analyzed to develop mean velocity and turbulent intensity profiles for all velocity components. A detailed comparison between the obtained results is demonstrative of the validity of the above hypothesis as each of the employed elements affects in a different manner and degree the flow field. Then a flow visualization technique, during which fluorescent dye is injected upstream of the element and images are captured for further analysis and comparison, was employed to visualize the flow structures shed downstream the aquatic elements. This method allows to further observe qualitatively and visually identify the different characteristics of the eddies advected downstream, conclusively confirming the results of the aforementioned experimental campaign.

Valyrakis, Manousos; Barcroft, Stephen; Yagci, Oral

2014-05-01

103

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

Microsoft Academic Search

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

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

104

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

PubMed Central

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

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

2014-01-01

105

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

PubMed

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

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

106

De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.  

PubMed Central

Apert syndrome, one of five craniosynostosis syndromes caused by allelic mutations of fibroblast growth-factor receptor 2 (FGFR2), is characterized by symmetrical bony syndactyly of the hands and feet. We have analyzed 260 unrelated patients, all but 2 of whom have missense mutations in exon 7, which affect a dipeptide in the linker region between the second and third immunoglobulin-like domains. Hence, the molecular mechanism of Apert syndrome is exquisitely specific. FGFR2 mutations in the remaining two patients are distinct in position and nature. Surprisingly, each patient harbors an Alu-element insertion of approximately 360 bp, in one case just upstream of exon 9 and in the other case within exon 9 itself. The insertions are likely to be pathological, because they have arisen de novo; in both cases this occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth-factor receptor [KGFR] and bacterially expressed kinase, respectively), which are differentially expressed in mouse limbs on embryonic day 13. Splicing of exon 9 was examined in RNA extracted from fibroblasts and keratinocytes from one patient with an Alu insertion and two patients with Pfeiffer syndrome who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provides the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome. PMID:9973282

Oldridge, M; Zackai, E H; McDonald-McGinn, D M; Iseki, S; Morriss-Kay, G M; Twigg, S R; Johnson, D; Wall, S A; Jiang, W; Theda, C; Jabs, E W; Wilkie, A O

1999-01-01

107

Integrated Genotypic Analysis of Hedgehog-Related Genes Identifies Subgroups of Keratocystic Odontogenic Tumor with Distinct Clinicopathological Features  

PubMed Central

Keratocystic odontogenic tumor (KCOT) arises as part of Gorlin syndrome (GS) or as a sporadic lesion. Gene mutations and loss of heterozygosity (LOH) of the hedgehog receptor PTCH1 plays an essential role in the pathogenesis of KCOT. However, some KCOT cases lack evidence for gene alteration of PTCH1, suggesting that other genes in the hedgehog pathway may be affected. PTCH2 and SUFU participate in the occurrence of GS-associated tumors, but their roles in KCOT development are unknown. To elucidate the roles of these genes, we enrolled 36 KCOT patients in a study to sequence their entire coding regions of PTCH1, PTCH2 and SUFU. LOH and immunohistochemical expression of these genes, as well as the downstream targets of hedgehog signaling, were examined using surgically-excised KCOT tissues. PTCH1 mutations, including four novel ones, were found in 9 hereditary KCOT patients, but not in sporadic KCOT patients. A pathogenic mutation of PTCH2 or SUFU was not found in any patients. LOH at PTCH1 and SUFU loci correlated with the presence of epithelial budding. KCOT harboring a germline mutation (Type 1) showed nuclear localization of GLI2 and frequent histological findings such as budding and epithelial islands, as well as the highest recurrence rate. KCOT with LOH but without a germline mutation (Type 2) less frequently showed these histological features, and the recurrence rate was lower. KCOT with neither germline mutation nor LOH (Type 3) consisted of two subgroups, Type 3A and 3B, which were characterized by nuclear and cytoplasmic GLI2 localization, respectively. Type 3B rarely exhibited budding and recurrence, behaving as the most amicable entity. The expression patterns of CCND1 and BCL2 tended to correlate with these subgroups. Our data indicates a significant role of PTCH1 and SUFU in the pathogenesis of KCOT, and the genotype-oriented subgroups constitute entities with different potential aggressiveness. PMID:23951062

Shimada, Yasuyuki; Katsube, Ken-ichi; Kabasawa, Yuji; Morita, Kei-ichi; Omura, Ken; Yamaguchi, Akira; Sakamoto, Kei

2013-01-01

108

Heterologous Expression Studies of Saccharomyces cerevisiae Reveal Two Distinct Trypanosomatid CaaX Protease Activities and Identify Their Potential Targets? †  

PubMed Central

The CaaX tetrapeptide motif typically directs three sequential posttranslational modifications, namely, isoprenylation, proteolysis, and carboxyl methylation. In all eukaryotic systems evaluated to date, two CaaX proteases (Rce1 and Ste24/Afc1) have been identified. Although the Trypanosoma brucei genome also encodes two putative CaaX proteases, the lack of detectable T. brucei Ste24 activity in trypanosome cell extracts has suggested that CaaX proteolytic activity within this organism is solely attributed to T. brucei Rce1 (J. R. Gillespie et al., Mol. Biochem. Parasitol. 153:115-124. 2007). In this study, we demonstrate that both T. brucei Rce1 and T. brucei Ste24 are enzymatically active when heterologously expressed in yeast. Using a-factor and GTPase reporters, we demonstrate that T. brucei Rce1 and T. brucei Ste24 possess partially overlapping specificities much like, but not identical to, their fungal and human counterparts. Of interest, a CaaX motif found on a trypanosomal Hsp40 protein was not cleaved by either T. brucei CaaX protease when examined in the context of the yeast a-factor reporter but was cleaved by both in the context of the Hsp40 protein itself when evaluated using an in vitro radiolabeling assay. We further demonstrate that T. brucei Rce1 is sensitive to small molecules previously identified as inhibitors of the yeast and human CaaX proteases and that a subset of these compounds disrupt T. brucei Rce1-dependent localization of our GTPase reporter in yeast. Together, our results suggest the conserved presence of two CaaX proteases in trypanosomatids, identify an Hsp40 protein as a substrate of both T. brucei CaaX proteases, support the potential use of small molecule CaaX protease inhibitors as tools for cell biological studies on the trafficking of CaaX proteins, and provide evidence that protein context influences T. brucei CaaX protease specificity. PMID:19820121

Mokry, David Z.; Manandhar, Surya P.; Chicola, Kristen A.; Santangelo, George M.; Schmidt, Walter K.

2009-01-01

109

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

PubMed Central

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

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

2014-01-01

110

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

E-print Network

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

Janke, Wolfhard

111

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

PubMed Central

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

2011-01-01

112

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

PubMed

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

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

2014-11-18

113

Two Types of Morphologically Distinct Fibers Comprising Gallionella ferruginea Twisted Stalks  

PubMed Central

Two morphologically distinct extracellular stalk fibers produced by Gallionella ferruginea were compared by electron microscopy and elemental analysis. The thick- and fine-fiber stalks were different in structure on a micrometer scale and in the site on the mother cell to which they were attached, but on a nanometer scale they were similar in ultrastructure and in the elemental composition of their basic fiber matrix. PMID:22452845

Suzuki, Tomoko; Hashimoto, Hideki; Ishihara, Hiromichi; Matsumoto, Nobuyuki; Kunoh, Hitoshi; Takada, Jun

2012-01-01

114

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

PubMed Central

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

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

2013-01-01

115

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

PubMed Central

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

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

2012-01-01

116

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

PubMed Central

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

Akamatsu, Matthew; Berro, Julien; Pu, Kai-Ming; Tebbs, Irene R.

2014-01-01

117

Journal of Theoretical Biology 238 (2006) 124145 Distinct modes of collagen type I proteolysis by matrix  

E-print Network

by matrix metalloproteinase (MMP) 2 and membrane type I MMP during the migration of a tip endothelial cell metalloproteinases (MMPs) are a family of enzymes responsible for the proteolytic processing of extracellular matrix the cells of the sprouting vessel bud to migrate into the ECM. Membrane type I matrix metalloproteinase (MT1

Popel, Aleksander S.

118

Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus.  

PubMed

Recent data have suggested the existence of direct signaling pathways between glial cells and neurons. Here we report the coexistence of distinct types of cells expressing astrocyte-specific markers within the hippocampus that display diverse morphological, molecular, and functional profiles. Usage of transgenic mice with GFAP promoter-controlled enhanced green fluorescent protein (EGFP) expression allowed the identification of astroglial cells after fresh isolation or in brain slices. Combining patch-clamp recordings and single-cell reverse transcription-PCR, we distinguished two morphologically distinct types of EGFP-positive cells, one expressing glutamate transporters and the other expressing ionotropic glutamate receptors. None of the EGFP-positive cells coexpressed glutamate receptors and transporters. Subpopulations of glutamate receptor-bearing EGFP-positive cells expressed AN2, the mouse homolog of the rat NG2 proteoglycan or transcripts for excitatory amino acid carrier 1, a neuronal glutamate transporter. Our data demonstrate the presence of distinct, independent populations of cells with astroglial properties in the developing hippocampus that can differently modulate neuronal signaling pathways. The observed heterogeneity of cells with GFAP promoter-regulated EGFP expression and S100beta/GFAP immunoreactivity challenges the hitherto accepted definition of astrocytes. PMID:12629179

Matthias, Katja; Kirchhoff, Frank; Seifert, Gerald; Hüttmann, Kerstin; Matyash, Marina; Kettenmann, Helmut; Steinhäuser, Christian

2003-03-01

119

Distinct AMPA-Type Glutamatergic Synapses in Developing Rat CA1 Hippocampus  

PubMed Central

We assessed synaptic ?-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) properties during synaptogenesis to describe the development of individual glutamatergic synapses on rat hippocampal CA1 principal neurons. Pharmacologically isolated AMPAR-mediated glutamatergic synaptic currents [evoked by stimulation of the Schaffer Collateral pathway, excitatory postsynaptic currents (EPSCs)], had significantly greater inward-rectification at ages P5–7 compared with P8–18. These inward rectifying EPSCs demonstrated paired-pulse dependent unblocking at positive holding potentials, consistent with voltage-dependent internal polyamine block. Measurements of paired-pulse facilitation did not support altered presynaptic properties associated with inward rectification. Using asynchronous EPSCs (aEPSCs) to analyze populations of individual synapses, we found that quantal amplitudes (Q) increased across early postnatal development (P5-P18) and were directly modulated by increases in the number of activated receptors. Quantal AMPAR decay kinetics (aEPSC ?decays) exhibited the highest coefficient of variation (CV) from P5 to 7 and became markedly less variable at P8–18. At P5–7, faster quantal kinetics coexisted with much slower kinetics; only slower quantal kinetics were found at P8–18. This supports diverse quantal synaptic properties limited to P5–7. Multivariate cluster analysis of Q, CV?decay, and median ?decay supported a segregation of neurons into two distinct age groups of P5–7 and P8–18, similar to the age-related segregation suggested by inward rectification. Taken together, these findings support synaptic, calcium permeable AMPARs at a subset of synapses onto CA1 pyramidal neurons exclusively at P5–7. These distinct synapses coexist with those sharing the properties of more mature synapses. These synapses disappear after P7 as activated receptor numbers increase with age. PMID:20685930

Stubblefield, Elizabeth A.

2010-01-01

120

A New Multi-label Classifier in Identifying the Functional Types of Human Membrane Proteins.  

PubMed

Membrane proteins were found to be involved in various cellular processes performing various important functions, which are mainly associated to their type. Given a membrane protein sequence, how can we identify its type(s)? Particularly, how can we deal with the multi-type problem since one membrane protein may simultaneously belong to two or more different types? To address these problems, which are obviously very important to both basic research and drug development, a new multi-label classifier was developed based on pseudo amino acid composition with multi-label k-nearest neighbor algorithm. The success rate achieved by the new predictor on the benchmark dataset by jackknife test is 73.94 %, indicating that the method is promising and the predictor may become a very useful high-throughput tool, or at least play a complementary role to the existing predictors in identifying functional types of membrane proteins. PMID:25433431

Zou, Hong-Liang; Xiao, Xuan

2014-11-30

121

Microbial community composition and in silico predicted metabolic potential reflect biogeochemical gradients between distinct peatland types.  

PubMed

It is not well understood how the ecological status and microbial community composition of spruce swamp forests (SSF) relate to those found in bogs and fens. To clarify this, we investigated biogeochemical parameters and microbial community composition in a bog, a fen and two SSF using high throughput barcoded sequencing of the small ribosomal subunit (SSU) variable region V4. The results demonstrated that the microbial community of SSF is positioned between those of bogs and fens, and this was confirmed by in silico predicted metabolic potentials. This corresponds well with the position of SSF on the trophic gradient and reflects distinct responses of microbial communities to environmental variables. Species richness and microbial diversity increased significantly from bog to fen, with SSF in between, reflecting the variation in pH, nutrient availability and peat decomposability. The archaeal community, dominated by hydrogenotrophic methanogens, was more similar in SSF and the bog compared with the fen. The composition of the bacterial community of SSF was intermediate between those of bog and fen. However, the production of CO2 (an indicator of peat decomposability) did not differ between SSF and bog, suggesting the limiting effect of low pH and poor litter quality on the functioning of the bacterial community in SSF. These results help to clarify the transitional position of SSF between bogs and fens and showed the strong effect of environmental conditions on microbial community composition and functioning. PMID:25195805

Urbanová, Zuzana; Bárta, Ji?í

2014-12-01

122

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

ERIC Educational Resources Information Center

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…

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

2010-01-01

123

Antigenic variation in three distinct determinants of an influenza type A haemagglutinin molecule  

Microsoft Academic Search

ALTHOUGH vaccines have been developed against many human viral pathogens, vaccination against influenza type A viruses has not been wholly successful. This is mainly due to the fact that the viral surface proteins, haemagglutinin and neuraminidase, are subject to antigenic evolution1. Major changes in antigenicity (antigenic shifts) are attributed to (1) the occasional occurrence of genetic reassortment between antigenically dissimilar

J. W. Yewdell; R. G. Webster; W. U. Gerhard

1979-01-01

124

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

SciTech Connect

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.

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

125

Distinct microbial communities within the endosphere and rhizosphere of Populus deltoides roots across contrasting soil types.  

PubMed

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. PMID:21764952

Gottel, Neil R; Castro, Hector F; Kerley, Marilyn; Yang, Zamin; Pelletier, Dale A; Podar, Mircea; Karpinets, Tatiana; Uberbacher, Ed; Tuskan, Gerald A; Vilgalys, Rytas; Doktycz, Mitchel J; Schadt, Christopher W

2011-09-01

126

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

SciTech Connect

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.

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

127

Foot-and-mouth disease type O viruses exhibit genetically and geographically distinct evolutionary lineages (topotypes)  

Microsoft Academic Search

Serotype O is the most prevalent of the seven serotypes of foot-and-mouth disease (FMD) virus and occurs in many parts of the world. The UPGMA method was used to construct a phylogenetic tree based on nucleotide sequences at the 3« end of the VP1 gene from 105 FMD type O viruses obtained from samples submitted to the OIE\\/FAO World Reference

A. R. Samuel; N. J. Knowles

2001-01-01

128

Acidification of morphologically distinct endosomes in mutant and wild- type Chinese hamster ovary cells  

Microsoft Academic Search

In the preceding paper (Yamashiro, D. J., and E R. Maxfield. 1987. J. Cell Biol. 105:2713-2721), we have shown that there is rapid acidification of en- dosomal compartments to pH 6.3 by 3 min in wild- type Chinese hamster ovary (CHO) cells. In contrast, early acidification of endosomes is markedly reduced in the CHO mutants, DTF 1-5-4 and DTF 1-5-1.

Darrell J. Yamashiro; Frederick R. Maxfield

1987-01-01

129

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

Microsoft Academic Search

SUMMARY The fungal type III polyketide synthase 20-oxoalkylre- sorcylic acid synthase (ORAS) primes with a range of acyl-Coenzyme A thioesters (C4-C20) and extends using malonyl-Coenzyme A to produce pyrones, res- orcinols, 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 A û resolution, the Phe-252\\/Gly

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

2008-01-01

130

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

PubMed Central

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

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

131

Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes.  

PubMed

Cardiac complications and heart failure are the leading cause of death in type 2 diabetic patients. Mitochondrial dysfunction is central in the pathogenesis of the type 2 diabetic heart. However, it is unclear whether this dysfunction is specific for a particular subcellular region. The purpose of this study was to determine whether mitochondrial dysfunction in the type 2 diabetic heart is specific to a spatially distinct subset of mitochondria. We investigated mitochondrial morphology, function, and proteomic composition of subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) in 18-wk-old db/db mice. Oxidative damage was assessed in subpopulations through the measurement of lipid peroxidation byproducts and nitrotyrosine residues. Proteomic profiles and posttranslational modifications were assessed in mitochondrial subpopulations using iTRAQ and multi-dimensional protein identification technologies, respectively. SSM from db/db hearts had altered morphology, including a decrease in size and internal complexity, whereas db/db IFM were increased in internal complexity. Db/db SSM displayed decreased state 3 respiration rates, electron transport chain activities, ATP synthase activities, and mitochondrial membrane potential and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/db SSM compared with db/db IFM. Inner mitochondrial membrane proteins, including electron transport chain, ATP synthesis, and mitochondrial protein import machinery, were predominantly decreased. We provide evidence that mitochondrial dysfunction in the type 2 diabetic heart is associated with a specific subcellular locale. Furthermore, mitochondrial morphological and functional indexes are impacted differently during type 2 diabetic insult and may result from the modulation of spatially distinct mitochondrial proteomes. PMID:20543078

Dabkowski, Erinne R; Baseler, Walter A; Williamson, Courtney L; Powell, Matthew; Razunguzwa, Trust T; Frisbee, Jefferson C; Hollander, John M

2010-08-01

132

Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes  

PubMed Central

Cardiac complications and heart failure are the leading cause of death in type 2 diabetic patients. Mitochondrial dysfunction is central in the pathogenesis of the type 2 diabetic heart. However, it is unclear whether this dysfunction is specific for a particular subcellular region. The purpose of this study was to determine whether mitochondrial dysfunction in the type 2 diabetic heart is specific to a spatially distinct subset of mitochondria. We investigated mitochondrial morphology, function, and proteomic composition of subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) in 18-wk-old db/db mice. Oxidative damage was assessed in subpopulations through the measurement of lipid peroxidation byproducts and nitrotyrosine residues. Proteomic profiles and posttranslational modifications were assessed in mitochondrial subpopulations using iTRAQ and multi-dimensional protein identification technologies, respectively. SSM from db/db hearts had altered morphology, including a decrease in size and internal complexity, whereas db/db IFM were increased in internal complexity. Db/db SSM displayed decreased state 3 respiration rates, electron transport chain activities, ATP synthase activities, and mitochondrial membrane potential and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/db SSM compared with db/db IFM. Inner mitochondrial membrane proteins, including electron transport chain, ATP synthesis, and mitochondrial protein import machinery, were predominantly decreased. We provide evidence that mitochondrial dysfunction in the type 2 diabetic heart is associated with a specific subcellular locale. Furthermore, mitochondrial morphological and functional indexes are impacted differently during type 2 diabetic insult and may result from the modulation of spatially distinct mitochondrial proteomes. PMID:20543078

Dabkowski, Erinne R.; Baseler, Walter A.; Williamson, Courtney L.; Powell, Matthew; Razunguzwa, Trust T.; Frisbee, Jefferson C.

2010-01-01

133

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

PubMed

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. PMID:23623688

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

2013-08-30

134

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

PubMed Central

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

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

2012-01-01

135

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

PubMed

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

Gale, Samuel D; Murphy, Gabe J

2014-10-01

136

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

PubMed Central

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

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

2014-01-01

137

Distinction of cell types in Dicyema japonicum (phylum Dicyemida) by expression patterns of 16 genes.  

PubMed

Dicyemids (phylum Dicyemida) are endoparasites, or endosymbionts, typically found in the renal sac of benthic cephalopod molluscs. The body organization of dicyemids is very simple, consisting of only 9 to 41 somatic cells. Dicyemids appear to have no differentiated tissues. Although categorization of somatic cells, to some types, is based on differences in the pattern of cilia and their position in the body, whether or not these cells are functionally different remains to be revealed. To provide insight into the functional differentiation, we performed whole mount in situ hybridization (WISH) to detect expression patterns of 16 genes, i.e., aquaglyceroporin, F-actin capping protein, aspartate aminotransferase, cathepsin-L-like cysteine peptidase, Ets domain-containing protein, glucose transporter, glucose-6-phosphate 1-dehydrogenase, glycine transporter, Hsp 70, Hsp 90, isocitrate dehydrogenase subunit alpha, Rad18, serine hydroxymethyltransferase, succinate-CoA ligase, valosin-containing protein, and 14-3-3 protein. In certain genes, regional specific expression patterns were observed among somatic cells of vermiform stages and infusoriform larvae of dicyemids. The WISH analyses also revealed that the Ets domain-containing protein and Rad18 are molecular markers for agametes. PMID:21506842

Ogino, Kazutoyo; Tsuneki, Kazuhiko; Furuya, Hidetaka

2011-08-01

138

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

PubMed Central

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

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

2014-01-01

139

Implications for the Petrogenesis of Distinct Silicic Magma Types from the Lower Pleistocene Guachipelin Caldera, NW Costa Rica  

NASA Astrophysics Data System (ADS)

Lower Pleistocene pyroclastic ash-flow deposits in NW Costa Rica represent sequential eruptions of high-silica (69-79%\\ SiO2) magmas from the Guachipelin Caldera. These high silica eruptions are not common in areas void of continental crust. The stratigraphic order of seven distinct units is identified by primary mineralogy and bulk chemical composition. Initial distinctions among separate stratigraphic units are defined based on pumice size, mineralogy, physical breaks, and color. First, six major units are identified based on field observations including mineralogy: glomerophyric plagioclase-amphibole (GPA), white biotite (WB), pink biotite (PB), amphibole (A), green unit rich in amphibole (GA), and plagioclase (PR). Further subdivisions are characterized by discrete chemical heterogeneities of trace elements within the macroscopic units. Most of the units identified in the field also have discrete ratios of trace elements (e.g. Nb/Ta): GPA (13.3-19.3), WB (7.6-14.6), PB (3.8-5.0), GA: (23.4-29.4); PR: (7.2-10.4). The amphibole unit (A) is the only one that presents two discrete ranges (6.5-9.5 and 11.5-13.0), which can be interpreted as an indication that the pumice fragments belong to two distinct units instead of one. These collective variations within the sequence provide the basis for petrogenetic interpretation. Differences in the incompatible element ratios behavior are consistent with partial melting (or melt segregation) of several different sources and/or partial melting of same source crust at varying degrees. Melt segregation (partial melting) from several different sources would require a complex plumbing system linking spatially distant crustal sources to a single shallow magma chamber or multiple magma chambers in the same area. In contrast, varying degrees of partial melting from a single crustal source could provide magma for recharge into a shallow chamber from a central conduit re-tapping the same source periodically. Considering the temporal (<0.5Ma) and spatial (single caldera) constraints of this sequence of eruptions, significant chemical variations of the magmas have occurred, which require processes to operate on relatively short time scales.

Deering, C. D.; Vogel, T. A.; Patino, L. C.; Alvarado, G. E.

2004-12-01

140

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

PubMed Central

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

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

2014-01-01

141

Four cell types with distinctive membrane properties and morphologies in lamina I of the spinal dorsal horn of the adult rat  

PubMed Central

Lamina I of the spinal dorsal horn plays an important role in the processing and relay of nociceptive information. Signal processing depends, in part, on neuronal membrane properties. Intrinsic membrane properties of lamina I neurons were therefore investigated using whole cell patch clamp recordings in a slice preparation of adult rat spinal cord. Based on responses to somatic current injection, four cell types were identified: tonic, which fire comparatively slowly but continuously throughout stimulation; phasic, which fire a high frequency burst of variable duration; delayed onset, which fire irregularly and with a marked delay to the first spike; and single spike, which typically fire only one action potential even when strongly depolarised. Classification by spiking pattern was further refined by identification of characteristic stimulus-response curves and quantification of several response parameters. Objectivity of the classification was confirmed by cluster analysis. Responses to stimulus trains and synaptic input as well as the kinetics of spontaneous synaptic events revealed differences in the signal processing characteristics of the cell types: tonic and delayed onset cells appeared to act predominantly as integrators whereas phasic and single spike cells acted as coincidence detectors. Intracellular labelling revealed a significant correlation between morphological and physiological cell types: tonic cells were typically fusiform, phasic cells were pyramidal, and delayed onset and single spike cells were multipolar. Thus, there are multiple physiological cells types in lamina I with specific morphological correlates and distinctive signal processing characteristics that confer significant differences in the transduction of input into spike trains. PMID:11897852

Prescott, Steven A; Koninck, Yves De

2002-01-01

142

Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated with Distinct Subsets of Systemic Sclerosis Patients in Three Independent Cohorts  

PubMed Central

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

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

143

Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor ?1 chain  

Microsoft Academic Search

The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (TH2)–mediated disease and associates with either the common ?-chain to form the type I IL-4R or with the IL-13R ?1 chain (IL-13R?1) to form the type II IL-4R. Here we used Il13ra1?\\/? mice to characterize the distinct functions of type I and type II IL-4 receptors

Thirumalai R Ramalingam; John T Pesce; Faruk Sheikh; Allen W Cheever; Margaret M Mentink-Kane; Mark S Wilson; Sean Stevens; David M Valenzuela; Andrew J Murphy; George D Yancopoulos; Joseph F Urban; Raymond P Donnelly; Thomas A Wynn

2007-01-01

144

Identifying the Types of Student and Teacher Behaviours Associated with Teacher Stress  

ERIC Educational Resources Information Center

The objectives of this study were to identify the student behaviours associated with teacher stress and determine the types of teacher behaviours that may elicit these stressful student behaviours. Student teachers (n = 186) and their supervising teachers (n = 77) completed a stressful student behaviour questionnaire, a teacher behaviour…

Geving, Allison M.

2007-01-01

145

Charge Transport in C60-Based Dumbbell-type Molecules: Mechanically Induced Switching between Two Distinct Conductance States.  

PubMed

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

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

146

Time-dependent bioaccumulation of distinct rod-type TiO2 nanoparticles: comparison by crystalline phase.  

PubMed

A complete understanding of the interaction between nanoparticles and biological systems, including nanoparticle uptake and distribution and the biological responses, could guide the design of safer and more effective nanoparticles than those currently available. In this study, we compared the distribution in mice over time of two rod-type titanium dioxide nanoparticles (TiNPs) that feature distinct phases, anatase (ATO) and brookite (BTO). Surface areas of BTO and ATO were estimated to be 102 and 268?m(2) ?g(-1) , respectively, and negative charge on the surface of ATO was higher than that of BTO in deionized water. Both TiNPs were rapidly distributed into tissues after injection. At 4?weeks after injection, both TiNPs were maximally accumulated in the spleen, followed by the liver, but the total accumulation of ATO in tissues measured in this study was more than that of BTO. Moreover, the cellular antioxidant function was similar although the levels of Ti measured in tissues were distinct between the two TiNPs. Based on these results, we suggest that the fate of TiNPs in the body may differ according to the size and surface charge of the TiNPs even when their shape is the same. PMID:24891253

Park, Eun-Jung; Lee, Gwang-Hee; Yoon, Cheolho; Kang, Min-Sung; Kim, Soo Nam; Cho, Myung-Haing; Kim, Jae-Ho; Kim, Dong-Wan

2014-11-01

147

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

PubMed

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

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

148

Exome Sequencing Identifies an MYH3 Mutation in a Family with Distal Arthrogryposis Type 1  

PubMed Central

Background: Few genes responsible for distal arthrogryposis type 1 are known, although genes coding for the proteins in the sarcomere have been implicated in other types of distal arthrogryposis. Cost-effective sequencing methods are now available to examine all genes in the human genome for the purpose of establishing the genetic basis of musculoskeletal disorders. Methods: A multigenerational family with distal arthrogryposis type 1 characterized by clubfoot and mild hand contractures was identified, and exome sequencing was performed on DNA from one of the affected family members. Linkage analysis was used to confirm whether a genetic variant segregated with distal arthrogryposis. Results: Exome sequencing identified 573 novel variants that were not present in control databases. A missense mutation in MYH3 (a gene coding for the heavy chain of myosin), causing an F437I amino acid substitution, was identified that segregated with distal arthrogryposis in this family. Linkage analysis confirmed that this MYH3 mutation was the only exome variant common to all six affected individuals. Conclusions: Identification of an MYH3 mutation in this family with distal arthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to include distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B (Sheldon-Hall syndrome). Exome sequencing is a useful and cost-effective method to discover causative genetic mutations, although data from extended families may be needed to confirm the importance of the hundreds of identified variants. Clinical Relevance: Distal arthrogryposis type 1 should be considered in the differential diagnosis of isolated clubfoot, particularly when hand contractures are present in any family member or when the clubfoot is severe and resistant to treatment. PMID:21531865

Alvarado, David M.; Buchan, Jillian G.; Gurnett, Christina A.; Dobbs, Matthew B.

2011-01-01

149

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

NASA Astrophysics Data System (ADS)

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

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

2011-02-01

150

Amplified Fragment Length Polymorphism Reveals Specific Epigenetic Distinctions between Mycobacterium avium Subspecies paratuberculosis Isolates of Various Isolation Types?  

PubMed Central

Amplified fragment length polymorphism (AFLP) was employed as a genetic analysis tool for the study of the genetic relatedness of Mycobacterium avium subsp. paratuberculosis isolates harvested from bovine fecal samples and from bovine or human tissues. This analysis revealed genetic differences between these two isolate types that were confirmed through cluster analysis. Dendrogram analysis separated these two isolate types based on the isolation scheme (tissue-associated versus fecal M. avium subsp. paratuberculosis isolates). Further sequence analysis of unique genetic regions from each isolation type revealed no genetic sequence differences. However, Clustal DNA alignments identified AFLP restriction enzyme sites that were undigested in the tissue-associated isolates. AFLP analysis also disclosed that the same AFLP restriction sites were digested in all of the fecal isolates. Sequence analysis further revealed a consensus sequence upstream of the undigested restriction sites for possible methyltransferase recognition in the tissue-associated M. avium subsp. paratuberculosis isolates. PMID:21471350

O'Shea, B.; Khare, S.; Klein, P.; Roussel, A.; Adams, L. G.; Ficht, T. A.; Rice-Ficht, A. C.

2011-01-01

151

Toward a theory of distinct types of "impulsive" behaviors: A meta-analysis of self-report and behavioral measures.  

PubMed

Impulsivity is considered a personality trait affecting behavior in many life domains, from recreational activities to important decision making. When extreme, it is associated with mental health problems, such as substance use disorders, as well as with interpersonal and social difficulties, including juvenile delinquency and criminality. Yet, trait impulsivity may not be a unitary construct. We review commonly used self-report measures of personality trait impulsivity and related constructs (e.g., sensation seeking), plus the opposite pole, control or constraint. A meta-analytic principal-components factor analysis demonstrated that these scales comprise 3 distinct factors, each of which aligns with a broad, higher order personality factor-Neuroticism/Negative Emotionality, Disinhibition versus Constraint/Conscientiousness, and Extraversion/Positive Emotionality/Sensation Seeking. Moreover, Disinhibition versus Constraint/Conscientiousness comprise 2 correlated but distinct subfactors: Disinhibition versus Constraint and Conscientiousness/Will versus Resourcelessness. We also review laboratory tasks that purport to measure a construct similar to trait impulsivity. A meta-analytic principal-components factor analysis demonstrated that these tasks constitute 4 factors (Inattention, Inhibition, Impulsive Decision-Making, and Shifting). Although relations between these 2 measurement models are consistently low to very low, relations between both trait scales and laboratory behavioral tasks and daily-life impulsive behaviors are moderate. That is, both independently predict problematic daily-life impulsive behaviors, such as substance use, gambling, and delinquency; their joint use has incremental predictive power over the use of either type of measure alone and furthers our understanding of these important, problematic behaviors. Future use of confirmatory methods should help to ascertain with greater precision the number of and relations between impulsivity-related components. PMID:24099400

Sharma, Leigh; Markon, Kristian E; Clark, Lee Anna

2014-03-01

152

The use of four band multispectral photography to identify forest cover types  

NASA Technical Reports Server (NTRS)

Four-band multispectral aerial photography and a color additive viewer were employed to identify forest cover types in Northern Alabama. The multispectral photography utilized the blue, green, red and near-infrared spectral regions and was made with black and white infrared film. On the basis of color differences alone, a differentiation between conifers and hardwoods was possible; however, supplementary information related to forest ecology proved necessary for the differentiation of various species of pines and hardwoods.

Downs, S. W., Jr.

1977-01-01

153

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

Microsoft Academic Search

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

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

154

Dissection of thousands of cell type-specific enhancers identifies dinucleotide repeat motifs as general enhancer features  

PubMed Central

Gene expression is determined by genomic elements called enhancers, which contain short motifs bound by different transcription factors (TFs). However, how enhancer sequences and TF motifs relate to enhancer activity is unknown, and general sequence requirements for enhancers or comprehensive sets of important enhancer sequence elements have remained elusive. Here, we computationally dissect thousands of functional enhancer sequences from three different Drosophila cell lines. We find that the enhancers display distinct cis-regulatory sequence signatures, which are predictive of the enhancers’ cell type-specific or broad activities. These signatures contain transcription factor motifs and a novel class of enhancer sequence elements, dinucleotide repeat motifs (DRMs). DRMs are highly enriched in enhancers, particularly in enhancers that are broadly active across different cell types. We experimentally validate the importance of the identified TF motifs and DRMs for enhancer function and show that they can be sufficient to create an active enhancer de novo from a nonfunctional sequence. The function of DRMs as a novel class of general enhancer features that are also enriched in human regulatory regions might explain their implication in several diseases and provides important insights into gene regulation. PMID:24714811

Yáñez-Cuna, J. Omar; Arnold, Cosmas D.; Stampfel, Gerald; Bory?, ?ukasz M.; Gerlach, Daniel; Rath, Martina; Stark, Alexander

2014-01-01

155

Identifying Complexes from Protein Interaction Networks According to Different Types of Neighborhood Density  

PubMed Central

Abstract To facilitate the realization of biological functions, proteins are often organized into complexes. While computational techniques are used to predict these complexes, detailed understanding of their organization remains inadequate. Apart from complexes that reside in very dense regions of a protein interaction network in which most algorithms are able to identify, we observe that many other complexes, while not residing in very dense regions, reside in regions with low neighborhood density. We develop an algorithm for identifying protein complexes by considering these two types of complexes separately. We test our algorithm on a few yeast protein interaction networks, and show that our algorithm is able to identify complexes more accurately than existing algorithms. A software program NDComplex for implementing the algorithm is available at http://faculty.cse.tamu.edu/shsze/ndcomplex. PMID:23210476

Fan, Jia-Hao; Chen, Jianer

2012-01-01

156

The embryonic genes Dkk3, Hoxd8, Hoxd9 and Tbx1 identify muscle types in a diet-independent and fiber-type unrelated way  

PubMed Central

Background The mouse skeletal muscle is composed of four distinct fiber types that differ in contractile function, number of mitochondria and metabolism. Every muscle type has a specific composition and distribution of the four fiber types. To find novel genes involved in specifying muscle types, we used microarray analysis to compare the gastrocnemius with the quadriceps from mice fed a low fat diet (LFD) or high fat diet (HFD) for 8 weeks. Additional qPCR analysis were performed in the gastrocnemius, quadriceps and soleus muscle from mice fed an LFD or HFD for 20 weeks. Results In mice fed the 8-week LFD 162 genes were differentially expressed in the gastrocnemius vs. the quadriceps. Genes with the strongest differences in expression were markers for oxidative fiber types (e.g. Tnni1) and genes which are known to be involved in embryogenesis (Dkk3, Hoxd8,Hoxd9 and Tbx1). Also Dkk2, Hoxa5, Hoxa10, Hoxc9, Hoxc10, Hoxc6 and Tbx15 were detectably, but not differentially expressed in adult muscle tissue. Expression of differentially expressed genes was not influenced by an 8-week or 20-week HFD. Comparing gastrocnemius, quadriceps and soleus, expression of Hoxd8 and Hoxd9 was not related with expression of markers for the four different fiber types. We found that the expression of both Hoxd8 and Hoxd9 was much higher in the gastrocnemius than in the quadriceps or soleus, whereas the expression of Dkk3 was high in quadriceps, but low in both gastrocnemius and soleus. Finally, expression of Tbx1 was high in quadriceps, intermediate in soleus and low in gastrocnemius. Conclusions We found that genes from the Dkk family, Hox family and Tbx family are detectably expressed in adult mouse muscle. Interestingly, expression of Dkk3, Hoxd8, Hoxd9 and Tbx1 was highly different between gastrocnemius, quadriceps and soleus. In fact, every muscle type showed a unique combination of expression of these four genes which was not influenced by diet. Altogether, we conclude that genes important for embryogenesis identify mouse muscle types in a diet-independent and fiber type-unrelated manner. PMID:20230627

2010-01-01

157

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

PubMed Central

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

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

2013-01-01

158

Laterally projecting cerebrospinal fluid-contacting cells in the lamprey spinal cord are of two distinct types.  

PubMed

Cerebrospinal fluid-contacting (CSF-c) cells are found in all vertebrates, but their function remains elusive. In the lamprey spinal cord, they surround the central canal and some have processes passing the gray matter to the lateral edge of the flattened spinal cord. Stimulation of CSF-c cells at the central canal elicits GABAergic inhibitory postsynaptic potentials (IPSPs) in intraspinal stretch receptor neurons (edge cells). Here, we characterize laterally projecting CSF-c cells according to their morphology, phenotype, and neuronal properties by using immunohistochemistry, retrograde tracing, calcium imaging, and whole-cell recordings. We identify two types of CSF-c cells. Type 1 cells have a bulb-like ending that protrudes into the central canal and a lateral process that ramifies ventrolaterally and laterally with a dense plexus surrounding the mechanosensitive dendrites of the edge cells. Most type 1 cells fire spontaneous action potentials that are abolished by tetrodotoxin, and all display spontaneous excitatory postsynaptic potentials and IPSPs that remain in the presence of tetrodotoxin. GABA and somatostatin are colocalized in type 1 cells, and they express both GABA and glutamate receptors. Type 2 cells, on the other hand, have a flat ending protruding into the central canal and a laterally projecting process that ramifies only at the lateral edge. These cells show immunoreactivity to taurine, but they do not express GABA or somatostatin, nor do they have any active neuronal properties. Type 2 cells might be a form of glia. Type 1 CSF-c cells are neurons and may play a modulatory role by influencing edge cells and thus the locomotor-related sensory feedback. PMID:24723248

Jalalvand, Elham; Robertson, Brita; Wallén, Peter; Hill, Russell H; Grillner, Sten

2014-06-01

159

Laterally projecting cerebrospinal fluid-contacting cells in the lamprey spinal cord are of two distinct types.  

PubMed

Cerebrospinal fluid-contacting (CSF-c) cells are found in all vertebrates, but their function remains elusive. In the lamprey spinal cord, they surround the central canal and some have processes passing the gray matter to the lateral edge of the flattened spinal cord. Stimulation of CSF-c cells at the central canal elicits GABAergic inhibitory postsynaptic potentials (IPSPs) in intraspinal stretch receptor neurons (edge cells). Here, we characterize laterally projecting CSF-c cells according to their morphology, phenotype, and neuronal properties by using immunohistochemistry, retrograde tracing, calcium imaging, and whole-cell recordings. We identify two types of CSF-c cells. Type 1 cells have a bulb-like ending that protrudes into the central canal and a lateral process that ramifies ventrolaterally and laterally with a dense plexus surrounding the mechanosensitive dendrites of the edge cells. Most type 1 cells fire spontaneous action potentials that are abolished by tetrodotoxin, and all display spontaneous excitatory postsynaptic potentials and IPSPs that remain in the presence of tetrodotoxin. GABA and somatostatin are colocalized in type 1 cells, and they express both GABA and glutamate receptors. Type 2 cells, on the other hand, have a flat ending protruding into the central canal and a laterally projecting process that ramifies only at the lateral edge. These cells show immunoreactivity to taurine, but they do not express GABA or somatostatin, nor do they have any active neuronal properties. Type 2 cells might be a form of glia. Type 1 CSF-c cells are neurons and may play a modulatory role by influencing edge cells and thus the locomotor-related sensory feedback. PMID:24436002

Jalalvand, Elham; Robertson, Brita; Wallén, Peter; Hill, Russell H; Grillner, Sten

2014-06-01

160

Using vertebrate prey capture locations to identify cover type selection patterns of nocturnally foraging Burrowing Owls.  

PubMed

Studies of habitat selection often measure an animal's use of space via radiotelemetry or GPS-based technologies. Such data tend to be analyzed using a resource selection function, despite the fact that the actual resources acquired are typically not recorded. Without explicit proof of resource use, conclusions from RSF models are based on assumptions regarding an animal's behavior and the resources gained. Conservation initiatives are often based on space-use models, and could be detrimental to the target species if these assumptions are incorrect. We used GPS dataloggers and digital video recorders to determine precise locations where nocturnally foraging Burrowing Owls acquired food resources (vertebrate prey). We compared land cover type selection patterns using a presence-only resource selection function (RSF) to a model that incorporated prey capture locations (CRSF). We also compared net prey returns in each cover type to better measure reward relative to foraging effort. The RSF method did not reflect prey capture patterns and cover-type rankings from this model were quite different from models that used only locations where prey was known to have been obtained. Burrowing Owls successfully foraged across all cover types; however, return vs. effort models indicate that different cover types were of higher quality than those identified using resource selection functions. Conclusions about the type of resources acquired should not be made from RSF-style models without evidence that the actual resource of interest was acquired. Conservation efforts based on RSF models alone may be ineffective or detrimental to the target species if the limiting resource and where it is acquired are not properly identified. PMID:25154089

Marsh, Alan; Bayne, Erin M; Wellicome, Troy I

2014-07-01

161

Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor ?1 chain  

PubMed Central

The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (TH2)–mediated disease and associates with either the common ?-chain to form the type I IL-4R or with the IL-13R ?1 chain (IL-13R?1) to form the type II IL-4R. Here we used Il13ra1?/? mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra?/? mice, which have weak TH2 responses, Il13ra1?/? mice had exacerbated TH2 responses. Il13ra1?/? mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13R?1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses. PMID:18066066

Ramalingam, Thirumalai R; Pesce, John T; Sheikh, Faruk; Cheever, Allen W; Mentink-Kane, Margaret M; Wilson, Mark S; Stevens, Sean; Valenzuela, David M; Murphy, Andrew J; Yancopoulos, George D; Urban, Joseph F; Donnelly, Raymond P; Wynn, Thomas A

2009-01-01

162

Identifying type I excitability using dynamics of stochastic neural firing patterns.  

PubMed

The stochastic firing patterns are simulated near saddle-node bifurcation on an invariant cycle corresponding to type I excitability in stochastic Morris-Lecar model. In absence of external periodic signal, the stochastic firing manifests continuous distribution in ISI histogram (ISIH), whose amplitude at first increases sharply and then decreases exponentially. In presence of the external periodic signal, stochastic firing patterns appear as two cases of integer multiple firing with multiple discrete peaks in ISIH. One manifests perfect exponential decay in all peaks and the other imperfect exponential decay except a lower first peak. These stochastic firing patterns simulated with or without external periodic signal can be demonstrated in the experiments on rat hippocampal CA1 pyramidal neurons. The exponential decay laws in the multiple peaks are also acquired using probability analysis method. The perfect decay law is determined by the independent characteristic within the firing while the imperfect decay law is from the inhibitory effect. In addition, the stochastic firing patterns corresponding to type I excitability are compared to those of type II excitability. The results not only reveal the dynamics of stochastic firing patterns with or without external signal corresponding to type I excitability, but also provide practical indicators to availably identify type I excitability. PMID:24294334

Jia, Bing; Gu, Huaguang

2012-12-01

163

Cell-type-specific transcriptional profiles of the dimorphic pathogen Penicillium marneffei reflect distinct reproductive, morphological, and environmental demands.  

PubMed

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

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

2013-11-01

164

Identifying Mobility Types in Cognitively Heterogeneous Older Adults Based on GPS-Tracking: What Discriminates Best?  

PubMed

Heterogeneity in older adults' mobility and its correlates have rarely been investigated based on objective mobility data and in samples including cognitively impaired individuals. We analyzed mobility profiles within a cognitively heterogeneous sample of N = 257 older adults from Israel and Germany based on GPS tracking technology. Participants were aged between 59 and 91 years (M = 72.9; SD = 6.4) and were either cognitively healthy (CH, n = 146), mildly cognitively impaired (MCI, n = 76), or diagnosed with an early-stage dementia of the Alzheimer's type (DAT, n = 35). Based on cluster analysis, we identified three mobility types ("Mobility restricted," "Outdoor oriented," "Walkers"), which could be predicted based on socio-demographic indicators, activity, health, and cognitive impairment status using discriminant analysis. Particularly demented individuals and persons with worse health exhibited restrictions in mobility. Our findings contribute to a better understanding of heterogeneity in mobility in old age. PMID:24652916

Wettstein, Markus; Wahl, Hans-Werner; Shoval, Noam; Auslander, Gail; Oswald, Frank; Heinik, Jeremia

2013-12-11

165

The evolution of three types of indoleamine 2,3 dioxygenases in fungi with distinct molecular and biochemical characteristics.  

PubMed

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme and known as a mammalian immunosuppressive molecule. In fungi, the primary role of IDO is to supply nicotinamide adenine dinucleotide (NAD(+)) via the kynurenine pathway. We previously reported that the koji-mold, Aspergillus oryzae has two IDO genes, IDO? and IDO?. In the present study, we found that A. oryzae also has the third IDO, IDO?. These three-types of IDOs are widely distributed among the Pezizomycotina fungi, although the black truffle, Tuber melanosporum has only one corresponding gene to IDO?/IDO?. The yeast, Saccharomyces cerevisiae has a single IDO gene. Generally, Pezizomycotina IDO? showed similar enzymatic properties to the yeast IDO, suggesting that the IDO? is a functional homologue of the S. cerevisiae IDO. In contrast to IDO?, the K(m) value of IDO? is higher. However, the reaction velocity of IDO? is very fast, resulting in comparable or higher catalytic efficiency than IDO?. Thus IDO? may functionally substitute for IDO? in fungal L-Trp metabolism. The enzymatic activity of IDO? was comparatively very low with the values of enzymatic parameters comparable to vertebrate IDO2 enzymes. IDO? and IDO? have similar gene structures, suggesting that they were generated by gene duplication which occurred rather early in Pezizomycotina evolution, although the timing of the duplication remains debatable. In contrast, the phylogenetic trees suggest that IDO?s form an evolutionarily distinct group of IDO enzymes, with a closer relationship to group I bacterial IDOs than other fungal IDOs. The ancestor of the IDO? family is likely to have diverged from other eukaryotic IDOs at a very early stage of eukaryotic evolution. PMID:22564706

Yuasa, Hajime J; Ball, Helen J

2012-08-01

166

Distinct subsynaptic localization of type 1 metabotropic glutamate receptors at glutamatergic and GABAergic synapses in the rodent cerebellar cortex.  

PubMed

Type 1 metabotropic glutamate (mGlu1) receptors play a pivotal role in different forms of synaptic plasticity in the cerebellar cortex, e.g. long-term depression at glutamatergic synapses and rebound potentiation at GABAergic synapses. These various forms of plasticity might depend on the subsynaptic arrangement of the receptor in Purkinje cells that can be regulated by protein-protein interactions. This study investigated, by means of the freeze-fracture replica immunogold labelling method, the subcellular localization of mGlu1 receptors in the rodent cerebellum and whether Homer proteins regulate their subsynaptic distribution. We observed a widespread extrasynaptic localization of mGlu1 receptors and confirmed their peri-synaptic enrichment at glutamatergic synapses. Conversely, we detected mGlu1 receptors within the main body of GABAergic synapses onto Purkinje cell dendrites. Although Homer proteins are known to interact with the mGlu1 receptor C-terminus, we could not detect Homer3, the most abundant Homer protein in the cerebellar cortex, at GABAergic synapses by pre-embedding and post-embedding immunoelectron microscopy. We then hypothesized a critical role for Homer proteins in the peri-junctional localization of mGlu1 receptors at glutamatergic synapses. To disrupt Homer-associated protein complexes, mice were tail-vein injected with the membrane-permeable dominant-negative TAT-Homer1a. Freeze-fracture replica immunogold labelling analysis showed no significant alteration in the mGlu1 receptor distribution pattern at parallel fibre-Purkinje cell synapses, suggesting that other scaffolding proteins are involved in the peri-synaptic confinement. The identification of interactors that regulate the subsynaptic localization of the mGlu1 receptor at neurochemically distinct synapses may offer new insight into its trafficking and intracellular signalling. PMID:25377770

Mansouri, Mahnaz; Kasugai, Yu; Fukazawa, Yugo; Bertaso, Federica; Raynaud, Fabrice; Perroy, Julie; Fagni, Laurent; Kaufmann, Walter A; Watanabe, Masahiko; Shigemoto, Ryuichi; Ferraguti, Francesco

2015-01-01

167

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

PubMed

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

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

2014-12-01

168

Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis  

PubMed Central

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (?/?) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (?/?) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient’s blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection. PMID:23029268

Ottenhoff, Tom H. M.; Zhang, Mingzi M.; Wong, Hazel E. E.; Sahiratmadja, Edhyana; Khor, Chiea Chuen; Alisjahbana, Bachti; van Crevel, Reinout; Marzuki, Sangkot; Seielstad, Mark; van de Vosse, Esther; Hibberd, Martin L.

2012-01-01

169

The use of proteomics in identifying differentially expressed serum proteins in humans with type 2 diabetes  

PubMed Central

Background The aim of the study was to optimize protocols for finding and identifying serum proteins that are differentially expressed in persons with normal glucose tolerance (NGT) compared to individuals with type 2 diabetes mellitus (T2DM). Serum from persons with NGT and persons with T2DM was profiled using ProteinChip arrays and time-of-flight mass spectra were generated by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Results Mass spectra from NGT- and T2DM-groups were compared. Fifteen proteins ranging from 5 to 79 kDa were differentially expressed (p < 0.05). Five of these proteins showed decreased and ten showed increased serum levels in individuals with T2DM. To be able to identify the proteins, the complexity of the sample was reduced by fractionation approaches. Subsequently, the purified fractions containing biomarkers were separated by one-dimensional SDS-polyacrylamide gel electrophoresis (SDS-PAGE) in two identical lanes. Protein bands of the first lane were excised and subjected to passive elution to recapture the biomarkers on ProteinChip arrays. The corresponding bands of the second lane were subjected to peptide-mass fingerprinting (PMF). Using this approach four of the differentially expressed proteins were identified as apolipoprotein C3 (9.4 kDa), transthyretin (13.9 kDa), albumin (66 kDa) and transferrin (79 kDa). Whereas apolipoprotein C3 and transthyretin were up-regulated, albumin and transferrin were down-regulated in T2DM. Conclusion Protocols for protein profiling by SELDI-TOF MS and protein identification by fractionation, SDS-PAGE and PMF were optimized for serum from humans with T2DM. With these protocols differentially expressed proteins were discovered and identified when serum from NGT- and T2DM-individuals was analyzed. PMID:17163994

Sundsten, Tea; Eberhardson, Michael; Göransson, Michael; Bergsten, Peter

2006-01-01

170

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

Introduction to the Special Issue on Hybrid Systems Hybrid systems contain two distinct types the dynamic behavior of such hybrid systems. In this way it will be possible to develop control strategies of the system. There are several reasons for using hybrid models to represent the dynamic behavior of interest

Antsaklis, Panos

171

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

E-print Network

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

Chambers, John

172

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

PubMed

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

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

2014-12-15

173

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

NASA Astrophysics Data System (ADS)

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.

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

2015-02-01

174

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

PubMed Central

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

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

175

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

PubMed

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

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

176

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

PubMed

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<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. PMID:20581827

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

2010-07-01

177

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

PubMed Central

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 combinedP < 5 × 10?8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. PMID:20581827

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

2011-01-01

178

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

NASA Astrophysics Data System (ADS)

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.

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

179

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

NASA Astrophysics Data System (ADS)

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.

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

2014-02-01

180

Targeted allelic expression profiling in human islets identifies cis-regulatory effects for multiple variants identified by type 2 diabetes genome-wide association studies.  

PubMed

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 (LD) 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, non-diabetic 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 5 of these genes using other linked exonic SNPs. Lastly, results of a targeted islet expression quantitative trait loci (eQTL) 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

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

2014-11-12

181

Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types  

PubMed Central

Summary The transcription factor GATA3 plays an essential role during T cell development and T helper 2 (Th2) cell differentiation. To understand GATA3-mediated gene regulation, we identified genome-wide GATA3 binding sites in ten well-defined developmental and effector T lymphocyte lineages. In the thymus, GATA3 directly regulated many critical factors, including Th-POK, Notch1 and T cell receptor subunits. In the periphery, GATA3 induced a large number of Th2 cell-specific as well as Th2 cell non-specific genes, including several transcription factors. Our data also indicate that GATA3 regulates both active and repressive histone modifications of many target genes at their regulatory elements near GATA3 binding sites. Overall, although GATA3 binding exhibited both shared and cell-specific patterns among various T cell lineages, many genes were either positively or negatively regulated by GATA3 in a cell type-specific manner, suggesting that GATA3-mediated gene regulation depends strongly on co-factors existing in different T cells. PMID:21867929

Wei, Gang; Abraham, Brian J.; Yagi, Ryoji; Jothi, Raja; Cui, Kairong; Sharma, Suveena; Narlikar, Leelavati; Northrup, Daniel L.; Tang, Qingsong; Paul, William E.; Zhu, Jinfang; Zhao, Keji

2011-01-01

182

Inflammation and Hyperglycemia Mediate Deaf1 Splicing in the Pancreatic Lymph Nodes via Distinct Pathways During Type 1 Diabetes.  

PubMed

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

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

183

Comparative Genetics: Synergizing Human and NOD Mouse Studies for Identifying Genetic Causation of Type 1 Diabetes  

PubMed Central

Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come. PMID:23804259

Driver, John P.; Chen, Yi-Guang; Mathews, Clayton E.

2012-01-01

184

A Machine Learning Approach for Identifying Novel Cell Type–Specific Transcriptional Regulators of Myogenesis  

PubMed Central

Transcriptional enhancers integrate the contributions of multiple classes of transcription factors (TFs) to orchestrate the myriad spatio-temporal gene expression programs that occur during development. A molecular understanding of enhancers with similar activities requires the identification of both their unique and their shared sequence features. To address this problem, we combined phylogenetic profiling with a DNA–based enhancer sequence classifier that analyzes the TF binding sites (TFBSs) governing the transcription of a co-expressed gene set. We first assembled a small number of enhancers that are active in Drosophila melanogaster muscle founder cells (FCs) and other mesodermal cell types. Using phylogenetic profiling, we increased the number of enhancers by incorporating orthologous but divergent sequences from other Drosophila species. Functional assays revealed that the diverged enhancer orthologs were active in largely similar patterns as their D. melanogaster counterparts, although there was extensive evolutionary shuffling of known TFBSs. We then built and trained a classifier using this enhancer set and identified additional related enhancers based on the presence or absence of known and putative TFBSs. Predicted FC enhancers were over-represented in proximity to known FC genes; and many of the TFBSs learned by the classifier were found to be critical for enhancer activity, including POU homeodomain, Myb, Ets, Forkhead, and T-box motifs. Empirical testing also revealed that the T-box TF encoded by org-1 is a previously uncharacterized regulator of muscle cell identity. Finally, we found extensive diversity in the composition of TFBSs within known FC enhancers, suggesting that motif combinatorics plays an essential role in the cellular specificity exhibited by such enhancers. In summary, machine learning combined with evolutionary sequence analysis is useful for recognizing novel TFBSs and for facilitating the identification of cognate TFs that coordinate cell type–specific developmental gene expression patterns. PMID:22412381

Kim, Yongsok; Tansey, Terese; Bloom, Molly J.; Ovcharenko, Ivan; Michelson, Alan M.

2012-01-01

185

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

PubMed Central

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

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

2013-01-01

186

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

Microsoft Academic Search

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

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

2008-01-01

187

Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages  

Microsoft Academic Search

CD4+ T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (TH1) or TH2 lineages and instead favor the idea of a distinct effector lineage we call 'TH-17'. The development of TH-17

Laurie E Harrington; Robin D Hatton; Paul R Mangan; Henrietta Turner; Theresa L Murphy; Kenneth M Murphy; Casey T Weaver

2005-01-01

188

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

E-print Network

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...

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

189

Individually distinct tumor-specific cell surface antigen identified by monoclonal antibody on a Rous sarcoma virus-induced mouse tumor.  

PubMed

Hybrid cell lines were prepared by the fusion of BALB/c myeloma P3U-1 cells with the lymphocytes of BALB/c mice that were immunized with syngeneic Rous sarcoma virus (RSV)-induced tumor CSA1M cells. Three clones of the hybrid progeny (3.4B2, 3.4C6, and 3.5C11) produced cytotoxic IgM antibodies against CSA1M cells. One of the clones, 3.5C11, was chosen for analysis of the detailed specificity. Both direct cytotoxicity assays and absorption tests revealed that monoclonal antibody from 3.5C11 was positive only with CSA1M cells and that it failed to react with other tumors, including 20 RSV-induced mouse tumors, and normal cells. The 3.5C11 monoclonal antibody alone, with or without exogenous complement, was suppressive in the therapy of ip injected CSA1M tumor in syngeneic hosts, and significant prolongation in survival was seen in the treated mice. These results clearly showed presence of an individually distinct tumor-specific cell surface antigen on an RSV-induced mouse tumor. PMID:6287079

Kuzumaki, N; Minakawa, H; Miyazaki, T; Haraguchi, S; Matsuo, T; Yoshida, T O

1982-08-01

190

Mutational analysis of the Verticillium dahliae protein elicitor PevD1 identifies distinctive regions responsible for hypersensitive response and systemic acquired resistance in tobacco.  

PubMed

In our previous study, PevD1 was characterized as a novel protein elicitor produced by Verticillium dahliae inducing hypersensitive response (HR) and systemic acquired resistance (SAR) in tobacco plants; however, the detailed mechanisms of PevD1's elicitor activity remain unclear. In this study, five mutant fragments of PevD1 were generated by polymerase chain reaction-based mutagenesis and the truncated proteins expressed in Escherichia coli were used to test their elicitor activities. Biological activity analysis showed that the N-terminal and C-terminal of PevD1 had distinct influence on HR and SAR elicitation. Fragment PevD1?N98, which spans the C-terminal 57 amino acids of PevD1, was critical for the induction of HR in tobacco plants. In contrast, fragment PevD1?C57, the N-terminal of 98 amino acids of PevD1, retained the ability to induce SAR against tobacco mosaic virus (TMV) but not induction of HR, suggesting that the induction of HR is not essential for SAR mediated by PevD1. Our results indicated that fragment PevD1?C57 could be a candidate peptide for plant protection against pathogens without causing negative effects. PMID:24080193

Liu, Wenxian; Zeng, Hongmei; Liu, Zhipeng; Yang, Xiufen; Guo, Lihua; Qiu, Dewen

2014-01-01

191

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

PubMed Central

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

Pipi, Elena; Marketou, Marietta; Tsirogianni, Alexandra

2014-01-01

192

A comprehensive search of topologically distinct local minimum structures of protonated water octamer and the classification of Osbnd H topological types  

NASA Astrophysics Data System (ADS)

The rooted digraph is used to topologically distinguish the isomers of protonated water (PW) cluster. We generated many PW octamer geometries and obtained 134 topologically distinct geometries of the PW octamers at the theoretical level of MP2/aug-cc-pVDZ. The temperature-dependent population ratios of those isomers were calculated. Dominant structures of PW octamers vary according to the temperature. The Osbnd H bonds of PW cluster were classified into 10 topological types according to the local hydrogen-bonding network. The vibrational frequency of the same topological type of the Osbnd H bond, which is transferable in different isomers, can be used as a vibrational spectral signature.

Akase, Dai; Teramae, Hiroyuki; Aida, Misako

2015-01-01

193

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

Microsoft Academic Search

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

Dennis M. Dacey; Barry B. Lee

1994-01-01

194

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

PubMed

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

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

2014-01-01

195

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

Microsoft Academic Search

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

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

196

Expression Profiling of Human Immune Cell Subsets Identifies miRNA-mRNA Regulatory Relationships Correlated with Cell Type Specific Expression  

PubMed Central

Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocyte and pDC specific, miR-150; lymphoid cell specific, miR-652 and miR-223; both myeloid cell specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs which negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA/mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA/mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p<9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity. PMID:22276136

Bergauer, Tobias; Ravindran, Palanikumar; Rossier, Michel F.; Ebeling, Martin; Badi, Laura; Reis, Bernhard; Bitter, Hans; D'Asaro, Matilde; Chiappe, Alberto; Sridhar, Sriram; Pacheco, Gonzalo Duran; Burczynski, Michael E.; Hochstrasser, Denis; Vonderscher, Jacky; Matthes, Thomas

2012-01-01

197

Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression.  

PubMed

Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocyte and pDC specific, miR-150; lymphoid cell specific, miR-652 and miR-223; both myeloid cell specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs which negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA/mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA/mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p<9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity. PMID:22276136

Allantaz, Florence; Cheng, Donavan T; Bergauer, Tobias; Ravindran, Palanikumar; Rossier, Michel F; Ebeling, Martin; Badi, Laura; Reis, Bernhard; Bitter, Hans; D'Asaro, Matilde; Chiappe, Alberto; Sridhar, Sriram; Pacheco, Gonzalo Duran; Burczynski, Michael E; Hochstrasser, Denis; Vonderscher, Jacky; Matthes, Thomas

2012-01-01

198

Assessment of the Genetic Diversity of Xanthomonas axonopodis pv. phaseoli and Xanthomonas fuscans subsp. fuscans as a Basis To Identify Putative Pathogenicity Genes and a Type III Secretion System of the SPI-1 Family by Multiple Suppression Subtractive Hybridizations?  

PubMed Central

Fluorescent amplified fragment length polymorphism revealed that strains of Xanthomonas axonopodis pv. phaseoli and Xanthomonas fuscans subsp. fuscans are genetically distinct and can be grouped into four genetic lineages. Four suppression subtractive hybridizations were then performed to isolate DNA fragments present in these bean pathogens and absent from closely related xanthomonads. Virulence gene candidates were identified such as homologs of hemagglutinins, TonB-dependent receptors, zinc-dependent metalloproteases, type III effectors, and type IV secretion system components. Unexpectedly, homologs of the type III secretion apparatus components (SPI-1 family), usually reported in animal pathogens and insect symbionts, were also detected. PMID:18359831

Alavi, Seyed Mehdi; Sanjari, Saeideh; Durand, Fabien; Brin, Chrystelle; Manceau, Charles; Poussier, Stéphane

2008-01-01

199

Analysis of the Arabidopsis shoot meristem transcriptome during floral transition identifies distinct regulatory patterns and a leucine-rich repeat protein that promotes flowering.  

PubMed

Flowering of Arabidopsis thaliana is induced by exposure to long days (LDs). During this process, the shoot apical meristem is converted to an inflorescence meristem that forms flowers, and this transition is maintained even if plants are returned to short days (SDs). We show that exposure to five LDs is sufficient to commit the meristem of SD-grown plants to flower as if they were exposed to continuous LDs. The MADS box proteins SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) and FRUITFULL (FUL) play essential roles in this commitment process and in the induction of flowering downstream of the transmissible FLOWERING LOCUS T (FT) signal. We exploited laser microdissection and Solexa sequencing to identify 202 genes whose transcripts increase in the meristem during floral commitment. Expression of six of these transcripts was tested in different mutants, allowing them to be assigned to FT-dependent or FT-independent pathways. Most, but not all, of those dependent on FT and its paralog TWIN SISTER OF FT (TSF) also relied on SOC1 and FUL. However, this dependency on FT and TSF or SOC1 and FUL was often bypassed in the presence of the short vegetative phase mutation. FLOR1, which encodes a leucine-rich repeat protein, was induced in the early inflorescence meristem, and flor1 mutations delayed flowering. Our data contribute to the definition of LD-dependent pathways downstream and in parallel to FT. PMID:22319055

Torti, Stefano; Fornara, Fabio; Vincent, Coral; Andrés, Fernando; Nordström, Karl; Göbel, Ulrike; Knoll, Daniela; Schoof, Heiko; Coupland, George

2012-02-01

200

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

PubMed Central

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

Hoehenwarter, Wolfgang; Brzobohatý, B?etislav

2013-01-01

201

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

PubMed

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

Nakamuta, Shoko; Nakamuta, Nobuaki; Taniguchi, Kazuyuki

2011-10-01

202

Tagging with Green Fluorescent Protein Reveals a Distinct Subcellular Distribution of L-Type and Non-L-Type Ca2+ Channels Expressed in Dysgenic Myotubes  

Microsoft Academic Search

Expression of cardiac L-type Ca2+ channels in dysgenic myotubes results in large Ca2+ currents and electrically evoked contractions resulting from Ca2+-entry dependent release of Ca2+ from the sarcoplasmic reticulum. By contrast, expression of either P\\/Q-type or N-type Ca2+ channels in dysgenic myotubes does not result in electrically evoked contractions despite producing comparably large Ca2+ currents. In this work we examined

Manfred Grabner; Robert T. Dirksen; Kurt G. Beam

1998-01-01

203

A distinct type of glycerol-3-phosphate acyltransferase with sn-2 preference and phosphatase activity producing 2-monoacylglycerol  

PubMed Central

The first step in assembly of membrane and storage glycerolipids is acylation of glycerol-3-phosphate (G3P). All previously characterized membrane-bound, eukaryotic G3P acyltransferases (GPATs) acylate the sn-1 position to produce lysophosphatidic acid (1-acyl-LPA). Cutin is a glycerolipid with omega-oxidized fatty acids and glycerol as integral components. It occurs as an extracellular polyester on the aerial surface of all plants, provides a barrier to pathogens and resistance to stress, and maintains organ identity. We have determined that Arabidopsis acyltransferases GPAT4 and GPAT6 required for cutin biosynthesis esterify acyl groups predominantly to the sn-2 position of G3P. In addition, these acyltransferases possess a phosphatase domain that results in sn-2 monoacylglycerol (2-MAG) rather than LPA as the major product. Such bifunctional activity has not been previously described in any organism. The possible roles of 2-MAGs as intermediates in cutin synthesis are discussed. GPAT5, which is essential for the accumulation of suberin aliphatics, also exhibits a strong preference for sn-2 acylation. However, phosphatase activity is absent and 2-acyl-LPA is the major product. Clearly, plant GPATs can catalyze more reactions than the sn-1 acylation by which they are currently categorized. Close homologs of GPAT4-6 are present in all land plants, but not in animals, fungi or microorganisms (including algae). Thus, these distinctive acyltransferases may have been important for evolution of extracellular glycerolipid polymers and adaptation of plants to a terrestrial environment. These results provide insight into the biosynthetic assembly of cutin and suberin, the two most abundant glycerolipid polymers in nature. PMID:20551224

Yang, Weili; Pollard, Mike; Li-Beisson, Yonghua; Beisson, Fred; Feig, Michael; Ohlrogge, John

2010-01-01

204

Identification and Characterization of a New and Distinct Molecular Subtype of Human T-Cell Lymphotropic Virus Type 2  

Microsoft Academic Search

Molecular studies have demonstrated the existence of at least two major subtypes of human T-cell lympho- tropic 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. DNAsfromperipheralbloodmononuclearcellsofalargenumberofinfectedindividuals,themajorityofwhom were intravenous drug abusers, were analyzed by using PCR with restriction

NOBUTAKA EIRAKU; PATRICIA NOVOA; MARIZETE DACOSTA FERREIRA; CLAUDE MONKEN; RICARDO ISHAK; ORLANDO DACOSTA FERREIRA; SHI WEI ZHU; ROSEMARIE LORENCO; MARLUISA ISHAK; VANIA AZVEDO; JOAO GUERREIRO; MARIA POMBO DEOLIVEIRA; PAULA LOUREIRO; NELSON HAMMERSCHLAK; SHINJI IJICHI; W. HALL; Emilo Ribas

1996-01-01

205

Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance  

PubMed Central

Mice with an impaired Type I interferon (IFN) signaling (IFNAR1- and IFN?-deficient mice) display an increased susceptibility toward v-ABL-induced B-cell leukemia/lymphoma. The enhanced leukemogenesis in the absence of an intact Type I IFN signaling is caused by alterations within the tumor environment. Deletion of Ifnar1 in tumor cells (as obtained in Ifnar1f/f CD19-Cre mice) failed to impact on disease latency or type. In line with this observation, the initial transformation and proliferative capacity of tumor cells were unaltered irrespective of whether the cells expressed IFNAR1 or not. v-ABL-induced leukemogenesis is mainly subjected to natural killer (NK) cell-mediated tumor surveillance. Thus, we concentrated on NK cell functions in IFNAR1 deficient animals. Ifnar1-/- NK cells displayed maturation defects as well as an impaired cytolytic activity. When we deleted Ifnar1 selectively in mature NK cells (by crossing Ncr1-iCre mice to Ifnar1f/f animals), maturation was not altered. However, NK cells derived from Ifnar1f/f Ncr1-iCre mice showed a significant cytolytic defect in vitro against the hematopoietic cell lines YAC-1 and RMA-S, but not against the melanoma cell line B16F10. Interestingly, this defect was not related to an in vivo phenotype as v-ABL-induced leukemogenesis was unaltered in Ifnar1f/f Ncr1-iCre compared with Ifnar1f/f control mice. Moreover, the ability of Ifnar1f/f Ncr1-iCre NK cells to kill B16F10 melanoma cells was unaltered, both in vitro and in vivo. Our data reveal that despite the necessity for Type I IFN in NK cell maturation the expression of IFNAR1 on mature murine NK cells is not required for efficient tumor surveillance. PMID:23170251

Mizutani, Tatsuaki; Neugebauer, Nina; Putz, Eva M.; Moritz, Nadine; Simma, Olivia; Zebedin-Brandl, Eva; Gotthardt, Dagmar; Warsch, Wolfgang; Eckelhart, Eva; Kantner, Hans-Peter; Kalinke, Ulrich; Lienenklaus, Stefan; Weiss, Siegfried; Strobl, Birgit; Müller, Mathias; Sexl, Veronika; Stoiber, Dagmar

2012-01-01

206

Definition of genetic events directing the development of distinct types of brain tumors from postnatal neural stem/progenitor cells.  

PubMed

Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2?, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. PMID:22719073

Hertwig, Falk; Meyer, Katharina; Braun, Sebastian; Ek, Sara; Spang, Rainer; Pfenninger, Cosima V; Artner, Isabella; Prost, Gaëlle; Chen, Xinbin; Biegel, Jaclyn A; Judkins, Alexander R; Englund, Elisabet; Nuber, Ulrike A

2012-07-01

207

Definition of Genetic Events Directing the Development of Distinct Types of Brain Tumors from Postnatal Neural Stem/Progenitor Cells  

PubMed Central

Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2?, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. PMID:22719073

Hertwig, Falk; Meyer, Katharina; Braun, Sebastian; Ek, Sara; Spang, Rainer; Pfenninger, Cosima V.; Artner, Isabella; Prost, Gaëlle; Chen, Xinbin; Biegel, Jaclyn A.; Judkins, Alexander R.; Englund, Elisabet; Nuber, Ulrike A.

2012-01-01

208

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...

209

Researchers Identify Novel Type of Antibody that Potently Inhibits HIV Infection  

Cancer.gov

A small antibody fragment that is highly effective in neutralizing the human immunodeficiency virus (HIV) by preventing the virus from entering cells has been identified by researchers at NCI. This finding may provide insight into the development of new treatments against HIV and other viruses, hopefully in the not too distant future.

210

Isolates of Burkholderia pseudomallei from Northern Australia Are Distinct by Multilocus Sequence Typing, but Strain Types Do Not Correlate with Clinical Presentation  

Microsoft Academic Search

Melioidosis is the disease caused by the saprophytic organism Burkholderia pseudomallei. Previous studies have suggested some strain tropism and differential virulence. In this study, we defined strains by multilocus sequence typing (MLST) of isolates taken from the Top End of Australia's Northern Territory and compared the results with those of other strains typed worldwide. We specifically sought clinical and geographical

Allen C. Cheng; Daniel Godoy; Mark Mayo; Daniel Gal; Brian G. Spratt; Bart J. Currie

2004-01-01

211

Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies.  

PubMed

CD20 is a cell-surface marker of normal and malignant B cells. Rituximab, a monoclonal antibody targeting CD20, has improved the treatment of malignant lymphomas. Therapeutic CD20 antibodies are classified as either type I or II based on different mechanisms of killing malignant B cells. To reveal the molecular basis of this distinction, we fine-mapped the epitopes recognized by both types. We also determined the first X-ray structure of a type II antibody by crystallizing the obinutuzumab (GA101) Fab fragment alone and in complex with a CD20 cyclopeptide. Despite recognizing an overlapping epitope, GA101 binds CD20 in a completely different orientation than type I antibodies. Moreover, the elbow angle of GA101 is almost 30° wider than in type I antibodies, potentially resulting in different spatial arrangements of 2 CD20 molecules bound to a single GA101 or rituximab molecule. Using protein tomography, different CD20 complexes were found to be associated with the 2 antibodies, and confocal microscopy showed different membrane compartmentalization of these subpopulations of the cellular CD20 pool. Our findings offer a possible molecular explanation for the different cellular responses elicited by type I and II antibodies. PMID:21444918

Niederfellner, Gerhard; Lammens, Alfred; Mundigl, Olaf; Georges, Guy J; Schaefer, Wolfgang; Schwaiger, Manfred; Franke, Andreas; Wiechmann, Kornelius; Jenewein, Stefan; Slootstra, Jerry W; Timmerman, Peter; Brännström, Annika; Lindstrom, Frida; Mössner, Ekkehard; Umana, Pablo; Hopfner, Karl-Peter; Klein, Christian

2011-07-14

212

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

PubMed Central

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

Firacative, Carolina; Duan, Shuyao; Meyer, Wieland

2014-01-01

213

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

PubMed Central

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

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

2014-01-01

214

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

PubMed Central

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

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

2013-01-01

215

Characterizing the successful student in general chemistry and physical science classes in terms of Jung's personality types as identified by the Myers-Briggs Type Indicator  

NASA Astrophysics Data System (ADS)

A student's success in a science class can depend upon previous experiences, motivation, and the level of interest in the subject. Since psychological type is intrinsic to a person's whole being, it can be influential upon the student's motivation and interests. Thus, a study of student psychological types versus the level of success in a class, as measured by a percentage, has potential to uncover certain personality characteristics which may be helpful to or which may hinder a student's learning environment. This study was initiated, using the Myers-Briggs Type Indicator, to evaluate any correlation between a student's personality type and his/her performance in a science class. A total of 1041 students from three classes: Chemistry 121/122, Chemistry 112, Physical Science 100, volunteered for the study. An analysis of variance (ANOVA) was used to determine the levels of significance among sixteen personality types' averages. The results reveal that for the Chemistry 1121/122 course, the average score of the INTJ personality type was 5.1 to 12.6 points higher than every other personality type. The ANOVA identifies 3 personality types with averages significantly below the INTJ at the p < 0.05 significance level. The ANOVA analysis for the Chemistry 112 course identified significances between student scores at p = 0.08. The significance level for the differences among scores for the Physical Science 100 course was determined at a level of p = 0.02. Significance levels for p < 0.05 and <0.01 were identified between several groups in this course. The data suggest, that although personality type may not predict a particular student's success in a science class, students with certain personality traits may be favored in a chemistry class due the structure of the instruction and the presentation of the subject matter.

Riley, Wayne David

1998-11-01

216

A novel acid ?-glucosidase mutation identified in a Pakistani family with glycogen storage disease type II  

Microsoft Academic Search

A novel mutation, C118t, in exon 2 of the acid a-glucosidase gene has been found in an infant with glycogen storage disease type II. This mutation is predicted to result in protein truncation. The phenotype was that of the severe infantile form of the disorder with lack of motor development, but with eye regard, social smile and vocalization. The parents

M. A. Kroos; A. E. Waitfield; M. Joosse; B. Winchester; A. J. J. Reuser; K. D. MacDermot

1997-01-01

217

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

NASA Astrophysics Data System (ADS)

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.

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

2015-02-01

218

A texture-based methodology for identifying tissue type in magnetic resonance images  

Microsoft Academic Search

We propose a methodology for discriminating between various types of normal and diseased brain tissue in medical images that utilizes vector quantization (VQ), an image compression technique, to extract discriminative texture features. Rather than focusing on images of the entire brain, we direct our attention to extracting local descriptors for individual regions of interest (ROIs) as determined by domain experts.

Michael Barnathan; Jingjing Zhang; Erickson Miranda; Vasileios Megalooikonomou; Scott Faro; Harvey Hensley; Luis Del Valle; Kamel Khalili; Jennifer Gordon; Feroze B. Mohamed

2008-01-01

219

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

PubMed

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

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

220

Two unique recombinant forms identified in incident HIV type 1 infections in Thai blood donors.  

PubMed

HIV-1 genetic diversity of recently seroconverting (<12 months) Thai repeated blood donors attending the National Blood Centre, Thai Red Cross Society (NBC, TRCS) from September 2007 until March 2008 was assessed. Ten HIV-1 recent seroconvertors (10/239,134 donations) were identified during the study period. The estimated median time to seroconversion was 67.3 days (range: 45.5-102.0 days), and viral load ranged from 307 to 341,805 copies HIV-1 RNA/ml. MHAbce, a real-time-based PCR genotyping assay, identified six CRF01_AE, two CRF01_AE/B recombinants, one subtype B, and one CRF01_AE/B dual infection. Nine samples were further characterized by full genome sequencing, identifying CRF01_AE (N=6), unique CRF01_AE/B recombinants (N=2), and subtype B (N=1). One recombinant contained 13 breakpoints located in gag, pol, vif, vpr, env, and nef while the other recombinant contained 10 breakpoints located in pol, vif, env, and nef. This study found two unique CRF01B recombinants circulating in 10 recent HIV-1-positive subjects from a blood donor population in Thailand. PMID:22587412

Rutvisuttinunt, Wiriya; Sirivichayakul, Sunee; Oota, Sineenart; Assawadarachai, Vatcharain; Poltavee, Kultida; Savadsuk, Hathairat; Pattanachaiwit, Supanit; Chaemchuen, Suwittra; Arroyo, Miguel A; Paris, Robert M; Michael, Nelson L; Kim, Jerome H; Ruxrungtham, Kiat; de Souza, Mark; Phanuphak, Praphan; Tovanabutra, Sodsai

2012-12-01

221

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

SciTech Connect

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.

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

222

Antp-type homeodomains have distinct DNA binding specificities that correlate with their different regulatory functions in embryos.  

PubMed

Much of the functional specificity of Drosophila homeotic selector proteins, in their ability to regulate specific genes and to assign specific segmental identities, appears to map within their different, but closely related homeodomains. For example, the Drosophila Dfd and human HOX4B (Hox 4.2) proteins, which have extensive structural similarity only in their respective homeodomains, both specifically activate the Dfd promoter. In contrast, a chimeric Dfd protein containing the Ubx homeodomain (Dfd/Ubx) specifically activates the Antp P1 promoter, which is normally targeted by Ubx. Using a variety of DNA binding assays, we find significant differences in DNA binding preferences between the Dfd, Dfd/Ubx and Ubx proteins when Dfd and Antp upstream regulatory sequences are used as binding substrates. No significant differences in DNA binding specificity were detected between the human HOX4B (Hox 4.2) and Drosophila Dfd proteins. All of these full-length proteins bound as monomers to high affinity DNA binding sites, and interference assays indicate that they interact with DNA in a way that is very similar to homeodomain polypeptides. These experiments indicate that the ninth amino acid of the recognition helix of the homeodomain, which is glutamine in all four of these Antp-type homeodomain proteins, is not sufficient to determine their DNA binding specificities. The good correlation between the in vitro DNA binding preferences of these four Antp-type homeodomain proteins and their ability to specifically regulate a Dfd enhancer element in the embryo, suggests that the modest binding differences that distinguish them make an important contribution to their unique regulatory specificities. PMID:1347746

Dessain, S; Gross, C T; Kuziora, M A; McGinnis, W

1992-03-01

223

The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene.  

PubMed

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved. PMID:21424531

Snowden, Julie S; Hu, Quan; Rollinson, Sara; Halliwell, Nicola; Robinson, Andrew; Davidson, Yvonne S; Momeni, Parastoo; Baborie, Atik; Griffiths, Timothy D; Jaros, Evelyn; Perry, Robert H; Richardson, Anna; Pickering-Brown, Stuart M; Neary, David; Mann, David M A

2011-07-01

224

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

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

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

225

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

Microsoft Academic Search

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

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

226

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

PubMed Central

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

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

2014-01-01

227

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.

228

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

PubMed Central

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

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

2014-01-01

229

CD8+ T-cell responses identify beta-cell autoimmunity in human type 1 diabetes.  

PubMed

Despite the understanding that type 1 diabetes pathogenesis is mediated by T-cells, detection of these rare lymphocytes remains largely elusive. Suitable T-cell assays are highly needed, since they could offer preclinical diagnoses and immune surrogate end points for clinical trials. Although CD4+ T-cell assays have met with limited success, CD8+ T-cells are increasingly recognized as key actors in the diabetes of the NOD mouse. CD8+ T-cells are likely to play a role also in humans and may provide new markers of beta-cell autoimmunity. Taking advantage of a panel of HLA-A2-restricted beta-cell epitopes derived from preproinsulin, GAD, and islet glucose-6-phosphatase catalytic subunit-related protein (IGRP), we have implemented an islet-specific CD8+ T-cell interferon-gamma enzyme-linked immunospot (ISL8Spot) assay. The ISL8Spot assay is capable of detecting and quantifying beta-cell-reactive CD8+ T-cells directly ex vivo, without any preliminary expansion, using either fresh or frozen samples. Positive ISL8Spot responses separate new-onset diabetic and healthy samples with high accuracy (86% sensitivity, 91% specificity), using as few as five immunodominant epitopes. Moreover, sensitivity reaches 100% when the ISL8Spot assay is complemented by antibody determinations. Combination of CD8+ T-cell measurements with immune intervention strategies may open new avenues toward type 1 diabetes prediction and prevention. PMID:17327428

Mallone, Roberto; Martinuzzi, Emanuela; Blancou, Philippe; Novelli, Giulia; Afonso, Georgia; Dolz, Manuel; Bruno, Graziella; Chaillous, Lucy; Chatenoud, Lucienne; Bach, Jean-Marie; van Endert, Peter

2007-03-01

230

Demonstration of two distinct cytopathic effects with syncytium formation-defective human immunodeficiency virus type 1 mutants.  

PubMed Central

The mechanism of human immunodeficiency virus type 1 (HIV-1) cytopathicity is poorly understood and might involve formation of multinucleated giant cells (syncytia), single-cell lysis, or both. In order to determine the contributions of the fusion domain to syncytium formation, single-cell lysis, and viral infectivity and to clarify the molecular details of these events, insertion mutations were made in the portion of env encoding this sequence in the functional HIV-1 proviral clone HXB2. Viruses produced from these mutant clones were found to have a partial (F3) or complete (F6) loss of syncytium-forming ability in acutely infected CEM, Sup T1, and MT4 T-cell lines. During the early stage of acute infection by F6 virus, there was a loss of the syncytial cytopathic effect, which resulted in increased cell viability, and a 1.9- to 2.6-fold increase in virus yield in the cell lines tested. In the late stage of acute infection, the single-cell cytopathic effect of F6 virus was similar to that of the parental HXB2 virus. The F3 and F6 viruses were also found to have a 1.7- to 43-fold reduction in infectivity compared with the HXB2 virus. The mutant F3 and F6 and parental HXB2 envelope proteins were expressed in vaccinia virus, and the mutant envelope proteins were observed to be defective in their ability to form syncytia. BSC-40 cells infected with vaccinia virus recombinants revealed no differences in kinetics of cleavage, cell surface expression, or CD4 binding capacity of the mutant and parental envelope proteins. These results demonstrate that a loss of syncytium formation results in an attenuation of infectivity and a loss of the syncytial cytopathic effect without a loss of single-cell lysis. These mutants may reflect in tissue culture the changes observed in the HIV isolates in vivo during disease progression, which exhibit marked differences in syncytium production. Images PMID:1717715

Dedera, D; Ratner, L

1991-01-01

231

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

NASA Astrophysics Data System (ADS)

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.

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

2012-06-01

232

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

PubMed

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 x 10(-8)) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 x 10(-12)), 10p15 (PRKCQ, P = 3.7 x 10(-9)), 15q24 (CTSH, P = 3.2 x 10(-15)) and 22q13 (C1QTNF6, P = 2.0 x 10(-8)). PMID:18978792

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

2008-12-01

233

Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes.  

PubMed

Juvenile diabetes (type 1) is an autoimmune disease in which CD4(+) T cells play a major role in pathogenesis characterized by insulitis and beta cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4(+) cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFkappaB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40(+)CD4(+) T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4(+)CD40(+) cells infiltrate the pancreatic islets causing beta-cell degranulation and ultimately diabetes. PMID:11891296

Wagner, David H; Vaitaitis, Gisela; Sanderson, Richard; Poulin, Michelle; Dobbs, Cathleen; Haskins, Kathryn

2002-03-19

234

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

NASA Astrophysics Data System (ADS)

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

2009-11-01

235

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

PubMed Central

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

Sorli, Christopher; Heile, Michael K

2014-01-01

236

Optical metabolic imaging identifies glycolytic levels, sub-types and early treatment response in breast cancer  

PubMed Central

Abnormal cellular metabolism is a hallmark of cancer, yet there is an absence of quantitative methods to dynamically image this powerful cellular function. Optical metabolic imaging (OMI) is a non-invasive, high-resolution, quantitative tool for monitoring cellular metabolism. OMI probes the fluorescence intensities and lifetimes of the autofluorescent metabolic co-enzymes reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD). We confirm that OMI correlates with cellular glycolytic levels across a panel of human breast cell lines, using standard assays of cellular rates of glucose uptake and lactate secretion (p<0.05, r=0.89). Additionally, OMI resolves differences in the basal metabolic activity of untransformed from malignant breast cells (p<0.05), and between breast cancer sub-types (p<0.05), defined by estrogen receptor (ER) and/or HER2 expression or absence. In vivo OMI is sensitive to metabolic changes induced by inhibition of HER2 with the antibody trastuzumab (Herceptin) in HER2-overexpressing human breast cancer xenografts in mice. This response was confirmed with tumor growth curves and stains for Ki67 and cleaved caspase-3. OMI resolved trastuzumab-induced changes in cellular metabolism in vivo as early as 48 hours post-treatment (p<0.05), while FDG-PET did not resolve any changes with trastuzumab up to 12-days post-treatment (p>0.05). In addition, OMI resolved cellular sub-populations of differing response in vivo that are critical for investigating drug resistance mechanisms. Importantly, OMI endpoints remained unchanged with trastuzumab-treatment in trastuzumab-resistant xenografts (p>0.05). OMI has significant implications for rapid cellular-level assessment of metabolic response to molecular expression and drug action, which would greatly accelerate drug development studies. PMID:24130112

Walsh, Alex J.; Cook, Rebecca S.; Manning, H. Charles; Hicks, Donna J.; Lafontant, Alec; Arteaga, Carlos L.; Skala, Melissa C.

2013-01-01

237

Identifying risk factors for clinically significant diabetic macula edema in patients with type 2 diabetes mellitus.  

PubMed

It is known that clinic blood pressure (BP), gender, cigarette smoking, dyslipidemia, anemia and thiazolidenediones (TZD) treatment are predictors for clinically significant diabetic macula edema (CSDME). We examined a most risky factor for CSDME in Japanese patients with type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) confirmed using optical coherence tomography by multiple regression analysis (MRA). As the risk factors, wakening-up BP was added to such factors. Seven diabetic Japanese patients with CSDME (group 1) and 124 subjects without CSDME (group 2) assonated with DR using optical coherence tomography were studied. The durations of T2DM in groups 1 and 2 were 15±10 years and 20±15 years, respectively. There was no statistically difference in means of gender, duration, age, body mass index (BMI), HbA1c, TC, LDL and TC/HDL, serum creatinine, urinary albumin excretion rate, and clinic BP between two groups. Morning systolic home BP (MSHBP), cigarette smoking and foveal thickness were significantly (p<0.001) higher in group 1 than group 2, whereas visual acuity was significantly (p<0.00?) lower in group 1 than in group 2. The patients in both groups had received various kinds of drugs for hyperglycemia, hypertension and others. There were no significant differences in the variables in both groups. MRA revealed that MSHBP, cigarette smoking and pioglitazone as TZD treatment were significantly positive predictors for CSDME, while BMI had a significantly negative predictor. Other variables were not significantly correlated to CSDME. The review summarizes a multiple regression analysis revealed that MSHBP makes an addition to predictive factors for CSDME among risk factors reported previously in patient with T2DM. PMID:23363297

Kamoi, Kyuzi; Takeda, Keiji; Hashimoto, Kaoru; Tanaka, Reiko; Okuyama, Shinya

2013-05-01

238

Glycoproteomics approach for identifying Glycobiomarker candidate molecules for tissue type classification of non-small cell lung carcinoma.  

PubMed

Histopathological classification of lung cancer has important implications in the application of clinical practice guidelines and the prediction of patient prognosis. Thus, we focused on discovering glycobiomarker candidates to classify the types of lung cancer tissue. First, we performed lectin microarray analysis of lung cancer tissue specimens and cell lines and identified Aleuria aurantia lectin (AAL), Hippeastrum hybrid lectin (HHL), and Concanavalia ensiformis agglutinin (ConA) as lectin probes specific to non-small cell lung carcinoma (NSCLC). LC-MS-based analysis was performed for the comprehensive identification of glycoproteins and N-linked glycosylation sites using lectin affinity capture of NSCLC-specific glycoforms of glycoproteins. This analysis identified 1092 AAL-bound glycoproteins (316 gene symbols) and 948 HHL/ConA-bound glycoproteins (279 gene symbols). The lectin microarray-assisted verification using 15 lung cancer cell lines revealed the NSCLC-specific expression of fibronectin. The glycosylation profiling of fibronectin indicated that the peanut agglutinin (PNA) signal appeared to differentiate two NSCLC types, adenocarcinoma and large cell carcinoma, whereas the protein expression level was similar between these types. Our glycoproteomics approach together with the concurrent use of an antibody and lectin is applicable to the quantitative and qualitative monitoring of variations in glycosylation of fibronectin specific to certain types of lung cancer tissue. PMID:25244057

Hirao, Yoshitoshi; Matsuzaki, Hideki; Iwaki, Jun; Kuno, Atsushi; Kaji, Hiroyuki; Ohkura, Takashi; Togayachi, Akira; Abe, Minako; Nomura, Masaharu; Noguchi, Masayuki; Ikehara, Yuzuru; Narimatsu, Hisashi

2014-11-01

239

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

PubMed Central

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

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

2014-01-01

240

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

NASA Technical Reports Server (NTRS)

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.

Joshi, Suresh M.

2012-01-01

241

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

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

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

242

Conformational changes of the bacterial type I ATP-binding cassette importer HisQMP2 at distinct steps of the catalytic cycle.  

PubMed

Prokaryotic solute binding protein-dependent ATP-binding cassette import systems are divided into type I and type II and mechanistic differences in the transport process going along with this classification are under intensive investigation. Little is known about the conformational dynamics during the catalytic cycle especially concerning the transmembrane domains. The type I transporter for positively charged amino acids from Salmonella enterica serovar Typhimurium (LAO-HisQMP2) was studied by limited proteolysis in detergent solution in the absence and presence of co-factors including ATP, ADP, LAO/arginine, and Mg(2+) ions. Stable peptide fragments could be obtained and differentially susceptible cleavage sites were determined by mass spectrometry as Lys-258 in the nucleotide-binding subunit, HisP, and Arg-217/Arg-218 in the transmembrane subunit, HisQ. In contrast, transmembrane subunit HisM was gradually degraded but no stable fragment could be detected. HisP and HisQ were equally resistant under pre- and post-hydrolysis conditions in the presence of arginine-loaded solute-binding protein LAO and ATP/ADP. Some protection was also observed with LAO/arginine alone, thus reflecting binding to the transporter in the apo-state and transmembrane signaling. Comparable digestion patterns were obtained with the transporter reconstituted into proteoliposomes and nanodiscs. Fluorescence lifetime spectroscopy confirmed the change of HisQ(R218) to a more apolar microenvironment upon ATP binding and hydrolysis. Limited proteolysis was subsequently used as a tool to study the consequences of mutations on the transport cycle. Together, our data suggest similar conformational changes during the transport cycle as described for the maltose ABC transporter of Escherichia coli, despite distinct structural differences between both systems. PMID:24021237

Heuveling, Johanna; Frochaux, Violette; Ziomkowska, Joanna; Wawrzinek, Robert; Wessig, Pablo; Herrmann, Andreas; Schneider, Erwin

2014-01-01

243

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

PubMed

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

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

244

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

PubMed Central

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

2013-01-01

245

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

PubMed

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 2 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 5 dogs and in 2 cats -a new finding for cats. No mixed infections were detected. The occurrence of 2 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

Enriquez, G F; Cardinal, M V; Orozco, M M; Lanati, L; Schijman, A G; Gürtler, R E

2013-03-01

246

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

PubMed Central

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

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

247

Distinct transformation tropism exhibited by human T lymphotropic virus type 1 (HTLV-1) and HTLV-2 is the result of postinfection T cell clonal expansion.  

PubMed

Human T lymphotropic virus type 1 (HTLV-1) and HTLV-2 are related but pathogenically distinct viruses. HTLV-1 mainly causes adult T cell leukemia, while HTLV-2 is not associated with leukemia. In vitro, HTLV-1 and HTLV-2 predominantly transform CD4(+) and CD8(+) T cells, respectively: the genetic determinant maps to the viral envelope. Herein, we investigate whether this transformation tropism occurs during initial infection or subsequently during the cellular transformation process. Since most individuals are chronically infected at the time of detection, we utilized an established rabbit model to longitudinally measure the early HTLV-1 and HTLV-2 infection and replication kinetics in purified CD4(+) and CD8(+) T cells. HTLV-1 and HTLV-2 were detected in both CD4(+) and CD8(+) T cells within 1 week postinoculation. In HTLV-1-infected rabbit CD4(+) T cells, proviral burden and tax/rex mRNA expression peaked early, and expression levels were directly proportional to each other. The late expression of the antisense transcript (Hbz or Aph-2) correlated directly with a late proviral burden peak in HTLV-1- or HTLV-2-infected rabbit CD8(+) T cells, respectively. This study provides the first in vivo evidence that these viruses do not exhibit cellular preference during initial infection. We further evaluated the transformation tropism of HTLV-1 and HTLV-2 over a 9-week period using in vitro cell growth/immortalization assays. At the early weeks, both HTLV-1 and HTLV-2 showed proportionate growth of CD4(+) and CD8(+) T cells. However, beyond week 5, the predominance of one particular T cell type emerged, supporting the conclusion that transformation tropism is a postinfection event due to selective clonal expansion over time. PMID:22278223

Kannian, Priya; Yin, Han; Doueiri, Rami; Lairmore, Michael D; Fernandez, Soledad; Green, Patrick L

2012-04-01

248

Characteristic patterns of dendritic remodeling in early-stage glaucoma: evidence from genetically identified retinal ganglion cell types.  

PubMed

Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and the second leading cause of blindness worldwide. The type and timing of cellular changes leading to RGC loss in glaucoma remain incompletely understood, including whether specific RGC subtypes are preferentially impacted at early stages of this disease. Here we applied the microbead occlusion model of glaucoma to different transgenic mouse lines, each expressing green fluorescent protein in 1-2 specific RGC subtypes. Targeted filling, reconstruction, and subsequent comparison of the genetically identified RGCs in control and bead-injected eyes revealed that some subtypes undergo significant dendritic rearrangements as early as 7 d following induction of elevated intraocular pressure (IOP). By comparing specific On-type, On-Off-type and Off-type RGCs, we found that RGCs that target the majority of their dendritic arbors to the scleral half or "Off" sublamina of the inner plexiform layer (IPL) undergo the greatest changes, whereas RGCs with the majority of their dendrites in the On sublamina did not alter their structure at this time point. Moreover, M1 intrinsically photosensitive RGCs, which functionally are On RGCs but structurally stratify their dendrites in the Off sublamina of the IPL, also underwent significant changes in dendritic structure 1 week after elevated IOP. Thus, our findings reveal that certain RGC subtypes manifest significant changes in dendritic structure after very brief exposure to elevated IOP. The observation that RGCs stratifying most of their dendrites in the Off sublamina are first to alter their structure may inform the development of new strategies to detect, monitor, and treat glaucoma in humans. PMID:25673829

El-Danaf, Rana N; Huberman, Andrew D

2015-02-11

249

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

USGS Publications Warehouse

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.

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

2008-01-01

250

Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type  

PubMed Central

Background The continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a ‘triple negative’ breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options. Methods The MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other ‘triple negative’ breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model. Results All of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated using the anti-CD73 antibody, which bound other ‘triple negative’ breast cancer cell lines and produced significant tumour growth inhibitory activity in a MDA-MB-231 xenograft model. Conclusions This study has demonstrated that multiple methods are required to successfully analyse the membranome of a desired cell type. It has also successfully demonstrated that phenotypic antibody screening provides a mechanism for rapidly discovering and evaluating antibody tractable targets, which can significantly accelerate the therapeutic discovery process. PMID:23406016

2013-01-01

251

ZnT8-Specific CD4+ T Cells Display Distinct Cytokine Expression Profiles between Type 1 Diabetes Patients and Healthy Adults  

PubMed Central

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

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

2013-01-01

252

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.  

PubMed

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D. PMID:22158537

Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng; Long, Jirong; Ong, Rick Twee Hee; Sim, Xueling; Takeuchi, Fumihiko; Wu, Ying; Go, Min Jin; Yamauchi, Toshimasa; Chang, Yi-Cheng; Kwak, Soo Heon; Ma, Ronald C W; Yamamoto, Ken; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Chang, Li-Ching; Chen, Yuan-Tsong; Gao, Yutang; Hu, Frank B; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Lee, Jeannette Jen-Mai; Lee, Nanette R; Li, Yun; Liu, Jian Jun; Lu, Wei; Nakamura, Jiro; Nakashima, Eitaro; Ng, Daniel Peng-Keat; Tay, Wan Ting; Tsai, Fuu-Jen; Wong, Tien Yin; Yokota, Mitsuhiro; Zheng, Wei; Zhang, Rong; Wang, Congrong; So, Wing Yee; Ohnaka, Keizo; Ikegami, Hiroshi; Hara, Kazuo; Cho, Young Min; Cho, Nam H; Chang, Tien-Jyun; Bao, Yuqian; Hedman, Åsa K; Morris, Andrew P; McCarthy, Mark I; Takayanagi, Ryoichi; Park, Kyong Soo; Jia, Weiping; Chuang, Lee-Ming; Chan, Juliana C N; Maeda, Shiro; Kadowaki, Takashi; Lee, Jong-Young; Wu, Jer-Yuarn; Teo, Yik Ying; Tai, E Shyong; Shu, Xiao Ou; Mohlke, Karen L; Kato, Norihiro; Han, Bok-Ghee; Seielstad, Mark

2012-01-01

253

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

PubMed Central

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

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

2007-01-01

254

Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus  

PubMed Central

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10?4, permutation p?=?1.0×10?3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10?7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.

2010-01-01

255

Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.  

PubMed

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10(-4), permutation p?=?1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

Bell, Christopher G; Finer, Sarah; Lindgren, Cecilia M; Wilson, Gareth A; Rakyan, Vardhman K; Teschendorff, Andrew E; Akan, Pelin; Stupka, Elia; Down, Thomas A; Prokopenko, Inga; Morison, Ian M; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M; Hattersley, Andrew T; McCarthy, Mark I; Beck, Stephan; Hitman, Graham A

2010-01-01

256

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

PubMed Central

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

2013-01-01

257

Identifying postpartum intervention approaches to prevent type 2 diabetes in women with a history of gestational diabetes  

PubMed Central

Background Women who develop gestational diabetes mellitus (GDM) have an increased risk for the development of type 2 diabetes. Despite this "window of opportunity," few intervention studies have targeted postpartum women with a history of GDM. We sought perspectives of women with a history of GDM to identify a) barriers and facilitators to healthy lifestyle changes postpartum, and b) specific intervention approaches that would facilitate participation in a postpartum lifestyle intervention program. Methods We used mixed methods to gather data from women with a prior history of GDM, including focus groups and informant interviews. Analysis of focus groups relied on grounded theory and used open-coding to categorize data by themes, while frequency distributions were used for the informant interviews. Results Of 38 women eligible to participate in focus groups, only ten women were able to accommodate their schedules to attend a focus group and 15 completed informant interviews by phone. We analyzed data from 25 women (mean age 35, mean pre-pregnancy BMI 28, 52% Caucasian, 20% African American, 12% Asian, 8% American Indian, 8% refused to specify). Themes from the focus groups included concern about developing type 2 diabetes, barriers to changing diet, and barriers to increasing physical activity. In one focus group, women expressed frustration about feeling judged by their physicians during their GDM pregnancy. Cited barriers to lifestyle change were identified from both methods, and included time and financial constraints, childcare duties, lack of motivation, fatigue, and obstacles at work. Informants suggested facilitators for lifestyle change, including nutrition education, accountability, exercise partners/groups, access to gyms with childcare, and home exercise equipment. All focus group and informant interview participants reported access to the internet, and the majority expressed interest in an intervention program delivered primarily via the internet that would include the opportunity to work with a lifestyle coach. Conclusion Time constraints were a major barrier. Our findings suggest that an internet-based lifestyle intervention program should be tested as a novel approach to prevent type 2 diabetes in postpartum women with a history of GDM. Trial Registration ClinicalTrials.gov: NCT01102530 PMID:21435246

2011-01-01

258

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)

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.

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

2014-10-01

259

Astrocytes and glioblastoma cells express novel octamer-DNA binding proteins distinct from the ubiquitous Oct-1 and B cell type Oct-2 proteins.  

PubMed Central

The 'octamer' sequence, ATGCAAAT or its complement ATTTGCAT, is a key element for the transcriptional regulation of immunoglobulin genes in B-lymphocytes as well as a number of housekeeping genes in all cell types. In lymphocytes, the octamer-binding protein Oct-2A and variants thereof are thought to contribute to the B-cell specific gene expression, while the ubiquitous protein Oct-1 seems to control general octamer site-dependent transcription. Various other genes, for example interleukin-1 and MHC class II genes, contain an octamer sequence in the promoter and are expressed in cells of both the immune and nervous systems. This prompted us to analyze the octamer-binding proteins in the latter cells. Using the electrophoretic mobility shift assay, at least six novel octamer binding proteins were detected in nuclear extracts of cultured mouse astrocytes. These proteins are differentially expressed in human glioblastoma and neuroblastoma cell lines. The nervous system-derived (N-Oct) proteins bound to the octamer DNA sequence in a manner which is indistinguishable from the Oct-1 and Oct-2A proteins. The relationship of the N-Oct proteins to Oct-1 and Oct-2A was analyzed by proteolytic clipping bandshift assays and by their reactivity towards antisera raised against recombinant Oct-1 and Oct-2A proteins. On the basis of these assays, all N-Oct-factors were found to be distinct from the ubiquitous Oct-1 and the lymphoid-specific Oct-2A proteins. In melanoma cells that contain the N-Oct-3 factor, a transfected lymphocyte-specific promoter was neither activated nor was it repressed upon contransfection with an Oct-2A expression vector. We therefore speculate that N-Oct-3 and other N-Oct factors have a specific role in gene expression in cells of the nervous system. Images PMID:2216722

Schreiber, E; Harshman, K; Kemler, I; Malipiero, U; Schaffner, W; Fontana, A

1990-01-01

260

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci  

PubMed Central

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ?50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ?2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10?9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10?6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10?7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10?15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10?8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups. PMID:22325160

Saxena, Richa; Elbers, Clara C.; Guo, Yiran; Peter, Inga; Gaunt, Tom R.; Mega, Jessica L.; Lanktree, Matthew B.; Tare, Archana; Castillo, Berta Almoguera; Li, Yun R.; Johnson, Toby; Bruinenberg, Marcel; Gilbert-Diamond, Diane; Rajagopalan, Ramakrishnan; Voight, Benjamin F.; Balasubramanyam, Ashok; Barnard, John; Bauer, Florianne; Baumert, Jens; Bhangale, Tushar; Böhm, Bernhard O.; Braund, Peter S.; Burton, Paul R.; Chandrupatla, Hareesh R.; Clarke, Robert; Cooper-DeHoff, Rhonda M.; Crook, Errol D.; Davey-Smith, George; Day, Ian N.; de Boer, Anthonius; de Groot, Mark C.H.; Drenos, Fotios; Ferguson, Jane; Fox, Caroline S.; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Gilhuijs-Pederson, Lisa A.; Glessner, Joseph T.; Goel, Anuj; Gong, Yan; Grant, Struan F.A.; Grobbee, Diederick E.; Hastie, Claire; Humphries, Steve E.; Kim, Cecilia E.; Kivimaki, Mika; Kleber, Marcus; Meisinger, Christa; Kumari, Meena; Langaee, Taimour Y.; Lawlor, Debbie A.; Li, Mingyao; Lobmeyer, Maximilian T.; Maitland-van der Zee, Anke-Hilse; Meijs, Matthijs F.L.; Molony, Cliona M.; Morrow, David A.; Murugesan, Gurunathan; Musani, Solomon K.; Nelson, Christopher P.; Newhouse, Stephen J.; O'Connell, Jeffery R.; Padmanabhan, Sandosh; Palmen, Jutta; Patel, Sanjey R.; Pepine, Carl J.; Pettinger, Mary; Price, Thomas S.; Rafelt, Suzanne; Ranchalis, Jane; Rasheed, Asif; Rosenthal, Elisabeth; Ruczinski, Ingo; Shah, Sonia; Shen, Haiqing; Silbernagel, Günther; Smith, Erin N.; Spijkerman, Annemieke W.M.; Stanton, Alice; Steffes, Michael W.; Thorand, Barbara; Trip, Mieke; van der Harst, Pim; van der A, Daphne L.; van Iperen, Erik P.A.; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Wolffenbuttel, Bruce H.R.; Young, Taylor; Zafarmand, M. Hadi; Zmuda, Joseph M.; Boehnke, Michael; Altshuler, David; McCarthy, Mark; Kao, W.H. Linda; Pankow, James S.; Cappola, Thomas P.; Sever, Peter; Poulter, Neil; Caulfield, Mark; Dominiczak, Anna; Shields, Denis C.; Bhatt, Deepak L.; Zhang, Li; Curtis, Sean P.; Danesh, John; Casas, Juan P.; van der Schouw, Yvonne T.; Onland-Moret, N. Charlotte; Doevendans, Pieter A.; Dorn, Gerald W.; Farrall, Martin; FitzGerald, Garret A.; Hamsten, Anders; Hegele, Robert; Hingorani, Aroon D.; Hofker, Marten H.; Huggins, Gordon S.; Illig, Thomas; Jarvik, Gail P.; Johnson, Julie A.; Klungel, Olaf H.; Knowler, William C.; Koenig, Wolfgang; März, Winfried; Meigs, James B.; Melander, Olle; Munroe, Patricia B.; Mitchell, Braxton D.; Bielinski, Susan J.; Rader, Daniel J.; Reilly, Muredach P.; Rich, Stephen S.; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schadt, Eric E.; Shuldiner, Alan R.; Silverstein, Roy; Kottke-Marchant, Kandice; Talmud, Philippa J.; Watkins, Hugh; Asselbergs, Folkert W.; de Bakker, Paul I.W.; McCaffery, Jeanne; Wijmenga, Cisca; Sabatine, Marc S.; Wilson, James G.; Reiner, Alex; Bowden, Donald W.; Hakonarson, Hakon; Siscovick, David S.; Keating, Brendan J.

2012-01-01

261

Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury.  

PubMed

Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified 5 genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional 9 assays of nociception and hypersensitivity, with the following goals: to replicate the previously identified 5 pain types; to test whether any of the newly added pain assays represent novel genetically distinct pain types; and to test the level of genetic relatedness among 9 commonly used neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the 2 previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The 4 included mechanical hypersensitivity assays are genetically distinct and do not comprise a single pain type as previously reported. Among the 9 neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least 4 genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, 2 itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types. PMID:24071598

Young, Erin E; Costigan, Michael; Herbert, Teri A; Lariviere, William R

2014-05-01

262

An “Exacerbate-reverse” Strategy in Yeast Identifies Histone Deacetylase Inhibition as a Correction for Cholesterol and Sphingolipid Transport Defects in Human Niemann-Pick Type C Disease*?  

PubMed Central

Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1? strains grown under viable aerobic conditions. Deletion of components of the yeast NuA4 histone acetyltransferase complex in ncr1? strains conferred anaerobic inviability and accumulation of multiple sterol intermediates. Thus, we hypothesize an imbalance in histone acetylation in human NP-C disease. Accordingly, we show that the majority of the 11 histone deacetylase (HDAC) genes are transcriptionally up-regulated in three genetically distinct fibroblast lines derived from patients with NP-C disease. A clinically approved HDAC inhibitor (suberoylanilide hydroxamic acid) reverses the dysregulation of the majority of the HDAC genes. Consequently, three key cellular diagnostic criteria of NP-C disease are dramatically ameliorated as follows: lysosomal accumulation of both cholesterol and sphingolipids and defective esterification of LDL-derived cholesterol. These data suggest HDAC inhibition as a candidate therapy for NP-C disease. We conclude that pathways that exacerbate lethality in a model organism can be reversed in human cells as a novel therapeutic strategy. This “exacerbate-reverse” approach can potentially be utilized in any model organism for any disease. PMID:21489983

Munkacsi, Andrew B.; Chen, Fannie W.; Brinkman, Matthew A.; Higaki, Katsumi; Gutiérrez, Giselle Domínguez; Chaudhari, Jagruti; Layer, Jacob V.; Tong, Amy; Bard, Martin; Boone, Charles; Ioannou, Yiannis A.; Sturley, Stephen L.

2011-01-01

263

A Genome-Wide Meta-Analysis of Six Type 1 Diabetes Cohorts Identifies Multiple Associated Loci  

PubMed Central

Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ?2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P?=?5.66×10?11) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P?=?3.50×10?9) resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P?=?8.06×10?9) lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D. PMID:21980299

Bradfield, Jonathan P.; Qu, Hui-Qi; Wang, Kai; Zhang, Haitao; Sleiman, Patrick M.; Kim, Cecilia E.; Mentch, Frank D.; Qiu, Haijun; Glessner, Joseph T.; Thomas, Kelly A.; Frackelton, Edward C.; Chiavacci, Rosetta M.; Imielinski, Marcin; Monos, Dimitri S.; Pandey, Rahul; Bakay, Marina; Grant, Struan F. A.; Polychronakos, Constantin; Hakonarson, Hakon

2011-01-01

264

Canine parvovirus type 2c identified from an outbreak of severe gastroenteritis in a litter in Sweden  

PubMed Central

A litter of recently-vaccinated puppies in Sweden experienced signs of severe haemorrhagic gastroenteritis. Canine parvovirus (CPV) was suspected as the cause of this outbreak on the basis of the clinical signs and the presence of parvoviral antigen in the faeces from one of the affected pups - confirmed using a commercial in-clinic faecal antigen ELISA test kit. A concern was raised about whether the vaccine (which contained a live, attenuated strain of CPV) could have caused the disease and so further faecal samples from the affected pups were submitted for laboratory virus isolation and identification. On cell culture, two out of four faecal samples were found to be virus-positive. This was confirmed as being canine parvovirus by immuno-staining with CPV specific monoclonal antibody. The virus was then tested using a series of PCR probes designed to confirm the identity of CPV and to distinguish the unique vaccine strain from field virus. This confirmed that the virus was indeed CPV but that it was not vaccine strain. The virus was then typed by sequencing the 426 amino acid region of the capsid gene which revealed this to be a type 2c virus. Since its emergence in the late 1970s, canine parvovirus 2 (CPV2) has spread worldwide and is recognised as an important canine pathogen in all countries. The original CPV2 rapidly evolved into two antigenic variants, CPV2a and CPV2b, which progressively replaced the original CPV2. More recently a new antigenic variant, CPV2c, has appeared. To date this variant has been identified in many countries worldwide but there have been no reports yet of its presence in any Scandinavian countries. This case report therefore represents the first published evidence of the involvement of CPV2c in a severe outbreak of typical haemorrhagic gastroenteritis in a susceptible litter of pups in Scandinavia. PMID:24016358

2013-01-01

265

Genome-wide association study in people of South Asian ancestry identifies six novel susceptibility loci for type 2 diabetes  

PubMed Central

We carried out a genome wide association study of type-2 diabetes (T2D) amongst 20,119 people of South Asian ancestry (5,561 with T2D); we identified 20 independent SNPs associated with T2D at P<10?4 for testing amongst a further 38,568 South Asians (13,170 with T2D). In combined analysis, common genetic variants at six novel loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) were associated with T2D (P=4.1×10?8 to P=1.9×10?11); SNPs at GRB14 were also associated with insulin sensitivity, and at ST6GAL1 and HNF4A with pancreatic beta-cell function respectively. Our findings provide additional insight into mechanisms underlying T2D, and demonstrate the potential for new discovery from genetic association studies in South Asians who have increased susceptibility to T2D. PMID:21874001

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 BM; Li, Xinzhing; Radha, Venkatesan; Rees, Simon D; Takeuchi, Fumihiko; Young, Robin; Aung, Tin; Basit, Abdul; Chidambaram, Manickam; Das, Debashish; Grunberg, Elin; Hedman, Åsa 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, Tim; 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

2013-01-01

266

System and method employing a self-organizing map load feature database to identify electric load types of different electric loads  

SciTech Connect

A method identifies electric load types of a plurality of different electric loads. The method includes providing a self-organizing map load feature database of a plurality of different electric load types and a plurality of neurons, each of the load types corresponding to a number of the neurons; employing a weight vector for each of the neurons; sensing a voltage signal and a current signal for each of the loads; determining a load feature vector including at least four different load features from the sensed voltage signal and the sensed current signal for a corresponding one of the loads; and identifying by a processor one of the load types by relating the load feature vector to the neurons of the database by identifying the weight vector of one of the neurons corresponding to the one of the load types that is a minimal distance to the load feature vector.

Lu, Bin; Harley, Ronald G.; Du, Liang; Yang, Yi; Sharma, Santosh K.; Zambare, Prachi; Madane, Mayura A.

2014-06-17

267

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

E-print Network

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

Paris-Sud XI, Université de

268

Intestinal T-cell and natural killer-cell lymphomas in Taiwan with special emphasis on 2 distinct cellular types: natural killer-like cytotoxic T cell and true natural killer cell.  

PubMed

Primary intestinal lymphomas are rare, especially the T-cell and natural killer (NK)-cell types. Enteropathy-type T-cell lymphoma (ETL) is the most characteristic of the intestinal T-cell and NK-cell lymphomas (ITNKLs) defined in the World Health Organization classification. However, typical ETL is rare in nonendemic areas for celiac disease, which include Taiwan. With the exception of ETLs, ITNKLs comprise heterogeneous subtypes such as anaplastic large cell lymphoma, nasal-type NK/T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Furthermore, the literature results with respect to the association between Epstein-Barr virus (EBV) and ITNKL are contradictory. To define the clinicopathological features of primary ITNKLs and develop a better understanding of their relationship with EBV in Taiwan, therefore, we investigated a sample of 11 patients based on the new World Health Organization classification using immunostaining, in situ hybridization for EBV detection, and polymerase chain reaction (PCR) for evaluation of T-cell receptor clonality. In conclusion, 2 distinct groups of primary ITNKLs were identified in our Taiwanese sample. The 6 group A cases were non-EBV-associated ETLs, prevalent in the jejunum and/or ileum. They were composed of monotonous round-ovoid medium-sized nuclei and had little pale cytoplasm. The immunophenotypes of these tumors were consistently CD3+, CD4-, CD8+, CD56+, T-cell intracellular antigen 1+, and Epstein-Barr early region- and monoclonal for T-cell receptor PCR, which indicated NK-like cytotoxic T-cell origin. The 5 group B cases were EBV-associated nasal-type NK/T-cell lymphomas prevalent in the ileum or cecum of younger patients. The neoplastic cells had polymorphous medium to large angulated nuclei and moderate cytoplasm, with immunologic phenotypes of CD4-, CD8-, variable cytoplasmic CD3varepsilon+, CD56+, T-cell intracellular antigen 1+, and Epstein-Barr early region 1+, and germ line PCR result for T-cell receptor, which indicated true NK-cell origin. The grave prognoses for the 2 groups did not differ significantly. PMID:18482744

Tung, Chun-Liang; Hsieh, Pin-Pen; Chang, Julia Hueimei; Chen, Ruey-Shyang; Chen, Yi-Ju; Wang, Jyh-Seng

2008-07-01

269

Identification of single and dual infections with distinct subtypes of human immunodeficiency virus type 1 by using restriction fragment length polymorphism analysis  

Microsoft Academic Search

The simultaneous presence of multiple HIV-1 subtypes has become common in communities with the growth of the pandemic. As a consequence, the potentiality for an increased frequency of HIV-1 mixed infections caused by viruses of distinct subtypes could be expected. Thus, there is a need to estimate the prevalence and geographic distribution of infections caused by viruses of a singular

Luiz M. Janini; Danuta Pieniazek; Jose M. Peralta; Mauro Schechter; Amilcar Tanuri; Ana C. P. Vicente; Nick Dela Torre; Norman J. Pieniazek; Chi-Cheng Luo; Marcia L. Kalish; Gerald Schochetman; Mark A. Rayfield

1996-01-01

270

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

PubMed

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

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

271

A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans  

PubMed Central

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 HbA1c 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

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

272

"Humanized" HLA transgenic NOD mice to identify pancreatic beta cell autoantigens of potential clinical relevance to type 1 diabetes.  

PubMed

The mechanistic basis by which the H2(g7) major histocompatibility complex (MHC) provides the primary risk factor for the development of T cell-mediated autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice involves contributions not only from the unusual A(g7) class II molecule, but also from the more common K(d) and/or D(b) class I variants it encodes. Similarly, transgenic studies in NOD mice have confirmed the possibility first suggested in association studies that in the proper genetic context the common human HLA-A2.1 class I variant can mediate diabetogenic CD8 T cell responses. T1D continues to develop in a further refined NOD stock that expresses human HLA-A2.1, but no murine class I molecules (designated NOD.beta2m-.HHD). Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an important antigenic target of diabetogenic CD8 cells in standard NOD mice. Three IGRP-derived peptides have also been identified that are presented by human HLA-A2.1 molecules to diabetogenic CD8 T cells in NOD.beta2m-.HHD mice. At least one of these IGRP peptides (265-273) can also be the target of autoreactive CD8 T cells in HLA-A2.1-expressing human T1D patients. Studies are currently under way to determine whether HLA-A2.1-restricted IGRP peptides can be used in a tolerance-inducing protocol that inhibits T1D development in NOD. beta2m-.HHD mice. If so, this knowledge could ultimately lead to the development of a similar T1D prevention protocol in humans. PMID:17376821

Serreze, David V; Marron, Michele P; Dilorenzo, Teresa P

2007-04-01

273

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

PubMed Central

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

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

2013-01-01

274

Endocytotic routes of cobra cardiotoxins depend on spatial distribution of positively charged and hydrophobic domains to target distinct types of sulfated glycoconjugates on cell surface.  

PubMed

Cobra cardiotoxins (CTX) are a family of three-fingered basic polypeptides known to interact with diverse targets such as heparan sulfates, sulfatides, and integrins on cell surfaces. After CTX bind to the membrane surface, they are internalized to intracellular space and exert their cytotoxicity via an unknown mechanism. By the combined in vitro kinetic binding, three-dimensional x-ray structure determination, and cell biology studies on the naturally abundant CTX homologues from the Taiwanese cobra, we showed that slight variations on the spatial distribution of positively charged or hydrophobic domains among CTX A2, A3, and A4 could lead to significant changes in their endocytotic pathways and action mechanisms via distinct sulfated glycoconjugate-mediated processes. The intracellular locations of these structurally similar CTX after internalization are shown to vary between the mitochondria and lysosomes via either dynamin2-dependent or -independent processes with distinct membrane cholesterol sensitivity. Evidence is presented to suggest that the shifting between the sulfated glycoconjugates as distinct targets of CTX A2, A3, and A4 might play roles in the co-evolutionary arms race between venomous snake toxins to cope with different membrane repair mechanisms at the cellular levels. The sensitivity of endocytotic routes to the spatial distribution of positively charged or hydrophobic domains may provide an explanation for the diverse endocytosis pathways of other cell-penetrating basic polypeptides. PMID:24898246

Lee, Shao-Chen; Lin, Chien-Chu; Wang, Chia-Hui; Wu, Po-Long; Huang, Hsuan-Wei; Chang, Chung-I; Wu, Wen-guey

2014-07-18

275

System and method employing a minimum distance and a load feature database to identify electric load types of different electric loads  

DOEpatents

A method identifies electric load types of a plurality of different electric loads. The method includes providing a load feature database of a plurality of different electric load types, each of the different electric load types including a first load feature vector having at least four different load features; sensing a voltage signal and a current signal for each of the different electric loads; determining a second load feature vector comprising at least four different load features from the sensed voltage signal and the sensed current signal for a corresponding one of the different electric loads; and identifying by a processor one of the different electric load types by determining a minimum distance of the second load feature vector to the first load feature vector of the different electric load types of the load feature database.

Lu, Bin; Yang, Yi; Sharma, Santosh K; Zambare, Prachi; Madane, Mayura A

2014-12-23

276

Structurally distinct hybrid polymer/lipid nanoconstructs harboring a type-I ribotoxin as cellular imaging and glioblastoma-directed therapeutic vectors.  

PubMed

A nanoformulation composed of a ribosome inactivating protein-curcin and a hybrid solid lipid nanovector has been devised against glioblastoma. The structurally distinct nanoparticles were highly compatible to human endothelial and neuronal cells. A sturdy drug release from the particles, recorded upto 72?h, was reflected in the time-dependent toxicity. Folate-targeted nanoparticles were specifically internalized by glioma, imparting superior toxicity and curbed an aggressively proliferating in vitro 3D cancer mass in addition to suppressing the anti-apoptotic survivin and cell matrix protein vinculin. Combined with the imaging potential of the encapsulated dye, the nanovector emanates as a multifunctional anti-cancer system. PMID:25181322

Mohamed, M Sheikh; Veeranarayanan, Srivani; Baliyan, Ankur; Poulose, Aby Cheruvathoor; Nagaoka, Yutaka; Minegishi, Hiroaki; Iwai, Seiki; Shimane, Yasuhiro; Yoshida, Yasuhiko; Maekawa, Toru; Kumar, D Sakthi

2014-12-01

277

Characterizing the successful student in general chemistry and physical science classes in terms of Jung's personality types as identified by the Myers-Briggs Type Indicator  

Microsoft Academic Search

A student's success in a science class can depend upon previous experiences, motivation, and the level of interest in the subject. Since psychological type is intrinsic to a person's whole being, it can be influential upon the student's motivation and interests. Thus, a study of student psychological types versus the level of success in a class, as measured by a

Wayne David Riley

1998-01-01

278

Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival  

PubMed Central

Type 1 von Willebrand disease (VWD) is characterized by a partial quantitative deficiency of von Willebrand factor (VWF). Few VWF gene mutations have been identified that cause dominant type 1 VWD. The decreased survival of VWF in plasma has recently been identified as a novel mechanism for type 1 VWD. We report 4 families with moderately severe type 1 VWD characterized by low plasma VWF:Ag and FVIII:C levels, proportionately low VWF:RCo, and dominant inheritance. A decreased survival of VWF in affected individuals was identified with VWF half-lives of 1 to 3 hours, whereas the half-life of VWF propeptide (VWFpp) was normal. DNA sequencing revealed a single (heterozygous) VWF mutation in affected individuals, S2179F in 2 families, and W1144G in 2 families, neither of which has been previously reported. We show that the ratio of steady-state plasma VWFpp to VWF:Ag can be used to identify patients with a shortened VWF half-life. An increased ratio distinguished affected from unaffected individuals in all families. A significantly increased VWFpp/VWF:Ag ratio together with reduced VWF:Ag may indicate the presence of a true genetic defect and decreased VWF survival phenotype. This phenotype may require an altered clinical therapeutic approach, and we propose to refer to this phenotype as type-1C VWD. PMID:16835381

Haberichter, Sandra L.; Balistreri, Michael; Christopherson, Pamela; Morateck, Patricia; Gavazova, Stefana; Bellissimo, Daniel B.; Manco-Johnson, Marilyn J.; Gill, Joan Cox; Montgomery, Robert R.

2006-01-01

279

Epitope Predictions Indicate the Presence of Two Distinct Types of Epitope-Antibody-Reactivities Determined by Epitope Profiling of Intravenous Immunoglobulins  

PubMed Central

Epitope-antibody-reactivities (EAR) of intravenous immunoglobulins (IVIGs) determined for 75,534 peptides by microarray analysis demonstrate that roughly 9% of peptides derived from 870 different human protein sequences react with antibodies present in IVIG. Computational prediction of linear B cell epitopes was conducted using machine learning with an ensemble of classifiers in combination with position weight matrix (PWM) analysis. Machine learning slightly outperformed PWM with area under the curve (AUC) of 0.884 vs. 0.849. Two different types of epitope-antibody recognition-modes (Type I EAR and Type II EAR) were found. Peptides of Type I EAR are high in tyrosine, tryptophan and phenylalanine, and low in asparagine, glutamine and glutamic acid residues, whereas for peptides of Type II EAR it is the other way around. Representative crystal structures present in the Protein Data Bank (PDB) of Type I EAR are PDB 1TZI and PDB 2DD8, while PDB 2FD6 and 2J4W are typical for Type II EAR. Type I EAR peptides share predicted propensities for being presented by MHC class I and class II complexes. The latter interaction possibly favors T cell-dependent antibody responses including IgG class switching. Peptides of Type II EAR are predicted not to be preferentially presented by MHC complexes, thus implying the involvement of T cell-independent IgG class switch mechanisms. The high extent of IgG immunoglobulin reactivity with human peptides implies that circulating IgG molecules are prone to bind to human protein/peptide structures under non-pathological, non-inflammatory conditions. A webserver for predicting EAR of peptide sequences is available at www.sysmed-immun.eu/EAR. PMID:24244326

Luštrek, Mitja; Lorenz, Peter; Kreutzer, Michael; Qian, Zilliang; Steinbeck, Felix; Wu, Di; Born, Nadine; Ziems, Bjoern; Hecker, Michael; Blank, Miri; Shoenfeld, Yehuda; Cao, Zhiwei; Glocker, Michael O.; Li, Yixue; Fuellen, Georg; Thiesen, Hans-Jürgen

2013-01-01

280

Distinct roles of L- and T-type voltage-dependent Ca2+ channels in regulation of lymphatic vessel contractile activity.  

PubMed

Lymph drainage maintains tissue fluid homeostasis and facilitates immune response. It is promoted by phasic contractions of collecting lymphatic vessels through which lymph is propelled back into the blood circulation. This rhythmic contractile activity (i.e. lymphatic pumping) increases in rate with increase in luminal pressure and relies on activation of nifedipine-sensitive voltage-dependent Ca(2+) channels (VDCCs). Despite their importance, these channels have not been characterized in lymphatic vessels. We used pressure- and wire-myography as well as intracellular microelectrode electrophysiology to characterize the pharmacological and electrophysiological properties of L-type and T-type VDCCs in rat mesenteric lymphatic vessels and evaluated their particular role in the regulation of lymphatic pumping by stretch. We complemented our study with PCR and confocal immunofluorescence imaging to investigate the expression and localization of these channels in lymphatic vessels. Our data suggest a delineating role of VDCCs in stretch-induced lymphatic vessel contractions, as the stretch-induced increase in force of lymphatic vessel contractions was significantly attenuated in the presence of L-type VDCC blockers nifedipine and diltiazem, while the stretch-induced increase in contraction frequency was significantly decreased by the T-type VDCC blockers mibefradil and nickel. The latter effect was correlated with a hyperpolarization. We propose that activation of T-type VDCCs depolarizes membrane potential, regulating the frequency of lymphatic contractions via opening of L-type VDCCs, which drive the strength of contractions. PMID:25326448

Lee, Stewart; Roizes, Simon; von der Weid, Pierre-Yves

2014-12-15

281

Inhibitors of the Aminoglycoside 6?-N-Acetyltransferase type Ib [AAC(6?)-Ib] Identified by In-Silico Molecular Docking  

PubMed Central

AAC(6?)-Ib is an important aminoglycoside resistance enzyme to target with enzymatic inhibitors. An in-silico screening approach was used to identify potential inhibitors from the ChemBridge library. Several compounds were identified, of which two of them, 4-[(2-{[1-(3-methylphenyl)-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene]methyl}phenoxy)methyl]benzoic acid and 2-{5-[(4,6-dioxo-1,3-diphenyl-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid, showed micromolar activity in inhibiting acetylation of kanamycin A. These compounds are predicted to bind the aminoglycoside binding site of AAC(6?)-Ib and exhibited competitive inhibition against kanamycin A. PMID:24011645

Lin, David L.; Tran, Tung; Adams, Christina; Alam, Jamal Y.; Herron, Steven; Tolmasky, Marcelo E.

2013-01-01

282

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

Microsoft Academic Search

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,

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

2004-01-01

283

The application of visceral adiposity index in identifying type 2 diabetes risks based on a prospective cohort in China  

PubMed Central

Background Visceral adiposity index (VAI), a novel sex-specific index for visceral fat measurement, has been proposed recently. We evaluate the efficacy of VAI in identifying diabetes risk in Chinese people, and compare the predictive ability between VAI and other body fatness indices, i.e., waist circumference (WC), body mass index (BMI) and waist- to- height ratio (WHtR). Methods Participants (n?=?3,461) were recruited from an ongoing cohort study in Jiangsu Province, China. Hazard ratio (HR) and corresponding 95% confidence interval (CI) between diabetes risk and different body fatness indices were evaluated by Cox proportional hazard regression model. Receiver operating characteristic (ROC) curve and area under curve (AUC) were applied to compare the ability of identifying diabetes risk between VAI, WC, WHtR and BMI. Results A total number of 160 new diabetic cases occurred during the follow-up, with an incidence of 4.6%. Significant positive associations were observed for VAI with blood pressure, fasting plasma glucose, triglyceride, WC, BMI and WHtR. Moreover, increased VAI was observed to be associated with higher diabetes risk with a positive dose–response trend (p for trend?identifying the risk of diabetes in large-scale epidemiologic studies. PMID:25002013

2014-01-01

284

Three Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutants with Distinct and Asymmetric Effects on Virulence in Mice Compared with Rabbits  

Microsoft Academic Search

Herpes simplex virus type 1 latency-associated transcript (LAT)-null mutants have decreased reactivation but normal virulence in rabbits and mice. We report here on dLAT1.5, a mutant with LAT nucleotides 76 to 1667 deleted. Following ocular infection of rabbits, dLAT1.5 reactivated at a lower rate than its wild-type parent McKrae (6.1 versus 11.8%; P 0.0025 (chi-square test)). Reactivation was restored in

GUEY-CHUEN PERNG; DANIEL ESMAILI; SUSAN M. SLANINA; ADA YUKHT; HOMAYON GHIASI; NELSON OSORIO; KEVIN R. MOTT; BARAK MAGUEN; LING JIN; ANTHONY B. NESBURN; STEVEN L. WECHSLER

2001-01-01

285

Distinctive Charge Density Distributions of Perovskite-Type Antiferroelectric Oxides PbZrO3 and PbHfO3 in Cubic Phase  

NASA Astrophysics Data System (ADS)

The electron charge density distributions of simple perovskite oxides, PbBO3 (B = Ti, Zr and Hf), in their cubic phase are investigated by analyzing high-energy synchrotron powder diffraction data by the maximum entropy method (MEM)/Rietveld method. Clear structural differences between the antiferroelectric and ferroelectric perovskites are revealed. In the cubic phase of PbZrO3 and PbHfO3 that undergo antiferroelectric phase transitions, the Pb atom is disordered around the special Wyckoff position. The thermal motion of the O atom is anisotropic, and the charge density distributions around the O atom are extended in the directions perpendicular to the Zr(Hf)-O covalent bond. None of these structural characteristics are observed in the cubic phase of PbTiO3 that undergoes ferroelectric phase transition. The distinctive structural features observed in PbZrO3 and PbHfO3 should provide a clue to the mechanism of antiferroelectric phase transition.

Kuroiwa, Yoshihiro; Fujiwara, Hiroshi; Sawada, Akikatsu; Aoyagi, Shinobu; Nishibori, Eiji; Sakata, Makoto; Takata, Masaki; Kawaji, Hitoshi; Atake, Tooru

2004-09-01

286

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)

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.

Pikin, S. A.

2008-09-01

287

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

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.

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

288

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

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

2012-01-01

289

Ketosis-prone type 2 diabetes mellitus in a patient with Sheehan’s syndrome: a rare convergence of two distinct endocrine entities  

PubMed Central

A 36-year-old housewife, previously diagnosed with Sheehan’s syndrome on glucocorticoid and thyroxine replacement therapy, presented with unprovoked diabetic ketoacidosis. Ketoacidosis was corrected with intravenous fluids and insulin therapy. Further evaluation was suggestive of type 2 diabetes mellitus. On follow-up, she experienced repeated episodes of hypoglycaemia and insulin was tapered and stopped. Adequate glycaemic control was maintained with metformin monotherapy. PMID:22665875

Naha, Kushal; Vivek, G; Dasari, Sowjanya; Prabhu, Mukhyaprana

2012-01-01

290

Arabidopsis Genes Encoding Mitochondrial Type II NAD(P)H Dehydrogenases Have Different Evolutionary Origin and Show Distinct Responses to Light1  

PubMed Central

In addition to proton-pumping complex I, plant mitochondria contain several type II NAD(P)H dehydrogenases in the electron transport chain. The extra enzymes allow the nonenergy-conserving electron transfer from cytoplasmic and matrix NAD(P)H to ubiquinone. We have investigated the type II NAD(P)H dehydrogenase gene families in Arabidopsis. This model plant contains two and four genes closely related to potato (Solanum tuberosum) genes nda1 and ndb1, respectively. A novel homolog, termed ndc1, with a lower but significant similarity to potato nda1 and ndb1, is also present. All genes are expressed in several organs of the plant. Among the nda genes, expression of nda1, but not nda2, is dependent on light and circadian regulation, suggesting separate roles in photosynthesis-associated and other respiratory NADH oxidation. Genes from all three gene families encode proteins exclusively targeted to mitochondria, as revealed by expression of green fluorescent fusion proteins and by western blotting of fractionated cells. Phylogenetic analysis indicates that ndc1 affiliates with cyanobacterial type II NADH dehydrogenase genes, suggesting that this gene entered the eukaryotic cell via the chloroplast progenitor. The ndc1 should then have been transferred to the nucleus and acquired a signal for mitochondrial targeting of the protein product. Although they are of different origin, the nda, ndb, and ndc genes carry an identical intron position. PMID:12972666

Michalecka, Agnieszka M.; Svensson, Å. Staffan; Johansson, Fredrik I.; Agius, Stephanie C.; Johanson, Urban; Brennicke, Axel; Binder, Stefan; Rasmusson, Allan G.

2003-01-01

291

Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes.  

PubMed

Acanthosis nigricans and hyperandrogenism are commonly found in patients with extreme target cell resistance to insulin, as in the type A and B syndromes of insulin resistance. However, the significance of concurrent acanthosis nigricans and hyperandrogenism in other clinical settings is not clear. We observed acanthosis nigricans to be present in 5% (15 of 300) of patients being evaluated for hyperandrogenism, and carried out studies of insulin binding and action in a group (7) of these women. Although none were diabetic, all were insulin resistant as assessed by hyperinsulinemia when fasting and after oral glucose administration. All patients were obese (mean IBW, 169%). However, when matched to hyperandrogenized women of similar body weight, patients with acanthosis nigricans were clearly more hyperinsulinemic. Insulin binding to monocytes and red cells was decreased in patients with acanthosis, and the extent of decrease was predicted by the fasting insulin level. There was also marked resistance to exogenous insulin during euglycemic insulin clamp studies in the two patients so tested. Anti-insulin receptor antibodies were not detectable, ruling out the type B syndrome. Unlike the type A syndrome, insulin binding to monocytes of these patients increased after acute (2/2) and chronic (1/1) caloric restriction. In the latter patient, acanthosis nigricans remitted as insulin resistance and the insulin binding defect improved. We conclude that acanthosis nigricans is present in as many as 5% of women with clinically significant hyperandrogenism. These women, although not diabetic, have fairly marked insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3881301

Flier, J S; Eastman, R C; Minaker, K L; Matteson, D; Rowe, J W

1985-02-01

292

DNA typing of ancient parasite eggs from environmental samples identifies human and animal worm infections in Viking-age settlement.  

PubMed

Abstract 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 offers excellent opportunities for studies of human parasite infections and of human and animal interactions of the past. PMID:25357228

Søe, Martin Jensen; Nejsum, Peter; Fredensborg, Brian Lund; Kapel, Christian Moliin Outzen

2014-10-30

293

Global biochemical profiling identifies beta-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans.  

PubMed

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like pepide-1 (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 coined the "incretin response". To determine the role(s) of K cells for the incretin response and T2DM, "DT" mice lacking GIP-producing cells were backcrossed 5 to 8 times onto the diabetogenic NONcNZO10/Ltj background. Like 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 WT mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetic complications in pre-diabetic DT/HF mice. Beta-hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting beta-hydroxypyruvate production from D-serine. In vitro, beta-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. Beta-hydroxypyruvate/D-serine ratios were lower in humans with impaired glucose tolerance compared to normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to beta-hydroxypyruvate/D-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and beta cells by regulating beta-hydroxypyruvate levels. PMID:25368100

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

2014-11-01

294

Identifying, by first-principles simulations, Cu[amyloid-?] species making Fenton-type reactions in Alzheimer's disease.  

PubMed

According to the amyloid cascade hypothesis, amyloid-? peptides (A?) play a causative role in Alzheimer's disease (AD), of which oligomeric forms are proposed to be the most neurotoxic by provoking oxidative stress. Copper ions seem to play an important role as they are bound to A? in amyloid plaques, a hallmark of AD. Moreover, Cu-A? complexes are able to catalyze the production of hydrogen peroxide and hydroxyl radicals, and oligomeric Cu-A? was reported to be more reactive. The flexibility of the unstructured A? peptide leads to the formation of a multitude of different forms of both Cu(I) and Cu(II) complexes. This raised the question of the structure-function relationship. We address this question for the biologically relevant Fenton-type reaction. Computational models for the Cu-A? complex in monomeric and dimeric forms were built, and their redox behavior was analyzed together with their reactivity with peroxide. A set of 16 configurations of Cu-A? was studied and the configurations were classified into 3 groups: (A) configurations that evolve into a linearly bound and nonreactive Cu(I) coordination; (B) reactive configurations without large reorganization between the two Cu redox states; and (C) reactive configurations with an open structure in the Cu(I)-A? coordination, which have high water accessibility to Cu. All the structures that showed high reactivity with H2O2 (to form HO(•)) fall into class C. This means that within all the possible configurations, only some pools are able to produce efficiently the deleterious HO(•), while the other pools are more inert. The characteristics of highly reactive configurations consist of a N-Cu(I)-N coordination with an angle far from 180° and high water crowding at the open side. This allows the side-on entrance of H2O2 and its cleavage to form a hydroxyl radical. Interestingly, the reactive Cu(I)-A? states originated mostly from the dimeric starting models, in agreement with the higher reactivity of oligomers. Our study gives a rationale for the Fenton-type reactivity of Cu-A? and how dimeric Cu-A? could lead to a higher reactivity. This opens a new therapeutic angle of attack against Cu-A?-based reactive oxygen species production. PMID:24313818

La Penna, Giovanni; Hureau, Christelle; Andreussi, Oliviero; Faller, Peter

2013-12-27

295

Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II.  

PubMed

Familial hyperaldosteronism type II (FH-II) is an inherited form of hyperaldosteronism associated with hypertension in most patients. The mutations that cause FH-II are unknown, but linkage analysis has mapped them to chromosome 7p22. As FH-II is clinically indistinguishable from sporadic primary aldosteronism, a common and treatable condition, unravelling the cause of FH-II has important implications for these sporadic cases. To investigate whether FH-II is caused by large deletions or insertions, we examined the virtual karyotype of four pairs of affected and unaffected individuals using high-density bead chips. We also sequenced the coding regions of five 7p22 candidate genes that were prioritized because of their putative role in cell growth. We found no evidence of single-nucleotide polymorphism (SNP) copy number variation between pairs, and from the widest gap on the chip, chromosome 7p22 deletions or insertions exceeding ?50 kb in these pedigrees can be excluded. We found 15 SNPs (two of which were novel), but none of them were non-synonymous and segregated with the disease in the FH-II pedigrees. We have been able to exclude large genomic deletions or insertions at 7p22 and refine the candidate gene list for this locus, but the mutations causing FH-II remain elusive. PMID:20927129

Carss, K J; Stowasser, M; Gordon, R D; O'Shaughnessy, K M

2011-09-01

296

Human Immunodeficiency Virus (HIV) Antibody Avidity Testing To Identify Recent Infection in Newly Diagnosed HIV Type 1 (HIV1)Seropositive Persons Infected with Diverse HIV1 Subtypes  

Microsoft Academic Search

A guanidine-based antibody avidity assay for the identification of recently acquired human immunodefi- ciency virus type 1 (HIV-1) infection was evaluated. The kinetics of maturation of antibody avidity were determined prospectively in 23 persons undergoing acute seroconversion followed for up to 1,075 days. Avidity indices (AI) of <0.75 and <0.80 reproducibly identified seroconversion within the previous 125 (95% confi- dence

A. Chawla; G. Murphy; C. Donnelly; C. L. Booth; M. Johnson; J. V. Parry; A. Phillips; A. M. Geretti

2007-01-01

297

Distinct characteristics of OxyR2, a new OxyR-type regulator, ensuring expression of Peroxiredoxin 2 detoxifying low levels of hydrogen peroxide in Vibrio vulnificus.  

PubMed

Two peroxiredoxins, Prx1 and Prx2, were previously identified in Vibrio vulnificus. Besides OxyR1, a homologue of Escherichia coli?OxyR (EcOxyR), OxyR2 that shares low homology with EcOxyR was first identified in V. vulnificus. OxyR2 activated prx2 during aerobic growth, while OxyR1 activated prx1 only when exposed to exogenous H2O2. OxyR2 was oxidized to form a reversible C206 to C215 disulphide bond by sensing low levels of H2O2, which were insufficient to oxidize OxyR1, and only the oxidized OxyR2 activated prx2. OxyR25CA, in which all cysteine residues except for C206 and C215 were replaced with alanines, and its mutants, OxyR25CA-C206S and OxyR25CA-C215S, were constructed. OxyR25CA and OxyR25CA-C215S directly bound to a specific binding sequence centred at -56.5 from the prx2 transcription start site, albeit with different binding affinities. The binding sequence consisted of four ATCGnt elements spaced by a helical turn and aligned in the twofold dyad symmetry, suggesting that OxyR2 binds DNA as a tetramer. OxyR25CA-C206S also directly bound to DNA comprising more extended sequences, indicating that oxidized and reduced OxyR2 adopt different conformational states, leading to altered DNA contacts. The oxyR2 mutation reduced cytotoxicity and growth during infection, indicating that OxyR2 is essential for the pathogenesis of V. vulnificus. PMID:25041181

Kim, Suyeon; Bang, Ye-Ji; Kim, Dukyun; Lim, Jong Gyu; Oh, Man Hwan; Choi, Sang Ho

2014-09-01

298

Distinctive Immunomodulatory and Inflammatory Properties of the Escherichia coli Type II Heat-Labile Enterotoxin LT-IIa and Its B Pentamer following Intradermal Administration?  

PubMed Central

The type I and type II heat-labile enterotoxins (LT-I and LT-II) are strong mucosal adjuvants when they are coadministered with soluble antigens. Nonetheless, data on the parenteral adjuvant activities of LT-II are still limited. Particularly, no previous study has evaluated the adjuvant effects and induced inflammatory reactions of LT-II holotoxins or their B pentameric subunits after delivery via the intradermal (i.d.) route to mice. In the present report, the adjuvant and local skin inflammatory effects of LT-IIa and its B subunit pentamer (LT-IIaB5) were determined. When coadministered with ovalbumin (OVA), LT-IIa and, to a lesser extent, LT-IIaB5 exhibited serum IgG adjuvant effects. In addition, LT-IIa but not LT-IIaB5 induced T cell-specific anti-OVA responses, particularly in respect to induction of antigen-specific cytotoxic CD8+ T cell responses. LT-IIa and LT-IIaB5 induced differential tissue permeability and local inflammatory reactions after i.d. injection. Of particular interest was the reduced or complete lack of local reactions, such as edema and tissue induration, in mice i.d. inoculated with LT-IIa and LT-IIaB5, respectively, compared with mice immunized with LT-I. In conclusion, the present results show that LT-IIa and, to a lesser extent, LT-IIaB5 exert adjuvant effects when they are delivered via the i.d. route. In addition, the low inflammatory effects of LT-IIa and LT-IIaB5 in comparison to those of LT-I support the usefulness of LT-IIa and LT-IIaB5 as parenterally delivered vaccine adjuvants. PMID:21677110

Mathias-Santos, Camila; Rodrigues, Juliana F.; Sbrogio-Almeida, Maria Elisabete; Connell, Terry D.; Ferreira, Luís C. S.

2011-01-01

299

Triton College: One Institution's Search for Distinctiveness.  

ERIC Educational Resources Information Center

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…

Townsend, Barbara K.; Catanzaro, James L.

1989-01-01

300

Evidence for distinct proportions of subducted oceanic crust and lithosphere in HIMU-type mantle beneath El Hierro and La Palma, Canary Islands  

NASA Astrophysics Data System (ADS)

Shield-stage high-MgO alkalic lavas from La Palma and El Hierro (Canary Islands) have been characterized for their O-Sr-Nd-Os-Pb isotope compositions and major-, trace-, and highly siderophile-element (HSE: Os, Ir, Ru, Pt, Pd, Re) abundances. New data are also reported for associated evolved rocks, and entrained xenoliths. Clear differences in Pd/Ir and isotopic ratios for high Os (>50 ppt) lavas from El Hierro (? 18O olivine = 5.17 ± 0.08‰; 87Sr/ 86Sr = 0.7029 to 0.7031; ? Nd = +5.7 to +7.1; 187Os/ 188Os = 0.1481 to 0.1750; 206Pb/ 204Pb = 19.1 to 19.7; Pd/Ir = 6 ± 3) versus those from La Palma (? 18O olivine = 4.87 ± 0.18‰; 87Sr/ 86Sr = 0.7031 to 0.7032; ? Nd = +5.0 to +6.4; 187Os/ 188Os = 0.1421 to 0.1460; 206Pb/ 204Pb = 19.5 to 20.2; Pd/Ir = 11 ± 4) are revealed from the dataset. Crustal or lithospheric assimilation during magma transport cannot explain variations in isotopic ratios or element abundances of the lavas. Shallow-level crystal-liquid fractionation of olivine, clinopyroxene and associated early-crystallizing minerals (e.g., spinel and HSE-rich phases) controlled compatible element and HSE abundances; there is also evidence for sub-aerial degassing of rhenium. High-MgO lavas are enriched in light rare earth elements, Nb, Ta, U, Th, and depleted in K and Pb, relative to primitive mantle abundance estimates, typical of HIMU-type oceanic island basalts. Trace element abundances and ratios are consistent with low degrees (2-6%) of partial melting of an enriched mantle source, commencing in the garnet stability field (?110 km). Western Canary Island lavas were sulphur undersaturated with estimated parental melt HSE abundances (in ppb) of 0.07 ± 0.05 Os, 0.17 ± 0.16 Ir, 0.34 ± 0.32 Ru, 2.6 ± 2.5 Pt, 1.4 ± 1.2 Pd, 0.39 ± 0.30 Re. These estimates indicate that Canary Island alkali basalts have lower Os, Ir and Ru, but similar Pt, Pd and Re contents to Hawai'ian tholeiites. The HIMU affinities of the lavas, in conjunction with the low ? 18O olivine and high 206Pb/ 204Pb for La Palma, and elevated 187Os/ 188Os for El Hierro implies melting of different proportions of recycled oceanic crust and lithosphere. Our preferred model to explain isotopic differences between the islands is generation from peridotitic mantle metasomatised by <10% pyroxenite/eclogite made from variable portions of similar aged recycled oceanic crust and lithosphere. The correspondence of radiogenic 206Pb/ 204Pb, 187Os/ 188Os, elevated Re/Os and Pt/Os, and low-? 18O in western Canary Island lavas provides powerful support for recycled oceanic crust and lithosphere to generate the spectrum of HIMU-type ocean island basalt signatures. Persistence of geochemical heterogeneities throughout the stratigraphies of El Hierro and La Palma demonstrate long-term preservation of these recycled components in their mantle sources over relatively short-length scales (˜50 km).

Day, James M. D.; Pearson, D. Graham; Macpherson, Colin G.; Lowry, David; Carracedo, Juan Carlos

2010-11-01

301

Distinct core and halo stellar populations and the formation history of the bright Coma cluster early-type galaxy NGC 4889  

NASA Astrophysics Data System (ADS)

We study the stellar population far into the halo of one of the two brightest galaxies in the Coma cluster, NGC 4889, based on deep medium-resolution spectroscopy with FOCAS at the Subaru 8.2-m telescope. We fit single stellar population models to the measured line-strength (Lick) indices (H?, Mgb, [MgFe]' and ). Combining with literature data, we construct radial profiles of metallicity, [?/Fe] element abundance ratio and age for NGC 4889, from the centre out to ~60kpc (~ 4 Re). We find evidence for different chemical and star formation histories for stars inside and outside 1.2 Re = 18 kpc radius. The inner regions are characterized by a steep [Z/H] gradient and high [?/Fe] at ~2.5 solar value. In the halo, between 18 and 60kpc, the [Z/H] is near-solar with a shallow gradient, while [?/Fe] shows a strong negative gradient, reaching solar values at 60kpc. We interpret these data in terms of different formation histories for both components. The data for the inner galaxy are consistent with a rapid, quasi-monolithic, dissipative merger origin at early redshifts, followed by one or at most a few dry mergers. Those for the halo argue for later accretion of stars from old systems with more extended star formation histories. The half-light radius of the inner component alone is estimated as ~6kpc, suggesting a significantly smaller size of this galaxy in the past. This may be the local stellar population signature of the size evolution found for early-type galaxies from high-redshift observations.

Coccato, Lodovico; Gerhard, Ortwin; Arnaboldi, Magda

2010-09-01

302

Snake River (SR)-type" Volcanism: a new Category of Voluminous Explosive Volcanism Defined by a Distinctive Facies-Association in part of the Yellowstone Hotspot Track, Central Snake River Plain, USA.  

NASA Astrophysics Data System (ADS)

Along parts of the Yellowstone hot-spot track voluminous silicic volcanic rocks record large-scale silicic volcanism that differs in several respects from typical large-scale silicic volcanism elsewhere. The volcanic facies associations are sufficiently distinctive to merit a new term: "Snake River (SR)-type" volcanism. This new category of volcanism is defined with reference to deposit characteristics because it involves styles of eruption that have not been witnessed, and which are not fully understood. The distinctive SR-type characteristics, summarised below, are best preserved within 13 - 8 Ma volcanic successions that cover an area of southern central Idaho and northern Nevada, which we propose as the "type" example. (1) SR-type rhyolite lavas are unusually large volume (50-200 km3) and extensive (>200 km2), with low aspect-ratios, whereas smaller domes or coulees that characterise many rhyolite fields elsewhere are scarce. (2) The ignimbrites are typically large volume (VEI 6-8) but contain few pumice lapilli or fiamme. They are better sorted than typical ignimbrites, and plot outside the commonly used ignimbrite sorting vs. median diameter field. (3) The ignimbrites are characteristically lithic poor, even near inferred source areas. (4) Abundant small angular clasts of dense obsidian and vitrophyre occur within many of the ignimbrites and the fallout deposits. (5) Most SR-type ignimbrites are high to extremely high-grade: they are intensely rheomorphic, even where they are thin; and many are dominated by lava-like lithofacies. Although few non-welded ignimbrites occur, moderately welded ignimbrites (e.g. of eutaxitic lapilli-tuff) are very scarce. (6) The fallout layers are unusual: instead of typical Plinian fallout layers of pumice lapilli, most are thin-bedded medium-grained ashfall layers, with large bubble-wall shards, easily visible without a hand lens. Many have been fused to vitrophyre by contact with overlying and underlying ignimbrite; this includes co-ignimbrite ashfall layers. (7) Ash pellets, ash-coated pellets, and accretionary lapilli are common, and even occur in welded lihologies. (8) Lacustrine-alluvial facies are abundant, and include rippled volcaniclastic sands and silts, ignimbrites with peperitic bases, pillow lavas, hyaloclastites and soils. Work is in progress to investigate the nature and origin of the unusual and enigmatic eruption styles manifested by SR-type volcanism. The eruptions were high mass-flux, sustained, and involved unusually fluidal, hot (950-1050C) metaluminous rhyolite magmas with low H2O and elevated contents of HFSE and halogens. There is a close bimodal association with "plains type" basaltic volcanism, the presence of shallow epicontinental lakes, and with low-delta 18O. The distinctive type of volcanism is regionally devastating, and seems to have occurred at several times in Earth history because several SR-type features occur within other volcanic provinces such as Trans-Pecos Texas, Etendeka-Parana, Lebombo, the English Lake District, the Proterozoic Keewanawan volcanics of Minnesota and the Yardea Dacite of Australia.

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

2006-12-01

303

55- and 75-kilodalton tumor necrosis factor receptors mediate distinct actions in regard to human immunodeficiency virus type 1 replication in primary human macrophages.  

PubMed Central

We report in this study that repeated tumor necrosis factor alpha (TNF-alpha) pretreatment, starting before and continued after infection by human immunodeficiency virus type 1 (HIV-1), inhibits replication of the monocytotropic Ada strain in primary tissue culture-differentiated macrophages (TCDM), as assessed by sixfold lower levels of reverse transcriptase (RT) activity than that in untreated cells and absence of syncytium formation in TCDM cultures. In order to determine the pathways involved in inhibition of HIV-1 replication in primary TCDM pretreated with TNF-alpha, we tested TNF-alpha mutants T55 and T75, which recognize either the 55-kDa (TNF-R1) or the 75-kDa (TNF-R2) TNF receptor, respectively. Pretreatment of TCDM with the T75 mutant decreased the RT activity compared with that in untreated infected control cells fivefold and almost totally inhibited syncytium formation. In contrast, when TCDM were pretreated with the T55 mutant alone, syncytia were observed and RT activity was decreased about one-half. These results suggest that the inhibition of HIV-1 replication in TCDM pretreated with TNF-alpha might be mediated mainly through the 75-kDa TNF receptor (TNF-R2) rather than through the 55-kDa receptor (TNF-R1). Inhibition of HIV-1 replication in TCDM was observed with both T75 mutant pretreatment and posttreatment, starting at 1 h or 3 days after infection, whereas posttreatment with the T55 mutant, but not pretreatment, stimulated HIV-1 growth in primary TCDM. Both pre- and posttreatment with TNF-alpha inhibited HIV-1 replication in primary TCDM. The stimulation of HIV-1 replication by TNF-alpha in a chronically infected promonocytic cell line, U1, which contains two copies of integrated provirus, was mediated through the 55-kDa TNF-R1 alone and not through the 75-kDa TNF-R2. These results demonstrate that the 55-kDa TNF-R1 is involved in postintegration stimulation of HIV-1 while the 75-kDa TNF-R2 is involved in the inhibition of an early step of the viral life cycle in primary human TCDM. PMID:9094699

Herbein, G; Gordon, S

1997-01-01

304

Distinct Increased Metabotropic Glutamate Receptor Type 5 (mGluR5) in Temporal Lobe Epilepsy With and Without Hippocampal Sclerosis  

PubMed Central

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

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

305

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study.  

PubMed

We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-?, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml·min(-1)·1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-?-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans. PMID:22205226

Simonson, Michael S; Tiktin, Margaret; Debanne, Sara M; Rahman, Mahboob; Berger, Bruce; Hricik, Donald; Ismail-Beigi, Faramarz

2012-04-01

306

Independent optical excitation of distinct neural populations  

E-print Network

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 ...

Klapoetke, Nathan Cao

307

Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis*  

PubMed Central

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

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

308

Oligodeoxynucleotides antisense to mRNA encoding protein kinase A, protein kinase C, and beta-adrenergic receptor kinase reveal distinctive cell-type-specific roles in agonist-induced desensitization.  

PubMed Central

The roles of three protein kinases, cyclic AMP-dependent protein kinase (protein kinase A), protein kinase C, and beta-adrenergic receptor kinase (beta ARK), implicated in agonist-induced desensitization of guanine nucleotide-binding protein (G-protein)-coupled receptors were explored in four different cell lines after 48 hr of incubation with oligodeoxynucleotides antisense to the mRNA encoding each kinase. Desensitization of beta 2-adrenergic receptors was analyzed in cell types in which the activities of the endogenous complement of protein kinases A and C and beta ARK were distinctly different. Protein kinase A was necessary for desensitization of rat osteosarcoma cells (ROS 17/2.8), whereas the contribution of beta ARK to desensitization was insignificant. In Chinese hamster ovary cells that stably express beta 2-adrenergic receptors and in smooth muscle cells (DDT1MF-2), oligodeoxynucleotides antisense to beta ARK mRNA nearly abolished desensitization, whereas oligodeoxynucleotides antisense to protein kinase A mRNA attenuated desensitization to a lesser extent. In human epidermoid carcinoma cells (A-431), oligodeoxynucleotides antisense to either protein kinase A mRNA or beta ARK mRNA attenuated agonist-induced desensitization, providing a third scenario in which two kinases constitute the basis for agonist-induced desensitization. In sharp contrast, oligodeoxynucleotides antisense to protein kinase C mRNA were found to enhance rather than attenuate desensitization in DDT1MF-2 and A-431 cell lines, demonstrating counterregulation between prominent protein kinases in desensitization. Using antisense oligodeoxynucleotides to "knock out" target protein kinases in vivo, we reveal distinctive cell-type-specific roles of protein kinase A, protein kinase C, and beta ARK in agonist-induced desensitization. PMID:7991605

Shih, M; Malbon, C C

1994-01-01

309

Identifying and Classifying Rocks  

NSDL National Science Digital Library

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 ...

Owen, Elisabeth

2010-11-03

310

Sapronosis: a distinctive type of infectious agent.  

PubMed

Sapronotic disease agents have evolutionary and epidemiological properties unlike other infectious organisms. Their essential saprophagic existence prevents coevolution, and no host-parasite virulence trade-off can evolve. However, the host may evolve defenses. Models of pathogens show that sapronoses, lacking a threshold of transmission, cannot regulate host populations, although they can reduce host abundance and even extirpate their hosts. Immunocompromised hosts are relatively susceptible to sapronoses. Some particularly important sapronoses, such as cholera and anthrax, can sustain an epidemic in a host population. However, these microbes ultimately persist as saprophages. One-third of human infectious disease agents are sapronotic, including nearly all fungal diseases. Recognition that an infectious disease is sapronotic illuminates a need for effective environmental control strategies. PMID:25028088

Kuris, Armand M; Lafferty, Kevin D; Sokolow, Susanne H

2014-08-01

311

Sapronosis: a distinctive type of infectious agent  

USGS Publications Warehouse

Sapronotic disease agents have evolutionary and epidemiological properties unlike other infectious organisms. Their essential saprophagic existence prevents coevolution, and no host–parasite virulence trade-off can evolve. However, the host may evolve defenses. Models of pathogens show that sapronoses, lacking a threshold of transmission, cannot regulate host populations, although they can reduce host abundance and even extirpate their hosts. Immunocompromised hosts are relatively susceptible to sapronoses. Some particularly important sapronoses, such as cholera and anthrax, can sustain an epidemic in a host population. However, these microbes ultimately persist as saprophages. One-third of human infectious disease agents are sapronotic, including nearly all fungal diseases. Recognition that an infectious disease is sapronotic illuminates a need for effective environmental control strategies.

Kuris, Armand M.; Lafferty, Kevin D.; Sokolow, Susanne H.

2014-01-01

312

FACULTY DISTINCTIONS ENDOWED CHAIRS  

E-print Network

FACULTY DISTINCTIONS ENDOWED CHAIRS Avruch, Kevin Henry Hart Rice Chair of Conflict Analysis Molecular Neuroscience Boehm-Davis, Deborah Psychology Boettke, Peter Economics Button, Kenneth Public Policy Cheuse, Alan English Conlan, Timothy Public and International Affairs De Jong, Kenneth Computer

313

High-content RNAi screening identifies the Type 1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity  

PubMed Central

Cytosolic aggregation of the nuclear RNA-binding protein (RBP) TDP-43 (43 kDa TAR DNA-binding domain protein) is a suspected direct or indirect cause of motor neuron deterioration in amyotrophic lateral sclerosis (ALS). In this study, we implemented a high-content, genome-wide RNAi screen to identify pathways controlling TDP-43 nucleocytoplasmic shuttling. We identified ?60 genes whose silencing increased the cytosolic localization of TDP-43, including nuclear pore complex components and regulators of G2/M cell cycle transition. In addition, we identified the type 1 inositol-1,4,5-trisphosphate (IP3) receptor (ITPR1), an IP3-gated, endoplasmic reticulum (ER)-resident Ca2+ channel, as a strong modulator of TDP-43 nucleocytoplasmic shuttling. Knockdown or chemical inhibition of ITPR1 induced TDP-43 nuclear export in immortalized cells and primary neurons and strongly potentiated the recruitment of TDP-43 to Ubiquilin-positive autophagosomes, suggesting that diminished ITPR1 function leads to autophagosomal clearance of TDP-43. The functional significance of the TDP-43-ITPR1 genetic interaction was tested in Drosophila, where mutant alleles of ITPR1 were found to significantly extended lifespan and mobility of flies expressing TDP-43 under a motor neuron driver. These combined findings implicate IP3-gated Ca2+ as a key regulator of TDP-43 nucleoplasmic shuttling and proteostasis and suggest pharmacologic inhibition of ITPR1 as a strategy to combat TDP-43-induced neurodegeneration in vivo. PMID:22872699

Kim, Sang Hwa; Zhan, Lihong; Hanson, Keith A.; Tibbetts, Randal S.

2012-01-01

314

An in vivo high-throughput screening approach targeting the type IV secretion system component VirB8 identified inhibitors of Brucella abortus 2308 proliferation.  

PubMed

As bacterial pathogens develop resistance against most currently used antibiotics, novel alternatives for treatment of microbial infectious diseases are urgently needed. Targeting bacterial virulence functions in order to disarm pathogens represents a promising alternative to classical antibiotic therapy. Type IV secretion systems, which are multiprotein complexes in the cell envelope that translocate effectors into host cells, are critical bacterial virulence factors in many pathogens and excellent targets for such "antivirulence" drugs. The VirB8 protein from the mammalian pathogen Brucella was chosen as a specific target, since it is an essential type IV secretion system component, it participates in multiple protein-protein interactions, and it is essential for the assembly of this translocation machinery. The bacterial two-hybrid system was adapted to assay VirB8 interactions, and a high-throughput screen identified specific small-molecule inhibitors. VirB8 interaction inhibitors also reduced the levels of VirB8 and of other VirB proteins, and many of them inhibited virB gene transcription in Brucella abortus 2308, suggesting that targeting of the secretion system has complex regulatory effects in vivo. One compound strongly inhibited the intracellular proliferation of B. abortus 2308 in a J774 macrophage infection model. The results presented here show that in vivo screens with the bacterial two-hybrid assay are suited to the identification of inhibitors of Brucella type IV secretion system function. PMID:21173315

Paschos, Athanasios; den Hartigh, Andreas; Smith, Mark A; Atluri, Vidya L; Sivanesan, Durga; Tsolis, Renée M; Baron, Christian

2011-03-01

315

Signature-Tagged Mutagenesis of Edwardsiella ictaluri Identifies Virulence-Related Genes, Including a Salmonella Pathogenicity Island 2 Class of Type III Secretion Systems?  

PubMed Central

Edwardsiella ictaluri is the leading cause of mortality in channel catfish culture, but little is known about its pathogenesis. The use of signature-tagged mutagenesis in a waterborne infection model resulted in the identification of 50 mutants that were unable to infect/survive in catfish. Nineteen had minitransposon insertions in miscellaneous genes in the chromosome, 10 were in genes that matched to hypothetical proteins, and 13 were in genes that had no significant matches in the NCBI databases. Eight insertions were in genes encoding proteins associated with virulence in other pathogens, including three in genes involved in lipopolysaccharide biosynthesis, three in genes involved in type III secretion systems (TTSS), and two in genes involved in urease activity. With the use of a sequence from a lambda clone carrying several TTSS genes, Blastn analysis of the partially completed E. ictaluri genome identified a 26,135-bp pathogenicity island containing 33 genes of a TTSS with similarity to the Salmonella pathogenicity island 2 class of TTSS. The characterization of a TTSS apparatus mutant indicated that it retained its ability to invade catfish cell lines and macrophages but was defective in intracellular replication. The mutant also invaded catfish tissues in numbers equal to those of invading wild-type E. ictaluri bacteria but replicated poorly and was slowly cleared from the tissues, while the wild type increased in number. PMID:17965213

Thune, Ronald L.; Fernandez, Denise H.; Benoit, Jennifer L.; Kelly-Smith, Maria; Rogge, Matthew L.; Booth, Natha J.; Landry, Christie A.; Bologna, Rachel A.

2007-01-01

316

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

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

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

317

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

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

Fujita, Masaaki; Zhu, Kan; Fujita, Chitose K; Zhao, Min; Lam, Kit S; Kurth, Mark J; Takada, Yoko K; Takada, Yoshikazu

2015-01-01

318

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 Central

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

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

319

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

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

Burren, Oliver S.; Guo, Hui; Wallace, Chris

2014-01-01

320

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes  

PubMed Central

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

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

321

Application of Multiple-Locus Variable Number Tandem Repeat Analysis to Identify Outbreak-Associated Neisseria meningitides Serogroup C Sequence Type 4821 in China  

PubMed Central

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

Shan, Xiaoying; Zhou, Haijian; Zhang, Ji; Zhu, Bingqing; Xu, Li; Hu, Guangchun; Bai, Aiying; Shao, Zhujun; Jiang, Baofa

2015-01-01

322

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus.  

PubMed

As a result of genome-wide association studies in larger sample sets, there has been an increase in identifying genes that influence susceptibility to individual immune-mediated diseases, as well as evidence that some genes are associated with more than one disease. In this study, we tested 17 single nucleotide polymorphisms (SNP) from 16 gene regions that have been reported in several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ankylosing spondylitis (AS) and Crohn's disease (CD) to determine whether the variants are also associated with type 1 diabetes (T1D). In up to 8010 cases and 9733 controls we found some evidence for an association with T1D in the regions containing genes: 2q32/STAT4, 17q21/STAT3, 5p15/ERAP1 (ARTS1), 6q23/TNFAIP3 and 12q13/KIF5A/PIP4K2C with allelic P-values ranging from 3.70 x 10(-3) to 3.20 x 10(-5). These findings extend our knowledge of susceptibility locus sharing across different autoimmune diseases, and provide convincing evidence that the RA/SLE locus 6q23/TNFAIP3 is a newly identified T1D locus. PMID:19110536

Fung, E Y M G; Smyth, D J; Howson, J M M; Cooper, J D; Walker, N M; Stevens, H; Wicker, L S; Todd, J A

2009-03-01

323

Neuraminidase inhibitor susceptibility testing of influenza type B viruses in China during 2010 and 2011 identifies viruses with reduced susceptibility to oseltamivir and zanamivir.  

PubMed

Influenza type B viruses are responsible for substantial morbidity and mortality in humans. Antiviral drugs are an important supplement to vaccination for reducing the public health impact of influenza virus infections. Influenza B viruses are not sensitive to M2 inhibitors which limit the current therapeutic options to two neuraminidase inhibitors (NAIs), oseltamivir and zanamivir, which are licensed in many countries. Drug resistance is a public health concern which has necessitated monitoring of influenza virus drug susceptibilities through active global surveillance. Here, we report the results of drug susceptibility surveillance of influenza type B viruses (n=680) collected in mainland China during two calendar years, 2010 and 2011, assessed using functional neuraminidase (NA) inhibition (NI) assays. Four influenza B viruses exhibited reduced susceptibilities to oseltamivir, but not zanamivir, and shared the amino acid substitution I221T (ATC?ACC), at this conserved residue in the NA active site (I222T in N2 numbering). Additionally, a single virus with reduced susceptibility to both oseltamivir and zanamivir was identified and contained an amino acid substitution D197N (GAC?AAC) at another conserved residue in the NA active site (D198N in N2 numbering). This report underlies the importance of continued influenza antiviral susceptibility surveillance globally, even in countries where the use of NAIs has been low or non-existing. PMID:23267831

Wang, Dayan; Sleeman, Katrina; Huang, Weijuan; Nguyen, Ha T; Levine, Marnie; Cheng, Yanhui; Li, Xiyan; Tan, Minju; Xing, Xiaohui; Xu, Xiyan; Klimov, Alexander I; Gubareva, Larisa V; Shu, Yuelong

2013-03-01

324

FACULTY DISTINCTIONS ENDOWED CHAIRS  

E-print Network

FACULTY DISTINCTIONS ENDOWED CHAIRS Avruch, Kevin Henry Hart Rice Chair of Conflict Analysis Policy and University Professor Goldstone, Jack A. Virginia E. and John T. Hazel, Jr. Endowed Chair Gooding, Deborah Sidney O. Dewberry Endowed Chair for Civil, Environmental and Infrastructure Engineering

325

On distinct character degrees  

Microsoft Academic Search

Berkovich, Chillag and Herzog characterized all finite groups G in which all the nonlinear irreducible characters of G have distinct degrees. In this paper we extend this result showing that a similar characterization holds for all finite solvable\\u000a groups G that contain a normal subgroup N, such that all the irreducible characters of G that do not contain N in

Maria Loukaki

2007-01-01

326

Psychostimulants, antidepressants and neurokinin-1 receptor antagonists ('motor disinhibitors') have overlapping, but distinct, effects on monoamine transmission: the involvement of L-type Ca2+ channels and implications for the treatment of ADHD.  

PubMed

Both psychostimulants and antidepressants target monoamine transporters and, as a consequence, augment monoamine transmission. These two groups of drugs also increase motor activity in preclinical behavioural screens for antidepressants. Substance P-preferring receptor (NK1R) antagonists similarly increase both motor activity in these tests and monoamine transmission in the brain. In this article, the neurochemical and behavioural responses to these three groups of drugs are compared. It becomes evident that NK1R antagonists represent a distinct class of compounds ('motor disinhibitors') that differ substantially from both psychostimulants and antidepressants, especially during states of heightened arousal or stress. Also, all three groups of drugs influence the activation of voltage-gated Ca(v)1.2 and Ca(v)1.3 L-type channels (LTCCs) in the brain, albeit in different ways. This article discusses evidence that points to disruption of these functional interactions between NK1R and LTCCs as a contributing factor in the cognitive and behavioural abnormalities that are prominent features of Attention Deficit Hyperactivity Disorder (ADHD). Arising from this is the interesting possibility that the hyperactivity and impulsivity (as in ADHD) and psychomotor retardation (as in depression) reflect opposite poles of a behavioural continuum. A better understanding of this pharmacological network could help explain why psychostimulants augment motor behaviour during stress (e.g., in preclinical screens for antidepressants) and yet reduce locomotor activity and impulsivity in ADHD. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID:24727210

Stanford, S Clare

2014-12-01

327

Formation of distinct chromatin conformation signatures epigenetically regulate macrophage activation.  

PubMed

Microbial-lipopolysacharide (LPS), interleukin 4 (IL-4) and interferon gamma (IFN-?) polarise macrophages into "innate", "alternative" and "classical", activation states by selective gene regulation. Expression of MARCO, CD200, CD200R1 (innate), MRC1 (alternative) and H2-Eb1 (classical) selectively marks these distinct activation states. Epigenetic events drive such activation upon stimuli and here we study one such mechanism, chromatin conformation signatures implicated in long-range chromatin interactions that regulate transcriptional switch and gene expression. The EpiSwitch™ technology was used to identify and analyse potential markers bordering such conformational signatures for these genes and juxtaposition of markers was compared between resting and activated macrophages. LPS, IL-4 and IFN-? selectively altered chromatin conformations of their responsive genes in wild type, but not in MyD88(-/-), IL-4R(-/-) and IFN-?R(-/-) macrophages. In addition, two distinct conformations were observed in CD200R1 after LPS and IFN-? stimulation. In summary, signal-specific alterations in chromatin conformation provide biomarkers that identify and determine distinct gene expression programmes during macrophage activation. PMID:24211766

Mukhopadhyay, Subhankar; Ramadass, Aroul Selvam; Akoulitchev, Alexandre; Gordon, Siamon

2014-01-01

328

Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compounds active against type VI secretion.  

PubMed

The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an ?-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A1 activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance. PMID:24798289

Sun, Kun; Bröms, Jeanette; Lavander, Moa; Gurram, Bharat Kumar; Enquist, Per-Anders; Andersson, C David; Elofsson, Mikael; Sjöstedt, Anders

2014-07-01

329

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

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

Go, Min Jin; Hwang, Joo-Yeon; Park, Tae-Joon; Kim, Young Jin; Oh, Ji Hee; Kim, Yeon-Jung; Han, Bok-Ghee

2014-01-01

330

Genome-wide analysis of small RNAs expressed by Yersinia pestis identifies a regulator of the Yop-Ysc type III secretion system.  

PubMed

Small noncoding RNA (sRNA) molecules are integral components of the regulatory machinery for many bacterial species and are known to posttranscriptionally regulate metabolic and stress-response pathways, quorum sensing, virulence factors, and more. The Yop-Ysc type III secretion system (T3SS) is a critical virulence component for the pathogenic Yersinia species, and the regulation of this system is tightly controlled at each step from transcription to translocation of effectors into host cells. The contribution of sRNAs to the regulation of the T3SS in Yersinia has been largely unstudied, however. Previously, our lab identified a role for the sRNA chaperone protein Hfq in the regulation of components of the T3SS in the gastrointestinal pathogen Yersinia pseudotuberculosis. Here we present data demonstrating a similar requirement for Hfq in the closely related species Yersinia pestis. Through deep sequencing analysis of the Y. pestis sRNA-ome, we found 63 previously unidentified putative sRNAs in this species. We identified a Yersinia-specific sRNA, Ysr141, carried by the T3SS plasmid pCD1 that is required for the production of multiple T3SS proteins. In addition, we show that Ysr141 targets an untranslated region upstream of yopJ to posttranscriptionally activate the synthesis of the YopJ protein. Furthermore, Ysr141 may be an unstable and/or processed sRNA, which could contribute to its function in the regulation of the T3SS. The discovery of an sRNA that influences the synthesis of the T3SS adds an additional layer of regulation to this tightly controlled virulence determinant of Y. pestis. PMID:24532772

Schiano, Chelsea A; Koo, Jovanka T; Schipma, Matthew J; Caulfield, Adam J; Jafari, Nadereh; Lathem, Wyndham W

2014-05-01

331

Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts*S?  

PubMed Central

Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap?/?) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, Scap?/? mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult Scap?/? mice. Although phospholipid synthesis was decreased in type II cells from adult Scap?/? mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts. PMID:19074148

Besnard, Valérie; Wert, Susan E.; Stahlman, Mildred T.; Postle, Anthony D.; Xu, Yan; Ikegami, Machiko; Whitsett, Jeffrey A.

2009-01-01

332

The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin.  

PubMed

The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n?=?155 and n?=?188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2?ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (?15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p?=?0.025) and 31% versus 49% (p?=?0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p?=?0.074; antagonist protocol: 34% versus 23%, p?=?0.075; overall population: 34% versus 22%, p?=?0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders. PMID:24576226

Arce, Joan-Carles; Klein, Bjarke M; La Marca, Antonio

2014-06-01

333

Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility.  

PubMed

Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P < 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (?10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P = 0.027), and IGSF8 (rs1131891, P = 0.02). Examination of published genome-wide association data identified significant associations (P < 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P = 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P = 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P = 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis. PMID:23673729

Mondal, Ashis K; Sharma, Neeraj K; Elbein, Steven C; Das, Swapan K

2013-07-01

334

A Novel Type of Peptidoglycan-binding Domain Highly Specific for Amidated d-Asp Cross-bridge, Identified in Lactobacillus casei Bacteriophage Endolysins*  

PubMed Central

Peptidoglycan hydrolases (PGHs) are responsible for bacterial cell lysis. Most PGHs have a modular structure comprising a catalytic domain and a cell wall-binding domain (CWBD). PGHs of bacteriophage origin, called endolysins, are involved in bacterial lysis at the end of the infection cycle. We have characterized two endolysins, Lc-Lys and Lc-Lys-2, identified in prophages present in the genome of Lactobacillus casei BL23. These two enzymes have different catalytic domains but similar putative C-terminal CWBDs. By analyzing purified peptidoglycan (PG) degradation products, we showed that Lc-Lys is an N-acetylmuramoyl-l-alanine amidase, whereas Lc-Lys-2 is a ?-d-glutamyl-l-lysyl endopeptidase. Remarkably, both lysins were able to lyse only Gram-positive bacterial strains that possess PG with d-Ala4?d-Asx-l-Lys3 in their cross-bridge, such as Lactococcus casei, Lactococcus lactis, and Enterococcus faecium. By testing a panel of L. lactis cell wall mutants, we observed that Lc-Lys and Lc-Lys-2 were not able to lyse mutants with a modified PG cross-bridge, constituting d-Ala4?l-Ala-(l-Ala/l-Ser)-l-Lys3; moreover, they do not lyse the L. lactis mutant containing only the nonamidated d-Asp cross-bridge, i.e. d-Ala4?d-Asp-l-Lys3. In contrast, Lc-Lys could lyse the ampicillin-resistant E. faecium mutant with 3?3 l-Lys3-d-Asn-l-Lys3 bridges replacing the wild-type 4?3 d-Ala4-d-Asn-l-Lys3 bridges. We showed that the C-terminal CWBD of Lc-Lys binds PG containing mainly d-Asn but not PG with only the nonamidated d-Asp-containing cross-bridge, indicating that the CWBD confers to Lc-Lys its narrow specificity. In conclusion, the CWBD characterized in this study is a novel type of PG-binding domain targeting specifically the d-Asn interpeptide bridge of PG. PMID:23733182

Regulski, Krzysztof; Courtin, Pascal; Kulakauskas, Saulius; Chapot-Chartier, Marie-Pierre

2013-01-01

335

A novel type of peptidoglycan-binding domain highly specific for amidated D-Asp cross-bridge, identified in Lactobacillus casei bacteriophage endolysins.  

PubMed

Peptidoglycan hydrolases (PGHs) are responsible for bacterial cell lysis. Most PGHs have a modular structure comprising a catalytic domain and a cell wall-binding domain (CWBD). PGHs of bacteriophage origin, called endolysins, are involved in bacterial lysis at the end of the infection cycle. We have characterized two endolysins, Lc-Lys and Lc-Lys-2, identified in prophages present in the genome of Lactobacillus casei BL23. These two enzymes have different catalytic domains but similar putative C-terminal CWBDs. By analyzing purified peptidoglycan (PG) degradation products, we showed that Lc-Lys is an N-acetylmuramoyl-L-alanine amidase, whereas Lc-Lys-2 is a ?-D-glutamyl-L-lysyl endopeptidase. Remarkably, both lysins were able to lyse only Gram-positive bacterial strains that possess PG with D-Ala(4)?D-Asx-L-Lys(3) in their cross-bridge, such as Lactococcus casei, Lactococcus lactis, and Enterococcus faecium. By testing a panel of L. lactis cell wall mutants, we observed that Lc-Lys and Lc-Lys-2 were not able to lyse mutants with a modified PG cross-bridge, constituting D-Ala(4)?L-Ala-(L-Ala/L-Ser)-L-Lys(3); moreover, they do not lyse the L. lactis mutant containing only the nonamidated D-Asp cross-bridge, i.e. D-Ala(4)?D-Asp-L-Lys(3). In contrast, Lc-Lys could lyse the ampicillin-resistant E. faecium mutant with 3?3 L-Lys(3)-D-Asn-L-Lys(3) bridges replacing the wild-type 4?3 D-Ala(4)-D-Asn-L-Lys(3) bridges. We showed that the C-terminal CWBD of Lc-Lys binds PG containing mainly D-Asn but not PG with only the nonamidated D-Asp-containing cross-bridge, indicating that the CWBD confers to Lc-Lys its narrow specificity. In conclusion, the CWBD characterized in this study is a novel type of PG-binding domain targeting specifically the D-Asn interpeptide bridge of PG. PMID:23733182

Regulski, Krzysztof; Courtin, Pascal; Kulakauskas, Saulius; Chapot-Chartier, Marie-Pierre

2013-07-12

336

Molecular epidemiology of 58 new African human T-cell leukemia virus type 1 (HTLV-1) strains: identification of a new and distinct HTLV-1 molecular subtype in Central Africa and in Pygmies.  

PubMed Central

To gain new insights on the origin, evolution, and modes of dissemination of human T-cell leukemia virus type I (HTLV-1), we performed a molecular analysis of 58 new African HTLV-1 strains (18 from West Africa, 36 from Central Africa, and 4 from South Africa) originating from 13 countries. Of particular interest were eight strains from Pygmies of remote areas of Cameroon and the Central African Republic (CAR), considered to be the oldest inhabitants of these regions. Eight long-term activated T-cell lines producing HTLV-1 gag and env antigens were established from peripheral blood mononuclear cell cultures of HTLV-1 seropositive individuals, including three from Pygmies. A fragment of the env gene encompassing most of the gp21 transmembrane region was sequenced for the 58 new strains, while the complete long terminal repeat (LTR) region was sequenced for 9 strains, including 4 from Pygmies. Comparative sequence analyses and phylogenetic studies performed on both the env and LTR regions by the neighbor-joining and DNA parsimony methods demonstrated that all 22 strains from West and South Africa belong to the widespread cosmopolitan subtype (also called HTLV-1 subtype A). Within or alongside the previously described Zairian cluster (HTLV-1 subtype B), we discovered a number of new HTLV-1 variants forming different subgroups corresponding mainly to the geographical origins of the infected persons, Cameroon, Gabon, and Zaire. Six of the eight Pygmy strains clustered together within this Central African subtype, suggesting a common origin. Furthermore, three new strains (two originating from Pygmies from Cameroon and the CAR, respectively, and one from a Gabonese individual) were particularly divergent and formed a distinct new phylogenetic cluster, characterized by specific mutations and occupying in most analyses a unique phylogenetic position between the large Central African genotype (HTLV-1 subtype B) and the Melanesian subtype (HTLV-1 subtype C). We have tentatively named this new HTLV-1 genotype HTLV-1 subtype D. While the HTLV-1 subtype D strains were not closely related to any known African strain of simian T-cell leukemia virus type 1 (STLV-1), other Pygmy strains and some of the new Cameroonian and Gabonese HTLV-1 strains were very similar (>98% nucleotide identity) to chimpanzee STLV-1 strains, reinforcing the hypothesis of interspecies transmission between humans and monkeys in Central Africa. PMID:8995656

Mahieux, R; Ibrahim, F; Mauclere, P; Herve, V; Michel, P; Tekaia, F; Chappey, C; Garin, B; Van Der Ryst, E; Guillemain, B; Ledru, E; Delaporte, E; de The, G; Gessain, A

1997-01-01

337

Genetic Screen of a Mutant Poxvirus Library Identifies an Ankyrin Repeat Protein Involved in Blocking Induction of Avian Type I Interferon  

PubMed Central

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

Laidlaw, Stephen M.; Robey, Rebecca; Davies, Marc; Giotis, Efstathios S.; Ross, Craig; Buttigieg, Karen; Goodbourn, Stephen

2013-01-01

338

Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India.  

PubMed

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

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

339

Cost-Effectiveness of Alternative Thresholds of the Fasting Plasma Glucose Test to Identify the Target Population for Type 2 Diabetes Prevention in Adults Aged ?45 Years  

PubMed Central

OBJECTIVE The study objective was to evaluate the cost-effectiveness of alternative fasting plasma glucose (FPG) thresholds to identify adults at high risk for type 2 diabetes for diabetes preventive intervention. RESEARCH DESIGN AND METHODS We used a validated simulation model to examine the change in lifetime quality-adjusted life years (QALYs) and medical costs when the FPG threshold was progressively lowered in 5-mg/dL decrements from 120 to 90 mg/dL. The study sample includes nondiabetic adults aged ?45 years in the United States using 2006–2010 data from the National Health and Nutrition Examination Survey. High-risk individuals were assumed to receive a lifestyle intervention, as that used in the Diabetes Prevention Program. We calculated cost per QALY by dividing the incremental cost by incremental QALY when lowering the threshold to the next consecutive level. Medical costs were assessed from a health care system perspective. We conducted univariate and probabilistic sensitivity analyses to assess the robustness of the results using different simulation scenarios and parameters. RESULTS Progressively lowering the FPG threshold would monotonically increase QALYs, cost, and cost per QALY. Reducing (in 5-mg/dL decrements) the threshold from 120 to 90 mg/dL cost $30,100, $32,900, $42,300, $60,700, $81,800, and $115,800 per QALY gained, respectively. The costs per QALY gained were lower for all thresholds under a lower-cost and less-effective intervention scenario. CONCLUSIONS Lowering the FPG threshold leads to a greater health benefit of diabetes prevention but reduces the cost-effectiveness. Using the conventional benchmark of $50,000 per QALY, a threshold of 105 mg/dL or higher would be cost effective. A lower threshold could be selected if the intervention cost could be lowered. PMID:24135386

Zhuo, Xiaohui; Zhang, Ping; Kahn, Henry S.; Gregg, Edward W.

2013-01-01

340

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells*  

PubMed Central

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

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

341

Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in neurofibromatosis type I (NF1) disease model cells.  

PubMed

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

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

2013-05-01

342

Monoclonal antibody OKB7, which identifies the 14OKd complement receptor type 2 (CR/sub 2/), also identifies a 72Kd secreted fragment of CR/sub 2/ that contains the C3d-binding site  

SciTech Connect

CR/sub 2/ is a 140-145Kd glycoprotein expressed on B lymphocytes which binds both C3d and Epstein-Barr virus (EBV). OKB7, an IgG/sub 2a/ monoclonal antibody to CR/sub 2/, blocks C3d and EBV binding, while HB-5, another monoclonal IgG/sub 2a/ anti-CR/sub 2/, does not. A 72Kd C3d-binding glycoprotein (gp72), isolated from Raji cell media, was previously thought to be CR/sub 2/ because a polyclonal rabbit anti-gp72 inhibited EC3d rosettes. ELISA assay demonstrated that OKB7, but not HB-5, bound to purified gp72 fixed to microtiter wells. Insoluble and soluble gp72 blocked Raji cell uptake of /sup 125/I-labeled OKB7, but not labeled anti-B2 or HB-5. Rabbit anti-gp72 immunoprecipitated bands at 140Kd and 72Kd from /sup 125/I-labelled and solubilized B cell membranes. Culture media from Raji cells grown in the presence /sup 3/H-labeled amino acids was sequentially immunoprecipitated by irrelevant antibody, OKB7, and HB-5. A single 72Kd radiolabeled band was demonstrated only with OKB7, and this was identical to that produced by the immunoprecipitation of /sup 125/I-labeled gp72 with rabbit anti-gp72. Thus, OKB7, which identifies the 140Kd CR/sub 2/ molecule, also identifies a 72Kd shed fragment of CR/sub 2/ isolated from Raji cell media, which contains the C3d-binding site.

Myones, B.L.; Ross, G.D.

1986-03-05

343

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.

344

Identifying Erosion  

NSDL National Science Digital Library

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!

Cosi

2009-01-01

345

Modular control of glutamatergic neuronal identity in C. elegans by distinct homeodomain proteins.  

PubMed

The choice of using one of many possible neurotransmitter systems is a critical step in defining the identity of an individual neuron type. We show here that the key defining feature of glutamatergic neurons, the vesicular glutamate transporter EAT-4/VGLUT, is expressed in 38 of the 118 anatomically defined neuron classes of the C. elegans nervous system. We show that distinct cis-regulatory modules drive expression of eat-4/VGLUT in distinct glutamatergic neuron classes. We identify 13 different transcription factors, 11 of them homeodomain proteins, that act in distinct combinations in 25 different glutamatergic neuron classes to initiate and maintain eat-4/VGLUT expression. We show that the adoption of a glutamatergic phenotype is linked to the adoption of other terminal identity features of a neuron, including cotransmitter phenotypes. Examination of mouse orthologs of these homeodomain proteins resulted in the identification of mouse LHX1 as a regulator of glutamatergic neurons in the brainstem. PMID:24243022

Serrano-Saiz, Esther; Poole, Richard J; Felton, Terry; Zhang, Feifan; De La Cruz, Estanisla Daniel; Hobert, Oliver

2013-10-24

346

Multilocus Sequence Typing Confirms the Close Genetic Interrelatedness of Three Distinct Flavescence Dorée Phytoplasma Strain Clusters and Group 16SrV Phytoplasmas Infecting Grapevine and Alder in Europe?  

PubMed Central

Vineyards of southern France and northern Italy are affected by the flavescence dorée (FD) phytoplasma, a quarantine pathogen transmitted by the leafhopper of Nearctic origin Scaphoideus titanus. To better trace propagation of FD strains and identify possible passage between the vineyard and wild plant compartments, molecular typing of phytoplasma strains was applied. The sequences of the two genetic loci map and uvrB-degV, along with the sequence of the secY gene, were determined among a collection of FD and FD-related phytoplasmas infecting grapevine, alder, elm, blackberry, and Spanish broom in Europe. Sequence comparisons and phylogenetic analyses consistently indicated the existence of three FD phytoplasma strain clusters. Strain cluster FD1 (comprising isolate FD70) displayed low variability and represented 17% of the disease cases in the French vineyard, with a higher incidence of the cases in southwestern France. Strain cluster FD2 (comprising isolates FD92 and FD-D) displayed no variability and was detected both in France (83% of the cases) and in Italy, whereas the more-variable strain cluster FD3 (comprising isolate FD-C) was detected only in Italy. The clonal property of FD2 and its wide distribution are consistent with diffusion through propagation of infected-plant material. German Palatinate grapevine yellows phytoplasmas (PGY) appeared variable and were often related to some of the alder phytoplasmas (AldY) detected in Italy and France. Finally, phylogenetic analyses concluded that FD, PGY, and AldY were members of the same phylogenetic subclade, which may have originated in Europe. PMID:17468266

Arnaud, Guillaume; Malembic-Maher, Sylvie; Salar, Pascal; Bonnet, Patrick; Maixner, Michael; Marcone, Carmine; Boudon-Padieu, Elisabeth; Foissac, Xavier

2007-01-01

347

Multilocus sequence typing confirms the close genetic interrelatedness of three distinct flavescence dorée phytoplasma strain clusters and group 16SrV phytoplasmas infecting grapevine and alder in Europe.  

PubMed

Vineyards of southern France and northern Italy are affected by the flavescence dorée (FD) phytoplasma, a quarantine pathogen transmitted by the leafhopper of Nearctic origin Scaphoideus titanus. To better trace propagation of FD strains and identify possible passage between the vineyard and wild plant compartments, molecular typing of phytoplasma strains was applied. The sequences of the two genetic loci map and uvrB-degV, along with the sequence of the secY gene, were determined among a collection of FD and FD-related phytoplasmas infecting grapevine, alder, elm, blackberry, and Spanish broom in Europe. Sequence comparisons and phylogenetic analyses consistently indicated the existence of three FD phytoplasma strain clusters. Strain cluster FD1 (comprising isolate FD70) displayed low variability and represented 17% of the disease cases in the French vineyard, with a higher incidence of the cases in southwestern France. Strain cluster FD2 (comprising isolates FD92 and FD-D) displayed no variability and was detected both in France (83% of the cases) and in Italy, whereas the more-variable strain cluster FD3 (comprising isolate FD-C) was detected only in Italy. The clonal property of FD2 and its wide distribution are consistent with diffusion through propagation of infected-plant material. German Palatinate grapevine yellows phytoplasmas (PGY) appeared variable and were often related to some of the alder phytoplasmas (AldY) detected in Italy and France. Finally, phylogenetic analyses concluded that FD, PGY, and AldY were members of the same phylogenetic subclade, which may have originated in Europe. PMID:17468266

Arnaud, Guillaume; Malembic-Maher, Sylvie; Salar, Pascal; Bonnet, Patrick; Maixner, Michael; Marcone, Carmine; Boudon-Padieu, Elisabeth; Foissac, Xavier

2007-06-01

348

inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations  

PubMed Central

The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non–type A (n = 26; 13%) patients. At diagnosis, non–type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non–type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non–type A and type A patients with wild-type KIT were similar. We also derived a fusion-type–associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed—among others—an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non–type A patients. We conclude that non–type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile. PMID:23160462

Schwind, Sebastian; Edwards, Colin G.; Nicolet, Deedra; Mrózek, Krzysztof; Maharry, Kati; Wu, Yue-Zhong; Paschka, Peter; Eisfeld, Ann-Kathrin; Hoellerbauer, Pia; Becker, Heiko; Metzeler, Klaus H.; Curfman, John; Kohlschmidt, Jessica; Prior, Thomas W.; Kolitz, Jonathan E.; Blum, William; Pettenati, Mark J.; Dal Cin, Paola; Carroll, Andrew J.; Caligiuri, Michael A.; Larson, Richard A.; Volinia, Stefano

2013-01-01

349

Whole-Genome Sequencing of Burkholderia pseudomallei Isolates from an Unusual Melioidosis Case Identifies a Polyclonal Infection with the Same Multilocus Sequence Type.  

PubMed

Twelve Burkholderia pseudomallei isolates collected over a 32-month period from a patient with chronic melioidosis demonstrated identical multilocus sequence types (STs). However, whole-genome sequencing suggests a polyclonal infection. This study is the first to report a mixed infection with the same ST. PMID:25339397

Price, Erin P; Sarovich, Derek S; Viberg, Linda; Mayo, Mark; Kaestli, Mirjam; Tuanyok, Apichai; Foster, Jeffrey T; Keim, Paul; Pearson, Talima; Currie, Bart J

2015-01-01

350

Emergence of a new lineage of dengue virus type 2 identified in travelers entering Western australia from indonesia, 2010-2012.  

PubMed

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

Ernst, Timo; McCarthy, Suzi; Chidlow, Glenys; Luang-Suarkia, Dagwin; Holmes, Edward C; Smith, David W; Imrie, Allison

2015-01-01

351

Emergence of a New Lineage of Dengue Virus Type 2 Identified in Travelers Entering Western Australia from Indonesia, 2010-2012  

PubMed Central

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

Ernst, Timo; McCarthy, Suzi; Chidlow, Glenys; Luang-Suarkia, Dagwin; Holmes, Edward C.; Smith, David W.; Imrie, Allison

2015-01-01

352

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes  

Microsoft Academic Search

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of approximately 2.5 million

R. J. Strawbridge; J. Dupuis; I. Prokopenko; A. Barker; E. Ahlqvist; D. Rybin; J. R. Petrie; M. E. Travers; N. Bouatia-Naji; A. S. Dimas; A. Nica; E. Wheeler; H. Chen; B. F. Voight; J. Taneera; S. Kanoni; J. F. Peden; F. Turrini; S. Gustafsson; C. Zabena; P. Almgren; D. J. Barker; D. Barnes; E. M. Dennison; J. G. Eriksson; P. Eriksson; E. Eury; L. Folkersen; C. S. Fox; T. M. Frayling; A. Goel; H. F. Gu; M. Horikoshi; B. Isomaa; A. U. Jackson; K. A. Jameson; E. Kajantie; J. Kerr-Conte; T. Kuulasmaa; J. Kuusisto; R. J. Loos; J. Luan; K. Makrilakis; A. K. Manning; M. T. Martinez-Larrad; N. Narisu; M. Nastase Mannila; J. Ohrvik; C. Osmond; L. Pascoe; F. Payne; A. A. Sayer; B. Sennblad; A. Silveira; A. Stancakova; K. Stirrups; A. J. Swift; A. C. Syvanen; T. Tuomi; F. van't Hooft; M. Walker; M. N. Weedon; W. Xie; B. Zethelius; H. Ongen; A. Malarstig; J. C. Hopewell; D. Saleheen; J. Chambers; S. Parish; J. Danesh; J. Kooner; C. G. Ostenson; L. Lind; C. C. Cooper; M. Serrano-Rios; E. Ferrannini; T. J. Forsen; R. Clarke; M. G. Franzosi; U. Seedorf; H. Watkins; P. Froguel; P. Johnson; P. Deloukas; F. S. Collins; M. Laakso; E. T. Dermitzakis; M. Boehnke; M. I. McCarthy; N. J. Wareham; L. Groop; F. Pattou; A. L. Gloyn; G. V. Dedoussis; V. Lyssenko; J. B. Meigs; I. Barroso; R. M. Watanabe; M. den Heijer; L. A. L. M. Kiemeney

2011-01-01

353

Listening and Questioning: The "Apophatic/Cataphatic" Distinction Revisited  

ERIC Educational Resources Information Center

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…

Waks, Leonard

2007-01-01

354

Cognitive Control of Distinct Vocalizations in Rhesus Monkeys  

E-print Network

Cognitive Control of Distinct Vocalizations in Rhesus Monkeys Steffen R. Hage, Natalja Gavrilov their vocal utterances has been a matter of debate for decades. We show that rhesus monkeys can be trained that a monkey learned to switch between two distinct call types from trial to trial in response to different

Nieder, Andreas

355

Use of Pulsed-Field Gel Electrophoresis and Flagellin Gene Typing in Identifying Clonal Groups of Campylobacter jejuni and Campylobacter coli in Farm and Clinical Environments  

PubMed Central

Although campylobacters have been isolated from a wide range of animal hosts, the association between campylobacters isolated from humans and animals in the farm environment is unclear. We used flagellin gene typing and pulsed-field gel electrophoresis (PFGE) to investigate the genetic diversity among isolates from animals (cattle, sheep, and turkey) in farm environments and sporadic cases of campylobacteriosis in the same geographical area. Forty-eight combined fla types were seen among the 315 Campylobacter isolates studied. Six were found in isolates from all four hosts and represented 50% of the total number of isolates. Seventy-one different SmaI PFGE macrorestriction profiles (mrps) were observed, with 86% of isolates assigned to one of 29 different mrps. Fifty-seven isolates from diverse hosts, times, and sources had an identical SmaI mrp and combined fla type. Conversely, a number of genotypes were unique to a particular host. We provide molecular evidence which suggests a link between campylobacters in the farm environment with those causing disease in the community. PMID:11282587

Fitzgerald, Collette; Stanley, Karen; Andrew, Sarah; Jones, Keith

2001-01-01

356

Counselor Identity: Conformity or Distinction?  

ERIC Educational Resources Information Center

The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

McLaughlin, Jerry E.; Boettcher, Kathryn

2009-01-01

357

Is Face Distinctiveness Gender Based?  

ERIC Educational Resources Information Center

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,…

Baudouin, Jean-Yves; Gallay, Mathieu

2006-01-01

358

[Morphologic types of bipolar cells identified by regular grids of their axonal varicosities in the inner synaptic layer of the clupeid retina].  

PubMed

A morphological structure of the inner plexiform layer in the acute vision area was studied in the retina of five Clupeidae species by a light microscope. It is shown that this layer is a three-dimensional regular grid formed by bulbous varicosities (synaptic complexes) of the axons of the bipolar cells. These varicosities arranged of different levels of the inner plexiform layer form mutually coordinated periodic grids differing in the orientation and periods. The analysis of this structure shows that not less than three types of bipolar cells take part in its organization. PMID:1207796

Podugol'nikova, T A; Maksimov, V V

1975-01-01

359

Identifying Type IIn supernova progenitors in our Galaxy: the circumstellar environment of the Galactic luminous blue variable candidate Gal 026.47+0.02  

NASA Astrophysics Data System (ADS)

New data from the Herschel Infrared Galactic Plane Survey (Hi-GAL) and the Expanded Very Large Array, together with ancillary multifrequency data from different archives, have provided a comprehensive picture of the circumstellar envelope (CSE) surrounding the Galactic luminous blue variable (LBV) candidate Gal 026.47+0.02. The high angular resolution of both the 70-?m and 6-cm maps has allowed us to appreciate finest details of the nebula, whose morphology is consistent with a series of nested tori. The inner torus, which is close to the central object, is fully ionized, indicating events of aspherical mass loss. We have derived the physical properties of the CSE, including, in particular, one of the highest current-day mass losses from the central object and a very massive nebula, which consists of, at least, 17 M? of ionized gas, with 1.2-3.2 × 10-2 M? in the form of dust. Altogether, the physical properties of Gal 026.47+0.02, including a very high stellar luminosity, point towards a very massive progenitor on the main sequence. According to the current models for Type IIn supernovae, the CSEs associated with possible progenitors have well constrained properties in both content and morphology. The derived physical characteristics of the nebula associated with Gal 026.47+0.02 actually satisfy all such requirements, providing some observational evidence of a direct link between a LBV and a possible Type IIn supernova.

Umana, G.; Ingallinera, A.; Trigilio, C.; Buemi, C. S.; Leto, P.; Agliozzo, C.; Noriega-Crespo, A.; Flagey, N.; Paladini, R.; Molinari, S.

2012-12-01

360

Functional analysis of the enteropathogenic Escherichia coli type III secretion system chaperone CesT identifies domains that mediate substrate interactions.  

PubMed

In many Gram-negative bacteria, a key indicator of pathogenic potential is the possession of a specialized type III secretion system, which is utilized to deliver virulence effector proteins directly into the host cell cytosol. Many of the proteins secreted from such systems require small cytosolic chaperones to maintain the secreted substrates in a secretion-competent state. One such protein, CesT, serves a chaperone function for the enteropathogenic Escherichia coli (EPEC) translocated intimin receptor (Tir) protein, which confers upon EPEC the ability to alter host cell morphology following intimate bacterial attachment. Using a combination of complementary biochemical approaches, functional domains of CesT that mediate intermolecular interactions, involved in both chaperone-chaperone and chaperone-substrate associations, were determined. The CesT N-terminal is implicated in chaperone dimerization, whereas the amphipathic alpha-helical region of the C-terminal, is intimately involved in substrate binding. By functional complementation of chaperone domains using the Salmonella SicA chaperone to generate chaperone chimeras, we show that CesT-Tir interaction proceeds by a mechanism potentially common to other type III secretion system chaperones. PMID:11849537

Delahay, Robin M; Shaw, Robert K; Elliott, Simon J; Kaper, James B; Knutton, Stuart; Frankel, Gad

2002-01-01

361

Molecular typing of Treponema pallidum in the Czech Republic during 2011 to 2013: increased prevalence of identified genotypes and of isolates with macrolide resistance.  

PubMed

From January 2011 to December 2013, a total of 262 samples, from 188 patients suspected of having syphilis were tested for the presence of treponemal DNA by PCR amplification of five chromosomal loci, including the polA (TP0105), tmpC (TP0319), TP0136, TP0548, and 23S rRNA genes. Altogether, 146 samples from 103 patients were PCR positive for treponemal DNA. A set of 81 samples from 62 PCR-positive patients were typeable, and among them, nine different genotypes were identified. Compared to a previous study in the Czech Republic during 2004 to 2010, the number of genotypes detected among syphilis patients in a particular year increased to six in both 2012 and 2013, although they were not the same six. The proportion of macrolide-resistant clinical isolates in this 3-year study was 66.7%. PMID:25100820

Grillová, Linda; P?trošová, Helena; Mikalová, Lenka; Strnadel, Radim; Dastychová, Eliška; Kuklová, Ivana; Kojanová, Martina; Kreidlová, Miluše; Va?ousová, Daniela; Hercogová, Jana; Procházka, P?emysl; Zákoucká, Hana; Krch?áková, Alena; Vašk?, Vladimír; Šmajs, David

2014-10-01