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  • Public Library of Science (PLoS)  (145,259)
  • 2015-2019  (145,259)
  • 1945-1949
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  • 1
    Publication Date: 2019-02-01
    Description: Habitat-forming species sustain biodiversity and ecosystem functioning in harsh environments through the amelioration of physical stress. Nonetheless, their role in shaping patterns of species distribution under future climate scenarios is generally overlooked. Focusing on coastal systems, we assess how habitat-forming species can influence the ability of stress-sensitive species to exhibit plastic responses, adapt to novel environmental conditions, or track suitable climates. Here, we argue that habitat-former populations could be managed as a nature-based solution against climate-driven loss of biodiversity. Drawing from different ecological and biological disciplines, we identify a series of actions to sustain the resilience of marine habitat-forming species to climate change, as well as their effectiveness and reliability in rescuing stress-sensitive species from increasingly adverse environmental conditions.
    Type: Article , PeerReviewed
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  • 2
    Publication Date: 2019-07-18
    Description: Almost all animals and plants are inhabited by diverse communities of microorganisms, the microbiota, thereby forming an integrated entity, the metaorganism. Natural selection should favor hosts that shape the community composition of these microbes to promote a beneficial host-microbe symbiosis. Indeed, animal hosts often pose selective environments, which only a subset of the environmentally available microbes are able to colonize. How these microbes assemble after colonization to form the complex microbiota is less clear. Neutral models are based on the assumption that the alternatives in microbiota community composition are selectively equivalent and thus entirely shaped by random population dynamics and dispersal. Here, we use the neutral model as a null hypothesis to assess microbiata composition in host organisms, which does not rely on invoking any adaptive processes underlying microbial community assembly. We show that the overall microbiota community structure from a wide range of host organisms, in particular including previously understudied invertebrates, is in many cases consistent with neutral expectations. Our approach allows to identify individual microbes that are deviating from the neutral expectation and are therefore interesting candidates for further study. Moreover, using simulated communities, we demonstrate that transient community states may play a role in the deviations from the neutral expectation. Our findings highlight that the consideration of neutral processes and temporal changes in community composition are critical for an in-depth understanding of microbiota-host interactions.
    Type: Article , PeerReviewed
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  • 3
    Publication Date: 2019-09-23
    Description: Aquatic ecosystems worldwide continue to experience unprecedented warming and ecological change. Warming increases metabolic rates of animals, plants, and microbes, accelerating their use of energy and materials, their population growth, and interaction rates. At a much larger biological scale, warming accelerates ecosystem-level processes, elevating fluxes of carbon and oxygen between biota and the atmosphere. Although these general effects of temperature at finer and broader biological scales are widely observed, they can lead to contradictory predictions for how warming affects the structure and function of ecological communities at the intermediate scale of biological organization. We experimentally tested the hypothesis that the presence of predators and their associated species interactions modify the temperature dependence of net ecosystem oxygen production and respiration. We tracked a series of independent freshwater ecosystems (370 L) over 9 weeks, and we found that at higher temperatures, cascading effects of predators on zooplankton prey and algae were stronger than at lower temperatures. When grazing was weak or absent, standing phytoplankton biomass declined by 85%–95% (〈1-fold) over the temperature gradient (19–30 °C), and by 3-fold when grazers were present and lacked predators. These temperature-dependent species interactions and consequent community biomass shifts occurred without signs of species loss or community collapse, and only modestly affected the temperature dependence of net ecosystem oxygen fluxes. The exponential increases in net ecosystem oxygen production and consumption were relatively insensitive to differences in trophic interactions among ecosystems. Furthermore, monotonic declines in phytoplankton standing stock suggested no threshold effects of warming across systems. We conclude that local changes in community structure, including temperature-dependent trophic cascades, may be compatible with prevailing and predictable effects of temperature on ecosystem functions related to fundamental effects of temperature on metabolism.
    Type: Article , PeerReviewed
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  • 4
    Publication Date: 2015-08-29
    Description: by Marc Breit, Michael Netzer, Klaus M. Weinberger, Christian Baumgartner The objectives of this work were the classification of dynamic metabolic biomarker candidates and the modeling and characterization of kinetic regulatory mechanisms in human metabolism with response to external perturbations by physical activity. Longitudinal metabolic concentration data of 47 individuals from 4 different groups were examined, obtained from a cycle ergometry cohort study. In total, 110 metabolites (within the classes of acylcarnitines, amino acids, and sugars) were measured through a targeted metabolomics approach, combining tandem mass spectrometry (MS/MS) with the concept of stable isotope dilution (SID) for metabolite quantitation. Biomarker candidates were selected by combined analysis of maximum fold changes (MFCs) in concentrations and P -values resulting from statistical hypothesis testing. Characteristic kinetic signatures were identified through a mathematical modeling approach utilizing polynomial fitting. Modeled kinetic signatures were analyzed for groups with similar behavior by applying hierarchical cluster analysis. Kinetic shape templates were characterized, defining different forms of basic kinetic response patterns, such as sustained, early, late, and other forms, that can be used for metabolite classification. Acetylcarnitine (C2), showing a late response pattern and having the highest values in MFC and statistical significance, was classified as late marker and ranked as strong predictor (MFC = 1.97, P 〈 0.001). In the class of amino acids, highest values were shown for alanine (MFC = 1.42, P 〈 0.001), classified as late marker and strong predictor. Glucose yields a delayed response pattern, similar to a hockey stick function, being classified as delayed marker and ranked as moderate predictor (MFC = 1.32, P 〈 0.001). These findings coincide with existing knowledge on central metabolic pathways affected in exercise physiology, such as β-oxidation of fatty acids, glycolysis, and glycogenolysis. The presented modeling approach demonstrates high potential for dynamic biomarker identification and the investigation of kinetic mechanisms in disease or pharmacodynamics studies using MS data from longitudinal cohort studies.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 5
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    Publication Date: 2015-08-29
    Description: by Åsmund Flobak, Anaïs Baudot, Elisabeth Remy, Liv Thommesen, Denis Thieffry, Martin Kuiper, Astrid Lægreid Discovery of efficient anti-cancer drug combinations is a major challenge, since experimental testing of all possible combinations is clearly impossible. Recent efforts to computationally predict drug combination responses retain this experimental search space, as model definitions typically rely on extensive drug perturbation data. We developed a dynamical model representing a cell fate decision network in the AGS gastric cancer cell line, relying on background knowledge extracted from literature and databases. We defined a set of logical equations recapitulating AGS data observed in cells in their baseline proliferative state. Using the modeling software GINsim, model reduction and simulation compression techniques were applied to cope with the vast state space of large logical models and enable simulations of pairwise applications of specific signaling inhibitory chemical substances. Our simulations predicted synergistic growth inhibitory action of five combinations from a total of 21 possible pairs. Four of the predicted synergies were confirmed in AGS cell growth real-time assays, including known effects of combined MEK-AKT or MEK-PI3K inhibitions, along with novel synergistic effects of combined TAK1-AKT or TAK1-PI3K inhibitions. Our strategy reduces the dependence on a priori drug perturbation experimentation for well-characterized signaling networks, by demonstrating that a model predictive of combinatorial drug effects can be inferred from background knowledge on unperturbed and proliferating cancer cells. Our modeling approach can thus contribute to preclinical discovery of efficient anticancer drug combinations, and thereby to development of strategies to tailor treatment to individual cancer patients.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2015-08-29
    Description: by Andrew Robinson, John P. McDonald, Victor E. A. Caldas, Meghna Patel, Elizabeth A. Wood, Christiaan M. Punter, Harshad Ghodke, Michael M. Cox, Roger Woodgate, Myron F. Goodman, Antoine M. van Oijen Spatial regulation is often encountered as a component of multi-tiered regulatory systems in eukaryotes, where processes are readily segregated by organelle boundaries. Well-characterized examples of spatial regulation are less common in bacteria. Low-fidelity DNA polymerase V (UmuD′ 2 C) is produced in Escherichia coli as part of the bacterial SOS response to DNA damage. Due to the mutagenic potential of this enzyme, pol V activity is controlled by means of an elaborate regulatory system at transcriptional and posttranslational levels. Using single-molecule fluorescence microscopy to visualize UmuC inside living cells in space and time, we now show that pol V is also subject to a novel form of spatial regulation. After an initial delay (~ 45 min) post UV irradiation, UmuC is synthesized, but is not immediately activated. Instead, it is sequestered at the inner cell membrane. The release of UmuC into the cytosol requires the RecA* nucleoprotein filament-mediated cleavage of UmuD→UmuD′. Classic SOS damage response mutants either block [ umuD (K97A)] or constitutively stimulate [ recA (E38K)] UmuC release from the membrane. Foci of mutagenically active pol V Mut (UmuD′ 2 C-RecA-ATP) formed in the cytosol after UV irradiation do not co-localize with pol III replisomes, suggesting a capacity to promote translesion DNA synthesis at lesions skipped over by DNA polymerase III. In effect, at least three molecular mechanisms limit the amount of time that pol V has to access DNA: (1) transcriptional and posttranslational regulation that initially keep the intracellular levels of pol V to a minimum; (2) spatial regulation via transient sequestration of UmuC at the membrane, which further delays pol V activation; and (3) the hydrolytic activity of a recently discovered pol V Mut ATPase function that limits active polymerase time on the chromosomal template.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 7
    Publication Date: 2015-08-29
    Description: by Karen E. Sears, Jennifer A. Maier, Marcelo Rivas-Astroza, Rachel Poe, Sheng Zhong, Kari Kosog, Jonathan D. Marcot, Richard R. Behringer, Chris J. Cretekos, John J. Rasweiler, Zoi Rapti Abstract Variation among individuals is a prerequisite of evolution by natural selection. As such, identifying the origins of variation is a fundamental goal of biology. We investigated the link between gene interactions and variation in gene expression among individuals and species using the mammalian limb as a model system. We first built interaction networks for key genes regulating early (outgrowth; E9.5–11) and late (expansion and elongation; E11-13) limb development in mouse. This resulted in an Early (ESN) and Late (LSN) Stage Network. Computational perturbations of these networks suggest that the ESN is more robust. We then quantified levels of the same key genes among mouse individuals and found that they vary less at earlier limb stages and that variation in gene expression is heritable. Finally, we quantified variation in gene expression levels among four mammals with divergent limbs (bat, opossum, mouse and pig) and found that levels vary less among species at earlier limb stages. We also found that variation in gene expression levels among individuals and species are correlated for earlier and later limb development. In conclusion, results are consistent with the robustness of the ESN buffering among-individual variation in gene expression levels early in mammalian limb development, and constraining the evolution of early limb development among mammalian species.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 8
    Publication Date: 2015-08-29
    Description: by Petros Damos, Polyxeni Soulopoulou Temperature implies contrasting biological causes of demographic aging in poikilotherms. In this work, we used the reliability theory to describe the consistency of mortality with age in moth populations and to show that differentiation in hazard rates is related to extrinsic environmental causes such as temperature. Moreover, experiments that manipulate extrinsic mortality were used to distinguish temperature-related death rates and the pertinence of the Weibull aging model. The Newton-Raphson optimization method was applied to calculate parameters for small samples of ages at death by estimating the maximum likelihoods surfaces using scored gradient vectors and the Hessian matrix. The study reveals for the first time that the Weibull function is able to describe contrasting biological causes of demographic aging for moth populations maintained at different temperature regimes. We demonstrate that at favourable conditions the insect death rate accelerates as age advances, in contrast to the extreme temperatures in which each individual drifts toward death in a linear fashion and has a constant chance of passing away. Moreover, slope of hazard rates shifts towards a constant initial rate which is a pattern demonstrated by systems which are not wearing out (e.g. non-aging) since the failure, or death, is a random event independent of time. This finding may appear surprising, because, traditionally, it was mostly thought as rule that in aging population force of mortality increases exponentially until all individuals have died. Moreover, in relation to other studies, we have not observed any typical decelerating aging patterns at late life (mortality leveling-off), but rather, accelerated hazard rates at optimum temperatures and a stabilized increase at the extremes.In most cases, the increase in aging-related mortality was simulated reasonably well according to the Weibull survivorship model that is applied. Moreover, semi log- probability hazard rate model illustrations and maximum likelihoods may be usefully in defining periods of mortality leveling off and provide clear evidence that environmental variability may affect parameter estimates and insect population failure rate. From a reliability theory standpoint, failure rates vary according to a linear function of age at the extremes indicating that the life system (i.e., population) is able to eliminate earlier failure and/or to keep later failure rates constant. The applied model was able to identify the major correlates of extended longevity and to suggest new ideas for using demographic concepts in both basic and applied population biology and aging.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2015-08-29
    Description: by Annick L. De Paepe, Geert Crombez, Valéry Legrain To react efficiently to potentially threatening stimuli, we have to be able to localize these stimuli in space. In daily life we are constantly moving so that our limbs can be positioned at the opposite side of space. Therefore, a somatotopic frame of reference is insufficient to localize nociceptive stimuli. Here we investigated whether nociceptive stimuli are mapped into a spatiotopic frame of reference, and more specifically a peripersonal frame of reference, which takes into account the position of the body limbs in external space, as well as the occurrence of external objects presented near the body. Two temporal order judgment (TOJ) experiments were conducted, during which participants had to decide which of two nociceptive stimuli, one applied to either hand, had been presented first while their hands were either uncrossed or crossed over the body midline. The occurrence of the nociceptive stimuli was cued by uninformative visual cues. We found that the visual cues prioritized the perception of nociceptive stimuli applied to the hand laying in the cued side of space, irrespective of posture. Moreover, the influence of the cues was smaller when they were presented far in front of participants’ hands as compared to when they were presented in close proximity. Finally, participants’ temporal sensitivity was reduced by changing posture. These findings are compatible with the existence of a peripersonal frame of reference for the localization of nociceptive stimuli. This allows for the construction of a stable representation of our body and the space closely surrounding our body, enabling a quick and efficient reaction to potential physical threats.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2015-08-29
    Description: by Elise Rousseau, Michael Joubert, Géraldine Trzepla, Jean Jacques Parienti, Thomas Freret, Marie Christine Vanthygem, Rachel Desailloud, Hervé Lefebvre, Antoine Coquerel, Yves Reznik, PHAD Study Group Background Adjustment of daily hydrocortisone dose on clinical criteria lacks sensitivity for fine tuning. Long term hydrocortisone (HC) over-replacement may lead to increased morbidity and mortality in patients with adrenal insufficiency (AI). Biochemical criteria may help detecting over- or under-replacement but have been poorly evaluated. Methods Multicenter, institutional, pharmacokinetic study on ACTH and cortisol plasma profiles during HC replacement in 27 AI patients compared to 29 matched controls. All AI patients were administered HC thrice daily at doses of 6, 10 and 14 mg/m 2 /d. Blood samples were drawn hourly from 0800h to 1900h. The main outcome measures were: i) plasma peak cortisol and cortisol area under the curve (AUC) in AI patients compared to controls, ii) correlations between cortisol AUC vs single-point cortisol or ACTH decrease from baseline (ΔACTH) and iii) the predictive value of the two latters for obtaining AI patients’ cortisol AUC in the control range. Results Cortisol peaks were observed 1h after each HC intake and a dose response was demonstrated for cortisol peak and cortisol AUC. The comparison of AI patients’ cortisol AUC to controls showed that 81.5% AI patients receiving 6mg/m 2 /d were adequately replaced, whereas most patients receiving higher doses were over-replaced. The correlation coefficient between 1000h/1400h cortisol concentrations and 0800-1900h cortisol AUC were 0.93/0.88 respectively, whereas the 0800-1200h ΔACTH fairly correlated with 0800-1900h cortisol AUC (R = 0.57). ROC curve analysis indicated that the 1000h and 1400h cortisol concentrations best predicted over-replacement. Conclusions Patients receiving a 6mg/m 2 hydrocortisone daily dose exhibited the most physiological daytime cortisol profile. Single point plasma cortisol correlated with daytime cortisol AUC in AI patients. Although hydrocortisone dose should be currently determined on clinical grounds, our data suggest that single point plasma cortisol may be an adjunct for further hydrocortisone dose adjustment in AI patients.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Public Library of Science (PLoS)
    Publication Date: 2015-08-29
    Description: by Michelle L. Van Sinderen, Gregory R. Steinberg, Sebastian B. Jørgensen, Jane Honeyman, Jenny D. Chow, Kerrie A. Herridge, Amy L. Winship, Evdokia Dimitriadis, Margaret E. E. Jones, Evan R. Simpson, Wah Chin Boon The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
    Publication Date: 2015-08-29
    Description: by Gabriel Sanfélix-Gimeno, Isabel Hurtado, José Sanfélix-Genovés, Cristóbal Baixauli-Pérez, Clara L. Rodríguez-Bernal, Salvador Peiró Inappropriate prescribing of antiosteoporotic medications has been observed; however, the joint study of both overuse and underuse has barely been attempted. Spain, with its high utilization rates, constitutes a good example to assess differences in over and under use according to diverse highly-influential osteoporosis guidelines (HIOG) worldwide. We used data of a population-based cross-sectional study including 824 post-menopausal women ≥50 years old living in the city of Valencia, Spain and aimed to estimate the percentage of women eligible for treatment, and the proportion of overuse and underuse of antiosteoporotic treatment according to HIOG. The prevalence of antiosteoporotic treatment in postmenopausal women ≥ 50 in Valencia was 20.9% (95%CI:17.6–24.4). The type of antiosteoporotic drugs prescribed varied greatly depending on the medical specialty responsible of the initial prescription. When applying the HIOG, the percentage of women 50 and over who should be treated varied from less than 9% to over 44%. In real terms, from the approximately eight million women of 50 years old and over in Spain, the number eligible for treatment would range from 0.7 to 3.8 million, depending on the guideline used. A huge proportion of inappropriate treatments was found when applying these guidelines to the Spanish population, combining a high overuse (42–78% depending on the guideline used) and underuse (7–41%). In conclusion, we found that the pharmacological management of osteoporosis in women of 50 and over in this population combines an important overuse and, to a lesser extent, underuse, although the level of inappropriateness varied strikingly depending on the CPG used. It seems urgent to reduce treatment overuse without neglecting underuse, as is urgent an attempt to reach wider agreement worldwide regarding osteoporosis management, in order to facilitate appropriate treatment and development of policies to reduce effectively treatment inappropriateness.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
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    Publication Date: 2015-08-29
    Description: by Naresh Sahebrao Nagpure, Iliyas Rashid, Ajey Kumar Pathak, Mahender Singh, Rameshwar Pati, Shri Prakash Singh, Uttam Kumar Sarkar Mitochondrial genome sequences have been widely used for evolutionary and phylogenetic studies. Among vertebrates, fish are an important, diverse group, and their mitogenome sequences are growing rapidly in public repositories. To facilitate mitochondrial genome analysis and to explore the valuable genetic information, we developed the Fish Mitogenome Resource (FMiR) database to provide a workbench for mitogenome annotation, species identification and microsatellite marker mining. The microsatellites are also known as simple sequence repeats (SSRs) and used as molecular markers in studies on population genetics, gene duplication and marker assisted selection. Here, easy-to-use tools have been implemented for mining SSRs and for designing primers to identify species/habitat specific markers. In addition, FMiR can analyze complete or partial mitochondrial genome sequence to identify species and to deduce relational distances among sequences across species. The database presently contains curated mitochondrial genomes from 1302 fish species belonging to 297 families and 47 orders reported from saltwater and freshwater ecosystems. In addition, the database covers information on fish species such as conservation status, ecosystem, family, distribution and occurrence downloaded from the FishBase and IUCN Red List databases. Those fish information have been used to browse mitogenome information for the species belonging to a particular category. The database is scalable in terms of content and inclusion of other analytical modules. The FMiR is running under Linux operating platform on high performance server accessible at URL http://mail.nbfgr.res.in/fmir.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
    Publication Date: 2015-08-31
    Description: by Olav Dalgard, Michelle Martinot-Peignoux, Hans Verbaan, Kristian Bjøro, Helmer Ring-Larsen, Patrick Marcellin The aim of this study was to determine in patients with HCV genotype 2 or 3 the performance at week 4 of two assays with different sensitivities for HCV RNA detection, for the prediction of SVR and stratification for treatment duration (14 and 24 weeks). Recruitment was from two trials comparing 14 and 24 weeks treatment to patients with rapid virological response (RVR) (n = 550). RVR was originally defined as HCV RNA
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 15
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    Publication Date: 2015-08-31
    Description: by Jamie K. Wong, Lei Chen, Yong Huang, Fatima A. Sehba, Roland H. Friedel, Hongyan Zou Stroke results in brain tissue damage from ischemia and oxidative stress. Molecular regulators of the protective versus deleterious cellular responses after cerebral ischemia remain to be identified. Here, we show that deletion of Smad1, a conserved transcription factor that mediates canonical bone morphogenetic protein (BMP) signaling, results in neuroprotection in an ischemia-reperfusion (I/R) stroke model. Uninjured mice with conditional deletion of Smad1 in the CNS ( Smad1 cKO) displayed upregulation of the reactive astrocyte marker GFAP and hypertrophic morphological changes in astrocytes compared to littermate controls. Additionally, cultured Smad1 -/- astrocytes exhibited an enhanced antioxidant capacity. When subjected to I/R injury by transient middle cerebral artery occlusion (tMCAO), Smad1 cKO mice showed enhanced neuronal survival and improved neurological recovery at 7 days post-stroke. This neuroprotective phenotype is associated with attenuated reactive astrocytosis and neuroinflammation, along with reductions in oxidative stress, p53 induction, and apoptosis. Our data suggest that Smad1-mediated signaling pathway is involved in stroke pathophysiology and may present a new potential target for stroke therapy.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
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    Publication Date: 2015-08-31
    Description: by Gloria Sanchez-Antolín, Carolina Almohalla-Alvarez, Pilar Bueno, Raquel Almansa, Verónica Iglesias, Lucia Rico, Alicia Ortega, Eva Muñoz-Conejero, Felix García-Pajares, Jesus F. Bermejo-Martin The role of systemic immunity in the pathogenesis of cirrhosis is not fully understood. Analysis of transcriptomic profiles in blood is an easy approach to obtain a wide picture of immune response at the systemic level. We studied gene expression profiles in blood from thirty cirrhotic patients and compared them against those of eight healthy volunteers. Most of our patients were male [n = 21, 70%] in their middle ages [57.4 ± 6.8 yr]. Alcohol abuse was the most frequent cause of cirrhosis (n = 22, 73%). Eleven patients had hepatocellular carcinoma (36.7%). Eight patients suffered from hepatitis C virus infection (26.7%). We found a signature constituted by 3402 genes which were differentially expressed in patients compared to controls (2802 over-expressed and 600 under-expressed). Evaluation of this signature evidenced the existence of an active pro-fibrotic transcriptomic program in the cirrhotic patients, involving the [extra-cellular matrix (ECM)-receptor interaction] & [TGF-beta signaling] pathways along with the [Cell adhesion molecules] pathway. This program coexists with alterations in pathways participating in [Glycine, serine and threonine metabolism], [Phenylalanine metabolism], [Tyrosine metabolism], [ABC transporters], [Purine metabolism], [Arachidonic acid metabolism]. In consequence, our results evidence the co-existence in blood of a genomic program mediating pro-fibrotic mechanisms and metabolic alterations in advanced cirrhosis. Monitoring expression levels of the genes involved in these programs could be of interest for predicting / monitoring cirrhosis evolution. These genes could constitute therapeutic targets in this disease.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
    Publication Date: 2015-08-31
    Description: by Shunsaku Nakagawa, Kumiko Nishihara, Hitomi Miyata, Haruka Shinke, Eri Tomita, Moto Kajiwara, Takeshi Matsubara, Noriyuki Iehara, Yoshinobu Igarashi, Hiroshi Yamada, Atsushi Fukatsu, Motoko Yanagita, Kazuo Matsubara, Satohiro Masuda In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 18
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    Publication Date: 2015-08-31
    Description: by Woo-Joo Song, Mi-Young Son, Hye-Won Lee, Hyemyung Seo, Jeong Hee Kim, Sul-Hee Chung The activity of beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is elevated during aging and in sporadic Alzheimer’s disease (AD), but the underlying mechanisms of this change are not well understood. p25/Cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathogenesis of several neurodegenerative diseases, including AD. Here, we describe a potential mechanism by which BACE activity is increased in AD brains. First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity. Then, we demonstrate that the level of phospho-BACE1 is increased in the brains of AD patients and in mammalian cells and transgenic mice that overexpress p25. Furthermore, the fraction of p25 prepared from iodixanol gradient centrifugation was unexpectedly protected by protease digestion, suggesting that p25/Cdk5-mediated BACE1 phosphorylation may occur in the lumen. These results reveal a link between p25 and BACE1 in AD brains and suggest that upregulated Cdk5 activation by p25 accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 19
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    Public Library of Science (PLoS)
    Publication Date: 2015-08-31
    Description: by Diana Fatykhova, Anne Rabes, Christoph Machnik, Kunchur Guruprasad, Florence Pache, Johanna Berg, Mario Toennies, Torsten T. Bauer, Paul Schneider, Maria Schimek, Stephan Eggeling, Timothy J. Mitchell, Andrea M. Mitchell, Rolf Hilker, Torsten Hain, Norbert Suttorp, Stefan Hippenstiel, Andreas C. Hocke, Bastian Opitz Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S . pneumoniae , which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans.
    Electronic ISSN: 1932-6203
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  • 20
    Publication Date: 2015-08-31
    Description: by Haoyi Wu, Sum Wai Chiang, Cheng Yang, Ziyin Lin, Jingping Liu, Kyoung-Sik Moon, Feiyu Kang, Bo Li, Ching Ping Wong Electrically small antennas (ESAs) are becoming one of the key components in the compact wireless devices for telecommunications, defence, and aerospace systems, especially for the spherical one whose geometric layout is more closely approaching Chu’s limit, thus yielding significant bandwidth improvements relative to the linear and planar counterparts. Yet broad applications of the volumetric ESAs are still hindered since the low cost fabrication has remained a tremendous challenge. Here we report a state-of-the-art technology to transfer electrically conductive composites (ECCs) from a planar mould to a volumetric thermoplastic substrate by using pad-printing technology without pattern distortion, benefit from the excellent properties of the ECCs as well as the printing-calibration method that we developed. The antenna samples prepared in this way meet the stringent requirement of an ESA (ka is as low as 0.32 and the antenna efficiency is as high as 57%), suggesting that volumetric electronic components i.e. the antennas can be produced in such a simple, green, and cost-effective way. This work can be of interest for the development of studies on green and high performance wireless communication devices.
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  • 21
    Publication Date: 2015-08-29
    Description: by Warunee Dansithong, Sharan Paul, Daniel R. Scoles, Stefan M. Pulst, Duong P. Huynh Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by loss of dopaminergic neurons of the substantia nigra. The hallmark of PD is the appearance of neuronal protein aggregations known as Lewy bodies and Lewy neurites, of which α-synuclein forms a major component. Familial PD is rare and is associated with missense mutations of the SNCA gene or increases in gene copy number resulting in SNCA overexpression. This suggests that lowering SNCA expression could be therapeutic for PD. Supporting this hypothesis, SNCA reduction was neuroprotective in cell line and rodent PD models. We developed novel cell lines expressing SNCA fused to the reporter genes luciferase ( luc ) or GFP with the objective to enable high-throughput compound screening (HTS) for small molecules that can lower SNCA expression. Because SNCA expression is likely regulated by far-upstream elements (including the NACP-REP1 located at 8852 bp upstream of the transcription site), we employed zinc finger nuclease (ZFN) genome editing to insert reporter genes in-frame downstream of the SNCA gene in order to retain native SNCA expression control. This ensured full retention of known and unknown up- and downstream genetic elements controlling SNCA expression. Treatment of cells with the histone deacetylase inhibitor valproic acid (VPA) resulted in significantly increased SNCA-luc and SNCA - GFP expression supporting the use of our cell lines for identifying small molecules altering complex modes of expression control. Cells expressing SNCA-luc treated with a luciferase inhibitor or SNCA siRNA resulted in Z ’-scores ≥ 0.75, suggesting the suitability of these cell lines for use in HTS. This study presents a novel use of genome editing for the creation of cell lines expressing α-synuclein fusion constructs entirely under native expression control. These cell lines are well suited for HTS for compounds that lower SNCA expression directly or by acting at long-range sites to the SNCA promoter and 5’-UTR.
    Electronic ISSN: 1932-6203
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  • 22
    Publication Date: 2015-08-29
    Description: by Asha C. Bowen, Antoine Mahé, Roderick J. Hay, Ross M. Andrews, Andrew C. Steer, Steven Y. C. Tong, Jonathan R. Carapetis Objective We conducted a comprehensive, systematic review of the global childhood population prevalence of impetigo and the broader condition pyoderma. Methods PubMed was systematically searched for impetigo or pyoderma studies published between January 1 1970 and September 30 2014. Two independent reviewers extracted data from each relevant article on the prevalence of impetigo. Findings Sixty-six articles relating to 89 studies met our inclusion criteria. Based on population surveillance, 82 studies included data on 145,028 children assessed for pyoderma or impetigo. Median childhood prevalence was 12·3% (IQR 4·2–19·4%). Fifty-eight (65%) studies were from low or low-middle income countries, where median childhood prevalences were 8·4% (IQR 4·2–16·1%) and 14·5% (IQR 8·3–20·9%), respectively. However, the highest burden was seen in underprivileged children from marginalised communities of high-income countries; median prevalence 19·4%, (IQR 3·9–43·3%). Conclusion Based on data from studies published since 2000 from low and low-middle income countries, we estimate the global population of children suffering from impetigo at any one time to be in excess of 162 million, predominantly in tropical, resource-poor contexts. Impetigo is an under-recognised disease and in conjunction with scabies, comprises a major childhood dermatological condition with potential lifelong consequences if untreated.
    Electronic ISSN: 1932-6203
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  • 23
    Publication Date: 2015-08-29
    Description: by Taro Kishi, Shinji Matsunaga, Nakao Iwata Objective We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia. Methods Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated. Results The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = −20.16, 95% CI = −25.01 to −15.30, 1889 patients, 3 trials, sTSO: WMD = −7.62, 95% CI = −11.03 to −4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia. Conclusions Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.
    Electronic ISSN: 1932-6203
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  • 24
    Publication Date: 2015-08-29
    Description: by Andrew Bonney, Darren J. Mayne, Bryan D. Jones, Lawrence Bott, Stephen E. J. Andersen, Peter Caputi, Kathryn M. Weston, Don C. Iverson Background Overweight and obesity lead to higher probability of individuals accessing primary care but adiposity estimates are rarely available at regional levels to inform health service planning. This paper analyses a large, community-derived clinical database of objectively measured body mass index (BMI) to explore relationships with area-level socioeconomic disadvantage for informing regional level planning activities. Materials and Methods The study included 91776 adults who had BMI objectively measured between 1 July 2009 and 30 June 2011 by a single pathology provider. Demographic data and BMI were extracted and matched to 2006 national census socioeconomic data using geocoding. Adjusted odds-ratios for overweight and obesity were calculated using sex-stratified logistic regression models with socioeconomic disadvantage of census collection district of residence as the independent variable. Results The prevalence of overweight or obesity was 79.2% (males) and 65.8% (females); increased with age to 74 years; and was higher in rural (74%) versus urban areas (71.4%) (p
    Electronic ISSN: 1932-6203
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  • 25
    Publication Date: 2015-08-29
    Description: by Agustín E. Martínez-González, Tíscar Rodríguez-Jiménez, José A. Piqueras, Pablo Vera-Villarroel, Antonio Godoy In recent years, there has been a considerable increase in the development of assessment tools for obsessive-compulsive symptomatology in children and adolescents. The Obsessive Compulsive Inventory-Child Version (OCI-CV) is a well-established assessment self-report, with special interest for the assessment of dimensions of Obsessive Compulsive Disorder (OCD). This instrument has shown to be useful for clinical and non-clinical populations in two languages (English and European Spanish). Thus, the aim of this study was to analyze the psychometric properties of the OCI-CV in a Chilean community sample. The sample consisted of 816 children and adolescents with a mean age of 14.54 years (SD = 2.21; range = 10–18 years). Factor structure, internal consistency, test-retest reliability, convergent/divergent validity, and gender/age differences were examined. Confirmatory factor analysis showed a 6-factor structure (Doubting/Checking, Obsessing, Hoarding, Washing, Ordering, and Neutralizing) with one second-order factor. Good estimates of reliability (including internal consistency and test-retest), evidence supporting the validity, and small age and gender differences (higher levels of OCD symptomatology among older participants and women, respectively) are found. The OCI-CV is also an adequate scale for the assessment of obsessions and compulsions in a general population of Chilean children and adolescents.
    Electronic ISSN: 1932-6203
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  • 26
    Publication Date: 2015-08-29
    Description: by Juan Ye, Lixia Lou, Kai Jin, Yufeng Xu, Xin Ye, Timothy Moss, Hayley McBain Aims To investigate the association of demographic, clinical and psychosocial variables with levels of anxiety and depression in participants wearing an ocular prosthesis after eye enucleation. Methods This cross-sectional study included 195 participants with an enucleated eye who were attending an ophthalmic clinic for prosthetic rehabilitation between July and November 2014. Demographic and clinical data, and self-reported feelings of shame, sadness and anger were collected. Participants also completed the National Eye Institute Visual Function Questionnaire, the Facial Appearance subscale of the Negative Physical Self Scale, and the Hospital Anxiety and Depression Scale. Regression models were used to identify the factors associated with anxiety and depression. Results The proportion of participants with clinical anxiety was 11.8% and clinical depression 13.8%. More anxiety and depression were associated with poorer vision-related quality of life and greater levels of appearance concerns. Younger age was related to greater levels of anxiety. Less educated participants and those feeling more angry about losing an eye are more prone to experience depression. Clinical variables were unrelated to anxiety or depression. Conclusions Anxiety and depression are more prevalent in eye-enucleated patients than the general population, which brings up the issues of psychiatric support in these patients. Psychosocial rather than clinical characteristics were associated with anxiety and depression. Longitudinal studies need to be conducted to further elucidate the direction of causality before interventions to improve mood states are developed.
    Electronic ISSN: 1932-6203
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  • 27
    Publication Date: 2015-08-29
    Description: by Jixue Zou, Zhigang Zhou, Liping Wan, Yin Tong, Youwen Qin, Chun Wang, Kun Zhou The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo . Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2'-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS.
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  • 28
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    Public Library of Science (PLoS)
    Publication Date: 2015-08-29
    Description: by Yan Zhao, Mingjie Zhang, Cynthia X. Shi, Yao Zhang, Weiping Cai, Qingxia Zhao, Yong Li, Huiqin Li, Xia Liu, Limeng Chen, Ye Ma, Fujie Zhang, Zhongfu Liu, Zunyou Wu Aim To identify the prevalence and predictors of abnormal renal function among HIV-positive Chinese patients prior to antiretroviral therapy (ART) initiation and to evaluate subsequent changes in renal function after ART exposure. Methods We conducted a nationwide cohort study of subjects who enrolled in the national Chinese ART program from January 1, 2012 to December 31, 2012. We estimated the glomerular filtration rate (eGFR) of subjects prior to and after initiating ART. Risk factors for abnormal renal function, as defined by eGFR
    Electronic ISSN: 1932-6203
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  • 29
    Publication Date: 2015-08-31
    Description: by Matilda Chelimo Saina, Xiuqiong Bi, Raphael Lihana, Raphael Lwembe, Azumi Ishizaki, Annie Panikulam, Tresa Palakudy, Rachel Musoke, Mary Owens, Elijah Maritim Songok, Hiroshi Ichimura Objectives Disease progression varies among HIV-1-infected individuals. The present study aimed to explore possible viral and host factors affecting disease progression in HIV-1-infected children. Methods Since 2000, 102 HIV-1 vertically-infected children have been followed-up in Kenya. Here we studied 29 children (15 male/14 female) who started antiretroviral treatment at 10 years of age (slow progressors; SP). Sequence variations in the HIV-1 gag and nef genes and the HLA class I-related epitopes were compared between the two groups. Results Based on nef sequences, HIV-1 subtypes A1/D were detected in 62.5%/12.5% of RP and 66.7%/20% of SP, with no significant difference in subtype distribution between groups (p = 0.8). In the ten Nef functional domains, only the PxxP 3 region showed significantly greater variation in RP (33.3%) than SP (7.7%, p = 0.048). Gag sequences did not significantly differ between groups. The reportedly protective HLA-A alleles, A*74:01, A*32:01 and A*26, were more commonly observed in SP (50.0%) than RP (11.1%, p = 0.010), whereas the reportedly disease-susceptible HLA-B*45:01 was more common in RP (33.3%) than SP (7.4%, p = 0.045). Compared to RP, SP showed a significantly higher median number of predicted HLA-B-related 12-mer epitopes in Nef (3 vs. 2, p = 0.037), HLA-B-related 11-mer epitopes in Gag (2 vs. 1, p = 0.029), and HLA-A-related 9-mer epitopes in Gag (4 vs. 1, p = 0.051). SP also had fewer HLA-C-related epitopes in Nef (median 4 vs. 5, p = 0.046) and HLA-C-related 11-mer epitopes in Gag (median 1 vs. 1.5, p = 0.044) than RP. Conclusions Compared to rapid progressors, slow progressors had more protective HLA-A alleles and more HLA-B-related epitopes in both the Nef and Gag proteins. These results suggest that the host factor HLA plays a stronger role in disease progression than the Nef and Gag sequence variations in HIV-1-infected Kenyan children.
    Electronic ISSN: 1932-6203
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  • 30
    Publication Date: 2015-08-31
    Description: by Horacio A. Ramirez, Liang Liang, Irena Pastar, Ashley M. Rosa, Olivera Stojadinovic, Thomas G. Zwick, Robert S. Kirsner, Anna G. Maione, Jonathan A. Garlick, Marjana Tomic-Canic Diabetes Mellitus (DM) is a chronic, severe disease rapidly increasing in incidence and prevalence and is associated with numerous complications. Patients with DM are at high risk of developing diabetic foot ulcers (DFU) that often lead to lower limb amputations, long term disability, and a shortened lifespan. Despite this, the effects of DM on human foot skin biology are largely unknown. Thus, the focus of this study was to determine whether DM changes foot skin biology predisposing it for healing impairment and development of DFU. Foot skin samples were collected from 20 patients receiving corrective foot surgery and, using a combination of multiple molecular and cellular approaches, we performed comparative analyses of non-ulcerated non-neuropathic diabetic foot skin (DFS) and healthy non-diabetic foot skin (NFS). MicroRNA (miR) profiling of laser captured epidermis and primary dermal fibroblasts from both DFS and NFS samples identified 5 miRs de-regulated in the epidermis of DFS though none reached statistical significance. MiR-31-5p and miR-31-3p were most profoundly induced. Although none were significantly regulated in diabetic fibroblasts, miR-29c-3p showed a trend of up-regulation, which was confirmed by qPCR in a prospective set of 20 skin samples. Gene expression profiling of full thickness biopsies identified 36 de-regulated genes in DFS (〉2 fold-change, unadjusted p-value ≤ 0.05). Of this group, three out of seven tested genes were confirmed by qPCR: SERPINB3 was up-regulated whereas OR2A4 and LGR5 were down-regulated in DFS. However no morphological differences in histology, collagen deposition, and number of blood vessels or lymphocytes were found. No difference in proliferative capacity was observed by quantification of Ki67 positive cells in epidermis. These findings suggest DM causes only subtle changes to foot skin. Since morphology, mRNA and miR levels were not affected in a major way, additional factors, such as neuropathy, vascular complications, or duration of DM, may further compromise tissue’s healing ability leading to development of DFUs.
    Electronic ISSN: 1932-6203
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  • 31
    Publication Date: 2015-08-31
    Description: by Stéphane Kerbrat, Benoit Vingert, Marie-Pierre Junier, Flavia Castellano, François Renault-Mihara, Silvina Dos Reis Tavares, Mathieu Surenaud, France Noizat-Pirenne, Jorge Boczkowski, Georges Guellaën, Hervé Chneiweiss, Sabine Le Gouvello TCR-dependent and costimulation signaling, cell division, and cytokine environment are major factors driving cytokines expression induced by CD4+ T cell activation. PEA-15 15 (Protein Enriched in Astrocyte / 15kDa) is an adaptor protein that regulates death receptor-induced apoptosis and proliferation signaling by binding to FADD and relocating ERK1/2 to the cytosol, respectively. By using PEA-15 -deficient mice, we examined the role of PEA-15 in TCR-dependent cytokine production in CD4+ T cells. TCR-stimulated PEA-15 -deficient CD4+ T cells exhibited defective progression through the cell cycle associated with impaired expression of cyclin E and phosphoRb, two ERK1/2-dependent proteins of the cell cycle. Accordingly, expression of the division cycle-dependent cytokines IL-2 and IFNγ, a Th1 cytokine, was reduced in stimulated PEA-15 -deficient CD4+ T cells. This was associated with abnormal subcellular compartmentalization of activated ERK1/2 in PEA-15 -deficient T cells. Furthermore, in vitro TCR-dependent differentiation of naive CD4 + CD62L+ PEA-15 -deficient T cells was associated with a lower production of the Th2 cytokine, IL-4, whereas expression of the Th17-associated molecule IL4I1 was enhanced. Finally, a defective humoral response was shown in PEA-15 -deficient mice in a model of red blood cell alloimmunization performed with Poly IC, a classical adjuvant of Th1 response in vivo . Collectively, our data suggest that PEA-15 contributes to the specification of the cytokine pattern of activated Th cells, thus highlighting a potential new target to interfere with T cell functional polarization and subsequent immune response.
    Electronic ISSN: 1932-6203
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  • 32
    Publication Date: 2015-08-31
    Description: by Jian Yin, Yi Wang, Hanlu Yin, Wenping Chen, Guangfu Jin, Hongxia Ma, Juncheng Dai, Jiaping Chen, Yue Jiang, Hui Wang, Zhian Liu, Zhibin Hu, Hongbing Shen Background It has been considered that the detection methods for circulating tumor cells (CTCs) based on epithelial cell adhesion molecule (EpCAM) underestimate the number of CTCs and may miss a metastatic subpopulation with cancer stem cell (CSC) properties. Therefore, we investigated EpCAM-positive and -negative CTCs in non-small cell lung cancer (NSCLC) patients at different stages, assessed the clinical value of these CTCs and explored their capacity in the following CSC model. Methods CTCs were enriched by the depletion of leukocytes with bi-antibodies using a magnetic bead separation technique and then identified by the expression of EpCAM and cytokeratin 7 and 8 using multi-parameter flow cytometry. We determined the distribution of CTCs classified by the expression of EpCAM in 46 NSCLC patients with stages I to IV, assessed the diagnostic value of these CTCs by longitudinal monitoring in 4 index patients during adjuvant therapy and characterized the stemness of these CTCs by the expression of CXCR4 and CD133 in 10 patients. Results EpCAM-negative (E-) CTCs were detected to be significantly higher than EpCAM-positive (E+) CTCs in stage IV ( p = 0.003). The patients with the percentage of E-CTCs more than 95% ( r 〉 95%) were detected to be significantly increased from 13.3% in stage I-II to 61.1% in stage IV ( p = 0.006). Kaplan–Meier analysis indicated that the patients with r 〉 95% had significantly shorter survival time than those with r ≤ 0.95 ( p = 0.041). Longitudinal monitoring of CTCs indicated that the patients with a high percentage of E-CTCs in the blood were not responsive to either chemotherapy or targeted therapy. Further characterization of CTCs revealed that a stem-like subpopulation of CXCR4+CD133+ CTCs were detected to be significantly more prevalent in E-CTCs than that in E+CTCs ( p = 0.005). Conclusions The enrichment of CTCs by the depletion of leukocytes with bi-antibodies is a valuable method for estimating the number of CTCs, which can be potentially applied in predicting the prognosis, monitoring the therapeutic effect of NSCLC patients and further analyzing the biology of CTCs.
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  • 33
    Publication Date: 2015-08-31
    Description: by Yanqiu Hu, Zhiyao Su, Wenbin Li, Jingpeng Li, Xiandong Ke We assessed the impact of species composition and stand structure on the spatial variation of forest carbon density using data collected from a 4-ha plot in a subtropical forest in southern China. We found that 1) forest biomass carbon density significantly differed among communities, reflecting a significant effect of community structure and species composition on carbon accumulation; 2) soil organic carbon density increased whereas stand biomass carbon density decreased across communities, indicating that different mechanisms might account for the accumulation of stand biomass carbon and soil organic carbon in the subtropical forest; and 3) a small number of tree individuals of the medium- and large-diameter class contributed predominantly to biomass carbon accumulation in the community, whereas a large number of seedlings and saplings were responsible for a small proportion of the total forest carbon stock. These findings demonstrate that both biomass carbon and soil carbon density in the subtropical forest are sensitive to species composition and community structure, and that heterogeneity in species composition and stand structure should be taken into account to ensure accurate forest carbon accounting.
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  • 34
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    Publication Date: 2015-08-31
    Description: by Kazuyoshi Kigawa, Masahiko Izumizaki, Setsuro Tsukada, Naoyuki Hakuta Proprioceptive signals coming from both arms are used to determine the perceived position of one arm in a two-arm matching task. Here, we examined whether the perceived position of one arm is affected by proprioceptive signals from the other arm in a one-arm pointing task in which participants specified the perceived position of an unseen reference arm with an indicator paddle. Both arms were hidden from the participant’s view throughout the study. In Experiment 1, with both arms placed in front of the body, the participants received 70–80 Hz vibration to the elbow flexors of the reference arm (= right arm) to induce the illusion of elbow extension. This extension illusion was compared with that when the left arm elbow flexors were vibrated or not. The degree of the vibration-induced extension illusion of the right arm was reduced in the presence of left arm vibration. In Experiment 2, we found that this kinesthetic interaction between the two arms did not occur when the left arm was vibrated in an abducted position. In Experiment 3, the vibration-induced extension illusion of one arm was fully developed when this arm was placed at an abducted position, indicating that the brain receives increased proprioceptive input from a vibrated arm even if the arm was abducted. Our results suggest that proprioceptive interaction between the two arms occurs in a one-arm pointing task when the two arms are aligned with one another. The position sense of one arm measured using a pointer appears to include the influences of incoming information from the other arm when both arms were placed in front of the body and parallel to one another.
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  • 35
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    Publication Date: 2015-08-31
    Description: by J. Casey Olson, Ayuko Takahashi, Michael P. Glotzbecker, Brian D. Snyder Early onset deformity of the spine and chest wall (initiated
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  • 36
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    Publication Date: 2015-08-31
    Description: by Lei Ding, Run Gao, Xiao-Qing Xiong, Xing-Ya Gao, Qi Chen, Yue-Hua Li, Yu-Ming Kang, Guo-Qing Zhu Background Chemical stimulation of white adipose tissue (WAT) induces adipose afferent reflex (AAR), and thereby causes a general sympathetic activation. Paraventricular nucleus (PVN) is important in control of sympathetic outflow. This study was designed to investigate the role of γ-aminobutyric acid (GABA) in PVN in regulating the AAR. Methodology/Principal Findings Experiments were carried out in anesthetized rats. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. AAR was evaluated by the RSNA and MAP responses to electrical stimulation of the right epididymal WAT (eWAT) afferent nerve. Electrical stimulation of eWAT afferent nerve increase RSNA. Bilateral microinjection of the GABA A receptor agonist isoguvacine or the GABA B receptor agonist baclofen attenuated the AAR. The effect of isoguvacine on the AAR was greater than that of baclofen. The GABA A receptor antagonist gabazine enhanced the AAR, while the GABA B receptor antagonist CGP-35348 had no significant effect on the AAR. Bilateral PVN microinjection of vigabatrin, a selective GABA-transaminase inhibitor, to increase endogenous GABA levels in the PVN abolished the AAR. The inhibitory effect of vigabatrin on the AAR was attenuated by the pretreatment with gabazine or CGP-35348. Pretreatment with combined gabazine and CGP-35348 abolished the effects of vigabatrin. Conclusions Activation of GABA A or GABA B receptors in the PVN inhibits the AAR. Blockade of GABA A receptors in the PVN enhances the AAR. Endogenous GABA in the PVN plays an important role in regulating the AAR.
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  • 37
    Publication Date: 2015-08-31
    Description: by Rita Crinelli, Marzia Bianchi, Lucia Radici, Elisa Carloni, Elisa Giacomini, Mauro Magnani The promoter of the polyubiquitin C gene ( UBC) contains putative heat shock elements (HSEs) which are thought to mediate UBC induction upon stress. However, the mapping and the functional characterization of the cis -acting determinants for its up-regulation have not yet been addressed. In this study, the sequence encompassing 916 nucleotides upstream of the transcription start site of the human UBC gene has been dissected by in silico , in vitro and in vivo approaches. The information derived from this analysis was used to study the functional role and the interplay of the identified HSEs in mediating the transcriptional activation of the UBC gene under conditions of proteotoxic stress, induced by the proteasome inhibitor MG132. Here we demonstrate that at least three HSEs, with different configurations, exist in the UBC promoter: two distal, residing within nucleotides -841/-817 and -715/-691, and one proximal to the transcription start site (nt -100/-65). All of them are bound by transcription factors belonging to the heat shock factor (HSF) family, as determined by bandshift, supershift and ChIP analyses. Site-directed mutagenesis of reporter constructs demonstrated that while the distal elements are involved in the up-regulation of UBC in response to proteasome inhibition, the proximal one appears rather to function as negative regulator of the stress-induced transcriptional activity. This is the first evidence that an HSE may exert a negative role on the transcription driven by other HSE motifs on the same gene promoter, highlighting a new level of complexity in the regulation of HSFs and in the control of ubiquitin levels.
    Electronic ISSN: 1932-6203
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  • 38
    Publication Date: 2015-08-31
    Description: by Sharmila Vaz, Nathan Wilson, Marita Falkmer, Angela Sim, Melissa Scott, Reinie Cordier, Torbjörn Falkmer Objective Teachers' attitudes toward inclusion are often based on the practical implementation of inclusive education rather than a specific ideology and understanding of inclusiveness. This study aimed to identify the factors associated with primary school teachers' attitudes towards inclusion of students with all disabilities in regular schools. Method Seventy four primary school teachers participated in a cross-sectional survey conducted in Western Australia. Teachers' attitudes and efficacy toward integration of students with disabilities were measured using the Opinions Relative to Integration of Students with Disabilities scale and Bandura's Teacher Efficacy scale respectively. Results Four teacher attributes—age, gender, teaching self-efficacy and training collectively explained 42% of the variability in teachers' attitude toward including students with disabilities. Conclusion The current study further contributes to the accumulation of knowledge that can unpack the complex pattern of factors that should be considered to promote positive attitudes towards inclusive schools.
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  • 39
    Publication Date: 2015-09-01
    Description: by Abdisalan Mohamed Noor, Eliud Kibuchi, Bernard Mitto, Drissa Coulibaly, Ogobara K. Doumbo, Robert W. Snow Background Seasonal malaria chemoprevention (SMC) has been shown to be highly efficacious against clinical malaria in areas where transmission is acutely seasonal. SMC targeting depends on a complex interplay of climate, malaria transmission and population distribution. In this study a spatial decision support framework was developed to identify health districts suitable for the targeting of SMC across seven Sahelian countries and northern states of Nigeria that are members of the Nouakchott Initiative. Methods A spatially explicit decision support framework that links information on seasonality, age-structured population, urbanization, malaria endemicity and the length of transmission season was developed to inform SMC targeting in health districts. Thresholds of seasonality, population and receptive risks were defined to delineate SMC suitable health districts and define the age range of children for targeting. Numbers of children were then computed for the period 2015–2020 in SMC districts. For 2015, this was combined with maps of length of malaria transmission seasons and WHO recommended treatment regimen to quantify the number of tablets required across the SMC health districts. Results A total of 597 Sahelian health districts were mapped, out of which 478 (80.1%) were considered suitable for SMC based on seasonality and endemicity thresholds. These districts had an estimated 119.8 million (85%) of the total population in 2015. In the six years from 2015–2020, it is estimated that a total of 158 million children 3m to
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  • 40
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    Publication Date: 2015-09-01
    Description: by Ling Wang, Stephanie M. Cossette, Kevin R. Rarick, Jill Gershan, Michael B. Dwinell, David R. Harder, Ramani Ramchandran
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  • 41
    Publication Date: 2015-09-01
    Description: by Badrul Arefin, Lucie Kucerova, Robert Krautz, Holger Kranenburg, Farjana Parvin, Ulrich Theopold Apart from their role in cellular immunity via phagocytosis and encapsulation, Drosophila hemocytes release soluble factors such as antimicrobial peptides, and cytokines to induce humoral responses. In addition, they participate in coagulation and wounding, and in development. To assess their role during infection with entomopathogenic nematodes, we depleted plasmatocytes and crystal cells, the two classes of hemocytes present in naïve larvae by expressing proapoptotic proteins in order to produce hemocyte-free (Hml-apo, originally called Hemo less ) larvae. Surprisingly, we found that Hml-apo larvae are still resistant to nematode infections. When further elucidating the immune status of Hml-apo larvae, we observe a shift in immune effector pathways including massive lamellocyte differentiation and induction of Toll- as well as repression of imd signaling. This leads to a pro-inflammatory state, characterized by the appearance of melanotic nodules in the hemolymph and to strong developmental defects including pupal lethality and leg defects in escapers. Further analysis suggests that most of the phenotypes we observe in Hml-apo larvae are alleviated by administration of antibiotics and by changing the food source indicating that they are mediated through the microbiota. Biochemical evidence identifies nitric oxide as a key phylogenetically conserved regulator in this process. Finally we show that the nitric oxide donor L-arginine similarly modifies the response against an early stage of tumor development in fly larvae.
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  • 42
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    Publication Date: 2015-09-01
    Description: by Luc de Chaisemartin, Tchao Meatchi, Georgia Malamut, Fahima Fernani-Oukil, Frédérique Hosking, Dorothée Rault, Fabienne Bellery, Christophe Cellier, Marie-Agnès Dragon-Durey Introduction The role of serological tests such as IgA anti-transglutaminase autoantibodies has become increasingly important in celiac disease (CD) diagnosis. However, the efficiency of these tests for patient follow-up is controversial. We investigated the correlation of 12 different serological tests, including recent deamidated gliadin and actin IgA tests, with villous atrophy (VA) in a retrospective cohort of treated celiac patients. Materials and Methods Serum samples were collected from 100 treated CD patients who had intestinal biopsy in the course of their follow-up. Antibodies against transglutaminase, deamidated gliadin peptides, and native gliadin were measured, along with IgA anti-actin. The biopsy slides were all blind-reviewed and scored according to Marsh classification. Results For all deamidated gliadin and transglutaminase tests, we found that a positive result was significantly associated with persistence of intestinal VA, with a diagnostic efficacy up to 80%. Furthermore, antibodies titers directly correlated with the degree of VA, indicating a strong link between disease activity and presence of antibodies in the serum. Interestingly, the tests with the highest association with persistent VA were those for deamidated gliadin IgG. Using a test positivity pattern analysis, we were also able to identify several groups of patients with distinct antibody profiles that showed significant differences in intestinal damage and diet compliance. Conclusions Altogether, these results show that deamidated gliadin antibodies are strongly correlated with VA and should be considered valuable tools in CD follow-up and that multiplex serologic analysis for treated CD represents a promising tool for personalized patient management.
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  • 43
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    Publication Date: 2015-09-01
    Description: by Changming Chen, Jiemin Yang, Jiayu Lai, Hong Li, Jiajin Yuan, Najam ul Hasan Abbasi The Eriksen Flanker task has been widely used as a measurement of cognitive control, however till now information is still scarce about how the neuroanatomical properties are related to performance in this task. Using voxel-based morphometry technique (VBM), the current study identified a set of distributed areas where the gray matter volume (GM) correlated positively with participants’ efficiency in interference inhibition. These areas included the bilateral prefrontal gyri, left insula and inferior temporal gyrus, the left inferior parietal lobule. Further analysis using a novel machine learning algorithm with balanced cross-validation procedure confirmed that in these areas the GM-behavioral association was unlikely a byproduct of outlier values, instead, the gray matter volume could predict reliably participants’ interference inhibition efficiency. These results underscore the importance of the fronto-parietal and insula systems to the brain functioning of interference inhibition from the neuroanatomical perspective.
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  • 44
    Publication Date: 2015-09-02
    Description: by Jiayu Wen, Erik Ladewig, Sol Shenker, Jaaved Mohammed, Eric C. Lai Mirtrons are microRNA (miRNA) substrates that utilize the splicing machinery to bypass the necessity of Drosha cleavage for their biogenesis. Expanding our recent efforts for mammalian mirtron annotation, we use meta-analysis of aggregate datasets to identify ~500 novel mouse and human introns that confidently generate diced small RNA duplexes. These comprise nearly 1000 total loci distributed in four splicing-mediated biogenesis subclasses, with 5'-tailed mirtrons as, by far, the dominant subtype. Thus, mirtrons surprisingly comprise a substantial fraction of endogenous Dicer substrates in mammalian genomes. Although mirtron-derived small RNAs exhibit overall expression correlation with their host mRNAs, we observe a subset with substantial differences that suggest regulated processing or accumulation. We identify characteristic sequence, length, and structural features of mirtron loci that distinguish them from bulk introns, and find that mirtrons preferentially emerge from genes with larger numbers of introns. While mirtrons generate miRNA-class regulatory RNAs, we also find that mirtrons exhibit many features that distinguish them from canonical miRNAs. We observe that conventional mirtron hairpins are substantially longer than Drosha-generated pre-miRNAs, indicating that the characteristic length of canonical pre-miRNAs is not a general feature of Dicer substrate hairpins. In addition, mammalian mirtrons exhibit unique patterns of ordered 5' and 3' heterogeneity, which reveal hidden complexity in miRNA processing pathways. These include broad 3'-uridylation of mirtron hairpins, atypically heterogeneous 5' termini that may result from exonucleolytic processing, and occasionally robust decapitation of the 5' guanine (G) of mirtron-5p species defined by splicing. Altogether, this study reveals that this extensive class of non-canonical miRNA bears a multitude of characteristic properties, many of which raise general mechanistic questions regarding the processing of endogenous hairpin transcripts.
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  • 45
    Publication Date: 2015-09-02
    Description: by Rudy Clausen, Buyong Ma, Ruth Nussinov, Amarda Shehu An important goal in molecular biology is to understand functional changes upon single-point mutations in proteins. Doing so through a detailed characterization of structure spaces and underlying energy landscapes is desirable but continues to challenge methods based on Molecular Dynamics. In this paper we propose a novel algorithm, SIfTER, which is based instead on stochastic optimization to circumvent the computational challenge of exploring the breadth of a protein’s structure space. SIfTER is a data-driven evolutionary algorithm, leveraging experimentally-available structures of wildtype and variant sequences of a protein to define a reduced search space from where to efficiently draw samples corresponding to novel structures not directly observed in the wet laboratory. The main advantage of SIfTER is its ability to rapidly generate conformational ensembles, thus allowing mapping and juxtaposing landscapes of variant sequences and relating observed differences to functional changes. We apply SIfTER to variant sequences of the H-Ras catalytic domain, due to the prominent role of the Ras protein in signaling pathways that control cell proliferation, its well-studied conformational switching, and abundance of documented mutations in several human tumors. Many Ras mutations are oncogenic, but detailed energy landscapes have not been reported until now. Analysis of SIfTER-computed energy landscapes for the wildtype and two oncogenic variants, G12V and Q61L, suggests that these mutations cause constitutive activation through two different mechanisms. G12V directly affects binding specificity while leaving the energy landscape largely unchanged, whereas Q61L has pronounced, starker effects on the landscape. An implementation of SIfTER is made available at http://www.cs.gmu.edu/~ashehu/?q=OurTools. We believe SIfTER is useful to the community to answer the question of how sequence mutations affect the function of a protein, when there is an abundance of experimental structures that can be exploited to reconstruct an energy landscape that would be computationally impractical to do via Molecular Dynamics.
    Print ISSN: 1553-734X
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  • 46
    Publication Date: 2015-09-02
    Description: by Sacha Jennifer van Albada, Moritz Helias, Markus Diesmann Network models are routinely downscaled compared to nature in terms of numbers of nodes or edges because of a lack of computational resources, often without explicit mention of the limitations this entails. While reliable methods have long existed to adjust parameters such that the first-order statistics of network dynamics are conserved, here we show that limitations already arise if also second-order statistics are to be maintained. The temporal structure of pairwise averaged correlations in the activity of recurrent networks is determined by the effective population-level connectivity. We first show that in general the converse is also true and explicitly mention degenerate cases when this one-to-one relationship does not hold. The one-to-one correspondence between effective connectivity and the temporal structure of pairwise averaged correlations implies that network scalings should preserve the effective connectivity if pairwise averaged correlations are to be held constant. Changes in effective connectivity can even push a network from a linearly stable to an unstable, oscillatory regime and vice versa. On this basis, we derive conditions for the preservation of both mean population-averaged activities and pairwise averaged correlations under a change in numbers of neurons or synapses in the asynchronous regime typical of cortical networks. We find that mean activities and correlation structure can be maintained by an appropriate scaling of the synaptic weights, but only over a range of numbers of synapses that is limited by the variance of external inputs to the network. Our results therefore show that the reducibility of asynchronous networks is fundamentally limited.
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  • 47
    Publication Date: 2015-09-02
    Description: by Goetz Bosse, Wiltrud Abels, Ferdinand Mtatifikolo, Baltazar Ngoli, Bruno Neuner, Klaus–Dieter Wernecke, Claudia Spies Introduction Surgical services are increasingly seen to reduce death and disability in Sub-Saharan Africa, where hospital-based mortality remains alarmingly high. This study explores two implementation approaches to improve the quality of perioperative care in a Tanzanian hospital. Effects were compared to a control group of two other hospitals in the region without intervention. Methods All hospitals conducted quality assessments with a Hospital Performance Assessment Tool. Changes in immediate outcome indicators after one and two years were compared to final outcome indicators such as Anaesthetic Complication Rate and Surgical Case Fatality Rate. Results Immediate outcome indicators for Preoperative Care in the intervention hospital improved (52.5% in 2009; 84.2% in 2011, p
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  • 48
    Publication Date: 2015-09-02
    Description: by Ling-Na Kong, Ying Guo, Bo Qin, Xin Peng, Wen-Fen Zhu Objective This study aimed to develop a set of indicators that could be used to measure and monitor the self-management performance for chronic hepatitis B (CHB) patients on antiviral therapy in China. Methods A two-round Delphi study via e-mail correspondence was conducted, with a group of 30 Chinese experts. The Delphi questionnaire consisted of 53 indicators identified from a literature review. Experts rated and scored the importance of indicators on a five-point Likert scale. Consensus was considered to be reached if a median score in the top tertile (4-5) and ≥80% of panel ratings in the top tertile (4-5) after Round 2. The included indicators were validated with a group of 106 CHB patients. Results The response rates for the first and second rounds were 90.9% (n=30) and 86.7% (n=26), respectively. Three new indicators were suggested in the first round. 55 indicators were included in the second round after modified. 45 (81.8%) indicators achieved on the level of consensus, all of which had an inter-quartile range of 1 or below. The final set included 4 domains and 45 indicators which were well accepted and understandable by CHB patients. Conclusion This Delphi study produced a set of 45 self-management indicators for CHB patients on antiviral therapy in China. These indicators could be used to measure and monitor the patients’ self-management performance, with the goal of improving the quality of life in this population.
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  • 49
    Publication Date: 2015-09-02
    Description: by Marquiza Sablón-Carrazana, Isaac Fernández, Alberto Bencomo, Reyna Lara-Martínez, Suchitil Rivera-Marrero, Guadalupe Domínguez, Rafaela Pérez-Perera, Luis Felipe Jiménez-García, Nelly F. Altamirano-Bustamante, Massiel Diaz-Delgado, Fernand Vedrenne, Lina Rivillas-Acevedo, Karina Pasten-Hidalgo, María de Lourdes Segura-Valdez, Sergio Islas-Andrade, Eulalia Garrido-Magaña, Alejandro Perera-Pintado, Anaís Prats-Capote, Chryslaine Rodríguez-Tanty, Myriam M. Altamirano-Bustamante The increasing prevalence of conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus and Cancer, poses a global challenge at many different levels. It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system. In this work, we apply a cross-functional approach that combines ideas, concepts and technologies from several disciplines in order to study, in silico and in vitro , the role of a novel chemical chaperones family (NCHCHF) in processes of protein aggregation in conformational diseases. Given that Serum Albumin (SA) is the most abundant protein in the blood of mammals, and Bovine Serum Albumin (BSA) is an off-the-shelf protein available in most labs around the world, we compared the ligandability of BSA:NCHCHF with the interaction sites in the Human Islet Amyloid Polypeptide (hIAPP):NCHCHF, and in the amyloid pharmacophore fragments (Aβ17–42 and Aβ16–21):NCHCHF. We posit that the merging of this interaction sites is a meta-structure of pharmacophore which allows the development of chaperones that can prevent protein aggregation at various states from: stabilizing the native state to destabilizing oligomeric state and protofilament. Furthermore to stabilize fibrillar structures, thus decreasing the amount of toxic oligomers in solution, as is the case with the NCHCHF. The paper demonstrates how a set of NCHCHF can be used for studying and potentially treating the various physiopathological stages of a conformational disease. For instance, when dealing with an acute phase of cytotoxicity, what is needed is the recruitment of cytotoxic oligomers, thus chaperone F, which accelerates fiber formation, would be very useful; whereas in a chronic stage it is better to have chaperones A, B, C, and D, which stabilize the native and fibril structures halting self-catalysis and the creation of cytotoxic oligomers as a consequence of fiber formation. Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP 20–29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers. In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.
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  • 50
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    Publication Date: 2015-09-02
    Description: by Peiteng Shi, Xiaohan Huang, Jun Wang, Jiang Zhang, Su Deng, Yahui Wu With the fast development of Internet and WWW, “information overload” has become an overwhelming problem, and collective attention of users will play a more important role nowadays. As a result, knowing how collective attention distributes and flows among different websites is the first step to understand the underlying dynamics of attention on WWW. In this paper, we propose a method to embed a large number of web sites into a high dimensional Euclidean space according to the novel concept of flow distance, which both considers connection topology between sites and collective click behaviors of users. With this geometric representation, we visualize the attention flow in the data set of Indiana university clickstream over one day. It turns out that all the websites can be embedded into a 20 dimensional ball, in which, close sites are always visited by users sequentially. The distributions of websites, attention flows, and dissipations can be divided into three spherical crowns (core, interim, and periphery). 20% popular sites (Google.com, Myspace.com, Facebook.com, etc.) attracting 75% attention flows with only 55% dissipations (log off users) locate in the central layer with the radius 4.1. While 60% sites attracting only about 22% traffics with almost 38% dissipations locate in the middle area with radius between 4.1 and 6.3. Other 20% sites are far from the central area. All the cumulative distributions of variables can be well fitted by “S”-shaped curves. And the patterns are stable across different periods. Thus, the overall distribution and the dynamics of collective attention on websites can be well exhibited by this geometric representation.
    Electronic ISSN: 1932-6203
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  • 51
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    Publication Date: 2015-09-02
    Description: by Verena D. Schmittmann, Sara Jahfari, Denny Borsboom, Alexander O. Savi, Lourens J. Waldorp Pairwise correlations are currently a popular way to estimate a large-scale network (〉 1000 nodes) from functional magnetic resonance imaging data. However, this approach generally results in a poor representation of the true underlying network. The reason is that pairwise correlations cannot distinguish between direct and indirect connectivity. As a result, pairwise correlation networks can lead to fallacious conclusions; for example, one may conclude that a network is a small-world when it is not. In a simulation study and an application to resting-state fMRI data, we compare the performance of pairwise correlations in large-scale networks (2000 nodes) against three other methods that are designed to filter out indirect connections. Recovery methods are evaluated in four simulated network topologies (small world or not, scale-free or not) in scenarios where the number of observations is very small compared to the number of nodes. Simulations clearly show that pairwise correlation networks are fragmented into separate unconnected components with excessive connectedness within components. This often leads to erroneous estimates of network metrics, like small-world structures or low betweenness centrality, and produces too many low-degree nodes. We conclude that using partial correlations, informed by a sparseness penalty, results in more accurate networks and corresponding metrics than pairwise correlation networks. However, even with these methods, the presence of hubs in the generating network can be problematic if the number of observations is too small. Additionally, we show for resting-state fMRI that partial correlations are more robust than correlations to different parcellation sets and to different lengths of time-series.
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  • 52
    Publication Date: 2015-09-02
    Description: by Benjamin J. Winter, Helen E. O'Connell, Scott Bowden, Marcus Carey, Damon P. Eisen Objectives To investigate whether polyomaviruses contribute to interstitial cystitis pathogenesis. Subjects and Methods A prospective study was performed with 50 interstitial cystitis cases compared with 50 age-matched, disease-free controls for the frequency of polyomaviruria. Associations between polyomaviruria and disease characteristics were analysed in cases. Polyomavirus in urine and bladder tissue was detected with species (JC virus vs. BK virus) specific, real-time PCR. Results Case patients were reflective of interstitial cystitis epidemiology with age range from 26–88 years (median 58) and female predominance (41/50 F). There was a significant increase in the frequency of polyomavirus shedding between cases and controls (p
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  • 53
    Publication Date: 2015-09-02
    Description: by Aneta Tarczewska, Małgorzata Kozłowska, Piotr Dobryszycki, Magdalena Kaus-Drobek, Michał Dadlez, Andrzej Ożyhar Two major lipophilic hormones, 20-hydroxyecdysone (20E) and juvenile hormone (JH), govern insect development and growth. While the mode of action of 20E is well understood, some understanding of JH-dependent signalling has been attained only in the past few years, and the crosstalk of the two hormonal pathways remains unknown. Two proteins, the calponin-like Chd64 and immunophilin FKBP39 proteins, have recently been found to play pivotal roles in the formation of dynamic, multiprotein complex that cross-links these two signalling pathways. However, the molecular mechanism of the interaction remains unexplored. The aim of this work was to determine structural elements of Chd64 to provide an understanding of molecular basis of multiple interactions. We analysed Chd64 in two unrelated insect species, Drosophila melanogaster (DmChd64) and Tribolium castaneum (TcChd64). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS), we showed that both Chd64 proteins have disordered tails that outflank the globular core. The folds of the globular cores of both Chd64 resemble the calponin homology (CH) domain previously resolved by crystallography. Monitoring the unfolding of DmChd64 and TcChd64 by far-ultraviolet (UV) circular dichroism (CD) spectroscopy, fluorescence spectroscopy and size-exclusion chromatography (SEC) revealed a highly complex process. Chd64 unfolds and forms of a molten globule (MG)—like intermediate state. Furthermore, our data indicate that in some conditions, Chd64 may exists in discrete structural forms, indicating that the protein is pliable and capable of easily acquiring different conformations. The plasticity of Chd64 and the existence of terminal intrinsically disordered regions (IDRs) may be crucial for multiple interactions with many partners.
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  • 54
    Publication Date: 2015-09-02
    Description: by Yo Saito, Tohru Fujiwara, Keiichi Ohashi, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Hideo Harigae Hematopoietic stem cells can self-renew and differentiate into all blood cell types. The transcription factor GATA-2 is expressed in both hematopoietic stem and progenitor cells and is essential for cell proliferation, survival, and differentiation. Recently, evidence from studies of aplastic anemia, MonoMAC syndrome, and lung cancer has demonstrated a mechanistic link between GATA-2 and human pathophysiology. GATA-2-dependent disease processes have been extensively analyzed; however, the transcriptional mechanisms upstream of GATA-2 remain less understood. Here, we conducted high-throughput small-interfering-RNA (siRNA) library screening and showed that YN-1, a human erythroleukemia cell line, expressed high levels of GATA-2 following the activation of the hematopoietic-specific 1S promoter. As transient luciferase reporter assay in YN-1 cells revealed the highest promoter activity in the 1S promoter fused with GATA-2 intronic enhancer (+9.9 kb/1S); therefore, we established a cell line capable of stably expressing +9.9 kb/1S-Luciferase. Subsequently, we screened 995 transcription factor genes and revealed that CITED2 acts as a GATA-2 activator in human hematopoietic cells. These results provide novel insights into and further identify the regulatory mechanism of GATA-2.
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  • 55
    Publication Date: 2015-09-02
    Description: by Solveig Gretarsdottir, Hannes Helgason, Anna Helgadottir, Asgeir Sigurdsson, Gudmar Thorleifsson, Audur Magnusdottir, Asmundur Oddsson, Valgerdur Steinthorsdottir, Thorunn Rafnar, Jacqueline de Graaf, Maryam S. Daneshpour, Mehdi Hedayati, Fereidoun Azizi, Niels Grarup, Torben Jørgensen, Henrik Vestergaard, Torben Hansen, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Lambertus A. Kiemeney, Oluf Pedersen, Patrick Sulem, Gudmundur Thorgeirsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, Kari Stefansson Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene ( LDLR ) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2–4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, P adj = 1.1 × 10 −80 and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, P adj = 1.3 × 10 −12 ) and confer protection against CAD (rs72658867-A, OR = 0.76 and P adj = 2.7 × 10 −8 and rs17248748-T, OR = 0.92 and P adj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G〉A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.
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  • 56
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    Publication Date: 2015-09-02
    Description: by Yali Dong, Cong Li, Yi Tao, Boyu Zhang People often deviate from their individual Nash equilibrium strategy in game experiments based on the prisoner’s dilemma (PD) game and the public goods game (PGG), whereas conditional cooperation, or conformity, is supported by the data from these experiments. In a complicated environment with no obvious “dominant” strategy, conformists who choose the average strategy of the other players in their group could be able to avoid risk by guaranteeing their income will be close to the group average. In this paper, we study the repeated PD game and the repeated m -person PGG, where individuals’ strategies are restricted to the set of conforming strategies. We define a conforming strategy by two parameters, initial action in the game and the influence of the other players’ choices in the previous round. We are particularly interested in the tit-for-tat (TFT) strategy, which is the well-known conforming strategy in theoretical and empirical studies. In both the PD game and the PGG, TFT can prevent the invasion of non-cooperative strategy if the expected number of rounds exceeds a critical value. The stability analysis of adaptive dynamics shows that conformity in general promotes the evolution of cooperation, and that a regime of cooperation can be established in an AllD population through TFT-like strategies. These results provide insight into the emergence of cooperation in social dilemma games.
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  • 57
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    Publication Date: 2015-09-02
    Description: by Adrian Allen, Eleanor Breadon, Andrew Byrne, Thomas Mallon, Robin Skuce, Pauline Groussaud, Amanda Dainty, Judith Graham, Kerri Jones, Lorraine Pollock, Adrian Whatmore Background Brucellosis is the most common bacterial zoonoses worldwide. Bovine brucellosis caused by Brucella abortus has far reaching animal health and economic impacts at both the local and national levels. Alongside traditional veterinary epidemiology, the use of molecular typing has recently been applied to inform on bacterial population structure and identify epidemiologically-linked cases of infection. Multi-locus variable number tandem repeat VNTR analysis (MLVA) was used to investigate the molecular epidemiology of a well-characterised Brucella abortus epidemic in Northern Ireland involving 387 herds between 1991 and 2012. Results MLVA identified 98 unique B . abortus genotypes from disclosing isolates in the 387 herds involved in the epidemic. Clustering algorithms revealed the relatedness of many of these genotypes. Combined with epidemiological information on chronology of infection and geographic location, these genotype data helped to identify 7 clonal complexes which underpinned the outbreak over the defined period. Hyper-variability of some VNTR loci both within herds and individual animals led to detection of multiple genotypes associated with single outbreaks. However with dense sampling, these genotypes could still be associated with specific clonal complexes thereby permitting inference of epidemiological links. MLVA- based epidemiological monitoring data were congruent with an independent classical veterinary epidemiology study carried out in the same territory. Conclusions MLVA is a useful tool in ongoing disease surveillance of B . abortus outbreaks, especially when combined with accurate epidemiological information on disease tracings, geographical clustering of cases and chronology of infection.
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  • 58
    Publication Date: 2015-09-02
    Description: by Bharani Manoharan, Helen C. Neale, John T. Hancock, Robert W. Jackson, Dawn L. Arnold The bacterial plant pathogen Pseudomonas syringae pv. phaseolicola ( Pph ) colonises the surface of common bean plants before moving into the interior of plant tissue, via wounds and stomata. In the intercellular spaces the pathogen proliferates in the apoplastic fluid and forms microcolonies (biofilms) around plant cells. If the pathogen can suppress the plant’s natural resistance response, it will cause halo blight disease. The process of resistance suppression is fairly well understood, but the mechanisms used by the pathogen in colonisation are less clear. We hypothesised that we could apply in vitro genetic screens to look for changes in motility, colony formation, and adhesion, which are proxies for infection, microcolony formation and cell adhesion. We made transposon (Tn) mutant libraries of Pph strains 1448A and 1302A and found 106/1920 mutants exhibited alterations in colony morphology, motility and biofilm formation. Identification of the insertion point of the Tn identified within the genome highlighted, as expected, a number of altered motility mutants bearing mutations in genes encoding various parts of the flagellum. Genes involved in nutrient biosynthesis, membrane associated proteins, and a number of conserved hypothetical protein (CHP) genes were also identified. A mutation of one CHP gene caused a positive increase in in planta bacterial growth. This rapid and inexpensive screening method allows the discovery of genes important for in vitro traits that can be correlated to roles in the plant interaction.
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  • 59
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    Publication Date: 2015-09-02
    Description: by Ting Hway Wong, Hai V. Nguyen, Ming Terk Chiu, Khuan Yew Chow, Marcus Eng Hock Ong, Gek Hsiang Lim, Nivedita Vikas Nadkarni, Dianne Carrol Tan Bautista, Jolene Yu Xuan Cheng, Lynette Mee Ann Loo, Dennis Chuen Chai Seow Background Frailty is associated with adverse outcomes including disability, mortality and risk of falls. Trauma registries capture a broad range of injuries. However, frail patients who fall comprise a large proportion of the injuries occurring in ageing populations and are likely to have different outcomes compared to non-frail injured patients. The effect of frail fallers on mortality is under-explored but potentially significant. Currently, many trauma registries define low falls as less than three metres, a height that is likely to include non-frailty falls. We hypothesized that the low fall from less than 0.5 metres, including same-level falls, is a surrogate marker of frailty and predicts long-term mortality in older trauma patients. Methods Using data from the Singapore National Trauma Registry, 2011–2013, matched till September 2014 to the death registry, we analysed adults aged over 45 admitted via the emergency department in public hospitals sustaining blunt injuries with an injury severity score (ISS) of 9 or more, excluding isolated hip fractures from same-level falls in the over 65. Patients injured by a low fall were compared to patients injured by high fall and other blunt mechanisms. Logistic regression was used to analyze 12-month mortality, controlling for mechanism of injury, ISS, revised trauma score (RTS), co-morbidities, gender, age and age-gender interaction. Different low fall height definitions, adjusting for injury regions, and analyzing the entire adult cohort were used in sensitivity analyses and did not change our findings. Results Of the 8111 adults in our cohort, patients who suffered low falls were more likely to die of causes unrelated to their injuries (p
    Electronic ISSN: 1932-6203
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  • 60
    Publication Date: 2015-09-02
    Description: by Matthias Rief, Sarah Feger, Peter Martus, Michael Laule, Marc Dewey, Eva Schönenberger Objectives To evaluate how well patients with coronary stents accept combined coronary computed tomography angiography (CTA) and myocardial CT perfusion (CTP) compared with conventional coronary angiography (CCA). Background While combined CTA and CTP may improve diagnostic accuracy compared with CTA alone, patient acceptance of CTA/CTP remains to be defined. Methods A total of 90 patients with coronary stents prospectively underwent CTA/CTP (both with contrast agent, CTP with adenosine) and CCA as part of the CARS-320 study. In this group, an intraindividual comparison of patient acceptance of CTA, CTP, and CCA was performed. Results CTP was experienced to be significantly more painful than CTA (p
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  • 61
    Publication Date: 2015-09-02
    Description: by Tao Tu, Kun Meng, Huiying Luo, Ossi Turunen, Lujia Zhang, Yanli Cheng, Xiaoyun Su, Rui Ma, Pengjun Shi, Yaru Wang, Peilong Yang, Bin Yao Intramolecular mobility and conformational changes of flexible loops have important roles in the structural and functional integrity of proteins. The Achaetomium sp. Xz8 endo-polygalacturonase (PG8fn) of glycoside hydrolase (GH) family 28 is distinguished for its high catalytic activity (28,000 U/mg). Structure modeling indicated that PG8fn has a flexible T3 loop that folds partly above the substrate in the active site, and forms a hydrogen bond to the substrate by a highly conserved residue Asn94 in the active site cleft. Our research investigates the catalytic roles of Asn94 in T3 loop which is located above the catalytic residues on one side of the substrate. Molecular dynamics simulation performed on the mutant N94A revealed the loss of the hydrogen bond formed by the hydroxyl group at O34 of pentagalacturonic acid and the crucial ND2 of Asn94 and the consequent detachment and rotation of the substrate away from the active site, and that on N94Q caused the substrate to drift away from its place due to the longer side chain. In line with the simulations, site-directed mutagenesis at this site showed that this position is very sensitive to amino acid substitutions. Except for the altered K m values from 0.32 (wild type PG8fn) to 0.75–4.74 mg/ml, all mutants displayed remarkably lowered k cat (~3–20,000 fold) and k cat / K m (~8–187,500 fold) values and significantly increased △(△G) values (5.92–33.47 kJ/mol). Taken together, Asn94 in the GH28 T3 loop has a critical role in positioning the substrate in a correct way close to the catalytic residues.
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  • 62
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    Publication Date: 2015-09-03
    Description: by Lauren A. Richardson
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 63
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    Publication Date: 2015-09-03
    Description: by Federica Del Chierico, Pamela Vernocchi, Andrea Petrucca, Paola Paci, Susana Fuentes, Giulia Praticò, Giorgio Capuani, Andrea Masotti, Sofia Reddel, Alessandra Russo, Cristina Vallone, Guglielmo Salvatori, Elsa Buffone, Fabrizio Signore, Giuliano Rigon, Andrea Dotta, Alfredo Miccheli, Willem M. de Vos, Bruno Dallapiccola, Lorenza Putignani The colonization and development of gut microbiota immediately after birth is highly variable and depends on several factors, such as delivery mode and modality of feeding during the first months of life. A cohort of 31 mother and neonate pairs, including 25 at-term caesarean (CS) and 6 vaginally (V) delivered neonates (DNs), were included in this study and 121 meconium/faecal samples were collected at days 1 through 30 following birth. Operational taxonomic units (OTUs) were assessed in 69 stool samples by phylogenetic microarray HITChip and inter- and intra-individual distributions were established by inter-OTUs correlation matrices and OTUs co-occurrence or co-exclusion networks. 1 H-NMR metabolites were determined in 70 stool samples, PCA analysis was performed on 55 CS DNs samples, and metabolome/OTUs co-correlations were assessed in 45 CS samples, providing an integrated map of the early microbiota OTUs-metabolome. A microbiota “core” of OTUs was identified that was independent of delivery mode and lactation stage, suggesting highly specialized communities that act as seminal colonizers of microbial networks. Correlations among OTUs, metabolites, and OTUs-metabolites revealed metabolic profiles associated with early microbial ecological dynamics, maturation of milk components, and host physiology.
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  • 64
    Publication Date: 2015-09-03
    Description: by Takashi Ueyama, Tomohiro Donishi, Satoshi Ukai, Yuta Yamamoto, Takuya Ishida, Shunji Tamagawa, Muneki Hotomi, Kazuhiro Shinosaki, Noboru Yamanaka, Yoshiki Kaneoke Tinnitus is the perception of phantom sound without an external auditory stimulus. Using neuroimaging techniques, such as positron emission tomography, electroencephalography, magnetoencephalography, and functional magnetic resonance imaging (fMRI), many studies have demonstrated that abnormal functions of the central nervous system are closely associated with tinnitus. In our previous research, we reported using resting-state fMRI that several brain regions, including the rectus gyrus, cingulate gyrus, thalamus, hippocampus, caudate, inferior temporal gyrus, cerebellar hemisphere, and medial superior frontal gyrus, were associated with tinnitus distress and loudness. To reconfirm these results and probe target regions for repetitive transcranial magnetic stimulation (rTMS), we investigated the regional cerebral blood flow (rCBF) between younger tinnitus patients (
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  • 65
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    Publication Date: 2015-09-03
    Description: by Leonardo Bonilha, Ezequiel Gleichgerrcht, Julius Fridriksson, Chris Rorden, Jesse L. Breedlove, Travis Nesland, Walter Paulus, Gunther Helms, Niels K. Focke Rationale Disruptions of brain anatomical connectivity are believed to play a central role in several neurological and psychiatric illnesses. The structural brain connectome is typically derived from diffusion tensor imaging (DTI), which may be influenced by methodological factors related to signal processing, MRI scanners and biophysical properties of neuroanatomical regions. In this study, we evaluated how these variables affect the reproducibility of the structural connectome. Methods Twenty healthy adults underwent 3 MRI scanning sessions (twice in the same MRI scanner and a third time in a different scanner unit) within a short period of time. The scanning sessions included similar T1 weighted and DTI sequences. Deterministic or probabilistic tractography was performed to assess link weight based on the number of fibers connecting gray matter regions of interest (ROI). Link weight and graph theory network measures were calculated and reproducibility was assessed through intra-class correlation coefficients, assuming each scanning session as a rater. Results Connectome reproducibility was higher with data from the same scanner. The probabilistic approach yielded larger reproducibility, while the individual variation in the number of tracked fibers from deterministic tractography was negatively associated with reproducibility. Links connecting larger and anatomically closer ROIs demonstrated higher reproducibility. In general, graph theory measures demonstrated high reproducibility across scanning sessions. Discussion Anatomical factors and tractography approaches can influence the reproducibility of the structural connectome and should be factored in the interpretation of future studies. Our results demonstrate that connectome mapping is a largely reproducible technique, particularly as it relates to the geometry of network architecture measured by graph theory methods.
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  • 66
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    Publication Date: 2015-09-03
    Description: by Juan Liu, Lina Gao, Dawei Zang Objectives To explore whether the levels of IFN-γ in cerebral spinal fluid (CSF) and serum are elevated in ALS patients and to analyze the correlations between the IFN-γ levels and disease progression. Methods CSF and serum samples were obtained from 52 ALS patients and 31 non-ALS patients. The levels of IFN-γ in CSF and serum were assessed, and disease progression parameters, including the disease interval (months from onset, MFO), the revised ALS Functional Rating Scale (ALSFRS-r) score and the disease progression rate (DPR) were analyzed by registered neurologists. All samples were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed using Prism software. Results Compared to the non-ALS patients, the ALS patients displayed significantly increased levels of IFN-γ in both CSF and serum, and these values consistently correlated with disease progression. Conclusions These results demonstrated that IFN-γ in CSF may serve as a biomarker of ALS differentiation and progression. CSF IFN-γ was a more reliable biomarker of disease diagnosis and progression than serum IFN-γ.
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  • 67
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    Publication Date: 2015-09-03
    Description: by Paola Pollegioni, Keith E. Woeste, Francesca Chiocchini, Stefano Del Lungo, Irene Olimpieri, Virginia Tortolano, Jo Clark, Gabriel E. Hemery, Sergio Mapelli, Maria Emilia Malvolti Common walnut ( Juglans regia L) is an economically important species cultivated worldwide for its wood and nuts. It is generally accepted that J . regia survived and grew spontaneously in almost completely isolated stands in its Asian native range after the Last Glacial Maximum. Despite its natural geographic isolation, J . regia evolved over many centuries under the influence of human management and exploitation. We evaluated the hypothesis that the current distribution of natural genetic resources of common walnut in Asia is, at least in part, the product of ancient anthropogenic dispersal, human cultural interactions, and afforestation. Genetic analysis combined with ethno-linguistic and historical data indicated that ancient trade routes such as the Persian Royal Road and Silk Road enabled long-distance dispersal of J . regia from Iran and Trans-Caucasus to Central Asia, and from Western to Eastern China. Ancient commerce also disrupted the local spatial genetic structure of autochthonous walnut populations between Tashkent and Samarkand (Central-Eastern Uzbekistan), where the northern and central routes of the Northern Silk Road converged. A significant association between ancient language phyla and the genetic structure of walnut populations is reported even after adjustment for geographic distances that could have affected both walnut gene flow and human commerce over the centuries. Beyond the economic importance of common walnut, our study delineates an alternative approach for understanding how the genetic resources of long-lived perennial tree species may be affected by the interaction of geography and human history.
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  • 68
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    Publication Date: 2015-09-03
    Description: by Mark G. Carls, Marie L. Larsen, Larry G. Holland Polynuclear aromatic hydrocarbons (PAHs) from sequestered MV Selendang Ayu oil were biologically available in 2008, 3.6 y after it was spilled along Unalaska Island, Alaska. Thermodynamically driven weathering was the most probable mechanism of organism exposure to PAHs. Alkane and PAH composition in oil changed over time as smaller constituents were preferentially lost, indicative of weathering. In contrast, composition of the largest compounds (biomarkers) including triterpanes, hopanes, and steranes remained unchanged. Smaller molecules (the PAHs) lost from stranded oil were observed in indigenous mussels and passive samplers deployed in July 2008. Concentration and composition of PAHs were significantly different than in a non-oiled reference area and patterns observed in mussels were repeated in passive samplers deployed in three zones (intertidal, subtidal, and water). Thus, hydrocarbons lost from one compartment (sequestered whole oil) were detectable in another (mussels and passive samplers) implying aqueous transfer. Quantities of mobile oil constituents were small, yielding uptake concentrations that are likely inconsequential for mussels, but the sensitivity provided by bioaccumulation and passive sampler uptake ensured that dissolved hydrocarbons were detectable.
    Electronic ISSN: 1932-6203
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  • 69
    Publication Date: 2015-09-03
    Description: by Agnieszka Latosinska, Konstantinos Vougas, Manousos Makridakis, Julie Klein, William Mullen, Mahmoud Abbas, Konstantinos Stravodimos, Ioannis Katafigiotis, Axel S. Merseburger, Jerome Zoidakis, Harald Mischak, Antonia Vlahou, Vera Jankowski High resolution proteomics approaches have been successfully utilized for the comprehensive characterization of the cell proteome. However, in the case of quantitative proteomics an open question still remains, which quantification strategy is best suited for identification of biologically relevant changes, especially in clinical specimens. In this study, a thorough comparison of a label-free approach (intensity-based) and 8-plex iTRAQ was conducted as applied to the analysis of tumor tissue samples from non-muscle invasive and muscle-invasive bladder cancer. For the latter, two acquisition strategies were tested including analysis of unfractionated and fractioned iTRAQ-labeled peptides. To reduce variability, aliquots of the same protein extract were used as starting material, whereas to obtain representative results per method further sample processing and MS analysis were conducted according to routinely applied protocols. Considering only multiple-peptide identifications, LC-MS/MS analysis resulted in the identification of 910, 1092 and 332 proteins by label-free, fractionated and unfractionated iTRAQ, respectively. The label-free strategy provided higher protein sequence coverage compared to both iTRAQ experiments. Even though pre-fraction of the iTRAQ labeled peptides allowed for a higher number of identifications, this was not accompanied by a respective increase in the number of differentially expressed changes detected. Validity of the proteomics output related to protein identification and differential expression was determined by comparison to existing data in the field (Protein Atlas and published data on the disease). All methods predicted changes which to a large extent agreed with published data, with label-free providing a higher number of significant changes than iTRAQ. Conclusively, both label-free and iTRAQ (when combined to peptide fractionation) provide high proteome coverage and apparently valid predictions in terms of differential expression, nevertheless label-free provides higher sequence coverage and ultimately detects a higher number of differentially expressed proteins. The risk for receiving false associations still exists, particularly when analyzing highly heterogeneous biological samples, raising the need for the analysis of higher sample numbers and/or application of adjustment for multiple testing.
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  • 70
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    Publication Date: 2015-09-03
    Description: by Peter E. Larsen, Frank R. Collart, Yang Dai The ability to obtain complete genome sequences from bacteria in environmental samples, such as soil samples from the rhizosphere, has highlighted the microbial diversity and complexity of environmental communities. However, new algorithms to analyze genome sequence information in the context of community structure are needed to enhance our understanding of the specific ecological roles of these organisms in soil environments. We present a machine learning approach using sequenced Pseudomonad genomes coupled with outputs of metabolic and transportomic computational models for identifying the most predictive molecular mechanisms indicative of a Pseudomonad’s ecological role in the rhizosphere: a biofilm, biocontrol agent, promoter of plant growth, or plant pathogen. Computational predictions of ecological niche were highly accurate overall with models trained on transportomic model output being the most accurate (Leave One Out Validation F-scores between 0.82 and 0.89). The strongest predictive molecular mechanism features for rhizosphere ecological niche overlap with many previously reported analyses of Pseudomonad interactions in the rhizosphere, suggesting that this approach successfully informs a system-scale level understanding of how Pseudomonads sense and interact with their environments. The observation that an organism’s transportome is highly predictive of its ecological niche is a novel discovery and may have implications in our understanding microbial ecology. The framework developed here can be generalized to the analysis of any bacteria across a wide range of environments and ecological niches making this approach a powerful tool for providing insights into functional predictions from bacterial genomic data.
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  • 71
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    Publication Date: 2015-09-03
    Description: by Valerie M. Villanueva, Lauren M. Oldfield, Graham F. Hatfull Temperate bacteriophages express transcription repressors that maintain lysogeny by down-regulating lytic promoters and confer superinfection immunity. Repressor regulation is critical to the outcome of infection—lysogenic or lytic growth—as well as prophage induction into lytic replication. Mycobacteriophage BPs and its relatives use an unusual integration-dependent immunity system in which the phage attachment site ( attP ) is located within the repressor gene ( 33 ) such that site-specific integration leads to synthesis of a prophage-encoded product (gp33 103 ) that is 33 residues shorter at its C-terminus than the virally-encoded protein (gp33 136 ). However, the shorter form of the repressor (gp33 103 ) is stable and active in repression of the early lytic promoter P R , whereas the longer virally-encoded form (gp33 136 ) is inactive due to targeted degradation via a C-terminal ssrA-like tag. We show here that both forms of the repressor bind similarly to the 33 – 34 intergenic regulatory region, and that BPs gp33 103 is a tetramer in solution. The BPs gp33 103 repressor binds to five regulatory regions spanning the BPs genome, and regulates four promoters including the early lytic promoter, P R . BPs gp33 103 has a complex pattern of DNA recognition in which a full operator binding site contains two half sites separated by a variable spacer, and BPs gp33 103 induces a DNA bend at the full operator site but not a half site. The operator site structure is unusual in that one half site corresponds to a 12 bp palindrome identified previously, but the other half site is a highly variable variant of the palindrome.
    Electronic ISSN: 1932-6203
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  • 72
    Publication Date: 2015-09-03
    Description: by Barbara Hoff Esbjørn, Sonja Breinholst, Janni Niclasen, Louise Fabritius Skovgaard, Katrine Lange, Marie Louise Reinholdt-Dunne The aim of this study was to enhance the understanding of cultural and sample differences in the assessment of attachment by examining the factor structure of the Experiences in Close Relationships-Revised (ECR-R). The ECR-R is a self-report measure of adult romantic attachment dimensions. The present study used a Danish sample with the purpose of addressing limitations in previous studies, such as the lack of diversity in cultural background, restricted sample characteristics, and poorly fitting structure models. Participants consisted of 253 parents of children between the ages of 7 and 12 years, 53% being mothers. The parents completed the paper version of the questionnaire. Confirmatory Factor Analyses were carried out to determine whether theoretically and empirically established models including one and two factors would also provide adequate fits in a Danish sample. A previous study using the original ECR suggested that Scandinavian samples may best be described using a five-factor solution. Our results indicated that the one- and two-factor models of the ECR-R did not fit the data well. Exploratory Factor Analysis revealed a five-factor model. Our study provides evidence that further investigation is needed to establish which model may provide the best model fit in the Scandinavian countries.
    Electronic ISSN: 1932-6203
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  • 73
    Publication Date: 2015-09-03
    Description: by Nawa Sugiyama, Andrew D. Somerville, Margaret J. Schoeninger From Roman gladiatorial combat to Egyptian animal mummies, the capture and manipulation of carnivores was instrumental in helping to shape social hierarchies throughout the ancient world. This paper investigates the historical inflection point when humans began to control animals not only as alimental resources but as ritual symbols and social actors in the New World. At Teotihuacan (A.D. 1–550), one of the largest pre-Hispanic cities, animal remains were integral components of ritual caches expressing state ideology and militarism during the construction of the Moon and the Sun Pyramids. The caches contain the remains of nearly 200 carnivorous animals, human sacrificial victims and other symbolic artifacts. This paper argues the presence of skeletal pathologies of infectious disease and injuries manifest on the carnivore remains show direct evidence of captivity. Stable isotope analysis (δ 13 C and δ 15 N) of bones and teeth confirms that some of these carnivores were consuming high levels of C 4 foods, likely reflecting a maize-based anthropocentric food chain. These results push back the antiquity of keeping captive carnivores for ritualistic purposes nearly 1000 years before the Spanish conquistadors described Moctezuma’s zoo at the Aztec capital. Mirroring these documents the results indicate a select group of carnivores at Teotihuacan may have been fed maize-eating omnivores, such as dogs and humans. Unlike historical records, the present study provides the earliest and direct archaeological evidence for this practice in Mesoamerica. It also represents the first systematic isotopic exploration of a population of archaeological eagles (n = 24) and felids (n = 29).
    Electronic ISSN: 1932-6203
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  • 74
    Publication Date: 2015-09-03
    Description: by P. Matthew Bronstad, Amanda Albu, Alex R. Bowers, Robert Goldstein, Eli Peli We determined whether binocular central scotomas above or below the preferred retinal locus affect detection of hazards (pedestrians) approaching from the side. Seven participants with central field loss (CFL), and seven age-and sex-matched controls with normal vision (NV), each completed two sessions of 5 test drives (each approximately 10 minutes long) in a driving simulator. Participants pressed the horn when detecting pedestrians that appeared at one of four eccentricities (-14°, -4°, left, 4°, or 14°, right, relative to car heading). Pedestrians walked or ran towards the travel lane on a collision course with the participant’s vehicle, thus remaining in the same area of the visual field, assuming participant's steady forward gaze down the travel lane. Detection rates were nearly 100% for all participants. CFL participant reaction times were longer (median 2.27s, 95% CI 2.13 to 2.47) than NVs (median 1.17s, 95%CI 1.10 to 2.13; difference p
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  • 75
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    Publication Date: 2015-09-03
    Description: by Katia Mattarozzi, Alexander Todorov, Michele Marzocchi, Alba Vicari, Paolo Maria Russo The present study explores whether and to what extent individual differences (i.e., gender and personality traits of perceiver) predict inferences of trustworthiness from emotionally neutral unfamiliar faces and the related confidence in judgment. Four hundred and ten undergraduate students participated in the study. Personality was assessed using the Big Five model (i.e., Extraversion, Neuroticism, Conscientiousness, Agreeableness and Openness to experience) and measures of trait anxiety and aggression. The results suggest that trustworthiness judgments are affected by the gender of the perceiver, although this effect depends on the valence of the face. Women tend to judge trustworthy-looking faces as significantly more trustworthy than men do, and this is particularly pronounced for judgments of female faces. There were no gender differences for judgments of untrustworthy-looking or neutral faces. Gender also seems to affect the confidence in judgment. Specifically, women were generally less confident than men in judging trustworthiness of unfamiliar faces. Personality also affected judgment. Both low agreeable individuals and high trait aggressive individuals tend to perceive unfamiliar faces as less trustworthy. The present findings suggest that both gender and personality traits are relevant for understanding how people evaluate the trustworthiness of others. Whom we decide to trust is a function not only of their facial features but also of gender and individual differences in personality traits.
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  • 76
    Publication Date: 2015-09-03
    Description: by Wei Gao, Heungnam Kim, Mitchell Ho Heparan sulfate proteoglycans (HSPGs) participate in many processes related to tumor development, including tumorigenesis and metastasis. HSPGs contain one or more heparan sulfate (HS) chains that are covalently linked to a core protein. Glypican-3 (GPC3) is a cell surface-associated HSPG that is highly expressed in hepatocellular carcinoma (HCC). GPC3 is involved in Wnt3a-dependent HCC cell proliferation. Our previous study reported that HS20, a human monoclonal antibody targeting the HS chains on GPC3, inhibited Wnt3a/β-catenin activation. In the current study, we showed that the HS chains of GPC3 could mediate HCC cells’ migration and motility. Knocking down GPC3 or targeting the HS chains by HS20 inhibited HCC cell migration and motility. However, HS20 had no effect on GPC3 knockdown cells or GPC3 negative cells. In addition, an antibody that recognizes the core protein of GPC3 did not change the rate of cell motility. HCC cell migration and motility did not respond to either canonical or non-canonical Wnt induction, but did increase under hepatocyte growth factor (HGF) treatment. HS20-treated HCC cells exhibited less ability for HGF-mediated migration and motility. Furthermore, HS20 inhibited in vitro HCC spheroid formation and liver tumor growth in mice. GPC3 interacted with HGF; however, a mutant GPC3 lacking the HS chain showed less interaction with HGF. Blocking the HS chains on GPC3 with HS20 reduced c-Met activation in HGF-treated HCC cells and 3D-cultured spheroids. Taken together, our study suggests that GPC3 is involved in HCC cell migration and motility through HS chain-mediated cooperation with the HGF/Met pathway, showing how HS targeting has potential therapeutic implications for liver cancer.
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  • 77
    Publication Date: 2015-09-03
    Description: by Eleonora Li Causi, Suraj C. Parikh, Lindsey Chudley, David M. Layfield, Christian H. Ottensmeier, Freda K. Stevenson, Gianfranco Di Genova CD4 + T helper memory (Th mem ) cells influence both natural and vaccine-boosted immunity, but mechanisms for their maintenance remain unclear. Pro-survival signals from the common gamma-chain cytokines, in particular IL-7, appear important. Previously we showed in healthy volunteers that a booster vaccination with tetanus toxoid (TT) expanded peripheral blood TT-specific Th mem cells as expected, but was accompanied by parallel increase of Th mem cells specific for two unrelated and non cross-reactive common recall antigens. Here, in a new cohort of healthy human subjects, we compare blood vaccine-specific and bystander Th mem cells in terms of differentiation stage, function, activation and proliferative status. Both responses peaked 1 week post-vaccination. Vaccine-specific cytokine-producing Th mem cells were predominantly effector memory, whereas bystander cells were mainly of central memory phenotype. Importantly, TT-specific Th mem cells were activated (CD38 High HLA-DR + ), cycling or recently divided (Ki-67 + ), and apparently vulnerable to death (IL-7Rα Low and Bcl-2 Low ). In contrast, bystander Th mem cells were resting (CD38 Low HLA-DR - Ki-67 - ) with high expression of IL-7Rα and Bcl-2. These findings allow a clear distinction between vaccine-specific and bystander Th mem cells, suggesting the latter do not derive from recent proliferation but from cells mobilized from as yet undefined reservoirs. Furthermore, they reveal the interdependent dynamics of specific and bystander T-cell responses which will inform assessments of responses to vaccines.
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    Public Library of Science (PLoS)
    Publication Date: 2015-09-03
    Description: by Zhiyong Yang, Wenjie Dong, Jinfeng Xiu, Rufeng Dai, Jieming Chou Environmentally extended input-output analysis (EEIOA) has long been used to quantify global and regional environmental impacts and to clarify emission transfers. Structural path analysis (SPA), a technique based on EEIOA, is especially useful for measuring significant flows in this environmental-economic system. This paper constructs an imports-adjusted single-region input-output (SRIO) model considering only domestic final use elements, and it uses the SPA technique to highlight crucial routes along the production chain in both final use and sectoral perspectives. The results indicate that future mitigation policies on household consumption should change direct energy use structures in rural areas, cut unreasonable demand for power and chemical products, and focus on urban areas due to their consistently higher magnitudes than rural areas in the structural routes. Impacts originating from government spending should be tackled by managing onsite energy use in 3 major service sectors and promoting cleaner fuels and energy-saving techniques in the transport sector. Policies on investment should concentrate on sectoral interrelationships along the production chain by setting up standards to regulate upstream industries, especially for the services, construction and equipment manufacturing sectors, which have high demand pulling effects. Apart from the similar methods above, mitigating policies in exports should also consider improving embodied technology and quality in manufactured products to achieve sustainable development. Additionally, detailed sectoral results in the coal extraction industry highlight the onsite energy use management in large domestic companies, emphasize energy structure rearrangement, and indicate resources and energy safety issues. Conclusions based on the construction and public administration sectors reveal that future mitigation in secondary and tertiary industries should be combined with upstream emission intensive industries in a systematic viewpoint to achieve sustainable development. Overall, SPA is a useful tool in empirical studies, and it can be used to analyze national environmental impacts and guide future mitigation policies.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Public Library of Science (PLoS)
    Publication Date: 2015-09-03
    Description: by Hannah Gaimster, David Summers During the transition from exponential to stationary phase E . coli produces a substantial quantity of the small, aromatic signalling molecule indole. In LB medium the supernatant indole concentration reaches a maximum of 0.5–1 mM. At this concentration indole has been implicated in many processes inducing acid resistance and the modulation of virulence. It has recently been shown that cell-associated indole transiently reaches a very high concentration (approx. 60 mM) during stationary phase entry, presumably because indole is being produced more rapidly than it can leave the cell. It is proposed that this indole pulse inhibits growth and cell division, causing the culture to enter stationary phase before nutrients are completely exhausted, with benefits for survival in long-term stationary phase. This study asks how E . coli cells rapidly upregulate indole production during stationary phase entry and why the indole pulse has a duration of only 10–15 min. We find that at the start of the pulse tryptophanase synthesis is triggered by glucose depletion and that this is correlates with the up-regulation of indole synthesis. The magnitude and duration of the resulting indole pulse are dependent upon the availability of exogenous tryptophan. Indole production stops when all the available tryptophan is depleted and the cell-associated indole equilibrates with the supernatant.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 80
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    Public Library of Science (PLoS)
    Publication Date: 2015-09-04
    Description: by John A. Gaynes, Hideo Otsuna, Douglas S. Campbell, John P. Manfredi, Edward M. Levine, Chi-Bin Chien Attractive growth cone turning requires Igf2bp1-dependent local translation of β-actin mRNA in response to external cues in vitro . While in vivo studies have shown that Igf2bp1 is required for cell migration and axon terminal branching, a requirement for Igf2bp1 function during axon outgrowth has not been demonstrated. Using a timelapse assay in the zebrafish retinotectal system, we demonstrate that the β-actin 3’UTR is sufficient to target local translation of the photoconvertible fluorescent protein Kaede in growth cones of pathfinding retinal ganglion cells (RGCs) in vivo . Igf2bp1 knockdown reduced RGC axonal outgrowth and tectal coverage and retinal cell survival. RGC-specific expression of a phosphomimetic Igf2bp1 reduced the density of