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  • Public Library of Science (PLoS)
  • 2010-2014  (26,680)
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  • 1
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    Public Library of Science (PLoS)
    In:  PLoS ONE vol. 9 no. 12, pp. e115750-e115750
    Publication Date: 2024-01-12
    Keywords: Multidisciplinary
    Repository Name: National Museum of Natural History, Netherlands
    Type: info:eu-repo/semantics/article
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  • 2
    Publication Date: 2024-02-07
    Description: Phylogeographic patterns and sex-biased dispersal were studied in riverine populations of West Indian (Trichechus manatus) and Amazonian manatees (T. inunguis) in South America, using 410bp D-loop (Control Region, Mitochondrial DNA) sequences and 15 nuclear microsatellite loci. This multi-locus approach was key to disentangle complex patterns of gene flow among populations. D-loop analyses revealed population structuring among all Colombian rivers for T. manatus, while microsatellite data suggested no structure. Two main populations of T. inunguis separating the Colombian and Peruvian Amazon were supported by analysis of the D-loop and microsatellite data. Overall, we provide molecular evidence for differences in dispersal patterns between sexes, demonstrating male-biased gene flow dispersal in riverine manatees. These results are in contrast with previously reported levels of population structure shown by microsatellite data in marine manatee populations, revealing low habitat restrictions to gene flow in riverine habitats, and more significant dispersal limitations for males in marine environments. © 2012 Satizábal et al.
    Repository Name: EPIC Alfred Wegener Institut
    Type: Article , isiRev
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  • 3
    Publication Date: 2024-03-28
    Description: Ecological indicators for monitoring strategies are expected to combine three major characteristics: ecological significance, statistical credibility, and cost-effectiveness. Strategies based on stranding networks rank highly in cost-effectiveness, but their ecological significance and statistical credibility are disputed. Our present goal is to improve the value of stranding data as population indicator as part of monitoring strategies by constructing the spatial and temporal null hypothesis for strandings. The null hypothesis is defined as: small cetacean distribution and mortality are uniform in space and constant in time. We used a drift model to map stranding probabilities and predict stranding patterns of cetacean carcasses under H0 across the North Sea, the Channel and the Bay of Biscay, for the period 1990–2009. As the most common cetacean occurring in this area, we chose the harbour porpoise Phocoena phocoena for our modelling. The difference between these strandings expected under H0 and observed strandings is defined as the stranding anomaly. It constituted the stranding data series corrected for drift conditions. Seasonal decomposition of stranding anomaly suggested that drift conditions did not explain observed seasonal variations of porpoise strandings. Long-term stranding anomalies increased first in the southern North Sea, the Channel and Bay of Biscay coasts, and finally the eastern North Sea. The hypothesis of changes in porpoise distribution was consistent with local visual surveys, mostly SCANS surveys (1994 and 2005). This new indicator could be applied to cetacean populations across the world and more widely to marine megafauna.
    Repository Name: National Museum of Natural History, Netherlands
    Type: info:eu-repo/semantics/article
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  • 4
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    Public Library of Science (PLoS)
    Publication Date: 2013-09-06
    Description: by Johnatan Aljadeff, Ronen Segev, Michael J. Berry, Tatyana O. Sharpee Many biological systems perform computations on inputs that have very large dimensionality. Determining the relevant input combinations for a particular computation is often key to understanding its function. A common way to find the relevant input dimensions is to examine the difference in variance between the input distribution and the distribution of inputs associated with certain outputs. In systems neuroscience, the corresponding method is known as spike-triggered covariance (STC). This method has been highly successful in characterizing relevant input dimensions for neurons in a variety of sensory systems. So far, most studies used the STC method with weakly correlated Gaussian inputs. However, it is also important to use this method with inputs that have long range correlations typical of the natural sensory environment. In such cases, the stimulus covariance matrix has one (or more) outstanding eigenvalues that cannot be easily equalized because of sampling variability. Such outstanding modes interfere with analyses of statistical significance of candidate input dimensions that modulate neuronal outputs. In many cases, these modes obscure the significant dimensions. We show that the sensitivity of the STC method in the regime of strongly correlated inputs can be improved by an order of magnitude or more. This can be done by evaluating the significance of dimensions in the subspace orthogonal to the outstanding mode(s). Analyzing the responses of retinal ganglion cells probed with Gaussian noise, we find that taking into account outstanding modes is crucial for recovering relevant input dimensions for these neurons.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 5
    Publication Date: 2013-09-07
    Description: by Lydia Nakiyingi, John Mark Bwanika, Bruce Kirenga, Damalie Nakanjako, Catherine Katabira, Gloria Lubega, Joseph Sempa, Barnabas Nyesiga, Heidi Albert, Yukari C. Manabe Introduction The existing diagnostic algorithms for sputum smear-negative tuberculosis (TB) are complicated, time-consuming, and often difficult to implement. The decision to initiate TB treatment in resource-limited countries is often largely based on clinical predictors. We sought to determine the clinical predictors and accuracy of empiric TB treatment initiation in HIV-infected sputum smear-negative TB suspects using sputum culture as a reference standard. Setting Out-patient HIV-TB integrated urban clinic in Kampala, Uganda. Methods HIV-infected TB suspects were screened using sputum smear microscopy, and mycobacterial sputum liquid and solid cultures were performed. Smear results were made available to the clinician who made a clinical decision on empiric TB treatment initiation for sputum smear-negative patients. Clinic records were reviewed for patients whose sputum smears were negative to collect data on socio-demographics, TB symptomatology, chest X-ray findings, CD4 cell counts and TB treatment initiation. Results Of 253 smear-negative TB suspects, 56% (142/253) were females, median age 38 IQR (31–44) years, with a median CD4 cell count of 291 IQR (150–482) cells/mm 3 . Of the 85 (33.6%) smear-negative patients empirically initiated on TB treatment, 35.3% (n = 30) were sputum culture positive compared to only 18 (10.7%) of the 168 untreated patients (p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-07
    Description: by Cyril Dégletagne, Damien Roussel, Jean Louis Rouanet, Fanny Baudimont, Elodie-Marie Moureaux, Steve Harvey, Claude Duchamp, Yvon Le Maho, Mireille Raccurt The evolutionary trade-off between tissue growth and mature function restricts the post natal development of polar birds. The present study uses an original integrative approach as it includes gene expression, plus biochemical and physiological analysis to investigate how Adélie penguin chicks achieve a rapid growth despite the energetic constraints linked to the cold and the very short breeding season in Antarctica. In pectoralis muscle, the main thermogenic tissue in birds, our data show that the transition from ectothermy to endothermy on Day 15 post- hatching is associated with substantial and coordinated changes in the transcription of key genes. While the early activation of genes controlling cell growth and differentiation (avGHR, avIGF-1R, T3Rβ) is rapidly down-regulated after hatching, the global increase in the relative expression of genes involved in thermoregulation (avUCP, avANT, avLPL) and transcriptional regulation (avPGC1α, avT3Rβ) underlie the muscular acquisition of oxidative metabolism. Adélie chicks only become real endotherms at 15 days of age with the development of an oxidative muscle phenotype and the ability to shiver efficiently. The persistent muscular expression of IGF-1 throughout growth probably acts as a local mediator to adjust muscle size and its oxidative capacity to anticipate the new physiological demands of future Dives in cold water. The up-regulation of T3Rβ mRNA levels suggests that circulating T3 may play an important role in the late maturation of skeletal muscle by reinforcing, at least in part, the paracrine action of IGF-1. From day 30, the metabolic shift from mixed substrate to lipid metabolism, with the markedly increased mRNA levels of muscle avLPL, avANT and avUCP, suggests the late development of a fatty acid-enhanced muscle non-shivering thermogenesis mechanism. This molecular control is the key to this finely-tuned strategy by which the Adélie penguin chick successfully heads for the sea on schedule.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 7
    Publication Date: 2013-09-07
    Description: by Philip Wing-Lok Ho, Zero Ho-Man Tse, Hui-Fang Liu, Song Lu, Jessica Wing-Man Ho, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho Xenoestrogens are either natural or synthetic compounds that mimic the effects of endogenous estrogen. These compounds, such as bisphenol-A (BPA), and phthalates, are commonly found in plastic wares. Exposure to these compounds poses major risk to human health because of the potential to cause endocrine disruption. There is huge demand for a wide range of chemicals to be assessed for such potential for the sake of public health. Classical in vivo assays for endocrine disruption are comprehensive but time-consuming and require sacrifice of experimental animals. Simple preliminary in vitro screening assays can reduce the time and expense involved. We previously demonstrated that catechol-O-methyltransferase (COMT) is transcriptionally regulated by estrogen via estrogen receptor (ER). Therefore, detecting corresponding changes of COMT expression in estrogen-responsive cells may be a useful method to estimate estrogenic effects of various compounds. We developed a novel cell-based ELISA to evaluate cellular response to estrogenicity by reduction of soluble-COMT expression in ER-positive MCF-7 cells exposed to estrogenic compounds. In contrast to various existing methods that only detect bioactivity, this method elucidates direct physiological effect in a living cell in response to a compound. We validated our assay using three well-characterized estrogenic plasticizers - BPA, benzyl butyl phthalate (BBP), and di-n-butyl phthalate (DBP). Cells were exposed to either these plasticizers or 17β-estradiol (E2) in estrogen-depleted medium with or without an ER-antagonist, ICI 182,780, and COMT expression assayed. Exposure to each of these plasticizers (10 -9 -10 -7 M) dose-dependently reduced COMT expression (p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2013-09-07
    Description: by Luca Laudani, Giuseppe Vannozzi, Zimi Sawacha, Ugo della Croce, Andrea Cereatti, Andrea Macaluso Maintaining adequate levels of physical activity is known to preserve health status and functional independence as individuals grow older. However, the relationship between determinants of physical activity (volume and intensity) and physiological factors underlying mobility (cardio-respiratory fitness, neuromuscular function and functional abilities) is still unclear. The aim of this study was to investigate the association between objectively quantified physical activity and a spectrum of physiological factors underlying mobility in young, middle-aged and older individuals living in a city district. Experiments were carried out on 24 young (28±2 years), 24 middle-aged (48±2 years) and 24 older (70±3 years) gender-matched volunteers. Physical activity was monitored by a wearable activity monitor to quantify volume and intensity of overall physical activity and selected habitual activities over 24 hours. Ventilatory threshold was assessed during an incremental cycling test. Torque, muscle fiber conduction velocity and agonist-antagonist coactivation were measured during maximal voluntary contraction of knee extensors and flexors. Ground reaction forces were measured during sit-to-stand and counter-movement jump. K-means cluster analysis was used to classify the participants’ physical activity levels based on parameters of volume and intensity. Two clusters of physical activity volume (i.e., high and low volume) and three clusters of physical activity intensity (i.e. high, medium and low intensity) were identified in all participants. Cardio-respiratory fitness was associated with volume of overall physical activity as well as lying, sitting, standing, walking and stair climbing. On the other hand, neuromuscular function and functional abilities showed a significant association with intensity of overall physical activity as well as postural transition, walking and stair climbing. As a practical application, the relative role played by volume and intensity of overall physical activity and selected habitual activities should be taken into account in the design of preventative training interventions to preserve mobility as individuals grow older.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
    Publication Date: 2013-09-07
    Description: by Daniel Garcia de la serrana, Ian A. Johnston Heat shock proteins 90 (Hsp90) have an essential role in sarcomere formation and differentiation in skeletal muscle and also act as molecular chaperones during protein folding impacting a wide range of physiological processes. We characterised and provided a phylogenetically consistent nomenclature for the complete repertoire of six Hsp90 paralogues present in duplicated salmonid fish genomes (Hsp90α1a, Hsp90α1b, Hsp90α2a, Hsp90α2b, Hsp90ß1a and Hsp90ß1b). The expression of paralogues in fast skeletal muscle was investigated using in vivo fasting-feeding experiments and primary myogenic cultures. Fasted juvenile Atlantic salmon ( Salmo salar ) showed a transient 2 to 8-fold increase in the expression of all 4 Hsp90α paralogues within 24h of satiation feeding. H sp90α1a and hsp90α1b also showed a pronounced secondary increase in expression after 10 days, concomitant with muscle differentiation and the expression of myogenin and sarcomeric proteins ( mlc2 , myhc ). Hsp90ß1b was constitutively expressed whereas Hsp90ß1a expression was downregulated 10-fold between fasted and fed individuals. Hsp90α1a and Hsp90α1b were upregulated 10 to 15-fold concomitant with myotube formation and muscle differentiation in vitro whereas other Hsp90 paralogues showed no change in expression. In cells starved of amino acid (AA) and serum for 72h the addition of AA, but not insulin-like growth factor 1, increased phosphorylation of mTor and expression of all 4 hsp90α paralogues and associated co-chaperones including hsp30 , tbcb , pdia4 , pdia6 , stga and fk504bp1 , indicating a general activation of the protein folding response. In contrast, Hsp90ß1a expression in vitro was unresponsive to AA treatment indicating that some other as yet uncharacterised signal(s) regulate its expression in response to altered nutritional state.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-07
    Description: by Monika Marejková, Květa Bláhová, Jan Janda, Angelika Fruth, Petr Petráš Background Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea-associated hemolytic uremic syndrome (D+ HUS) worldwide, but no systematic study of EHEC as the causative agents of HUS was performed in the Czech Republic. We analyzed stools of all patients with D+ HUS in the Czech Republic between 1998 and 2012 for evidence of EHEC infection. We determined virulence profiles, phenotypes, antimicrobial susceptibilities and phylogeny of the EHEC isolates. Methodology/Principal Findings Virulence loci were identified using PCR, phenotypes and antimicrobial susceptibilities were determined using standard procedures, and phylogeny was assessed using multilocus sequence typing. During the 15-year period, EHEC were isolated from stools of 39 (69.4%) of 56 patients. The strains belonged to serotypes [ fliC types] O157:H7/NM[ fliC H7 ] (50% of which were sorbitol-fermenting; SF), O26:H11/NM[ fliC H11 ], O55:NM[ fliC H7 ], O111:NM[ fliC H8 ], O145:H28[ fliC H28 ], O172:NM[ fliC H25 ], and Orough:NM[ fliC H25 ]. O26:H11/NM[ fliC H11 ] was the most common serotype associated with HUS (41% isolates). Five stx genotypes were identified, the most frequent being stx 2a (71.1% isolates). Most strains contained EHEC- hlyA encoding EHEC hemolysin, and a subset (all SF O157:NM and one O157:H7) harbored cdt-V encoding cytolethal distending toxin. espP α encoding serine protease EspPα was found in EHEC O157:H7, O26:H11/NM, and O145:H28, whereas O172:NM and Orough:NM strains contained espP γ. All isolates contained eae encoding adhesin intimin, which belonged to subtypes β (O26), γ (O55, O145, O157), γ2/θ (O111), and ε (O172, Orough). Loci encoding other adhesins ( efa1, lpfA O26 , lpfA O157OI-141 , lpfA O157OI-154 , iha ) were usually associated with particular serotypes. Phylogenetic analysis demonstrated nine sequence types (STs) which correlated with serotypes. Of these, two STs (ST660 and ST1595) were not found in HUS-associated EHEC before. Conclusions/Significance EHEC strains, including O157:H7 and non-O157:H7, are frequent causes of D+ HUS in the Czech Republic. Identification of unusual EHEC serotypes/STs causing HUS calls for establishment of an European collection of HUS-associated EHEC, enabling to study properties and evolution of these important pathogens.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-07
    Description: by Hanneke K. M. Meeren, Beatrice de Gelder, Seppo P. Ahlfors, Matti S. Hämäläinen, Nouchine Hadjikhani Evidence from functional neuroimaging indicates that visual perception of human faces and bodies is carried out by distributed networks of face and body-sensitive areas in the occipito-temporal cortex. However, the dynamics of activity in these areas, needed to understand their respective functional roles, are still largely unknown. We monitored brain activity with millisecond time resolution by recording magnetoencephalographic (MEG) responses while participants viewed photographs of faces, bodies, and control stimuli. The cortical activity underlying the evoked responses was estimated with anatomically-constrained noise-normalised minimum-norm estimate and statistically analysed with spatiotemporal cluster analysis. Our findings point to distinct spatiotemporal organization of the neural systems for face and body perception. Face-selective cortical currents were found at early latencies (120–200 ms) in a widespread occipito-temporal network including the ventral temporal cortex (VTC). In contrast, early body-related responses were confined to the lateral occipito-temporal cortex (LOTC). These were followed by strong sustained body-selective responses in the orbitofrontal cortex from 200–700 ms, and in the lateral temporal cortex and VTC after 500 ms latency. Our data suggest that the VTC region has a key role in the early processing of faces, but not of bodies. Instead, the LOTC, which includes the extra-striate body area (EBA), appears the dominant area for early body perception, whereas the VTC contributes to late and post-perceptual processing.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
    Publication Date: 2013-09-07
    Description: by Volkhard Göber, Andreas Hohl, Brigitta Gahl, Florian Dick, Verena Eigenmann, Thierry P. Carrel, Hendrik T. Tevaearai Background Peak levels of troponin T (TnT) reliably predict morbidity and mortality after cardiac surgery. However, the therapeutic window to manage CABG-related in-hospital complications may close before the peak is reached. We investigated whether early TnT levels correlate as well with complications after coronary artery bypass grafting (CABG) surgery. Methods A 12 month consecutive series of patients undergoing elective isolated CABG procedures (mini-extra-corporeal circuit, Cardioplegic arrest) was analyzed. Logistic regression modeling was used to investigate whether TnT levels 6 to 8 hours after surgery were independently associated with in-hospital complications (either post-operative myocardial infarction, stroke, new-onset renal insufficiency, intensive care unit (ICU) readmission, prolonged ICU stay (〉48 hours), prolonged need for vasopressors (〉24 hours), resuscitation or death). Results A total of 290 patients, including 36 patients with complications, was analyzed. Early TnT levels (odds ratio (OR): 6.8, 95% confidence interval (CI): 2.2-21.4, P=.001), logistic EuroSCORE (OR: 1.2, 95%CI: 1.0-1.3, P=.007) and the need for vasopressors during the first 6 postoperative hours (OR: 2.7, 95%CI: 1.0-7.1, P=.05) were independently associated with the risk of complications. With consideration of vasopressor use during the first 6 postoperative hours, the sum of specificity (0.958) and sensitivity (0.417) of TnT for subsequent complications was highest at a TnT cut-off value of 0.8 ng/mL. Conclusion Early TnT levels may be useful to guide ICU management of CABG patients. They predict clinically relevant complications within a potential therapeutic window, particularly in patients requiring vasopressors during the first postoperative hours, although with only moderate sensitivity.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-07
    Description: by Valentine S. Moullé, Christelle Le Foll, Erwann Philippe, Nadim Kassis, Claude Rouch, Nicolas Marsollier, Linh-Chi Bui, Christophe Guissard, Julien Dairou, Anne Lorsignol, Luc Pénicaud, Barry E. Levin, Céline Cruciani-Guglielmacci, Christophe Magnan Variations in plasma fatty acid (FA) concentrations are detected by FA sensing neurons in specific brain areas such as the hypothalamus. These neurons play a physiological role in the control of food intake and the regulation of hepatic glucose production. Le Foll et al. previously showed in vitro that at least 50% of the FA sensing in ventromedial hypothalamic (VMH) neurons is attributable to the interaction of long chain FA with FA translocase/CD36 (CD36). The present work assessed whether in vivo effects of hypothalamic FA sensing might be partly mediated by CD36 or intracellular events such as acylCoA synthesis or β-oxidation. To that end, a catheter was implanted in the carotid artery toward the brain in male Wistar rats. After 1 wk recovery, animals were food-deprived for 5 h, then 10 min infusions of triglyceride emulsion, Intralipid +/− heparin (IL, IL H , respectively) or saline/heparin (S H ) were carried out and food intake was assessed over the next 5 h. Experimental groups included: 1) Rats previously injected in ventromedian nucleus (VMN) with shRNA against CD36 or scrambled RNA; 2) Etomoxir (CPT1 inhibitor) or saline co-infused with IL H /S H ; and 3) Triacsin C (acylCoA synthase inhibitor) or saline co-infused with IL H /S H . IL H significantly lowered food intake during refeeding compared to S H (p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-07
    Description: by Paul A. Stevenson, Jan Rillich Population density has profound influences on the physiology and behaviour of many animal species. Social isolation is generally reported to lead to increased aggressiveness, while grouping lowers it. We evaluated the effects of varying degrees of isolation and grouping on aggression in a territorial insect, the Mediterranean field cricket, Gryllus bimaculatus . Substantiating early observations, we show that dyadic contests between weight-matched, adult male crickets taken from groups rarely escalate beyond threat displays, whereas interactions between pairs of previously isolated crickets typically escalate to physical fights lasting several seconds. No significant differences were found between 1, 2 and 6-day isolates, or between individuals grouped for a few hours or lifelong. Unexpectedly, crickets grouped in immediate proximity within individual mesh cages that precluded fighting while permitting visual, olfactory and mechanical, antennal contact, were as aggressive as free isolates. This suggests that reduced aggression of grouped animals may be an acquired result of fighting. Supporting this notion, isolated crickets initially engage in vigorous fights when first grouped, but fighting intensity and duration rapidly decline to the level of life-long grouped crickets within only 10 min. Furthermore, grouped crickets become as aggressive as life-long isolates after only 3 hours of isolation, and on the same time course required for crickets to regain their aggressiveness after social defeat. We conclude that the reduced aggressiveness of grouped crickets is a manifestation of the loser effect resulting from social subjugation, while isolation allows recovery to a state of heightened aggressiveness, which in crickets can be considered as the default condition. Given the widespread occurrence of the loser effect in the Animal Kingdom, many effects generally attributed to social isolation are likely to be a consequence of recovery from social subjugation.
    Electronic ISSN: 1932-6203
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  • 15
    Publication Date: 2013-09-07
    Description: by Horst Kierdorf, Uwe Kierdorf, Kai Frölich, Carsten Witzel We studied the structural characteristics and periodicities of regular incremental markings in sheep enamel using fluorochrome injections for vital labeling of forming enamel and backscattered electron imaging in the scanning electron microscope. Microscopic analysis of mandibular first molars revealed the presence of incremental markings with a daily periodicity (laminations) that indicated successive positions of the forming front of interprismatic enamel. In addition to the laminations, incremental markings with a sub-daily periodicity were discernible both in interprismatic enamel and in enamel prisms. Five sub-daily increments were present between two consecutive laminations. Backscattered electron imaging revealed that each sub-daily growth increment consisted of a broader and more highly mineralized band and a narrower and less mineralized band (line). The sub-daily markings in the prisms of sheep enamel morphologically resembled the (daily) prisms cross striations seen in primate enamel. Incremental markings with a supra-daily periodicity were not observed in sheep enamel. Based on the periodicity of the incremental markings, maximum mean daily apposition rates of 17.0 µm in buccal enamel and of 13.4 µm in lingual enamel were recorded. Enamel extension rates were also high, with maximum means of 180 µm/day and 217 µm/day in upper crown areas of buccal and lingual enamel, respectively. Values in more cervical crown portions were markedly lower. Our results are in accordance with previous findings in other ungulate species. Using the incremental markings present in primate enamel as a reference could result in a misinterpretation of the incremental markings in ungulate enamel. Thus, the sub-daily growth increments in the prisms of ungulate enamel might be mistaken as prism cross striations with a daily periodicity, and the laminations misidentified as striae of Retzius with a supra-daily periodicity. This would lead to a considerable overestimation of crown formation times in ungulate teeth.
    Electronic ISSN: 1932-6203
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  • 16
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-07
    Description: by Zhu Huang, Xiao-Dong Pan, Ping-Gu Wu, Jian-Long Han, Qing Chen Environmental pollution with toxic heavy metals can lead to the possible contamination of the rice. Selected metals (As, Cd, Hg and Pb) and their accumulation in rice collected from Zhejiang, China were analyzed to evaluate the potential health risk to the local adults and children. The mean levels found in rice were as follows: As, 0.080 mg/kg; Cd, 0.037 mg/kg; Hg, 0.005 mg/kg; Pb, 0.060 mg/kg. The estimated daily intakes (EDIs) were calculated in combination of the rice consumption data. The mean intakes of As, Cd, Hg and Pb through rice were estimated to be 0.49, 0.23, 0.03 and 0.37 µg/kg bw/day for adults, and 0.34, 0.29, 0.04 and 0.47 µg/kg bw/day for children. The 97.5th percentile (P97.5) daily intakes of As, Cd, Hg and Pb were 1.02, 0.64, 0.37 and 1.26 µg/kg bw/day for adults, and 0.63, 0.83, 0.47 and 1.63 µg/kg bw/day for children. The risk assessment in mean levels showed that health risk associated with these elements through consumption of rice was absent. However, estimates in P97.5 level of Cd and Pb for children, and Hg for adults have exceeded the respective safe limits.
    Electronic ISSN: 1932-6203
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  • 17
    Publication Date: 2013-09-08
    Description: by Simone Picelli, Justo Lorenzo Bermejo, Jenny Chang-Claude, Michael Hoffmeister, Ceres Fernández-Rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellví-Bel, Members of the EPICOLON Consortium (Gastrointestinal Oncology Group of the Spanish Gastroenterological Association): , Alessio Naccarati, Barbara Pardini, Ludmila Vodickova, Heiko Müller, Bente A. Talseth-Palmer, Geoffrey Stibbard, Paolo Peterlongo, Carmela Nici, Silvia Veneroni, Li Li, Graham Casey, Albert Tenesa, Susan M. Farrington, Ian Tomlinson, Victor Moreno, Tom van Wezel, Juul Wijnen, Malcolm Dunlop, Paolo Radice, Rodney J. Scott, Pavel Vodicka, Clara Ruiz-Ponte, Hermann Brenner, Stephan Buch, Henry Völzke, Jochen Hampe, Clemens Schafmayer, Annika Lindblom In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.
    Electronic ISSN: 1932-6203
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  • 18
    Publication Date: 2013-09-08
    Description: by Takashi Ochiai, Yuji Suehiro, Katsuhiro Nishinari, Takeo Kubo, Hideaki Takeuchi Background Coordinated movement in social animal groups via social learning facilitates foraging activity. Few studies have examined the behavioral cause-and-effect between group members that mediates this social learning. Methodology/Principal Findings We first established a behavioral paradigm for visual food learning using medaka fish and demonstrated that a single fish can learn to associate a visual cue with a food reward. Grouped medaka fish (6 fish) learn to respond to the visual cue more rapidly than a single fish, indicating that medaka fish undergo social learning. We then established a data-mining method based on Kullback-Leibler divergence (KLD) to search for candidate behaviors that induce alignment and found that high-speed movement of a focal fish tended to induce alignment of the other members locally and transiently under free-swimming conditions without presentation of a visual cue. The high-speed movement of the informed and trained fish during visual cue presentation appeared to facilitate the alignment of naïve fish in response to some visual cues, thereby mediating social learning. Compared with naïve fish, the informed fish had a higher tendency to induce alignment of other naïve fish under free-swimming conditions without visual cue presentation, suggesting the involvement of individual recognition in social learning. Conclusions/Significance Behavioral cause-and-effect studies of the high-speed movement between fish group members will contribute to our understanding of the dynamics of social behaviors. The data-mining method used in the present study is a powerful method to search for candidates factors associated with inter-individual interactions using a dataset for time-series coordinate data of individuals.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 19
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    In: PLoS ONE
    Publication Date: 2013-09-08
    Description: by Anthony Singhal, Simona Monaco, Liam D. Kaufman, Jody C. Culham Behavioral and neuropsychological research suggests that delayed actions rely on different neural substrates than immediate actions; however, the specific brain areas implicated in the two types of actions remain unknown. We used functional magnetic resonance imaging (fMRI) to measure human brain activation during delayed grasping and reaching. Specifically, we examined activation during visual stimulation and action execution separated by a 18-s delay interval in which subjects had to remember an intended action toward the remembered object. The long delay interval enabled us to unambiguously distinguish visual, memory-related, and action responses. Most strikingly, we observed reactivation of the lateral occipital complex (LOC), a ventral-stream area implicated in visual object recognition, and early visual cortex (EVC) at the time of action. Importantly this reactivation was observed even though participants remained in complete darkness with no visual stimulation at the time of the action. Moreover, within EVC, higher activation was observed for grasping than reaching during both vision and action execution. Areas in the dorsal visual stream were activated during action execution as expected and, for some, also during vision. Several areas, including the anterior intraparietal sulcus (aIPS), dorsal premotor cortex (PMd), primary motor cortex (M1) and the supplementary motor area (SMA), showed sustained activation during the delay phase. We propose that during delayed actions, dorsal-stream areas plan and maintain coarse action goals; however, at the time of execution, motor programming requires re-recruitment of detailed visual information about the object through reactivation of (1) ventral-stream areas involved in object perception and (2) early visual areas that contain richly detailed visual representations, particularly for grasping.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 20
    Publication Date: 2013-09-08
    Description: by Annabel Meyer, Andreas Focks, Viviane Radl, Daniel Keil, Gerhard Welzl, Ingo Schöning, Steffen Boch, Sven Marhan, Ellen Kandeler, Michael Schloter Understanding factors driving the ecology of N cycling microbial communities is of central importance for sustainable land use. In this study we report changes of abundance of denitrifiers, nitrifiers and nitrogen-fixing microorganisms (based on qPCR data for selected functional genes) in response to different land use intensity levels and the consequences for potential turnover rates. We investigated selected grassland sites being comparable with respect to soil type and climatic conditions, which have been continuously treated for many years as intensely used meadows ( IM ), intensely used mown pastures ( IP ) and extensively used pastures ( EP ), respectively. The obtained data were linked to above ground biodiversity pattern as well as water extractable fractions of nitrogen and carbon in soil. Shifts in land use intensity changed plant community composition from systems dominated by s-strategists in extensive managed grasslands to c-strategist dominated communities in intensive managed grasslands. Along the different types of land use intensity, the availability of inorganic nitrogen regulated the abundance of bacterial and archaeal ammonia oxidizers. In contrast, the amount of dissolved organic nitrogen determined the abundance of denitrifiers ( nirS and nirK ). The high abundance of nifH carrying bacteria at intensive managed sites gave evidence that the amounts of substrates as energy source outcompete the high availability of inorganic nitrogen in these sites. Overall, we revealed that abundance and function of microorganisms involved in key processes of inorganic N cycling (nitrification, denitrification and N fixation) might be independently regulated by different abiotic and biotic factors in response to land use intensity.
    Electronic ISSN: 1932-6203
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  • 21
    Publication Date: 2013-09-08
    Description: by Xiaofeng Wang, Liang Zhang, Zixian Chen, Yushui Ma, Yuan Zhao, Abudouaini Rewuti, Feng Zhang, Da Fu, Yusong Han Background The association between polymorphisms on 5p12 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two wildly studied polymorphisms (rs10941679 and rs4415084) on 5p12. Methods Databases including Pubmed, EMBASE, Web of Science, EBSCO, and Cochrane Library databases were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias. Results A total of 19 articles involving 100,083 cases and 163,894 controls were included. An overall random-effects per-allele OR of 1.09 (95% CI: 1.06–1.12; P =  4.5×10 −8 ) and 1.09 (95% CI: 1.05–1.12; P  = 4.2×10 −7 ) was found for the rs10941679 and rs4415084 polymorphism respectively. Significant results were found in Asians and Caucasians when stratified by ethnicity; whereas no significant associations were found among Africans/African-Americans. Similar results were also observed using dominant or recessive genetic models. In addition, we find both rs4415084 and rs10941679 conferred significantly greater risks of ER-positive breast cancer than of ER-negative tumors. Conclusions Our findings demonstrated that rs10941679-G allele and rs4415084-T allele might be risk-conferring factors for the development of breast cancer, especially in Caucasians and East-Asians.
    Electronic ISSN: 1932-6203
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  • 22
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    In: PLoS ONE
    Publication Date: 2013-09-10
    Description: by Dongnhu T. Truong, Ashley Bonet, Amanda R. Rendall, Glenn D. Rosen, Roslyn H. Fitch Disruption of neuronal migration in humans is associated with a wide range of behavioral and cognitive outcomes including severe intellectual disability, language impairment, and social dysfunction. Furthermore, malformations of cortical development have been observed in a number of neurodevelopmental disorders (e.g. autism and dyslexia), where boys are much more commonly diagnosed than girls (estimates around 4 to 1). The use of rodent models provides an excellent means to examine how sex may modulate behavioral outcomes in the presence of comparable abnormal neuroanatomical presentations. Initially characterized by Rosen et al. 2012, the BXD29- Tlr4lps−2J /J mouse mutant exhibits a highly penetrant neuroanatomical phenotype that consists of bilateral midline subcortical nodular heterotopia with partial callosal agenesis. In the current study, we confirm our initial findings of a severe impairment in rapid auditory processing in affected male mice. We also report that BXD29- Tlr4lps−2J /J (mutant) female mice show no sparing of rapid auditory processing, and in fact show deficits similar to mutant males. Interestingly, female BXD29- Tlr4lps−2J /J mice do display superiority in Morris water maze performance as compared to wild type females, an affect not seen in mutant males. Finally, we report new evidence that BXD29- Tlr4lps−2J /J mice, in general, show evidence of hyper-social behaviors. In closing, the use of the BXD29- Tlr4lps−2J /J strain of mice – with its strong behavioral and neuroanatomical phenotype – may be highly useful in characterizing sex independent versus dependent mechanisms that interact with neural reorganization, as well as clinically relevant abnormal behavior resulting from aberrant neuronal migration.
    Electronic ISSN: 1932-6203
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  • 23
    Publication Date: 2013-09-11
    Description: by Peng Zhao, Xue-mei Zhou, Li-yao Zhang, Wei Wang, Li-gang Ma, Li-bo Yang, Xiong-bo Peng, Peter V. Bozhkov, Meng-xiang Sun Plant zygote divides asymmetrically into an apical cell that develops into the embryo proper and a basal cell that generates the suspensor, a vital organ functioning as a conduit of nutrients and growth factors to the embryo proper. After the suspensor has fulfilled its function, it is removed by programmed cell death (PCD) at the late stages of embryogenesis. The molecular trigger of this PCD is unknown. Here we use tobacco ( Nicotiana tabacum ) embryogenesis as a model system to demonstrate that the mechanism triggering suspensor PCD is based on the antagonistic action of two proteins: a protease inhibitor, cystatin NtCYS, and its target, cathepsin H-like protease NtCP14. NtCYS is expressed in the basal cell of the proembryo, where encoded cystatin binds to and inhibits NtCP14, thereby preventing precocious onset of PCD. The anti-cell death effect of NtCYS is transcriptionally regulated and is repressed at the 32-celled embryo stage, leading to increased NtCP14 activity and initiation of PCD. Silencing of NtCYS or overexpression of NtCP14 induces precocious cell death in the basal cell lineage causing embryonic arrest and seed abortion. Conversely, overexpression of NtCYS or silencing of NtCP14 leads to profound delay of suspensor PCD. Our results demonstrate that NtCYS-mediated inhibition of NtCP14 protease acts as a bipartite molecular module to control initiation of PCD in the basal cell lineage of plant embryos.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 24
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    Publication Date: 2013-09-11
    Description: by William Henry Gilbert
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 25
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    Publication Date: 2013-09-11
    Description: by Kaheina Aizel, Valérie Biou, Jorge Navaza, Lionel V. Duarte, Valérie Campanacci, Jacqueline Cherfils, Mahel Zeghouf The mechanisms whereby guanine nucleotide exchange factors (GEFs) coordinate their subcellular targeting to their activation of small GTPases remain poorly understood. Here we analyzed how membranes control the efficiency of human BRAG2, an ArfGEF involved in receptor endocytosis, Wnt signaling, and tumor invasion. The crystal structure of an Arf1–BRAG2 complex that mimics a membrane-bound intermediate revealed an atypical PH domain that is constitutively anchored to the catalytic Sec7 domain and interacts with Arf. Combined with the quantitative analysis of BRAG2 exchange activity reconstituted on membranes, we find that this PH domain potentiates nucleotide exchange by about 2,000-fold by cumulative conformational and membrane-targeting contributions. Furthermore, it restricts BRAG2 activity to negatively charged membranes without phosphoinositide specificity, using a positively charged surface peripheral to but excluding the canonical lipid-binding pocket. This suggests a model of BRAG2 regulation along the early endosomal pathway that expands the repertoire of GEF regulatory mechanisms. Notably, it departs from the auto-inhibitory and feedback loop paradigm emerging from studies of SOS and cytohesins. It also uncovers a novel mechanism of unspecific lipid-sensing by PH domains that may allow sustained binding to maturating membranes.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
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  • 26
    Publication Date: 2013-09-11
    Description: by Shuncang Zhang, Pengda Ma, Dongfeng Yang, Wenjing Li, Zongsuo Liang, Yan Liu, Fenghua Liu Salvia miltiorrhiza Bunge is one of the most renowned traditional medicinal plants in China. Phenolic acids that are derived from the rosmarinic acid pathway, such as rosmarinic acid and salvianolic acid B, are important bioactive components in S. miltiorrhiza . Accumulations of these compounds have been reported to be induced by various elicitors, while little is known about transcription factors that function in their biosynthetic pathways. We cloned a subgroup 4 R2R3 MYB transcription factor gene ( SmMYB39 ) from S. miltiorrhiza and characterized its roles through overexpression and RNAi-mediated silencing. As the results showed, the content of 4-coumaric acid, rosmarinic acid, salvianolic acid B, salvianolic acid A and total phenolics was dramatically decreased in SmMYB39 -overexpressing S. miltiorrhiza lines while being enhanced by folds in SmMYB39 -RNAi lines. Quantitative real-time PCR and enzyme activities analyses showed that SmMYB39 negatively regulated transcripts and enzyme activities of 4-hydroxylase (C4H) and tyrosine aminotransferase (TAT). These data suggest that SmMYB39 is involved in regulation of rosmarinic acid pathway and acts as a repressor through suppressing transcripts of key enzyme genes.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 27
    Publication Date: 2013-09-11
    Description: by Sang-Eun Yeon, Da Yoon No, Sang-Hoon Lee, Suk Woo Nam, Il-Hoan Oh, Jaehwi Lee, Hyo-Jeong Kuh Intrinsic drug resistance of pancreatic ductal adenocarcinoma (PDAC) warrants studies using models that are more clinically relevant for identifying novel resistance mechanisms as well as for drug development. Tumor spheroids (TS) mimic in vivo tumor conditions associated with multicellular resistance and represent a promising model for efficient drug screening, however, pancreatic cancer cells often fail to form spheroids using conventional methods such as liquid overlay. This study describes the induction of TS of human pancreatic cancer cells (Panc-1, Aspc-1, Capan-2) in concave polydimethylsiloxane (PDMS) microwell plates and evaluation of their usefulness as an anticancer efficacy test model. All three cell lines showed TS formation with varying degree of necrosis inside TS. Among these, Panc-1 spheroid with spherical morphology, a rather rough surface, and unique adhesion structures were successfully produced with no notable necrosis in concave microwell plates. Panc-1 TS contained growth factors or enzymes such as TGF-β1, CTGF, and MT1-MMP, and extracellular matrix proteins such as collagen type I, fibronectin, and laminin. Panc-1 cells grown as TS showed changes in stem cell populations and in expression levels of miRNAs that may play roles in chemoresistance. Visualization of drug penetration and detection of viability indicators, such as Ki-67 and MitoSOX, were optimized for TS for quantitative analysis. Water-soluble tetrazolium (MTS) and acid phosphatase (APH) assays were also successfully optimized. Overall, we demonstrated that concave PDMS microwell plates are a novel platform for preparation of TS of weakly aggregating cells and that Panc-1 spheroids may represent a novel three-dimensional model for anti-pancreatic cancer drug screening.
    Electronic ISSN: 1932-6203
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  • 28
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    In: PLoS ONE
    Publication Date: 2013-09-11
    Description: by Duncan Howie, Hugo Garcia Rueda, Marion H. Brown, Herman Waldmann Most T cell responses to pathogens or self antigens are modulated through the action of regulatory T cells and tissue-specific inhibitory mechanisms. To this end, several receptor-ligand pairs have evolved which either augment or diminish T cell function. Here we describe the tissue ligand SECTM1A (Secreted and transmembrane1A) as an alternative murine CD7 ligand. We show that SECTM1A, like SECTM1B, binds strongly to CD7, and that SECTM1B was able to compete with SECTM1A for CD7 binding. SECTM1A is ubiquitously expressed and has two major alternative transcripts which differ in expression between tissues. Both immobilised soluble forms of SECTM1A and SECTM1B and cell surface anchored forms demonstrated opposing effects on CD4+ T cell activation. Whereas SECTM1A acted as a co-stimulator of T cells, enhancing IL-2 production and proliferation, SECTM1B proved inhibitory to TCR mediated T cell activation. Surprisingly, both functional outcomes proved to be CD7-independent, indicating the existence of alternative receptors for both ligands. We used a SECTM1A-Fc fusion protein to immunoprecipitate potential alternative ligands from detergent lysates of CD7 −/− T cells and, using mass spectrometry, identified GITR as a SECTM1A binder. SECTM1A was found to bind to activated CD4+ and CD8+ T cells as well as to CHO cells expressing cell surface GITR. Binding of SECTM1A to activated primary T cells was inhibited by either GITRL-Fc or anti GITR antibodies. Thus SECTM1A and SECTM1B represent novel reciprocal alternative ligands which may function to modulate the activation of effector and regulatory T cells. The ability of SECTM1A to activate T cells may be explained by its ability to bind to GITR.
    Electronic ISSN: 1932-6203
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  • 29
    Publication Date: 2013-09-11
    Description: by Wei-Jun Zhou, Ren-Ying Wang, Yan Li, Dong-Rui Chen, Er-Zhen Chen, Ding-Liang Zhu, Ping-Jin Gao Objective β-blockers (BBs) with different pharmacological properties may have heterogeneous effects on sympathetic nervous activity (SNA) and central aortic pressure (CAP), which are independent cardiovascular factors for hypertension. Hence, we analyzed the effects of bisoprolol and atenolol on SNA and CAP in hypertensive patients. Methods This was a prospective, randomized, controlled study in 109 never-treated hypertensive subjects randomized to bisoprolol (5 mg) or atenolol (50 mg) for 4–8 weeks. SNA, baroreflex sensitivity (BRS) and heart rate (HR) variability (HRV) were measured using power spectral analysis using a Finometer. CAP and related parameters were determined using the SphygmoCor device (pulse wave analysis). Results Both drugs were similarly effective in reducing brachial BP. However, central systolic BP (−14±10 mm Hg vs −6±9 mm Hg; P
    Electronic ISSN: 1932-6203
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  • 30
    Publication Date: 2013-09-11
    Description: by Catherine J. Mondloch, Nicole L. Nelson, Matthew Horner The accuracy and speed with which emotional facial expressions are identified is influenced by body postures. Two influential models predict that these congruency effects will be largest when the emotion displayed in the face is similar to that displayed in the body: the emotional seed model and the dimensional model. These models differ in whether similarity is based on physical characteristics or underlying dimensions of valence and arousal. Using a 3-alternative forced-choice task in which stimuli were presented briefly (Exp 1a) or for an unlimited time (Exp 1b) we provide evidence that congruency effects are more complex than either model predicts; the effects are asymmetrical and cannot be accounted for by similarity alone. Fearful postures are especially influential when paired with facial expressions, but not when presented in a flanker task (Exp 2). We suggest refinements to each model that may account for our results and suggest that additional studies be conducted prior to drawing strong theoretical conclusions.
    Electronic ISSN: 1932-6203
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  • 31
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    In: PLoS ONE
    Publication Date: 2013-09-11
    Description: by Robert Savit, Maria Riolo, Rick Riolo Co-adaptation (or co-evolution), the parallel feedback process by which agents continuously adapt to the changes induced by the adaptive actions of other agents, is a ubiquitous feature of complex adaptive systems, from eco-systems to economies. We wish to understand which general features of complex systems necessarily follow from the (meta)-dynamics of co-adaptation, and which features depend on the details of particular systems. To begin this project, we present a model of co-adaptation (“The Stigmergy Game”) which is designed to be as a priori featureless as possible, in order to help isolate and understand the naked consequences of co-adaptation. In the model, heterogeneous, co-adapting agents, observe, interact with and change the state of an environment. Agents do not, ab initio , directly interact with each other. Agents adapt by choosing among a set of random “strategies,” particular to each agent. Each strategy is a complete specification of an agent's actions and payoffs. A priori , all environmental states are equally likely and all strategies have payoffs that sum to zero, so without co-adaptation agents would on average have zero “wealth”. Nevertheless, the dynamics of co-adaptation generates a structured environment in which only a subset of environmental states appear with high probability (niches) and in which agents accrue positive wealth. Furthermore, although there are no direct agent-agent interactions, there are induced non-trivial inter-agent interactions mediated by the environment. As a function of the population size and the number of possible environmental states, the system can be in one of three dynamical regions. Implications for a basic understanding of complex adaptive systems are discussed.
    Electronic ISSN: 1932-6203
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  • 32
    Publication Date: 2013-09-11
    Description: by Sandra Laner-Plamberger, Florian Wolff, Alexandra Kaser-Eichberger, Stefan Swierczynski, Cornelia Hauser-Kronberger, Anna-Maria Frischauf, Thomas Eichberger Sustained hedgehog (Hh) signaling mediated by the GLI transcription factors is implicated in many types of cancer. Identification of Hh/GLI target genes modulating the activity of other pathways involved in tumor development promise to open new ways for better understanding of tumor development and maintenance. Here we show that SOCS1 is a direct target of Hh/GLI signaling in human keratinocytes and medulloblastoma cells. SOCS1 is a potent inhibitor of interferon gamma (IFN-y)/STAT1 signaling. IFN-у/STAT1 signaling can induce cell cycle arrest, apoptosis and anti-tumor immunity. The transcription factors GLI1 and GLI2 activate the SOCS1 promoter, which contains five putative GLI binding sites, and GLI2 binding to the promoter was shown by chromatin immunoprecipitation. Consistent with a role of GLI in SOCS1 regulation, STAT1 phosphorylation is reduced in cells with active Hh/GLI signaling and IFN-у/STAT1 target gene activation is decreased. Furthermore, IFN-у signaling is restored by shRNA mediated knock down of SOCS1. Here, we identify SOCS1 as a novel Hh/GLI target gene, indicating a negative role of Hh/GLI pathway in IFN-y/STAT1 signaling.
    Electronic ISSN: 1932-6203
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  • 33
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    In: PLoS ONE
    Publication Date: 2013-09-11
    Description: by Xuting Xu, Yunliang Wang, Lingyan Wang, Qi Liao, Lan Chang, Leiting Xu, Yi Huang, Huadan Ye, Limin Xu, Cheng Chen, Xiaowei Shen, Fuqiang Zhang, Meng Ye, Qinwen Wang, Shiwei Duan Aims The aim of this study was to evaluate the combined contribution of 8 polymorphisms to the risk of Alzheimer's disease (AD). Methods Through a comprehensive literature search for genetic variants involved in the AD association study, we harvested a total of 6 genes (8 polymorphisms) for the current meta-analyses. These genes consisted of A2M (5bp I/D and V1000I), ABCA2 (rs908832), CHAT (1882G 〉A, 2384G 〉A), COMT (Val158Met), HTR6 (267C 〉T) and LPL (Ser447Ter). Results A total of 33 studies among 9,453 cases and 10,833 controls were retrieved for the meta-analyses of 8 genetic variants. It was showed that A2M V1000I (odd ratio (OR) = 1.26, 95% confidence interval (CI) = 1.07–1.49, P = 0.007), rs908832 allele of ABCA2 (OR = 1.55, 95% CI = 1.12–2.16, P = 0.009), 2384G 〉A of CHAT (OR = 1.22, 95% CI = 1.00–1.49, P = 0.05) and Ser447Ter of LPL in the Northern-American population (OR = 0.56, 95% CI = 0.35–0.91, P = 0.02) were significantly associated with the risk of AD. No association was found between the rest of the 5 polymorphisms and the risk of AD. Conclusion Our results showed that A2M V1000I polymorphism in German, Korean, Chinese, Spanish, Italian and Polish populations, rs90883 of ABCA2 gene in French, American, Swiss, Greek and Japanese populations, 2384G 〉A of CHAT gene in British and Korean populations and LPL Ser447Ter in the Northern-American population were associated with the risk of AD.
    Electronic ISSN: 1932-6203
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  • 34
    Publication Date: 2013-09-12
    Description: by Katerina Douka, Christopher A. Bergman, Robert E. M. Hedges, Frank P. Wesselingh, Thomas F. G. Higham The Out-of-Africa model holds that anatomically modern humans (AMH) evolved and dispersed from Africa into Asia, and later Europe. Palaeoanthropological evidence from the Near East assumes great importance, but AMH remains from the region are extremely scarce. ‘Egbert’, a now-lost AMH fossil from the key site of Ksar Akil (Lebanon) and ‘Ethelruda’, a recently re-discovered fragmentary maxilla from the same site, are two rare examples where human fossils are directly linked with early Upper Palaeolithic archaeological assemblages. Here we radiocarbon date the contexts from which Egbert and Ethelruda were recovered, as well as the levels above and below the findspots. In the absence of well-preserved organic materials, we primarily used marine shell beads, often regarded as indicative of behavioural modernity. Bayesian modelling allows for the construction of a chronostratigraphic framework for Ksar Akil, which supports several conclusions. The model-generated age estimates place Egbert between 40.8–39.2 ka cal BP (68.2% prob.) and Ethelruda between 42.4–41.7 ka cal BP (68.2% prob.). This indicates that Egbert is of an age comparable to that of the oldest directly-dated European AMH (Peştera cu Oase). Ethelruda is older, but on current estimates not older than the modern human teeth from Cavallo in Italy. The dating of the so-called “transitional” or Initial Upper Palaeolithic layers of the site may indicate that the passage from the Middle to Upper Palaeolithic at Ksar Akil, and possibly in the wider northern Levant, occurred later than previously estimated, casting some doubts on the assumed singular role of the region as a locus for human dispersals into Europe. Finally, tentative interpretations of the fossil's taxonomy, combined with the chronometric dating of Ethelruda's context, provides evidence that the transitional/IUP industries of Europe and the Levant, or at least some of them, may be the result of early modern human migration(s).
    Electronic ISSN: 1932-6203
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  • 35
    Publication Date: 2013-09-12
    Description: by Thomas Lund, Johan Hviid Andersen, Trine Nøhr Winding, Karin Biering, Merete Labriola Background Most previous studies on reliance on social benefits have focused on health, sickness absence, work environment and socioeconomic status in adulthood. Extending the focus to include early life circumstances may improve our understanding of processes leading to educational and occupational marginalisation and exclusion. The aim of this study was to investigate if multiple negative life events in childhood determined future labour market participation, and to identify important negative life events for labour market participation in young adulthood. Methods Of a cohort of 3,681 born in 1989 in the county of Ringkjoebing, Denmark, 3,058 (83%) completed a questionnaire in 2004. They were followed in a register on social benefits for 12 months in 2010-2011. Logistic regression analyses were used to investigate associations between negative life events in childhood and future labour market participation, taking into account effects of socio-economic position, school performance, educational plans, vocational expectations and general health. Results A total of 17.1% (19.9% males, 14.4% females) received social benefits for at least 4 weeks during follow-up. Labour market participation decreased with number of negative life events, especially for females: Females who had experienced their parents’ divorce, had been abused, or had witnessed a violent event, showed decreased labour market participation, when adjusting for SES, school performance, educational plans, vocational expectations and general health at baseline. Attributable fractions ranged from 2.4% (parents’ alcohol/drug abuse) to 16.1% (parents’ divorce) for women. For men, risk estimates were lower and insignificant in the most adjusted models. Attributable fractions ranged from 1.0% (parents’ alcohol/drug abuse) to 4.9% for witnessing a violent event. Conclusions Information on childhood conditions may increase the understanding of determinants of labour market participation for young adults. Knowledge of negative life events in childhood should be taken into account when considering determinants of labour market participation and identifying high-risk groups.
    Electronic ISSN: 1932-6203
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  • 36
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    In: PLoS ONE
    Publication Date: 2013-09-12
    Description: by Britt G. de Jong, Aart Lammers, Leonora A. A. Oberendorf, Mike G. B. Nieuwland, Huub F. J. Savelkoul, Henk K. Parmentier Specificity, antibody isotype distribution and levels of natural antibodies (NAb) may be potential informative parameters for immune mediated natural disease resistance, immune modulation, and maintenance of physiological homeostasis. A large proportion of mammalian NAb have affinity for or are directed against self-antigens; so called natural auto antibodies (N(A)Ab). In the present study we showed the presence and typed levels and isotypes (total immunoglobulins, IgG and IgM) of N(A)Ab in plasma binding the ‘auto-antigen’ complex chicken liver cell lysate (CLL) of one-year old chickens from different genotype and phenotype backgrounds by ELISA and quantitative Western blotting. Higher levels of N(A)Ab binding CLL were found in plasma from chickens genetically selected for high specific antibody responses. In all birds, extensive staining patterns of plasma antibodies binding CLL were found for all isotypes, with IgG binding the highest number of CLL antigens and also showing the highest variation in staining patterns between individuals. Patterns of IgM antibodies binding CLL appeared to be more similar in all lines. Significant differences of binding patterns of N(A)Ab (antigen fragments of CLL and staining intensity) were detected between the different chicken lines, and lines could be clustered on the basis of their auto-antibody profile. In addition, also individual differences within lines were found. The present results indicate that analysis of the levels and the N(A)Ab repertoire of poultry like in mammals could provide a new way of distinguishing differences of immune competence and immune maturation between individuals, and could provide tools to select birds for health traits, or optimize hygiene and husbandry procedures.
    Electronic ISSN: 1932-6203
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  • 37
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-12
    Description: by Pei-Yi Chu, Chih-Jen Cheng, Yi-Chang Wu, Yu-Wei Fang, Tom Chau, Shinichi Uchida, Sei Sasaki, Sung-Sen Yang, Shih-Hua Lin Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na + -Cl − cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo . Wnk4 D561A/+ mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP- Osr1 −/− ) and Spak knockout ( Spak −/− ) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 D561A/+ , KSP- Osr1 −/− , and Spak −/− mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 D561A/+ .KSP- Osr1 −/− remained phenotypically PHA II while Wnk4 D561A/+ . Spak −/− mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 D561A/+ and Wnk4 D561A/+ .KSP- Osr1 −/− mice while phosphorylated Ncc normalized in Wnk4 D561A/+ . Spak −/− mice. Furthermore, Wnk4 D561A/+ .KSP- Osr1 −/− mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 D561A/+ . Spak −/− mice exhibited normal responses. Wnk4D561A/+.Spak −/− . KSP-Osr1 −/− triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.
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  • 38
    Publication Date: 2013-09-12
    Description: by Magdalena Migocka, Anna Warzybok, Anna Papierniak, Grażyna Kłobus Studies in the last few years have shed light on the process of nitrate accumulation within plant cells, achieving molecular identification and partial characterization of the genes and proteins involved in this process. However, contrary to the plasma membrane-localized nitrate transport activities, the kinetics of active nitrate influx into the vacuole and its adaptation to external nitrate availability remain poorly understood. In this work, we have investigated the activity and regulation of the tonoplast-localized H + /NO 3 − antiport in cucumber roots in response to N starvation and NO 3 − induction. The time course of nitrate availability strongly influenced H + /NO 3 − antiport activity at the tonoplast of root cells. However, under N starvation active nitrate accumulation within the vacuole still occurred. Hence, either a constitutive H + -coupled transport system specific for nitrate operates at the tonoplast, or nitrate uses another transport protein of broader specificity to different anions to enter the vacuole via a proton-dependent process. H + /NO 3 − antiport in cucumber was significantly stimulated in NO 3 − -induced plants that were supplied with nitrate for 24 hours following 6-day-long N starvation. The cytosolic fraction isolated from the roots of NO 3 − -induced plants significantly stimulated H + /NO 3 − antiport in tonoplast membranes isolated from cucumbers growing on nitrate. The stimulatory effect of the cytosolic fraction was completely abolished by EGTA and the protein kinase inhibitor staurosporine and slightly enhanced by the phosphatase inhibitors okadaic acid and cantharidin. Hence, we conclude that stimulation of H + /NO 3 − antiport at the tonoplast of cucumber roots in response to nitrate provision may occur through the phosphorylation of a membrane antiporter involving Ca-dependent, staurosporine-sensitive protein kinase.
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  • 39
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-12
    Description: by I-Cheng Chen, Hsuan-Yuan Lin, Ya-Chin Hsiao, Chiung-Mei Chen, Yih-Ru Wu, Hsin-Chieh Shiau, Yu-Fang Shen, Kuo-Shiu Huang, Ming-Tsan Su, Hsiu-Mei Hsieh-Li, Guey-Jen Lee-Chen Spinocerebellar ataxia type 8 (SCA8) involves the expansion of CTG/CAG repeats from the overlapping ataxin 8 opposite strand ( ATXN8OS ) and ataxin 8 ( ATXN8 ) genes located on chromosome 13q21. Although being transcribed, spliced and polyadenylated in the CTG orientation, ATXN8OS does not itself appear to be protein coding, as only small open reading frames (ORFs) were noted. In the present study we investigated the translation of a novel 102 amino acids containing-ORF in the ATXN8OS RNA. Expression of chimeric construct with an in-frame ORF-EGFP gene demonstrated that ATXN8OS RNA is translatable. Using antiserum raised against ORF, ATXN8OS ORF expression was detected in various human cells including lymphoblastoid, embryonic kidney 293, neuroblastoma IMR-32, SK-N-SH, SH-SY5Y cells and human muscle tissue. The biological role of the ATXN8OS ORF and its connection to SCA8 remains to be determined.
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  • 40
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    In: PLoS ONE
    Publication Date: 2013-09-12
    Description: by Carel P. van Schaik, Laura Damerius, Karin Isler The ability to plan for the future beyond immediate needs would be adaptive to many animal species, but is widely thought to be uniquely human. Although studies in captivity have shown that great apes are capable of planning for future needs, it is unknown whether and how they use this ability in the wild. Flanged male Sumatran orangutans ( Pongo abelii ) emit long calls, which females use to maintain earshot associations with them. We tested whether long calls serve to communicate a male's ever-changing predominant travel direction to facilitate maintaining these associations. We found that the direction in which a flanged male emits his long calls predicts his subsequent travel direction for many hours, and that a new call indicates a change in his main travel direction. Long calls given at or near the night nest indicate travel direction better than random until late afternoon on the next day. These results show that male orangutans make their travel plans well in advance and announce them to conspecifics. We suggest that such a planning ability is likely to be adaptive for great apes, as well as in other taxa.
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  • 41
    Publication Date: 2013-09-13
    Description: by M. H. Eileen Tan, X. Edward Zhou, Fen-Fen Soon, Xiaodan Li, Jun Li, Eu-Leong Yong, Karsten Melcher, H. Eric Xu Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor’s structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.
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  • 42
    Publication Date: 2013-09-13
    Description: by Ayako Suzuki, Sachiyo Mimaki, Yuki Yamane, Akikazu Kawase, Koutatsu Matsushima, Makito Suzuki, Koichi Goto, Sumio Sugano, Hiroyasu Esumi, Yutaka Suzuki, Katsuya Tsuchihara We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinoma patients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may be used for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normal tissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available.
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  • 43
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    In: PLoS ONE
    Publication Date: 2013-09-13
    Description: by Lin Huang Objective: Ischemic pre-conditioning and post-conditioning are useful manipulations to reduce the undesirable effects of ischemia-reperfusion skin flap each. But the impact of post-conditioning on the pre-conditioning skin flap is not manifested. Here we investigated the influence of ischemic post-conditioning in a preconditioned axial pattern skin flap model.Method: We used the skin flap in 40 rabbits and divided them into 5 groups randomly. At first we induced the ischemic pre-conditioning of the flap which was applied by 2 periods of 15 minutes of ischemia/15 minutes of reperfusion cycle. Next post-conditioning was performed by 6 cycles of 10 seconds of repeated ischemia/reperfusion periods at different times of just after the reperfusion,5 minutes after the reperfusion,10 minutes after the reperfusion. The animals were allocated into 5 groups: group 1 (Ischemia Group); group 2: (Pre-conditioning Group); group 3: (Pre-conditioning+ Post-conditioning Group); group 4 (Pre-conditioning+ Post-conditioning 5 minutes later Group); group5 (Pre-conditioning+ Post-conditioning 10 minutes later). The neutrophil count was assessed with histologic analysis before the dissection of the skin flap. Flap viability was assessed 1 week after the operation, and surviving flap area was recorded as a percentage of the whole flap area. LSD test was used for statistical analysis among different groups to evaluate the effects of ischemic pre-conditioning against ischemia.Result: Among the varying groups, the neutrophil count varied: Group 1 was50.12±5.91; Group 2, 30.00±2.00, and Group 3, 18.87±3; Group 4, 22.50±1.92; Group 5, 30.12±1.88.The mean± SD surviving areas of the flaps for groups 1, 2, 3, 4 and 5 were 31.76±4.59, 51.26±3.24,82.18±5.28,66.85±3.87 and 51.13±2.90 respectively. Spearman correlation analysis shows an increase relation between neutrophil count and flap survival rate in the different groups (P
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  • 44
    Publication Date: 2013-09-13
    Description: by Hiroyuki Nishi, Taichi Sakaguchi, Shigeru Miyagawa, Yasushi Yoshikawa, Satsuki Fukushima, Shunsuke Saito, Takayoshi Ueno, Toru Kuratani, Yoshiki Sawa Background Although microRNA (miRNA) regulates initiation and/or progression of atrial fibrillation (AF) in canine AF models, the underlying mechanism in humans remains unclear. We speculated that certain miRNAs in atrial tissue are related to AF, and evaluated the relationship of miRNA expression in human atrial tissue in cardiac surgery patients. Methods Right atrial tissues from 29 patients undergoing cardiovascular surgery were divided into 3 groups [A: chronic AF or unsuccessful maze, n=6; B: successful maze, n=10; C: sinus rhythm (SR) n=13]. miRNA expression was determined using high density microarrays and with Reverse transcriptase-polymerase chain reaction (RT-PCR). Fibrosis was examined using Masson trichrome staining. Results miRNA microarray analysis showed elevated miRNA-21, miRNA-23b, miRNA-199b, and miRNA-208b in AF as compared to SR groups. RT-PCR showed elevated miRNA-21 (1.9-fold) and miRNA-208b (4.2-fold) in AF as compared to the SR groups. miRNA-21 expression increased from Group C to A (A: 2.1-fold, B: 1.8-fold, C: 1.0-fold). Fibrosis increased from C to A (A: 43.0±12.9%, B: 21.3±6.1%, C: 11.9±3.1%). Percent fibrosis and miRNA-21 expression were correlated (r=0.508, p
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  • 45
    Publication Date: 2013-09-13
    Description: by Habiba I. Ali, Amjad H. Jarrar, Mohamed El Sadig, Karin B. Yeatts Background Diet therapy is the cornerstone for the management of gestational diabetes mellitus (GDM). Carbohydrate is the primary nutrient affecting postprandial blood glucose levels. Hence, knowledge of food containing carbohydrates can assist women with GDM optimize glycemic control. Despite that, there is a paucity of research on carbohydrate-related knowledge of women with GDM. The United Arab Emirates (UAE) has one of the highest prevalence of diabetes (19.2%) in the world. This study compared diet and knowledge of carbohydrate-containing foods among pregnant women with and without GDM in the UAE. Methods The sample consisted of multi-ethnic women with GDM (n = 94) and a control group of healthy pregnant women (n = 90) attending prenatal clinics in three hospitals in Al Ain, UAE. Data were collected using a questionnaire and a 24-hour recall. Knowledge of food sources of carbohydrate, dietary patterns, and nutrient intakes of the two groups were compared. Results There were no significant differences in the mean knowledge score of food sources of carbohydrate between women with GDM and that of pregnant women without GDM. Similarly, there were no significant differences in energy and nutrient intakes between the two groups with the exception of percent energy from protein. Women with GDM reported significantly lower intake of fruits and fruit juices (P = 0.012) and higher consumption of milk and yogurt (P = 0.004) compared to that of women without GDM. Twenty-two percent of women with GDM indicated they never visited a dietitian for counseling while 65% reported they visited a dietitian only once or twice during the pregnancy. Predictors of carbohydrate knowledge score were perceived knowledge of diet and GDM and parity among women with GDM and parity and educational level among those without GDM. Conclusion The results of the study highlight the urgent need to provide nutrition education for women with GDM in the UAE.
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  • 46
    Publication Date: 2013-09-14
    Description: by Soumya Lipsa Rath, Sanjib Senapati Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a conserved catalytic core. This makes the design of inhibitors specific for a particular CDK difficult. There is, however, growing need for CDK5 specific inhibitors to treat various neurodegenerative diseases. Recently, cis-substituted cyclobutyl-4-aminoimidazole inhibitors have been identified as potent CDK5 inhibitors that gave up to 30-fold selectivity over CDK2. Available IC 50 values also indicate a higher potency of this class of inhibitors over commercially available drugs, such as roscovitine. To understand the molecular basis of higher potency and selectivity of these inhibitors, here, we present molecular dynamics simulation results of CDK5/p25 and CDK2/CyclinE complexed with a series of cyclobutyl-substituted imidazole inhibitors and roscovitine. The atomic details of the stereospecificity and selectivity of these inhibitors are obtained from energetics and binding characteristics to the CDK binding pocket. The study not only complements the experimental findings, but also provides a wealth of detailed information that could help the structure-based drug designing processes.
    Electronic ISSN: 1932-6203
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  • 47
    Publication Date: 2013-09-14
    Description: by Valente Aritua, Diann Achor, Frederick G. Gmitter, Gene Albrigo, Nian Wang Huanglongbing (HLB) is the most destructive disease that affects citrus worldwide. The disease has been associated with Candidatus Liberibacter. HLB diseased citrus plants develop a multitude of symptoms including zinc and copper deficiencies, blotchy mottle, corky veins, stunting, and twig dieback. Ca . L. asiaticus infection also seriously affects the roots. Previous study focused on gene expression of leaves and fruit to Ca . L. asiaticus infection. In this study, we compared the gene expression levels of stems and roots of healthy plants with those in Ca . L. asiaticus infected plants using microarrays. Affymetrix microarray analysis showed a total of 988 genes were significantly altered in expression, of which 885 were in the stems, and 111 in the roots. Of these, 551 and 56 were up-regulated, while 334 and 55 were down-regulated in the stem and root samples of HLB diseased trees compared to healthy plants, respectively. Dramatic differences in the transcriptional responses were observed between citrus stems and roots to Ca . L. asiaticus infection, with only 8 genes affected in both the roots and stems. The affected genes are involved in diverse cellular functions, including carbohydrate metabolism, cell wall biogenesis, biotic and abiotic stress responses, signaling and transcriptional factors, transportation, cell organization, protein modification and degradation, development, hormone signaling, metal handling, and redox. Microscopy analysis showed the depletion of starch in the roots of the infected plants but not in healthy plants. Collapse and thickening of cell walls were observed in HLB affected roots, but not as severe as in the stems. This study provides insight into the host response of the stems and roots to Ca . L. asiaticus infection.
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  • 48
    Publication Date: 2013-09-14
    Description: by Hong Ding, Xin Sun, Wei-wei Chang, Liu Zhang, Xi-ping Xu Background The government of China promulgated new medical care reform policies in March 2009. After that, provincial-level governments launched new medical care reform which focusing on local comprehensive medical care reform (LCMR). Anhui Province is an example of an area affected by LCMR, in which the LCMR was started in October 2009 and implemented in June 2010. The objective of this study was to compare the job satisfaction (JS) of community health workers (CHWs) before and after the reform in Anhui Province. Methods A baseline survey was carried out among 813 community health workers (CHWs) of 57 community health centers (CHCs) (response rate: 94.1%) and an effect evaluation survey among 536 CHWs of 30 CHCs (response rate: 92.3%) in 2009 and 2012 respectively. A self-completion questionnaire was used to assess the JS of the CHWs (by the job satisfaction scale, JSS). Results The average scores of total JS and satisfaction with pay, contingent rewards, operating procedures and communication in the effect evaluation survey were statistically significantly higher than those of the baseline survey ( P
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  • 49
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    In: PLoS ONE
    Publication Date: 2013-09-14
    Description: by Gerda G. Fillenbaum, Sergio L. Blay, Carl F. Pieper, Katherine E. King, Sergio B. Andreoli, Fábio L. Gastal Objectives In high income, developed countries, health status tends to improve as income increases, but primarily through the 50 th -66 th percentile of income. It is unclear whether the same limitation holds in middle income countries, and for both general assessments of health and specific conditions. Methods Data were obtained from Brazil, a middle income country. In-person interviews with a representative sample of community residents age ≥60 (N=6963), in the southern state of Rio Grande do Sul, obtained information on demographic characteristics including household income and number of persons supported, general health status (self-rated health, functional status), depression, and seven physician-diagnosed, self-reported health conditions. Analyses used household income (adjusted for number supported and economies of scale) together with higher order income terms, and controlled for demographics and comorbidities, to ascertain nonlinearity between income and general and specific health measures. Results In fully controlled analyses income was associated with general measures of health (linearly with self-rated health, nonlinearly with functional status). For specific health measures there was a consistent linear association with depression, pulmonary disorders, renal disorders, and sensory impairment. For musculoskeletal, cardiovascular (negative association), and gastrointestinal disorders this association no longer held when comorbidities were controlled. There was no association with diabetes. Conclusion Contrary to findings in high income countries, the association of household-size-adjusted income with health was generally linear, sometimes negative, and sometimes absent when comorbidities were controlled.
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  • 50
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    In: PLoS ONE
    Publication Date: 2013-09-14
    Description: by Sudheer Gupta, Pallavi Kapoor, Kumardeep Chaudhary, Ankur Gautam, Rahul Kumar, Open Source Drug Discovery Consortium , Gajendra P. S. Raghava Background Over the past few decades, scientific research has been focused on developing peptide/protein-based therapies to treat various diseases. With the several advantages over small molecules, including high specificity, high penetration, ease of manufacturing, peptides have emerged as promising therapeutic molecules against many diseases. However, one of the bottlenecks in peptide/protein-based therapy is their toxicity. Therefore, in the present study, we developed in silico models for predicting toxicity of peptides and proteins. Description We obtained toxic peptides having 35 or fewer residues from various databases for developing prediction models. Non-toxic or random peptides were obtained from SwissProt and TrEMBL. It was observed that certain residues like Cys, His, Asn, and Pro are abundant as well as preferred at various positions in toxic peptides. We developed models based on machine learning technique and quantitative matrix using various properties of peptides for predicting toxicity of peptides. The performance of dipeptide-based model in terms of accuracy was 94.50% with MCC 0.88. In addition, various motifs were extracted from the toxic peptides and this information was combined with dipeptide-based model for developing a hybrid model. In order to evaluate the over-optimization of the best model based on dipeptide composition, we evaluated its performance on independent datasets and achieved accuracy around 90%. Based on above study, a web server, ToxinPred has been developed, which would be helpful in predicting (i) toxicity or non-toxicity of peptides, (ii) minimum mutations in peptides for increasing or decreasing their toxicity, and (iii) toxic regions in proteins. Conclusion ToxinPred is a unique in silico method of its kind, which will be useful in predicting toxicity of peptides/proteins. In addition, it will be useful in designing least toxic peptides and discovering toxic regions in proteins. We hope that the development of ToxinPred will provide momentum to peptide/protein-based drug discovery (http://crdd.osdd.net/raghava/toxinpred/).
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  • 51
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    Publication Date: 2013-09-14
    Description: by Peter Walentek, Isabelle Schneider, Axel Schweickert, Martin Blum Breakage of bilateral symmetry in amphibian embryos depends on the development of a ciliated epithelium at the gastrocoel roof during early neurulation. Motile cilia at the gastrocoel roof plate (GRP) give rise to leftward flow of extracellular fluids. Flow is required for asymmetric gene expression and organ morphogenesis. Wnt signaling has previously been involved in two steps, Wnt/ß-catenin mediated induction of Foxj1 , a regulator of motile cilia, and Wnt/planar cell polarity (PCP) dependent cilia polarization to the posterior pole of cells. We have studied Wnt11b in the context of laterality determination, as this ligand was reported to activate canonical and non-canonical Wnt signaling. Wnt11b was found to be expressed in the so-called superficial mesoderm (SM), from which the GRP derives. Surprisingly, Foxj1 was only marginally affected in loss-of-function experiments, indicating that another ligand acts in this early step of laterality specification. Wnt11b was required, however, for polarization of GRP cilia and GRP morphogenesis, in line with the known function of Wnt/PCP in cilia-driven leftward flow. In addition Xnr1 and Coco expression in the lateral-most GRP cells, which sense flow and generate the first asymmetric signal, was attenuated in morphants, involving Wnt signaling in yet another process related to symmetry breakage in Xenopus .
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  • 52
    Publication Date: 2013-09-14
    Description: by Heng Zhao, Jiani Liu, Shinong Pan, Yingwei Sun, Qi Li, Fei Li, Li Ma, Qiyong Guo Purpose Although superoxide dismutase (SOD) and malondialdehyde (MDA) affect Delayed Onset Muscle Soreness (DOMS), their effects are unclear in rectus femoris muscles (RFM) of rats with different eccentric exercise programs and time points. The purpose of this study is to investigate the effects of the various eccentric exercise programs at different time points on the SOD mRNA expression and MDA using rat as the animal model. Methods 248 male rats were randomly divided into 4 groups: control group (CTL, n  = 8), once-only exercise group (OEG, n  = 80), continuous exercise group (CEG, n  = 80), and intermittent exercise group (IEG, n =  80). Each exercise group was divided into 10 subgroups that exercised 0.5 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, or 168 h. Rats were sacrificed and their SOD mRNA expression, and MDA concentrations of skeletal muscle tissue were measured. Results The specimen in all eccentric exercise programs showed increased RFM SOD1 mRNA expression levels at 0.5 h ( P 〈 0.05), and decreased RFM SOD3 mRNA expression at 0.5 h ( P 〈 0.05). The continuous eccentric exercise (CE) significantly enhanced muscle SOD2 mRNA level at 0.5 h ( P 〈 0.05). After once-only eccentric exercise (OE), SOD1 , SOD2 , and SOD3 mRNA expression significantly increased at 96 h, whereas MDA concentrations decreased at 96 h. After CE, the correlation coefficients of SOD1 , SOD2 , SOD3 mRNA expression levels and MDA concentrations were −0.814, −0.763, −0.845 (all P 〈 0.05) at 12 h. Conclusion Regular eccentric exercise, especially CE could enhance SOD1 and SOD2 mRNA expression in acute stage and the SOD2 mRNA expression correlates to MDA concentration in vivo , which may improve the oxidative adaption ability of skeletal muscles.
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  • 53
    Publication Date: 2013-09-14
    Description: by Qian Fan, Zheng M. Huang, Matthieu Boucher, Xiying Shang, Lin Zuo, Henriette Brinks, Wayne Bond Lau, Jianke Zhang, J. Kurt Chuprun, Erhe Gao Aim As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure. Methods Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed. Results FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R-induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20±3.90% in NLC to 26.83±4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3. Conclusion Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure.
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  • 54
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    Publication Date: 2013-09-14
    Description: by Shuang Li, Ting Hu, Yile Chen, Hang Zhou, Xiong Li, Xiaodong Cheng, Ru Yang, Shixuan Wang, Xing Xie, Ding Ma Radiotherapy is the standard treatment for cervical cancer, but causes radiotherapy-induced complications. Recently, chemotherapy has been more extensively utilized. Here, we perform a large-scale comparison of chemotherapy and radiotherapy. From 2002 to 2008, 2,268 patients were grouped according to adjuvant radiotherapy or chemotherapy before and/or after surgery, and we compared the 5-year overall survival (OS) and disease-free survival (DFS) rates, recurrence rates, side effects, quality of life (QoL), and sexual activity. There were no significant differences between the treatment groups for the 5-year OS and DFS rates (OS: p =  0.053, DFS: p  = 0.095), although marginally improved outcomes were observed in the chemotherapy group (OS: 86.5% vs. 82.8%; DFS: 84.5% vs. 81.4%). However, patients with early-stage disease, clinical response, and younger age had increased 5-year OS and DFS rates following chemotherapy compared to radiotherapy ( p
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  • 55
    Publication Date: 2013-09-14
    Description: by Anne-Sophie Ay, Nazim Benzerdjerb, Henri Sevestre, Ahmed Ahidouch, Halima Ouadid-Ahidouch Orai channels have been associated with cell proliferation, survival and metastasis in several cancers. The present study investigates the expression and the role of Orai3 in cell proliferation in non-small cell lung cancer (NSCLC). We show that Orai3 is over-expressed in cancer tissues as compared to the non-tumoral ones. Furthermore, Orai3 staining is stronger in high grade tumors. Pharmacological inhibition or knockdown of Orai3 significantly reduced store operated calcium entry (SOCE), inhibited cell proliferation and arrested cells of two NSCLC cell lines in G0/G1 phase. These effects were concomitant with a down-regulation of cyclin D1, cyclin E, CDK4 and CDK2 expression. Moreover, Orai3 silencing decreased Akt phosphorylation levels. In conclusion, Orai3 constitutes a native SOCE pathway in NSCLC that controls cell proliferation and cell cycle progression likely via Akt pathway.
    Electronic ISSN: 1932-6203
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  • 56
    Publication Date: 2013-09-14
    Description: by Katherine Scranton, Menelaos Stavrinides, Nicholas J. Mills, Perry de Valpine Life history variation is a general feature of arthropod systems, but is rarely included in models of field or laboratory data. Most studies assume that local processes occur identically across individuals, ignoring any genetic or phenotypic variation in life history traits. In this study, we tested whether field populations of Pacific spider mites ( Tetranychus pacificus ) on grapevines ( Vitis vinifera ) display significant intraspecific life history variation associated with host plant cultivar. To address this question we collected individuals from sympatric vineyard populations where either Zinfandel or Chardonnay were grown. We then conducted a “common garden experiment” of mites on bean plants ( Phaseolus lunatus ) in the laboratory. Assay populations were sampled non-destructively with digital photography to quantify development times, survival, and reproductive rates. Two classes of models were fit to the data: standard generalized linear mixed models and a time-to-event model, common in survival analysis, that allowed for interval-censored data and hierarchical random effects. We found a significant effect of cultivar on development time in both GLMM and time-to-event analyses, a slight cultivar effect on juvenile survival, and no effect on reproductive rate. There were shorter development times and a trend towards higher juvenile survival in populations from Zinfandel vineyards compared to those from Chardonnay vineyards. Lines of the same species, originating from field populations on different host plant cultivars, expressed different development times and slightly different survival rates when reared on a common host plant in a common environment.
    Electronic ISSN: 1932-6203
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  • 57
    Publication Date: 2013-09-14
    Description: by Yi Ding, Lirong Song, Bojan Sedmak Due to the stratospheric ozone depletion, several organisms will become exposed to increased biologically active UVB (280–320 nm) radiation, not only at polar but also at temperate and tropical latitudes. Bloom forming cyanobacteria are exposed to UVB radiation on a mass scale, particularly during the surface bloom and scum formation that can persist for long periods of time. All buoyant species of cyanobacteria are at least periodically exposed to higher irradiation during their vertical migration to the surface that usually occurs several times a day. The aim of this study is to assess the influence on cyanobacteria of UVB radiation at realistic environmental intensities. The effects of two UVB intensities of 0.5 and 0.99 W/m 2 in up to 0.5 cm water depth were studied in vitro on Microcystis aeruginosa strains, two microcystin producing and one non-producing. After UVB exposure their ability to proliferate was estimated by cell counting, while cell fitness and integrity were evaluated using light microscopy, autofluorescence and immunofluorescence. Gene damage was assessed by TUNEL assay and SYBR Green staining of the nucleoide area. We conclude that UVB exposure causes damage to the genetic material, cytoskeletal elements, higher sedimentation rates and consequent cell death. In contrast to microcystin producers (PCC7806 and FACHB905), the microcystin non-producing strain PCC7005 is more susceptible to the deleterious effects of radiation, with weak recovery ability. The ecological relevance of the results is discussed using data from eleven years’ continuous UVB radiation measurements within the area of Ljubljana city (Slovenia, Central Europe). Our results suggest that increased solar radiation in temperate latitudes can have its strongest effect during cyanobacterial bloom formation in spring and early summer. UVB radiation in this period may significantly influence strain composition of cyanobacterial blooms in favor of microcystin producers.
    Electronic ISSN: 1932-6203
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  • 58
    Publication Date: 2013-09-14
    Description: by Yimin, Masashi Kohanawa, Songji Zhao, Michitaka Ozaki, Sanae Haga, Guangxian Nan, Yuji Kuge, Nagara Tamaki Staphylococcus aureus is a common pathogen that causes a wide range of infectious diseases. The function of TLRs, specifically TLR2, during S. aureus infection is still debated. In this study, we investigated the extent to which TLR2 contributes to the host innate response against the bacterial infection using TLR2-deficient mice. Intravenous inoculation with S. aureus resulted in all TLR2-deficient mice dying within 4 d, along with a high bacterial burden in the livers. However, histological examination showed the same degree of macrophage and neutrophil accumulation in the livers of infected TLR2-deficient mice as that in infected wild-type (WT) mice. TLR2-deficient mouse macrophages also showed normal phagocytic activity, although they failed to express CD36 that appeared on the surface of WT mouse cells upon challenge with heat-killed S. aureus . These data indicate that TLR2, as well as CD36, does not directly affect S. aureus clearance and that CD36 expression on macrophages depends on the presence of TLR2. In vivo infection with S. aureus caused significantly elevated production of TNF-α and IL-6 in the livers and blood of TLR2-deficient mice compared with those in WT mice, while the hepatic and serum levels of IL-10 decreased in these mice. In contrast, lower expression of IL-6 and IL-10, but not of TNF-α, at both the gene and protein levels was found in TLR2-deficient mouse macrophages compared to that in WT mouse cells, in response to challenge with heat-killed S. aureus . These findings suggest that the S. aureus -induced pro-inflammatory cytokine response is not dependent on macrophages and that TLR2 deficiency results in decreased IL-10 release by macrophages, which contributes to dysregulated cytokine balance, impaired bacterial clearance, and mouse death. Therefore, TLR2 possesses a protective function during S. aureus infection by regulating pro- and anti-inflammatory cytokine responses.
    Electronic ISSN: 1932-6203
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  • 59
    Publication Date: 2013-09-14
    Description: by Kepa B. Uribe, César Martín, Aitor Etxebarria, David González-Bullón, Geraxane Gómez-Bilbao, Helena Ostolaza Humans infected with Bordetella pertussis , the whooping cough bacterium, show evidences of impaired host defenses. This pathogenic bacterium produces a unique adenylate cyclase toxin (ACT) which enters human phagocytes and catalyzes the unregulated formation of cAMP, hampering important bactericidal functions of these immune cells that eventually cause cell death by apoptosis and/or necrosis. Additionally, ACT permeabilizes cells through pore formation in the target cell membrane. Recently, we demonstrated that ACT is internalised into macrophages together with other membrane components, such as the integrin CD11b/CD18 (CR3), its receptor in these immune cells, and GM1. The goal of this study was to determine whether ACT uptake is restricted to receptor-bearing macrophages or on the contrary may also take place into cells devoid of receptor and gain more insights on the signalling involved. Here, we show that ACT is rapidly eliminated from the cell membrane of either CR3-positive as negative cells, though through different entry routes, which depends in part, on the target cell physiology and characteristics. ACT-induced Ca 2+ influx and activation of non-receptor Tyr kinases into the target cell appear to be common master denominators in the different endocytic strategies activated by this toxin. Very importantly, we show that, upon incubation with ACT, target cells are capable of repairing the cell membrane, which suggests the mounting of an anti-toxin cell repair-response, very likely involving the toxin elimination from the cell surface.
    Electronic ISSN: 1932-6203
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  • 60
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    In: PLoS ONE
    Publication Date: 2013-09-14
    Description: by Haitao Jiang, Linlin Qu, Rongrong Dou, Lianfang Lu, Sishan Bian, Weiming Zhu Background Transplantation of bone marrow mesenchymal stem cells (MSCs) provides a promising therapeutic efficiency for a variety of disorders caused by ischemia or reperfusion impairment. We have previously demonstrated the efficacy of MSCs in mitigating intestinal ischemia/reperfusion (I/R) injuries in rats, but the mechanism by which MSCs engraft ameliorates I/R injuries has largely been unknown. The present study aimed at investigating probable mechanisms by which MSCs exert their function. Methods Male donor derived rat MSCs were implanted into intestine of female recipient rat by direct submucosal injection after superior mesenteric artery clamping and unclamping. The homed MSCs were detected by Y chromosome in situ hybridization probe, and the tumor necrosis factor-α (TNF-α) content in intestinal mucosa was determined by ELISA. Expression of proliferative cell nuclear antigen (PCNA) in bowel mucosa was assayed by real-time PCR and intestinal mucosa expression of phosphorylation extracellular signal-regulated kinase (pERK1/2) and nuclear factor-κB (NF-κB) were evaluated by western blot. Results Four and seven days after MSCs transplantation, the TNF-α content of bowel mucosa in MSCs group was significantly lower than that in saline group. The PCNA in bowel mucosa showed higher expression in MSCs treated group than the saline group, both at 4 and 7 days after cell transplantation. The expression of intestinal mucosal pERK1/2 in MSCs treated group was markedly higher than that in saline group, and the expression of NF-κB in MSCs treated group was noticeably decreased than that in saline group at 4 and 7 days post MSCs transplantation. Conclusion The present investigation provides novel evidence that MSCs have the potential to reduce intestinal I/R injuries probably due to their ability to accelerate cell proliferation and decrease the inflammatory response within intestinal mucosa after ischemia and reperfusion.
    Electronic ISSN: 1932-6203
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  • 61
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    In: PLoS ONE
    Publication Date: 2013-09-14
    Description: by Katherine M. Hiller, Lisa Stoneking, Alice Min, Suzanne Michelle Rhodes The science of surveillance is rapidly evolving due to changes in public health information and preparedness as national security issues, new information technologies and health reform. As the Emergency Department has become a much more utilized venue for acute care, it has also become a more attractive data source for disease surveillance. In recent years, influenza surveillance from the Emergency Department has increased in scope and breadth and has resulted in innovative and increasingly accepted methods of surveillance for influenza and influenza-like-illness (ILI). We undertook a systematic review of published Emergency Department-based influenza and ILI syndromic surveillance systems. A PubMed search using the keywords “syndromic”, “surveillance”, “influenza” and “emergency” was performed. Manuscripts were included in the analysis if they described (1) data from an Emergency Department (2) surveillance of influenza or ILI and (3) syndromic or clinical data. Meeting abstracts were excluded. The references of included manuscripts were examined for additional studies. A total of 38 manuscripts met the inclusion criteria, describing 24 discrete syndromic surveillance systems. Emergency Department-based influenza syndromic surveillance has been described worldwide. A wide variety of clinical data was used for surveillance, including chief complaint/presentation, preliminary or discharge diagnosis, free text analysis of the entire medical record, Google flu trends, calls to teletriage and help lines, ambulance dispatch calls, case reports of H1N1 in the media, markers of ED crowding, admission and Left Without Being Seen rates. Syndromes used to capture influenza rates were nearly always related to ILI (i.e. fever +/− a respiratory or constitutional complaint), however, other syndromes used for surveillance included fever alone, “respiratory complaint” and seizure. Two very large surveillance networks, the North American DiSTRIBuTE network and the European Triple S system have collected large-scale Emergency Department-based influenza and ILI syndromic surveillance data. Syndromic surveillance for influenza and ILI from the Emergency Department is becoming more prevalent as a measure of yearly influenza outbreaks.
    Electronic ISSN: 1932-6203
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  • 62
    Publication Date: 2013-09-15
    Description: by Zhenghui Hu, Heye Zhang, Jinwei Yuan, Minhua Lu, Siping Chen, Huafeng Liu The purpose of ultrasound elastography is to identify lesions by reconstructing the hardness characteristics of tissue reconstructed from ultrasound data. Conventional quasi-static ultrasound elastography is easily applied to obtain axial strain components along the compression direction, with the results inverted to represent the distribution of tissue hardness under the assumption of constant internal stresses. However, previous works of quasi-static ultrasound elastography have found it difficult to obtain the lateral and shear strain components, due to the poor lateral resolution of conventional ultrasound probes. The physical nature of the strain field is a continuous vector field, which should be fully described by the axial, lateral, and shear strain components, and the clinical value of lateral and shear strain components of deformed tissue is gradually being recognized by both engineers and clinicians. Therefore, a biomechanical-model-constrained filtering framework is proposed here for recovering a full displacement field at a high spatial resolution from the noisy ultrasound data. In our implementation, after the biomechanical model constraint is integrated into the state-space equation, both the axial and lateral displacement components can be recovered at a high spatial resolution from the noisy displacement measurements using a robust filter, which only requires knowledge of the worst-case noise levels in the measurements. All of the strain components can then be calculated by applying a gradient operator to the recovered displacement field. Numerical experiments on synthetic data demonstrated the robustness and effectiveness of our approach, and experiments on phantom data and in-vivo clinical data also produced satisfying results.
    Electronic ISSN: 1932-6203
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  • 63
    Publication Date: 2013-09-15
    Description: by Sumanti Gupta, Anirban Bhar, Moniya Chatterjee, Sampa Das Reactive oxygen species are known to play pivotal roles in pathogen perception, recognition and downstream defense signaling. But, how these redox alarms coordinate in planta into a defensive network is still intangible. Present study illustrates the role of Fusarium oxysporum f.sp ciceri Race1 (Foc1) induced redox responsive transcripts in regulating downstream defense signaling in chickpea. Confocal microscopic studies highlighted pathogen invasion and colonization accompanied by tissue damage and deposition of callose degraded products at the xylem vessels of infected roots of chickpea plants. Such depositions led to the clogging of xylem vessels in compatible hosts while the resistant plants were devoid of such obstructions. Lipid peroxidation assays also indicated fungal induced membrane injury. Cell shrinkage and gradual nuclear adpression appeared as interesting features marking fungal ingress. Quantitative real time polymerase chain reaction exhibited differential expression patterns of redox regulators, cellular transporters and transcription factors during Foc1 progression. Network analysis showed redox regulators, cellular transporters and transcription factors to coordinate into a well orchestrated defensive network with sugars acting as internal signal modulators. Respiratory burst oxidase homologue, cationic peroxidase, vacuolar sorting receptor, polyol transporter, sucrose synthase, and zinc finger domain containing transcription factor appeared as key molecular candidates controlling important hubs of the defense network. Functional characterization of these hub controllers may prove to be promising in understanding chickpea–Foc1 interaction and developing the case study as a model for looking into the complexities of wilt diseases of other important crop legumes.
    Electronic ISSN: 1932-6203
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  • 64
    Publication Date: 2013-09-15
    Description: by Sandra Pérez-Rial, Laura del Puerto-Nevado, Raúl Terrón-Expósito, Álvaro Girón-Martínez, Nicolás González-Mangado, Germán Peces-Barba This study investigates the role of proinflammatory monocytes recruited from blood circulation and recovered in bronchoalveolar lavage (BAL) fluid in mediating the lung damage in a model of acute cigarette smoke (CS)-induced lung inflammation in two strains of mice with different susceptibility to develop emphysema (susceptible -C57BL/6J and non susceptible -129S2/SvHsd). Exposure to whole-body CS for 3 consecutive research cigarettes in one single day induced acute inflammation in the lung of mice. Analysis of BAL fluid showed more influx of recently migrated monocytes at 72 h after CS-exposition in susceptible compared to non susceptible mice. It correlated with an increase in MMP-12 and TNF-α protein levels in the lung tissue, and with an increment of NF-κB translocation to the nucleus measured by electrophoretic mobility shift assay in C57BL/6J mice. To determine the functional role of these proinflammatory monocytes in mediating CS-induced airway inflammation, alveolar macrophages and blood monocytes were transiently removed by pretreatment with intratracheal and intravenous liposome-encapsulated CL 2 MDP, given 2 and 4 days prior to CS exposure and their repopulation was studied. Monocytes/macrophages were maximally depleted 48 h after last liposome application and subsequently recently migrated monocytes reappeared in BAL fluid of susceptible mice at 72 h after CS exposure. Recently migrated monocytes influx to the lung correlated with an increase in the MMP-12 protein level in the lung tissue, indicating that the increase in proinflammatory monocytes is associated with a major tissue damaging. Therefore our data confirm that the recruitment of proinflammatory recently migrated monocytes from the blood are responsible for the increase in MMP-12 and has an important role in the pathogenesis of lung disease induced by acute lung inflammation. These results could contribute to understanding the different susceptibility to CS of these strains of mice.
    Electronic ISSN: 1932-6203
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  • 65
    Publication Date: 2013-09-15
    Description: by Jasmeet Assi, Gunjan Srivastava, Ajay Matta, Martin C. Chang, Paul G. Walfish, Ranju Ralhan Introduction Molecular markers for predicting breast cancer patients at high risk of recurrence are urgently needed for more effective disease management. The impact of alterations in extracellular matrix components on tumor aggressiveness is under intense investigation. Overexpression of Transglutaminase 2 (TG2), a multifunctional enzyme, in cancer cells impacts epithelial mesenchymal transition, growth, invasion and interactions with tumor microenvironment. The objective of our study is to determine the clinical relevance of stromal TG2 overexpression and explore its potential to identify breast cancers at high risk of recurrence. Methods This retrospective study is based on immunohistochemical analysis of TG2 expression in normal breast tissues (n = 40) and breast cancers (n = 253) with clinical, pathological and follow-up data available for up to 12 years. TG2 expression was correlated with clinical and pathological parameters as well as disease free survival (DFS) of breast cancer patients. Results Stromal TG2 overexpression was observed in 114/253 (45.0%) breast cancer tissues as compared to breast normal tissues. Among invasive ductal carcinomas (IDC) of the breast, 97/168 (57.7%) showed strong TG2 expression in tumor stroma. Importantly, IDC patients showing stromal TG2 accumulation had significantly reduced DFS (mean DFS = 110 months) in comparison with patients showing low expression (mean DFS = 130 months) in Kaplan-Meier survival analysis (p
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  • 66
    Publication Date: 2013-09-15
    Description: by Runqing Mu, Wenxiang Chen, Baishen Pan, Lanlan Wang, Xiaoke Hao, Xianzhang Huang, Rui Qiao, Min Zhao, Chuanbao Zhang, Wei Guo, Hengjian Huang, Yueyun Ma, Junhua Zhuang, Jie Zhang, Hong Shang Background Reference intervals of Liver function tests are very important for the screening, diagnosis, treatment, and monitoring of liver diseases. We aim to establish common reference intervals of liver function tests specifically for the Chinese adult population. Methods A total of 3210 individuals (20–79 years) were enrolled in six representative geographical regions in China. Analytes of ALT, AST, GGT, ALP, total protein, albumin and total bilirubin were measured using three analytical systems mainly used in China. The newly established reference intervals were based on the results of traceability or multiple systems, and then validated in 21 large hospitals located nationwide qualified by the National External Quality Assessment (EQA) of China. Results We had been established reference intervals of the seven liver function tests for the Chinese adult population and found there were apparent variances of reference values for the variables for partitioning analysis such as gender(ALT, GGT, total bilirubin), age(ALP, albumin) and region(total protein). More than 86% of the 21 laboratories passed the validation in all subgroup of reference intervals and overall about 95.3% to 98.8% of the 1220 validation results fell within the range of the new reference interval for all liver function tests. In comparison with the currently recommended reference intervals in China, the single side observed proportions of out of range of reference values from our study for most of the tests deviated significantly from the nominal 2.5% such as total bilirubin (15.2%), ALP (0.2%), albumin (0.0%). Most of reference intervals in our study were obviously different from that of other races. Conclusion These used reference intervals are no longer applicable for the current Chinese population. We have established common reference intervals of liver function tests that are defined specifically for Chinese population and can be universally used among EQA-approved laboratories located all over China.
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  • 67
    Publication Date: 2013-09-15
    Description: by Raj Vuppalanchi, Tiebing Liang, Chirayu Pankaj Goswami, Rohit Nalamasu, Lang Li, David Jones, Rongrong Wei, Wanqing Liu, Vishal Sarasani, Sarath Chandra Janga, Naga Chalasani Background and Aim Liver cirrhosis is associated with decreased hepatic cytochrome P4503A (CYP3A) activity but the pathogenesis of this phenomenon is not well elucidated. In this study, we examined if certain microRNAs (miRNA) are associated with decreased hepatic CYP3A activity in cirrhosis. Methods Hepatic CYP3A activity and miRNA microarray expression profiles were measured in cirrhotic (n=28) and normal (n=12) liver tissue. Hepatic CYP3A activity was measured via midazolam hydroxylation in human liver microsomes. Additionally, hepatic CYP3A4 protein concentration and the expression of CYP3A4 mRNA were measured. Analyses were conducted to identify miRNAs which were differentially expressed between two groups but also were significantly associated with lower hepatic CYP3A activity. Results Hepatic CYP3A activity in cirrhotic livers was 1.7-fold lower than in the normal livers (0.28 ± 0.06 vs. 0.47 ± 0.07mL* min -1 *mg protein -1 (mean ± SEM), P=0.02). Six microRNAs (miR-155, miR-454, miR-582-5p, let-7f-1*, miR-181d, and miR-500) had 〉1.2-fold increase in cirrhotic livers and also had significant negative correlation with hepatic CYP3A activity (range of r = -0.44 to -0.52, P
    Electronic ISSN: 1932-6203
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  • 68
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    In: PLoS ONE
    Publication Date: 2013-09-15
    Description: by Go Muto, Hitoshi Kotani, Taisuke Kondo, Rimpei Morita, Sanae Tsuruta, Takashi Kobayashi, Hervé Luche, Hans Joerg Fehling, Matthew Walsh, Yongwon Choi, Akihiko Yoshimura Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 + Tregs into Rag2 -/- mice revealed that TRAF6-deficient Tregs converted into Foxp3 - cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3 + to Foxp3 - (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.
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  • 69
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    In: PLoS ONE
    Publication Date: 2013-09-15
    Description: by Yuan-Fei Peng, Ying-Hong Shi, Ying-Hao Shen, Zhen-Bin Ding, Ai-Wu Ke, Jian Zhou, Shuang-Jian Qiu, Jia Fan Background Autophagy is an important adaptive survival mechanism, which has been postulated to be involved in cancer metastasis. The purpose of this study was to investigate autophagy in metastasis of hepatocellular carcinoma (HCC). Methods Immunohistochemical analysis of autophagic activity in metastatic and paired primary HCC tissues using LC3 as autophagosome marker was performed in samples from 216 HCC patients diagnosed with metastasis (including 158 intravascular, 42 intrabiliary, 8 lymph node, 4 bone and 4 lung metastases). Then a mouse model of pulmonary metastasis was established using a highly metastatic HCC cell line (HCCLM3). Autophagy in pulmonary metastases and paired primary tumors were analyzed by LC3 immunohistochemistry, transmission electron microscopy (TEM) and western blot analysis. Further, mouse model of pulmonary metastasis and in vitro cell migration, invasion and detachment models were established using a stable GFP-LC3-expressing HCCLM3 cell line (HCCLM3-GFP-LC3). Autophagic alterations during metastatic colonization, migration, invasion and detachment were determined by GFP-LC3 analysis and western blot analysis. Results LC3 immunohistochemistry of metastases and primary tumors from HCC patients revealed significantly higher LC3 expression in metastases than primary HCC, which suggested a higher level of autophagy in HCC metastases. Further immunohistochemical, TEM, western blot and in vivo GFP-LC3 analyses of lung metastases and primary tumors in mouse model of pulmonary metastasis confirmed that metastatic colonies displayed higher level of autophagy than primary tumors and the early metastatic colonies displayed highest level. The dynamic monitoring of autophagy in cell migration, invasion and detachment showed that autophagy did not significantly alter in those processes. Conclusions Autophagy is activated in metastatic colonization but not in invasion, migration and detachment of HCC cells. Autophagy may play a role in HCC metastasis via promoting metastatic colonization of HCC cells.
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  • 70
    Publication Date: 2013-09-15
    Description: by Christina Martina Stürzel, David Palesch, Mohammad Khalid, Silke Wissing, Nicole Fischer, Jan Münch The gammaretrovirus termed xenotropic murine leukemia virus-related virus (XMRV) was described to be isolated from prostate cancer tissue biopsies and from blood of patients suffering from chronic fatigue syndrome. However, many studies failed to detect XMRV and to verify these disease associations. Data suggesting the contamination of specimens in particular by PCR-based methods and recent reports demonstrating XMRV generation via recombination of two murine leukemia virus precursors raised serious doubts about XMRV being a genuine human pathogen. To elucidate cell tropism of XMRV, we generated replication competent XMRV reporter viruses encoding a green fluorescent protein or a secretable luciferase as tools to analyze virus infection of human cell lines or primary human cells. Transfection of proviral DNAs into LNCaP prostate cancer cells resulted in readily detectably reporter gene expression and production of progeny virus. Inoculation of known XMRV susceptible target cells revealed that these virions were infectious and expressed the reporter gene, allowing for a fast and highly sensitive quantification of XMRV infection. Both reporter viruses were capable of establishing a spreading infection in LNCaP and Raji B cells and could be easily passaged. However, after inoculation of primary human blood cells such as CD4 T cells, macrophages or dendritic cells, infection rates were very low, and a spreading infection was never established. In line with these results we found that supernatants derived from these XMRV infected primary cell types did not contain infectious virus. Thus, although XMRV efficiently replicated in some human cell lines, all tested primary cells were largely refractory to XMRV infection and did not support viral spread. Our results provide further evidence that XMRV is not a human pathogen.
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  • 71
    Publication Date: 2013-09-15
    Description: by Karin Hadas, Voahanginirina Randriamboavonjy, Amro Elgheznawy, Alexander Mann, Ingrid Fleming Diabetes is characterized by a dysregulation of glucose homeostasis and platelets from patients with diabetes are known to be hyper-reactive and contribute to the accelerated development of vascular diseases. Since many of the deleterious effects of glucose have been attributed to its metabolite methylgyloxal (MG) rather than to hyperglycemia itself, the aim of the present study was to characterize the effects of MG on platelet function. Washed human platelets were pre-incubated for 15 min with MG and platelet aggregation, adhesion on matrix-coated slides and signaling (Western blot) were assessed ex vivo . In vivo , the effect of MG on thrombus formation was determined using the FeCl 3 -induced carotid artery injury model. MG potentiated thrombin-induced platelet aggregation and dense granule release, but inhibited platelet spreading on fibronectin and collagen. In vivo , MG accelerated thrombus formation but decreased thrombus stability. At the molecular level, MG increased intracellular Ca 2+ and activated classical PKCs at the same time as inhibiting PI3K/Akt and the β3-integrin outside-in signaling. In conclusion, these findings indicate that the enhanced MG concentration measured in diabetic patients can directly contribute to the platelet dysfunction associated with diabetes characterized by hyperaggregability and reduced thrombus stability.
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  • 72
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    In: PLoS ONE
    Publication Date: 2013-09-15
    Description: by Rui Zhang, Peng Xu, Lanjin Guo, Yangsong Zhang, Peiyang Li, Dezhong Yao Linear discriminant analysis (LDA) is one of the most popular classification algorithms for brain-computer interfaces (BCI). LDA assumes Gaussian distribution of the data, with equal covariance matrices for the concerned classes, however, the assumption is not usually held in actual BCI applications, where the heteroscedastic class distributions are usually observed. This paper proposes an enhanced version of LDA, namely z-score linear discriminant analysis (Z-LDA), which introduces a new decision boundary definition strategy to handle with the heteroscedastic class distributions. Z-LDA defines decision boundary through z-score utilizing both mean and standard deviation information of the projected data, which can adaptively adjust the decision boundary to fit for heteroscedastic distribution situation. Results derived from both simulation dataset and two actual BCI datasets consistently show that Z-LDA achieves significantly higher average classification accuracies than conventional LDA, indicating the superiority of the new proposed decision boundary definition strategy.
    Electronic ISSN: 1932-6203
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  • 73
    Publication Date: 2013-09-15
    Description: by Bhautesh Dinesh Jani, David Purves, Sarah Barry, Jonathan Cavanagh, Gary McLean, Frances S. Mair Background Depression screening in chronic disease is advocated but its impact on routine practice is uncertain. We examine the effects of a programme of incentivised depression screening in chronic disease within a UK primary care setting. Methods and Findings Cross sectional analysis of anonymised, routinely collected data (2008-9) from family practices in Scotland serving a population of circa 1.8 million. Primary care registered patients with at least one of three chronic diseases, coronary heart disease, diabetes and stroke, underwent incentivised depression screening using the Hospital Anxiety and Depression Score (HADS).125143 patients were identified with at least one chronic disease. 10670 (8.5%) were under treatment for depression and exempt from screening. Of remaining, HADS were recorded for 35537 (31.1%) patients. 7080 (19.9% of screened) had raised HADS (≥8); majority had indications of mild depression with HADS between 8 and 10. Over 6 months, 572 (8%) of those with raised HADS (≥8) were initiated on antidepressants, while 696 (2.4%) patients with normal HADS (
    Electronic ISSN: 1932-6203
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  • 74
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    In: PLoS ONE
    Publication Date: 2013-09-15
    Description: by Hyo Won Choi, Benjamin Jansen, David Birrer, Ghassan S. Kassab Transient displacement of blood in vessel lumen with saline injection is necessary in the conductance method for measurement of arterial cross-sectional area (CSA). The displacement of blood is dictated by the interactions between arterial flow hemodynamics and saline injection dynamics. The objective of the present study is to understand how the accuracy of conductance measurements is affected by the saline injection. Computational simulations were performed to assess the error in predictions of arterial CSA using conductance measurements over a range of peripheral artery diameters (i.e., 4, 7, and 10 mm) with an introducing catheter (6 Fr.) for various blood flow and saline injection rates. The simulation results were validated using the conductance measurements of the phantoms with known diameters (i.e., 7 and 10 mm). The results demonstrated that a minimum ratio of saline injection rate to blood flow rate of 3 is needed to fully displace the blood and result in accurate measurement of CSA for the peripheral artery sizes considered. Furthermore, the error was shown to be minimized as the detection electrodes are positioned between the distal to the mixing zone induced by saline injection and far downstream (4–8 cm from the injection catheter tip). The present study shows that even for the large peripheral arteries (7–10 mm) where mixing can occur, an appropriate injection rate and detection position can produce accurate measurement of lumen size.
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  • 75
    Publication Date: 2013-09-16
    Description: by Jing Meng, Zixiang Xu, Jing Guo, Yunxia Yue, Xiao Sun Microbial fuel cells (MFCs) are a class of ideal technologies that function via anaerobic respiration of electricigens, which bring current generation and environmental restoration together. An in-depth understanding of microbial metabolism is of great importance in engineering microbes to further improve their respiration. We employed flux balance analysis and selected Fe(iii) as a substitute for the electrode to simulate current-generating metabolism of Geobacter sulfurreducens PCA with a fixed acetate uptake rate. Simulation results indicated the fluxes of reactions directing acetate towards dissimilation to generate electrons increased under the suboptimal growth condition, resulting in an increase in the respiration rate and a decrease in the growth rate. The results revealed the competitive relationship between oxidative respiration and cell growth during the metabolism of microbe current generation. The results helped us quantitatively understand why microbes growing slowly have the potential to make good use of fuel in MFCs. At the same time, slow growth does not necessarily result in speedy respiration. Alternative respirations may exist under the same growth state due to redundant pathways in the metabolic network. The big difference between the maximum and minimum respiration mainly results from the total formate secretion. With iterative flux variability analysis, a relatively ideal model of variant of G. sulfurreducens PCA was reconstructed by deleting several enzymes in the wild model, which could reach simultaneous suboptimal growth and maximum respiration. Under this ideal condition, flux towards extracellular electron transfer rather than for biosynthesis is beneficial for the conversion of organic matter to electricity without large accumulations of biomass and electricigens may maximize utilization of limited fuel. Our simulations will provide an insight into the enhanced current-generating mechanism and identify theoretical range of respiration rates for guiding strain improvement in MFCs.
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  • 76
    Publication Date: 2013-09-16
    Description: by Sergio Raposeiras-Roubín, Bruno K. Rodiño-Janeiro, Beatriz Paradela-Dobarro, Lilian Grigorian-Shamagian, José M. García-Acuña, Pablo Aguiar-Souto, Michel Jacquet-Hervet, María V. Reino-Maceiras, José R. González-Juanatey, Ezequiel Álvarez Objective Advanced glycation end products (AGEs) have pathophysiological implications in cardiovascular diseases. The aim of our study was to evaluate the prognostic value of fluorescent AGEs and its soluble receptor (sRAGE) in the context of acute coronary syndrome (ACS), both in-hospital phase and follow-up period. Methods A prospective clinical study was performed in patients with debut’s ACS. The endpoints were the development of cardiac events (cardiac deaths, re-infarction and new-onset heart failure) during in-hospital phase and follow-up period (366 days, inter-quartile range: 273–519 days). 215 consecutive ACS patients admitted to the coronary care unit (62.7±13.0 years, 24.2% female) were included. 47.4% had a diagnosis of ST segment elevation myocardial infarction. AGEs and sRAGE were analysed by fluorescence spectroscopy and competitive ELISA, respectively. Risk scores (GRACE, TIMI, PURSUIT) were calculated retrospectively using prospective data. The complexity of coronary artery disease was evaluated by SYNTAX score. Results The mean fluorescent AGEs and sRAGE levels were 57.7±45.1 AU and 1045.4±850.0 pg/mL, respectively. 19 patients presented cardiac events during in-hospital phase and 29 during the follow-up. In-hospital cardiac events were significantly associated with higher sRAGE levels ( p  = 0.001), but not long-term cardiac events ( p  = 0.365). Regarding fluorescent AGE the opposite happened. After multivariate analysis correcting by gender, left ventricular ejection fraction, glucose levels, haemoglobin, GRACE and SYNTAX scores, sRAGE was significantly associated with in-hospital prognosis, whereas fluorescent AGEs was significantly associated with long-term prognosis. Conclusions We conclude that elevated values of sRAGE are associated with worse in-hospital prognosis, whereas high fluorescent AGE levels are associated with more follow-up events.
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  • 77
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-17
    Description: by Junsuke Nakase, Anri Inaki, Takafumi Mochizuki, Tatsuhiro Toratani, Masahiro Kosaka, Yoshinori Ohashi, Junichi Taki, Tetsutaro Yahata, Seigo Kinuya, Hiroyuki Tsuchiya Purpose This study investigated the effect of the FIFA 11+ warm-up program on whole body muscle activity using positron emission tomography. Methods Ten healthy male volunteers were divided into a control group and a group that performed injury prevention exercises (The 11+). The subjects of the control group were placed in a sitting position for 20 min and 37 MBq of 18 F-fluorodeoxyglucose (FDG) was injected intravenously. The subjects then remained seated for 45 min. The subjects of the exercise group performed part 2 of the 11+for 20 min, after which FDG was injected. They then performed part 2 of the 11+for 20 min, and rested for 25 min in a sitting position. Positron emission tomography-computed tomography images were obtained 50 min after FDG injection in each group. Regions of interest were defined within 30 muscles. The standardized uptake value was calculated to examine the FDG uptake of muscle tissue per unit volume. Results FDG accumulation within the abdominal rectus, gluteus medius and minimus were significantly higher in the exercise group than in the control group (P
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  • 78
    Publication Date: 2013-09-17
    Description: by Dobromir Dimitrov, Marie-Claude Boily, Jeannie Marrazzo, Richard Beigi, Elizabeth R. Brown Background HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention. Methods and Findings A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RR HIV/preg  = 1). It may also prevent 8–15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RR MTCT/preg ). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RR HIV/preg  = 1) to 25% (RR HIV/preg  = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RR HIV/preg  = 1, RR MTCT/preg  = 1) and 25% (RR HIV/preg  = 2, RR MTCT/preg  = 4) to the reduction in the residual MTCT. Conclusion Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated.
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  • 79
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    In: PLoS ONE
    Publication Date: 2013-09-17
    Description: by Eyal Kalie, Minoo Razi, Sharon A. Tooze Melanosomes are lysosome-related organelles that serve as specialized sites of melanin synthesis and storage in melanocytes. The progression of melanosomes through the different stages of their formation requires trafficking of specific proteins and membrane constituents in a sequential manner, which is likely to deploy ubiquitous cellular machinery along with melanocyte-specific proteins. Recent evidence revealed a connection between melanogenesis and the autophagy machinery, suggesting a novel role for members of the latter in melanocytes. Here we focused on ULK1, a key autophagy protein which is negatively regulated by mTORC1, to assess its potential role in melanogenesis in MNT-1 cells. We found that ULK1 depletion causes an increase in melanin levels, suggesting an inhibitory function for this protein in melanogenesis. Furthermore, this increase was accompanied by increased transcription of MITF (microphthalmia-associated transcription factor) and tyrosinase and by elevated protein levels of tyrosinase, the rate-limiting factor in melanin biogenesis. We also provide evidence to show that ULK1 function in this context is independent of the canonical ULK1 autophagy partners, ATG13 and FIP200. Furthermore we show that regulation of melanogenesis by ULK1 is independent of mTORC1 inhibition. Our data thus provide intriguing insights regarding the involvement of the key regulatory autophagy machinery in melanogenesis.
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  • 80
    Publication Date: 2013-09-17
    Description: by Hitoshi Tsujimoto, Kun Liu, Paul J. Linser, Peter Agre, Jason L. Rasgon Background Aquaporin (AQP) water channels are important for water homeostasis in all organisms. Malaria transmission is dependent on Anopheles mosquitoes. Water balance is a major factor influencing mosquito survival, which may indirectly affect pathogen transmission. Methodology/Principal Findings We obtained full-length mRNA sequences for Anopheles gambiae aquaporin 1 (AgAQP1) and identified two splice variants for the gene. In vitro expression analysis showed that both variants transported water and were inhibited by Hg 2+ . One splice variant (AgAQP1A) was exclusively expressed in adult female ovaries indicating a function in mosquito reproduction. The other splice variant (AgAQP1B) was expressed in the midgut, malpighian tubules and the head in adult mosquitoes. Immunolabeling showed that in malpighian tubules, AgAQP1 is expressed in principal cells in the proximal portion and in stellate cells in the distal portion. Moreover, AgAQP1 is expressed in Johnston’s organ (the “ear”), which is important for courtship behavior. Conclusions And Significance These results suggest that AgAQP1 may play roles associated with mating (courtship) and reproduction in addition to water homeostasis in this important African malaria vector.
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  • 81
    Publication Date: 2013-09-17
    Description: by Xin Yang, Man-Tang Qiu, Jing-Wen Hu, Feng Jiang, Ming Li, Jie Wang, Qin Zhang, Rong Yin, Lin Xu Background Evidence suggest that IL-18 gene polymorphisms may be risk factors for several cancers. Increasing studies investigating the association between IL-18 gene promoter polymorphisms (−607 C〉A and −137G〉C) and cancer risk have yielded conflicting results. Methodology/Principal Findings We performed a meta-analysis of 26 studies including 4096 cases and 5222 controls. We assessed the strength of the association of IL-18 gene promoter −607 C〉A and −137G〉C polymorphisms with cancer risk and performed sub-group analyses by cancer types, ethnicities, source of controls and sample size. The pooled results revealed a significant increased risk of cancer susceptibility for −607 C〉A (CA vs. CC: OR = 1.19, 95%CI: 1.04, 1.37, P heterogeneity  = 0.033; CA/AA vs. CC: OR = 1.17, 95% CI: 1.01, 1.34, P heterogeneity  = 0.007), but no significant association for −137 G〉C was observed with overall cancer risk. Sub-group analyses revealed that an increased risk of nasopharyngeal carcinoma was both found for −607 C〉A (CA/AA vs. CC: OR = 1.32, 95% CI: 1.04, 1.69, P heterogeneity  = 0.823) and −137G〉C (GC/CC vs. GG: OR = 1.57, 95%CI: 1.26, 1.96, P heterogeneity  = 0.373). Consistent with the results of the genotyping analyses, the −607A/−137C and −607C/−137C haplotypes were associated with a significantly increased risk of nasopharyngeal carcinoma as compared with the −607C/−137G haplotype (−607A/−137C vs. −607C/−137G: OR = 1.26, 95%CI: 1.13, 1.40; P heterogeneity  = 0.569; −607C/−137C vs. −607C/−137G: OR = 1.14, 95%CI: 1.03, 1.27; P heterogeneity  = 0.775). As for gastrointestinal cancer, we also found that −607 C〉A polymorphism was significantly associated with increased cancer risk (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50, P heterogeneity  = 0.458). Further sub-group analysis revealed that −137G〉C polymorphism contributed to cancer risk in Asians but not in Caucasians (GC/CC vs. GG: OR = 1.31, 95%CI: 1.05, 1.64, P heterogeneity A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the −137 G〉C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increases the risk of nasopharyngeal carcinoma.
    Electronic ISSN: 1932-6203
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  • 82
    Publication Date: 2013-09-17
    Description: by Naama Dror, Mathilda Mandel, Gad Lavie Failure of conventional therapies to alleviate glioblastoma (GBM) fosters search for novel therapeutic strategies. These include epigenetic modulators as histone deacetylase inhibitors (HDACi), which relax abnormally compact tumor cell chromatin organization, enabling cells to overcome blockage in differentiation. However, in clinical settings, HDACi efficacy is confined to subsets of hematologic malignancies. We reasoned that molecules targeting multiple epigenetic mechanisms may exhibit superior anti-cancer activities. We focused on the redox perylene-quinone Hypericin (HYP) and showed that HYP targets Hsp90 for polyubiquitination, degradation and inactivation. Hsp90 is implicated in mediating inheritable epigenetic modifications transferable to progeny. We therefore examined if HYP can induce epigenetic alterations in GBM cells and show here that HYP indeed, targets multiple mechanisms in human glioblastoma tumor cell lines via unique manners. These elicit major epigenetic signature changes in key developmentally regulated genes. HYP induces neuroglial tumor cell differentiation modulating the cytoarchitecture, neuroglial differentiation antigen expression and causes exit from cell proliferation cycles. Such activities characterize HDACi however HYP is not an HDAC inhibitor. Instead, HYP effectively down-regulates expression of Class-I HDACs, creating marked deficiencies in HDACs cellular contents, leading to histones H3 and H4 hyperacetylation. Expression of EZH2, the Polycomb repressor complex-2 catalytic subunit, which trimethylates histone H3K27 is also suppressed. The resulting histone hyperacetylation and diminished H3K27-trimethylation relax chromatin structure, activating gene transcription including differentiation-promoting genes. DNMT profiles are also modulated increasing global DNA methylation. HYP induces unique epigenetic down-regulations of HDACs, EZH2 and DNMTs, remodeling chromatin structure and culminating in tumor cell differentiation. These modulations generate clinically significant anti-GBM effects obtained in a clinical trial performed in patients with recurrent, progressive disease. Despite this advanced disease stage, patients responded to HYP, displaying stable disease and partial responses; patients on compassionate therapy survived for up to 34 months. Hypericin may constitute a novel anti-glioblastoma therapeutic paradigm.
    Electronic ISSN: 1932-6203
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  • 83
    Publication Date: 2013-09-17
    Description: by Noriyuki Seta, Yuka Okazaki, Hiroshi Miyazaki, Takashi Kato, Masataka Kuwana Background We previously described a primitive cell population derived from human circulating CD14 + monocytes, named monocyte-derived multipotential cells (MOMCs), which are capable of differentiating into mesenchymal and endothelial lineages. To generate MOMCs in vitro, monocytes are required to bind to fibronectin and be exposed to soluble factor(s) derived from circulating CD14 − cells. The present study was conducted to identify factors that induce MOMC differentiation. Methods We cultured CD14 + monocytes on fibronectin in the presence or absence of platelets, CD14 − peripheral blood mononuclear cells, platelet-conditioned medium, or candidate MOMC differentiation factors. The transformation of monocytes into MOMCs was assessed by the presence of spindle-shaped adherent cells, CD34 expression, and the potential to differentiate in vitro into mesenchymal and endothelial lineages. Results The presence of platelets or platelet-conditioned medium was required to generate MOMCs from monocytes. A screening of candidate platelet-derived soluble factors identified stromal cell-derived factor (SDF)-1 as a requirement for generating MOMCs. Blocking an interaction between SDF-1 and its receptor CXCR4 inhibited MOMC generation, further confirming SDF-1′s critical role in this process. Finally, circulating MOMC precursors were found to reside in the CD14 + CXCR4 high cell population. Conclusion The interaction of SDF-1 with CXCR4 is essential for the transformation of circulating monocytes into MOMCs.
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  • 84
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    In: PLoS ONE
    Publication Date: 2013-09-17
    Description: by Melonie M. Walcott, Pauline E. Jolly, John E. Ehiri, Ellen Funkhouser, Mirjam C. Kempf, Deborah Hickman, Maung Aung, Kui Zhang Objectives To determine the prevalence of male circumcision (MC) among men in the western region of Jamaica, and to identify factors associated with acceptability of MC for self, infants (
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  • 85
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    In: PLoS ONE
    Publication Date: 2013-09-17
    Description: by Soichi Ito, Hiroki Miyashita, Yasuhiro Suzuki, Miho Kobayashi, Susumu Satomi, Yasufumi Sato Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium. We previously reported that tumor growth and tumor angiogenesis were augmented in VASH1 (−/−) mice. Here we examined whether VASH1 plays any role in cancer metastasis. When Lewis lung carcinoma (LLC) cells were inoculated in the footpad to observe spontaneous metastasis, a significant increase in lung metastasis together with inguinal lymph node metastasis was evident in the VASH1 (−/−) mice. Histological analyses revealed that vessels of the footpad tumor in VASH1 (−/−) mice were more immature, having fewer mural cells. However, when LLC cells were injected into a tail vein, the extent of lung metastasis was unchanged between wild-type mice and VASH1 (−/−) mice. When VASH1 in endothelial cells in culture was knocked-down by siRNA, we observed a decrease in the content of ZO-1, a component of tight junctions, which decrease resulted in increased transmigration of cancer cells across the endothelial cell monolayer. These results indicate that endogenous VASH1 tightens the endothelial barrier and makes tumor vessels resistant to cancer metastasis.
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  • 86
    Publication Date: 2013-09-17
    Description: by Elisa J. Hoekstra, Lars von Oerthel, Lars P. van der Heide, Willemieke M. Kouwenhoven, Jesse V. Veenvliet, Iris Wever, Yong-Ri Jin, Jeong K. Yoon, Annemarie J. A. van der Linden, Frank C. P. Holstege, Marian J. Groot Koerkamp, Marten P. Smidt Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA) neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a -deficient (dreher) mice, by means of gene expression profiling. Transcriptome analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a . Subsequent expression analysis on brain sections, confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2 , C130021l20Rik , Calb2 and Rspo2 . In line with a specific, rostral-lateral (prosomer 2/3) loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt /b-catenin signaling activator Rspo2 in this domain. Subsequent analysis of Rspo2−/− embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. To conclude, our study revealed that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the regulation of the Wnt activator Rspo2 .
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  • 87
    Publication Date: 2013-09-17
    Description: by Chaorong Tang, Xiaohu Xiao, Heping Li, Yujie Fan, Jianghua Yang, Jiyan Qi, Huibo Li Increasing demand for natural rubber prompts studies into the mechanisms governing the productivity of rubber tree ( Hevea brasiliensis ). It is very interesting to notice that a rubber tree of clone PR107 in Yunnan, China is reported to yield more than 20 times higher than the average rubber tree. This super-high-yielding (SHY) rubber tree (designated as SY107), produced 4.12 kg of latex (cytoplasm of rubber producing laticifers, containing about 30% of rubber) per tapping, more than 7-fold higher than that of the control. This rubber tree is therefore a good material to study how the rubber production is regulated at a molecular aspect. A comprehensive cDNA-AFLP transcript profiling was performed on the latex of SY107 and its average counterparts by using the 384 selective primer pairs for two restriction enzyme combinations ( Apo I/ Mse I and Taq I/ Mse I). A total of 746 differentially expressed (DE) transcript-derived fragments (TDFs) were identified, of which the expression patterns of 453 TDFs were further confirmed by RT-PCR. These RT-PCR confirmed TDFs represented 352 non-redundant genes, of which 215 had known or partially known functions and were grouped into 10 functional categories. The top three largest categories were transcription and protein synthesis (representing 24.7% of the total genes), defense and stress (15.3%), and primary and secondary metabolism (14.0%). Detailed analysis of the DE-genes suggests notable characteristics of SHY phenotype in improved sucrose loading capability, rubber biosynthesis-preferred sugar utilization, enhanced general metabolism and timely stress alleviation. However, the SHY phenotype has little correlation with rubber-biosynthesis pathway genes.
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  • 88
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    In: PLoS ONE
    Publication Date: 2013-09-17
    Description: by Luigi Maiorano, Giovanni Amori, Massimo Capula, Alessandra Falcucci, Monica Masi, Alessandro Montemaggiori, Julien Pottier, Achilleas Psomas, Carlo Rondinini, Danilo Russo, Niklaus E. Zimmermann, Luigi Boitani, Antoine Guisan We identified hotspots of terrestrial vertebrate species diversity in Europe and adjacent islands. Moreover, we assessed the extent to which by the end of the 21 st century such hotspots will be exposed to average monthly temperature and precipitation patterns which can be regarded as extreme if compared to the climate experienced during 1950-2000. In particular, we considered the entire European sub-continent plus Turkey and a total of 1149 species of terrestrial vertebrates. For each species, we developed species-specific expert-based distribution models (validated against field data) which we used to calculate species richness maps for mammals, breeding birds, amphibians, and reptiles. Considering four global circulation model outputs and three emission scenarios, we generated an index of risk of exposure to extreme climates, and we used a bivariate local Moran’s I to identify the areas with a significant association between hotspots of diversity and high risk of exposure to extreme climates. Our results outline that the Mediterranean basin represents both an important hotspot for biodiversity and especially for threatened species for all taxa. In particular, the Iberian and Italian peninsulas host particularly high species richness as measured over all groups, while the eastern Mediterranean basin is particularly rich in amphibians and reptiles; the islands (both Macaronesian and Mediterranean) host the highest richness of threatened species for all taxa occurs. Our results suggest that the main hotspots of biodiversity for terrestrial vertebrates may be extensively influenced by the climate change projected to occur over the coming decades, especially in the Mediterranean bioregion, posing serious concerns for biodiversity conservation.
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  • 89
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    In: PLoS ONE
    Publication Date: 2013-09-17
    Description: by Sudeshna Ghosh, Nitin Kumar Pandey, Atanu Singha Roy, Debi Ranjan Tripathy, Amit Kumar Dinda, Swagata Dasgupta Glycation causes severe damage to protein structure that could lead to amyloid formation in special cases. Here in this report, we have shown for the first time that hen egg white lysozyme (HEWL) does not undergo amyloid formation even after prolonged glycation in the presence of D-glucose, D-fructose and D-ribose. Cross-linked oligomers were formed in all the cases and ribose was found to be the most potent among the three sugars. Ribose mediated oligomers, however, exhibit Thioflavin T binding properties although microscopic images clearly show amorphous and globular morphology of the aggregates. Our study demonstrates that the structural damage of hen egg white lysozyme due to glycation generates unstructured aggregates.
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  • 90
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    In: PLoS ONE
    Publication Date: 2013-09-18
    Description: by Young Ae Cho, Jeongseon Kim, Hae Dong Woo, Moonsu Kang Background Diet is a major source of cadmium intake among the non-smoking general population. Recent studies have determined that cadmium exposure may produce adverse health effects at lower exposure levels than previously predicted. We conducted a meta-analysis to combine and analyze the results of previous studies that have investigated the association of dietary cadmium intake and cancer risk. Methods We searched PubMed, EMBASE, and MEDLINE database for case-control and cohort studies that assessed the association of dietary cadmium intake and cancer risk. We performed a meta-analysis using eight eligible studies to summarize the data and summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model. Results Overall, dietary cadmium intake showed no statistically significant association with cancer risk (RR = 1.10; 95% CI: 0.99–1.22, for highest vs. lowest dietary cadmium group). However, there was strong evidence of heterogeneity, and subgroup analyses were conducted using the study design, geographical location, and cancer type. In subgroup analyses, the positive associations between dietary cadmium intake and cancer risk were observed among studies with Western populations (RR = 1.15; 95% CI: 1.08–1.23) and studies investigating some hormone-related cancers (prostate, breast, and endometrial cancers). Conclusion Our analysis found a positive association between dietary cadmium intake and cancer risk among studies conducted in Western countries, particularly with hormone-related cancers. Additional experimental and epidemiological studies are required to verify our findings.
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  • 91
    Publication Date: 2013-09-18
    Description: by Shun-Min Yang, Kuo-Feng Hua, Yu-Chuan Lin, Ann Chen, Jia-Ming Chang, Louis Kuoping Chao, Chen-Lung Ho, Shuk-Man Ka The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litsea cubeba , a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-κB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri-glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti-oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model.
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  • 92
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-18
    Description: by Joon Park, Indira Munagala, Hui Xu, Derek Blankenship, Patrick Maffucci, Damien Chaussabel, Jacques Banchereau, Virginia Pascual, Charlotte Cunningham-Rundles About half of all subjects with common variable immune deficiency (CVID) are afflicted with inflammatory complications including hematologic autoimmunity, granulomatous infiltrations, interstitial lung disease, lymphoid hyperplasia and/or gastrointestinal inflammatory disease. The pathogenesis of these conditions is poorly understood but singly and in aggregate, these lead to significantly increased (11 fold) morbidity and mortality, not experienced by CVID subjects without these complications. To explore the dysregulated networks in these subjects, we applied whole blood transcriptional profiling to 91 CVID subjects, 47 with inflammatory conditions and 44 without, in comparison to subjects with XLA and healthy controls. As compared to other CVID subjects, males with XLA or healthy controls, the signature of CVID subjects with inflammatory complications was distinguished by a marked up-regulation of IFN responsive genes. Chronic up-regulation of IFN pathways is known to occur in autoimmune disease due to activation of TLRs and other still unclarified cytoplasmic sensors. As subjects with inflammatory complications were also more likely to be lymphopenic, have reduced B cell numbers, and a greater reduction of B, T and plasma cell networks, we suggest that more impaired adaptive immunity in these subjects may lead to chronic activation of innate IFN pathways in response to environmental antigens. The unbiased use of whole blood transcriptome analysis may provides a tool for distinguishing CVID subjects who are at risk for increased morbidity and earlier mortality. As more effective therapeutic options are developed, whole blood transcriptome analyses could also provide an efficient means of monitoring the effects of treatment of the inflammatory phenotype.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 93
    Publication Date: 2013-09-18
    Description: by Patrícia P. Corsetti, Leonardo A. de Almeida, Natália B. Carvalho, Vasco Azevedo, Teane M. A. Silva, Henrique C. Teixeira, Ana C. Faria, Sergio C. Oliveira IL-10 is a cytokine that regulates the balance between pathogen clearance and immunopathology. Brucella abortus is an intracellular bacterium that causes chronic disease in humans and domestic animals. Here we evaluated the contribution of IL-10 in host immune response and pathology during B. abortus infection. To assess the role of IL-10 in vivo , IL-10 knockout (KO) or 129 Sv/Ev (wild-type) mice were infected with B. abortus and the number of viable bacteria from the spleen was determined at 1, 2, 3, 6 and 14-weeks postinfection. IL-10 KO mice showed reduced bacterial loads in the spleen when compared to wild-type mice during all time points studied. Additionally, at 14-weeks postinfection IL-10 KO mice had totally cleared the infection. This clearance was preceded by an enhanced IFN-γ, TNF-α and IL-17 responses in both the serum and the spleen of IL-10 KO mice. Additionally, dendritic cells from infected IL-10 KO mice produced elevated levels of IL-12 and TNF-α compared to wild-type animals. Histopathology analysis was performed and both KO and wild-type mice developed multifocal granulomas and necrosis in the liver. However, at six-weeks postinfection reduced numbers of granulomas was detected in IL-10 KO mice compared to wild-type animals. This reduced liver pathology at later stage of infection was accompanied by increased numbers of CD4+CD25+foxp3+ T cells and expression of TGF- β in IL-10 KO splenocytes. Taken together, our findings demonstrate that IL-10 modulates the proinflammatory immune response to B. abortus infection and the lack of IL-10 increases resistance to Brucella infection.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 94
    Publication Date: 2013-09-18
    Description: by Gilberto Vargas-Alarcón, Carlos Posadas-Romero, Teresa Villarreal-Molina, Edith Alvarez-León, Javier Angeles, Maite Vallejo, Rosalinda Posadas-Sánchez, Guillermo Cardoso, Aida Medina-Urrutia, Eric Kimura-Hayama Aim The rs1412444 and rs2246833 polymorphisms within the LIPA gene were recently found to be significantly associated with coronary artery disease (CAD) in genome-wide association studies in Caucasian and Asian populations. The aim of the present study was to replicate this association in an independent population with a different genetic background. Methods The rs1412444 and rs2246833 polymorphisms of the LIPA gene were genotyped by 5′ exonuclease TaqMan genotyping assays in a sample of 899 Mexican patients with premature CAD, 270 individuals with subclinical atherosclerosis, and 677 healthy unrelated controls. Haplotypes were constructed after linkage disequilibrium analysis. Results Under recessive and additive models, the rs1412444 T and rs2246833 T alleles were associated with an increased risk of premature CAD when compared to controls adjusting for age, gender, BMI, and total cholesterol (OR = 1.53, P Rec = 0.0013 and OR = 1.34, P Add = 5 × 10 -4 for rs1412444 and OR = 1.45, P Rec = 0.0039 and OR = 1.28, P Add = 0.0023 for rs2246833). The effect of the two polymorphisms on various metabolic cardiovascular risk factors was analyzed in premature CAD and controls (CAC score = 0). The T alleles in both polymorphisms after adjusting for age, gender, BMI, and medication were associated with hypo-α-lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus using recessive and additive models. The polymorphisms were in strong linkage disequilibrium and, based on SNP functional prediction software, only the rs1412444 polymorphism seemed to be functional. Conclusions These results indicate that the rs1412444 and rs2246833 of the LIPA gene are shared susceptibility polymorphisms for CAD among different ethnicities.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 95
    Publication Date: 2013-09-18
    Description: by Guanglin Cui, Runan Zhu, Yuan Qian, Jie Deng, Linqing Zhao, Yu Sun, Fang Wang Human respiratory syncytial virus (HRSV) outranks other viral agents as the cause of respiratory tract diseases in children worldwide. Molecular epidemiological study of the virus provides useful information for the development of globally effective vaccine. We investigated the circulating pattern and genetic variation in the attachment glycoprotein genes of HRSV in Beijing during 5 consecutive seasons from 2007 to 2012. Out of 19,942 tested specimens, 3,160 (15.8%) were HRSV antigen-positive. The incidence of HRSV infection in males was significantly higher than in females. Of the total 723 (23.1%) randomly selected HRSV antigen-positive samples, 462 (63.9%) and 239 (33.1%) samples were identified as subgroup A and B, respectively. Subgroups A and B co-circulated in the 5 consecutive HRSV seasons, which showed a shifting mixed pattern of subgroup dominance. Complete G gene sequences were obtained from 190 HRSV-A and 72 HRSV-B by PCR for phylogenetic analysis. Although 4 new genotypes, NA3 and NA4 for HRSV-A and BA-C and CB1 for HRSV-B, were identified here, they were not predominant; NA1 and BA9 were the prevailing HRSV-A and -B genotypes, respectively. We provide the first report of a 9 consecutive nucleotide insertion in 3 CB1 genotype strains. One Beijing strain of ON1 genotype with a 72 nucleotide insertion was found among samples collected in February 2012. The reversion of codon states in glycosylation sites to previous ones were found from HRSV strains in this study, suggesting an immune-escape strategy of this important virus.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 96
    Publication Date: 2013-09-18
    Description: by Lisa Seifert, Michaela Harbeck, Astrid Thomas, Nadja Hoke, Lothar Zöller, Ingrid Wiechmann, Gisela Grupe, Holger C. Scholz, Julia M. Riehm Yersinia pestis has been identified as the causative agent of the Black Death pandemic in the 14 th century. However, retrospective diagnostics in human skeletons after more than 600 years are critical. We describe a strategy following a modern diagnostic algorithm and working under strict ancient DNA regime for the identification of medieval human plague victims. An initial screening and DNA quantification assay detected the Y. pestis specific pla gene of the high copy number plasmid pPCP1. Results were confirmed by conventional PCR and sequence analysis targeting both Y. pestis specific virulence plasmids pPCP1 and pMT1. All assays were meticulously validated according to human clinical diagnostics requirements (ISO 15189) regarding efficiency, sensitivity, specificity, and limit of detection (LOD). Assay specificity was 100% tested on 41 clinically relevant bacteria and 29 Y. pseudotuberculosis strains as well as for DNA of 22 Y. pestis strains and 30 previously confirmed clinical human plague samples. The optimized LOD was down to 4 gene copies. 29 individuals from three different multiple inhumations were initially assessed as possible victims of the Black Death pandemic. 7 samples (24%) were positive in the pPCP1 specific screening assay. Confirmation through second target pMT1 specific PCR was successful for 4 of the positive individuals (14%). A maximum of 700 and 560 copies per µl aDNA were quantified in two of the samples. Those were positive in all assays including all repetitions, and are candidates for future continuative investigations such as whole genome sequencing. We discuss that all precautions taken here for the work with aDNA are sufficient to prevent external sample contamination and fulfill the criteria of authenticity. With regard to retrospective diagnostics of a human pathogen and the uniqueness of ancient material we strongly recommend using a careful strategy and validated assays as presented in our study.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 97
    Publication Date: 2013-09-18
    Description: by Lina Ma, Xueqing Liu, Yanyang Zhao, Beidong Chen, Xingguang Li, Ruomei Qi Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL-stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL-treated cells, and ginkgolide B downregulated Nrf2 expression. These results suggest that ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 98
    Publication Date: 2013-09-18
    Description: by Beatriz Blanco Redondo, Melanie Bunz, Partho Halder, Madhumala K. Sadanandappa, Barbara Mühlbauer, Felix Erwin, Alois Hofbauer, Veronica Rodrigues, K. VijayRaghavan, Mani Ramaswami, Dirk Rieger, Christian Wegener, Charlotte Förster, Erich Buchner Several novel synaptic proteins have been identified by monoclonal antibodies (mAbs) of the Würzburg hybridoma library generated against homogenized Drosophila brains, e.g. cysteine string protein, synapse-associated protein of 47 kDa, and Bruchpilot. However, at present no routine technique exists to identify the antigens of mAbs of our library that label only a small number of cells in the brain. Yet these antibodies can be used to reproducibly label and thereby identify these cells by immunohistochemical staining. Here we describe the staining patterns in the Drosophila brain for ten mAbs of the Würzburg hybridoma library. Besides revealing the neuroanatomical structure and distribution of ten different sets of cells we compare the staining patterns with those of antibodies against known antigens and GFP expression patterns driven by selected Gal4 lines employing regulatory sequences of neuronal genes. We present examples where our antibodies apparently stain the same cells in different Gal4 lines suggesting that the corresponding regulatory sequences can be exploited by the split-Gal4 technique for transgene expression exclusively in these cells. The detection of Gal4 expression in cells labeled by mAbs may also help in the identification of the antigens recognized by the antibodies which then in addition to their value for neuroanatomy will represent important tools for the characterization of the antigens. Implications and future strategies for the identification of the antigens are discussed.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 99
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-18
    Description: by Xiaojing Zhang, Haixia Zhu, Xiaomin Wu, Meilin Wang, Dongying Gu, Weida Gong, Zhi Xu, Yongfei Tan, Yongling Gong, Jianwei Zhou, Cuiju Tang, Na Tong, Jinfei Chen, Zhengdong Zhang Purpose Recently, genetic polymorphism (rs3803662C〉T) in TOX3 was reported to induce the risk of breast cancer. In this study, we hypothesized that rs3803662 could influence gastric cancer survival outcomes. Methods With multiplex SNaPshot method, we genotyped TOX3 rs3803662 in 880 gastric patients with surgical resection. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, Cox regression analysis models and the log-rank test. Results There was no association in the analyses of rs3803662 and survival of gastric cancer. However, the stratified analysis by histology showed that rs3803662 CT/TT genotype was associated with a significantly better survival for diffuse-type gastric cancer (log-rank p  = 0.030, hazard ratio [HR]  = 0.67, 95% confidence interval [CI]  = 0.46–0.96), than the CC genotype. In addition, this favorable effect was especially obvious among gastric cancer patients with tumor size 〉5 cm, T3 and T4 depth of invasion, lymph node metastasis, no drinking, no distant metastasis, no chemotherapy and gastric cardia cancer. Conclusions TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 100
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    Unknown
    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2013-09-18
    Description: by Megumi Shigematsu, Tetsuhiro Ogawa, Wataru Tanaka, Kazutoshi Takahashi, Hiroko K. Kitamoto, Makoto Hidaka, Haruhiko Masaki The killer yeast species Pichia acaciae produces a heteromeric killer protein, PaT, that causes DNA damage and arrests the cell cycle of sensitive Saccharomyces cerevisiae in the S phase. However, the mechanism by which DNA damage occurs remains elusive. A previous study has indicated that Orf2p, a subunit of PaT, specifically cleaves an anticodon loop of an S. cerevisiae transfer RNA (tRNA Gln mcm5s2UUG ). This finding raised a question about whether the DNA damage is a result of the tRNA cleavage or whether Orf2p directly associates with and cleaves the genomic DNA of sensitive yeast cells. We showed that Orf2p cleaves genomic DNA in addition to cleaving tRNA in vitro . This DNA cleavage requires the same Orf2p residue as that needed for tRNA cleavage, His299. The expression of Orf2p, in which His299 was substituted to alanine, abolished the cell cycle arrest of the host cell. Moreover, the translation impairment induced by tRNA cleavage enabled Orf2p to enter the nucleus, thereby inducing histone phosphorylation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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