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Find video protocols related to scientific articles indexed in Pubmed.
Formation Principles for Vanadium Selenites: The Role of pH on Product Composition.
Inorg Chem
PUBLISHED: 11-03-2014
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A series of organically templated vanadium selenites has been prepared under mild hydrothermal conditions. Single crystals of [C5H14N2][(VO)3(SeO3)2(HSeO3)4], [C5H14N2][VO(SeO3)2], [(R)-C5H14N2][(VO)3(SeO3)2(HSeO3)4], and [(S)-C5H14N2][(VO)3(SeO3)2(HSeO3)4] were grown from VOSO4, SeO2, and 2-methylpiperazine. Controlling the initial pH of the reaction mixture allows for one to select between the compounds found in the VOSO4/SeO2/2-methylpiperazine system, as the solution pH directly affects the relative ratio of the HSeO3(-) and SeO3(2-) concentrations. Moreover, partial resolution of racemic 2-methylpiperazine is observed in [C5H14N2][(VO)3(SeO3)2(HSeO3)4], which is understood through the use of a one-dimensional Ising model. The use of enantiomerically pure 2-methylpiperazine results in fully ordered and fully resolved structures.
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BRCA1 Suppresses Epithelial-to-Mesenchymal Transition and Stem Cell Dedifferentiation during Mammary and Tumor Development.
Cancer Res.
PUBLISHED: 09-19-2014
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BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis. Cancer Res; 74(21); 6161-72. ©2014 AACR.
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Sequestrate fungi from Patagonian Nothofagus forests: Cystangium (Russulaceae, Basidiomycota).
Mycologia
PUBLISHED: 09-19-2014
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Six species of Cystangium, a genus of sequestrate taxa related to Russula, were collected in Patagonia (Argentina and Chile) during autumn 2001. Two species, C. depauperatum Singer & A.H. Sm. and C. nothofagi (E. Horak) Trappe, Castellano & T. Lebel, were already known from this region, while four new species, C. domingueziae, C. gamundiae, C. grandihyphatum and C. longisterigmatum, are described, illustrated and a key to the species is provided. In addition, sequences of the ITS (rDNA) region were obtained to explore the phylogenetic relationships of our South American Cystangium species.
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Computational design of novel enzymes without cofactors.
Methods Mol. Biol.
PUBLISHED: 09-13-2014
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In this review we present a recently developed computational method to design de novo enzymes. Starting from the three-dimensional arrangement of the transition state structure and the catalytic side chains around it (theozyme), RosettaMatch identifies successful placements of the theozyme into protein scaffolds. Subsequently, RosettaEnzDes (for EnzymeDesign) redesigns the active site around the theozyme for binding and stabilization of the transition state and the catalytic residues. The resulting computationally designed enzymes are expressed and experimentally tested for catalytic activity.
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Intraoperative ultrasound to facilitate removal of a submucosal foreign body.
J Clin Ultrasound
PUBLISHED: 08-22-2014
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A 61-year-old man with a history of fish bone ingestion and poorly localized symptoms was seen. His clinical examination was unremarkable, but CT demonstrated a foreign body deeply embedded within his tongue. Intraoperative ultrasound (US) guidance facilitated identification of a bone, allowing a needle to be placed as a guide to dissection. Repeat US scanning through the incision permitted precisely targeted surgery. CT and US are the most effective imaging techniques for localizing fish bones. Intraoperative US can be used to accurately locate a submucosal fish bone in mobile tissue such as the tongue, and focused, image-guided dissection can reduce surgical tissue trauma. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 42:565-568, 2014.
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Culturable fungal assemblages growing within Cenococcum sclerotia in forest soils.
FEMS Microbiol. Ecol.
PUBLISHED: 08-08-2014
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The ectomycorrhizal fungus Cenococcum geophilum (Ascomycota, Dothideomycetes) forms black, round to irregular sclerotia in forest soils. Fungi that colonize the sclerotia appear to affect sclerotia viability and may play an important role in the life history of Cenococcum. Some of the fungi could also affect nutrient cycling by decomposing Cenococcum sclerotia, which are melanized and recalcitrant to decay. We used a culture-based method to document the fungal communities growing inside surface-sterilized sclerotia that were collected from forest soils. Cenococcum was successfully isolated from 297 of 971 sclerotia whereas 427 sclerotia hosted fungi other than Cenococcum. DNA barcoding of the internal transcribed spacer rDNA followed by grouping at 97% sequence similarity yielded 85 operational taxonomic units (OTUs) that consisted primarily of Ascomycota (e.g. Chaetothyriales, Eurotiales, Helotiales, Pleosporales) and a few Basidiomycota and Mucoromycotina. Although most fungal OTUs were infrequently cultured, several OTUs such as members of Asterostroma, Cladophialophora, Oidiodendron, and Pleosporales were common and found across many sites. Our results suggest that Cenococcum sclerotia act as a substrate for diverse fungi. The occurrence of several OTUs in sclerotia across many sites suggests that these fungi may be active parasites of Cenococcum sclerotia or may preferentially use sclerotia as a nutrient source.
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Virtual reality job interview training for individuals with psychiatric disabilities.
J. Nerv. Ment. Dis.
PUBLISHED: 08-08-2014
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Services are available to help support existing employment for individuals with psychiatric disabilities; however, there is a gap in services targeting job interview skills that can help obtain employment. We assessed the feasibility and efficacy of Virtual Reality Job Interview Training (VR-JIT) in a randomized controlled trial. Participants were randomized to VR-JIT (n = 25) or treatment-as-usual (TAU) (n = 12) groups. VR-JIT consisted of 10 hours of simulated job interviews with a virtual character and didactic online training. The participants attended 95% of laboratory-based training sessions and found VR-JIT easy to use and felt prepared for future interviews. The VR-JIT group improved their job interview role-play performance (p ? 0.05) and self-confidence (p ? 0.05) between baseline and follow-up as compared with the TAU group. VR-JIT performance scores increased over time (R = 0.65). VR-JIT demonstrated initial feasibility and efficacy at improving job interview skills and self-confidence. Future research may help clarify whether this intervention is efficacious in community-based settings.
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An analysis of the impact of pre-analytical factors on the urine proteome: Sample processing time, temperature and proteolysis.
Proteomics Clin Appl
PUBLISHED: 07-22-2014
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We have examined the impact of sample processing time delay, temperature and the addition of protease inhibitors on the urinary proteome and peptidome, an important aspect of biomarker studies.
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Predictability of the terrestrial carbon cycle.
Glob Chang Biol
PUBLISHED: 06-16-2014
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Terrestrial ecosystems play a crucial role in the global carbon cycle and in the regulation of climate change. Anthropogenic CO2 emissions increased from 2.4 Pg C in 1960 to 8.7 Pg C per year in 2008 while terrestrial ecosystems absorbed roughly 30% during that period (Le Quere et al., 2009). If that absorption capacity were to change, in either direction, it would have a large impact on atmospheric CO2 concentrations, resulting in a strong feedback effect on climate (Denman et al., 2007, Friedlingstein et al., 2006). It is, therefore, imperative to accurately predict dynamics of the terrestrial carbon cycle in order to accurately predict future changes in the Earth's climate. Here, we examine the current state of the art of predictive modeling of the global carbon cycle, and outline how an understanding of the intrinsic predictability of its components can be used to guide future experimental research and develop the next generation of carbon cycle models. This article is protected by copyright. All rights reserved.
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Simulated job interview improves skills for adults with serious mental illnesses.
Stud Health Technol Inform
PUBLISHED: 05-31-2014
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Adults with serious mental illnesses (e.g., Autism Spectrum Disorder [ASD], schizophrenia, post-traumatic stress disorder [PTSD]) often have difficulties obtaining employment. The Job Interview Training System with Molly Porter, developed in collaboration with Yale and Northwestern Universities and vocational rehabilitation specialists with funding from The National Institutes of Health (R43/44MH080496), allows learners to practice job interviews on computers in a stress free environment. The system includes user-driven educational materials, an interactive job application, a practice simulation with a fictional interviewer (Molly Porter), and extensive feedback. SIMmersion's PeopleSIM™ technology allows each conversation with Molly to provide a unique interview experience, enabling users to gain confidence while building skills. The on-screen coach provides insight during the conversation, and a comprehensive after-action review provides learners with feedback on the entire interview. In a randomized control trial, the system was proven effective at improving participants' interview skills and confidence. Ninety-six (96) unemployed adults with ASD (n=26), schizophrenia/other (n=37) or PTSD (n=33) were recruited. Participants were randomized into control (n=32) and experimental (n=64) conditions. The control group was "wait-listed" to receive training, and the experimental group used the training system with Molly Porter. Both groups completed pre- and post-intervention role-play interviews and self-assessment questionnaires. Analyses of covariance showed that the simulation provided a highly significant training effect, with experimental group participants scoring better in the role-play interviews and self-assessing higher than control group participants. By increasing skills and confidence, this system may ultimately reduce the length of unemployment for adults with mental illnesses.
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Opportunities for knowledge translation in the decade of road traffic safety.
J Orthop Trauma
PUBLISHED: 05-27-2014
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The United Nations has identified road traffic safety as an important objective for the decade 2011-2020. It has implemented a 5-tiered program: improving health care services, improving management of road safety, improving road network safety, improving vehicular safety, and improving road safety legislation. A small body of practical research has been generated by the medical and surgical (including orthopaedic) communities regarding the road traffic safety, but a substantial amount of work remains to be performed. This article will review published research in each of the 5 tiers of the Decade of Action for Road Traffic Safety and will identify areas where research is insufficient or absent, such that new research programming and funding can be developed.
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Basal ganglia and thalamic morphology in schizophrenia and bipolar disorder.
Psychiatry Res
PUBLISHED: 05-15-2014
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In this study, we examined the morphology of the basal ganglia and thalamus in bipolar disorder (BP), schizophrenia-spectrum disorders (SCZ-S), and healthy controls (HC) with particular interest in differences related to the absence or presence of psychosis. Volumetric and shape analyses of the basal ganglia and thalamus were performed in 33 BP individuals [12 without history of psychotic features (NPBP) and 21 with history of psychotic features (PBP)], 32 SCZ-S individuals [28 with SCZ and 4 with schizoaffective disorder], and 27 HC using FreeSurfer-initiated large deformation diffeomorphic metric mapping. Significant volume differences were found in the caudate and globus pallidus, with volumes smallest in the NPBP group. Shape abnormalities showing inward deformation of superior regions of the caudate were observed in BP (and especially in NPBP) compared with HC. Shape differences were also found in the globus pallidus and putamen when comparing BP and SCZ-S groups. No significant differences were seen in the nucleus accumbens and thalamus. In summary, structural abnormalities in the caudate and globus pallidus are present in BP and SCZ-S. Differences were more apparent in the NPBP subgroup. The findings herein highlight the potential importance of separately examining BP subgroups in neuroimaging studies.
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Model reduction for slow-fast stochastic systems with metastable behaviour.
J Chem Phys
PUBLISHED: 05-10-2014
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The quasi-steady-state approximation (or stochastic averaging principle) is a useful tool in the study of multiscale stochastic systems, giving a practical method by which to reduce the number of degrees of freedom in a model. The method is extended here to slow-fast systems in which the fast variables exhibit metastable behaviour. The key parameter that determines the form of the reduced model is the ratio of the timescale for the switching of the fast variables between metastable states to the timescale for the evolution of the slow variables. The method is illustrated with two examples: one from biochemistry (a fast-species-mediated chemical switch coupled to a slower varying species), and one from ecology (a predator-prey system). Numerical simulations of each model reduction are compared with those of the full system.
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Virtual reality job interview training in adults with autism spectrum disorder.
J Autism Dev Disord
PUBLISHED: 05-08-2014
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The feasibility and efficacy of virtual reality job interview training (VR-JIT) was assessed in a single-blinded randomized controlled trial. Adults with autism spectrum disorder were randomized to VR-JIT (n = 16) or treatment-as-usual (TAU) (n = 10) groups. VR-JIT consisted of simulated job interviews with a virtual character and didactic training. Participants attended 90 % of laboratory-based training sessions, found VR-JIT easy to use and enjoyable, and they felt prepared for future interviews. VR-JIT participants had greater improvement during live standardized job interview role-play performances than TAU participants (p = 0.046). A similar pattern was observed for self-reported self-confidence at a trend level (p = 0.060). VR-JIT simulation performance scores increased over time (R(2) = 0.83). Results indicate preliminary support for the feasibility and efficacy of VR-JIT, which can be administered using computer software or via the internet.
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The histologic and biomechanical response of two commercially available small glenoid anchors for use in labral repairs.
J Shoulder Elbow Surg
PUBLISHED: 04-13-2014
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This study examined histologic characteristics and biomechanical performance of 2 commercially available, small glenoid anchors.
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Genistein Protects Female Nonobese Diabetic Mice from Developing Type 1 Diabetes When Fed a Soy- and Alfalfa-free Diet.
Toxicol Pathol
PUBLISHED: 04-10-2014
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The objective of this study was to determine the effects of the phytoestrogen genistein (GEN) on the time of onset and/or the incidence of type 1 diabetes (T1D) in female nonobese diabetic (NOD) mice, when administered GEN by gavage once every day for up to 180 days. Five groups of mice (approximately 24 animals/group; 6-7 weeks of age) were included: naive control, vehicle control (25 mM Na2CO3 in water), and 3 GEN treatment groups (2 mg/kg, 6 mg/kg, and 20 mg/kg). Mice were maintained on a soy- and alfalfa-free diet (5K96) during the study and were monitored for blood glucose changes every week. When compared to the vehicle control, exposure to 2-mg/kg GEN produced significant decreases ranging from 55 to 79% in the total incidences of diabetes (blood glucose ? 250 mg/dl) and severe diabetes (blood glucose ? 400 mg/dl) starting at week 14 of the study. However, during the later stages of the study (i.e., after week 23), the 2-mg/kg dose had no effect on disease incidence. In animals treated with 6-mg/kg and 20-mg/kg GEN, significant decreases in the total incidence of diabetes were observed starting at week 16, while the incidence of severe diabetes was significantly decreased with the changes being observed initially at weeks 18 and 17 for the 6-mg/kg and 20-mg/kg GEN treatment groups, respectively. Several lines of evidence, including histopathological analysis, suggested that GEN protected the pancreas from autoimmune destruction. However, this protective effect of GEN was absent when female NOD mice were maintained on NTP-2000 rodent diet, which contained 5% soybean meal and 7.5% alfalfa meal (the total concentrations of phytoestrogens ranged between 95 and 134 mg/kg). In summary, oral dosing of GEN reduced the incidence and increased the time to onset of T1D in female NOD mice but only when fed a soy- and alfalfa-free diet.
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Relative potency for altered humoral immunity induced by polybrominated and polychlorinated dioxins/furans in female B6C3F1/N mice.
Toxicol. Sci.
PUBLISHED: 04-08-2014
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The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment.
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Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model.
PLoS Biol.
PUBLISHED: 04-01-2014
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Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures.
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p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation.
Mol. Cell. Biol.
PUBLISHED: 03-31-2014
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Pituitary tumors develop in about one-quarter of the population, and most arise from the anterior lobe (AL). The pituitary gland is particularly sensitive to genetic alteration of genes involved in the cyclin-dependent kinase (CDK) inhibitor (CKI)-CDK-retinoblastoma protein (Rb) pathway. Mice heterozygous for the Rb mutation develop pituitary tumors, with about 20% arising from the AL. Perplexingly, none of the CKI-deficient mice reported thus far develop pituitary AL tumors. In this study, we show that deletion of p19(Ink4d) (p19), a CKI gene, in mice results in spontaneous development of tumors in multiple organs and tissues. Specifically, more than one-half of the mutant mice developed pituitary hyperplasia or tumors predominantly in the AL. Tumor development is associated with increased cell proliferation and enhanced activity of Cdk4 and Cdk6 and phosphorylation of Rb protein. Though Cdk4 is indispensable for postnatal pituitary cell proliferation, it is not required for the hyperproliferative pituitary phenotype caused by p19 loss. Loss of p19 phosphorylates Rb in Cdk4(-/-) pituitary AL cells and mouse embryonic fibroblasts (MEFs) and rescues their proliferation defects, at least partially, through the activation of Cdk6. These results provide the first genetic evidence that p19 is a tumor suppressor and the major CKI gene that controls pituitary AL cell proliferation.
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Mesenchymal stem cells differentially modulate effector CD8+ T cell subsets and exacerbate experimental autoimmune encephalomyelitis.
Stem Cells
PUBLISHED: 03-19-2014
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Mesenchymal stem cells (MSC) have emerged as a promising candidate for inflammatory suppression and disease amelioration, especially of neuro-inflammatory diseases such as multiple sclerosis (MS). Auto-reactive CD4+ and CD8+ T cells acquire pathogenic IFN?-producing- (Type I) and IL-17A-producing- (Type 17) effector phenotypes in MS and its animal model experimental autoimmune encephalomyelitis (EAE). Although MSC have been extensively demonstrated to suppress pathogenic effector CD4+ T cells and CD4+ T cell-mediated EAE, surprisingly few studies have addressed their modulation of effector CD8+ T cells represented in MS or their impact on CD8+ T cell-mediated EAE. We find that MSC differentially modulate CD8+ T cell development depending on effector T cell subtype. MSC drive activated low-IFN? producers toward an enhanced high-IFN? Tc1-like phenotype but strongly inhibit the production of IL-17A and Tc17 polarization in vitro. These observations are underscored by differential MSC modulation of T cell activation, proliferation, and signature transcription factor up-regulation. In addition, effector CD8+ T cells co-cultured with MSC exhibited increased production of IL-2, a molecule known to enhance IFN?, yet suppress IL-17A, production. Based on these in vitro effects on CD8+ T cells, we next evaluated their impact on the severity of EAE. To better evaluate CD8+ T cells, we immunized mice with MOG37-50 , which is a CD8-targeted epitope. Our results revealed a worsening of disease, consistent with their in vitro stimulation of Tc1 cells. These findings highlight the emerging duality of MSC in immune modulation and provide implications for their future use in immune-related diseases.
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Content Analysis of CMS Healthcare Innovation Awards from a Physiatric Perspective.
PM R
PUBLISHED: 03-14-2014
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On June 15, 2012, Centers for Medicare and Medicaid Services (CMS) announced the 107 recipients of the Healthcare Innovation Awards (HCIA). The 107 awardees received a total of $874, 074, 900 in funding, with a projected 3-year savings of $1, 863, 119, 104. Using a word frequency calculator, a content analysis was performed on the document announcing the projects receiving funding in the 2012 HCIA program. Results were tabulated and categorized to look for prevailing themes and trends. The words generated by the word frequency calculator were grouped into common roots and tabulated to better understand how CMS was rewarding value. Some of the most common words were 'manage, community, coordinate, team, system' and 'integrate.' Additionally, the job positions that the projects propose to create were tabulated and grouped into categories. Physicians, including physiatrists, were not often mentioned, while nursing and non-clinical positions were frequently listed. This content analysis showed that the concepts emphasized in the HCIA projects parallel fundamental physiatric principles. The findings may help physiatrists understand how reform is unfolding, prepare for the evolving healthcare landscape and recognize future opportunities.
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Sol-gel solution-deposited InGaZnO thin film transistors.
ACS Appl Mater Interfaces
PUBLISHED: 03-14-2014
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Thin film transistors (TFTs) fabricated by solution processing of sol-gel oxide semiconductor precursors in the group In-Ga-Zn are described. The TFT mobility varies over a wide range depending on the precursor materials, the composition, and the processing variables, with the highest mobility being about 30 cm(2)/(V s) for IZO and 20 cm(2)/(V s) for IGZO. The positive dark bias stress effect decreases markedly as the mobility increases and the high mobility devices are quite stable. The negative bias illumination stress effect is also weaker in the higher mobility TFTs, and some different characteristic properties are observed. The TFT mobility, threshold voltage, and bias stress properties are discussed in terms of the formation of self-compensated donor and acceptor states, based on the chemistry and thermodynamics of the sol-gel process.
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Performance-based empathy mediates the influence of working memory on social competence in schizophrenia.
Schizophr Bull
PUBLISHED: 03-05-2014
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Empathic deficits have been linked to poor functioning in schizophrenia, but this work is mostly limited to self-report data. This study examined whether performance-based empathy measures account for incremental variance in social competence and social attainment above and beyond self-reported empathy, neurocognition, and clinical symptoms. Given the importance of working memory in theoretical models of empathy and in the prediction of functioning in schizophrenia, we also examined whether empathy mediates the relationship between working memory and functioning. Sixty outpatients and 45 healthy controls were compared on performance-based measures of 3 key components of empathic responding, including facial affect perception, emotional empathy (affective responsiveness), and cognitive empathy (emotional perspective-taking). Participants also completed measures of self-reported empathy, neurocognition, clinical symptoms, and social competence and attainment. Patients demonstrated lower accuracy than controls across the 3 performance-based empathy measures. Among patients, these measures showed minimal relations to self-reported empathy but significantly correlated with working memory and other neurocognitive functions as well as symptom levels. Furthermore, cognitive empathy explained significant incremental variance in social competence (?R (2) = .07, P < .05) and was found to mediate the relation between working memory and social competence. Performance-based measures of empathy were sensitive to functionally relevant disturbances in schizophrenia. Working memory deficits appear to have an important effect on these disruptions in empathy. Empathy is emerging as a promising new area for social cognitive research and for novel recovery-oriented treatment development.
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Alterations in Brain Activation During Cognitive Empathy Are Related to Social Functioning in Schizophrenia.
Schizophr Bull
PUBLISHED: 03-04-2014
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Impaired cognitive empathy (ie, understanding the emotional experiences of others) is associated with poor social functioning in schizophrenia. However, it is unclear whether the neural activity underlying cognitive empathy relates to social functioning. This study examined the neural activation supporting cognitive empathy performance and whether empathy-related activation during correctly performed trials was associated with self-reported cognitive empathy and measures of social functioning. Thirty schizophrenia outpatients and 24 controls completed a cognitive empathy paradigm during functional magnetic resonance imaging. Neural activity corresponding to correct judgments about the expected emotional expression in a social interaction was compared in schizophrenia subjects relative to control subjects. Participants also completed a self-report measure of empathy and 2 social functioning measures (social competence and social attainment). Schizophrenia subjects demonstrated significantly lower accuracy in task performance and were characterized by hypoactivation in empathy-related frontal, temporal, and parietal regions as well as hyperactivation in occipital regions compared with control subjects during accurate cognitive empathy trials. A cluster with peak activation in the supplementary motor area (SMA) extending to the anterior midcingulate cortex (aMCC) correlated with social competence and social attainment in schizophrenia subjects but not controls. These results suggest that neural correlates of cognitive empathy may be promising targets for interventions aiming to improve social functioning and that brain activation in the SMA/aMCC region could be used as a biomarker for monitoring treatment response.
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Empathy, depressive symptoms, and social functioning among individuals with schizophrenia.
Psychiatry Res
PUBLISHED: 02-13-2014
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Empathy deficits have been associated with schizophrenia and depression. We compared whether individuals with schizophrenia with and without co-occurring depressive symptoms differed on self-reported and performance-based measures of empathy and social functioning. We also examined the relationships among depressive symptoms, empathy, clinical symptoms, and social functioning. Twenty-eight individuals with schizophrenia and depressive symptoms, 32 individuals with schizophrenia without depressive symptoms, and 44 control subjects were compared on assessments of depressive symptoms, empathy, global neurocognition, clinical symptoms, and social functioning. Both groups of individuals with schizophrenia scored higher than controls on the Interpersonal Reactivity Index personal distress subscale. Individuals with schizophrenia and co-occurring depressive symptoms scored significantly higher than individuals with schizophrenia without depressive symptoms on the personal distress subscale. Personal distress and depressive symptoms were significantly correlated among individuals with schizophrenia and co-occurring depressive symptoms, while both measures negatively correlated with social functioning. Emotional empathy was related to clinical symptoms in both groups of individuals with schizophrenia. Personal distress partially mediated the relationship between co-occurring depressive symptoms and social functioning. Personal distress may be an important implication for social functioning among individuals with schizophrenia and co-occurring depressive symptoms, and should be examined further as a potential treatment target.
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Whirling disease dynamics: an analysis of intervention strategies.
Prev. Vet. Med.
PUBLISHED: 01-21-2014
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Whirling disease (WD), a severe and widespread disease of salmonids, is caused by the myxosporean parasite Myxobolus cerebralis. It is further characterized by a unique two-host life cycle, utilizing the oligochaete Tubifex tubifex as an intermediate host. M. cerebralis is an invasive species that has been affecting populations in the United States including epidemics that killed in excess of 90% of populations in Colorado and Montana streams within the past 20 years. Currently, there is no known cure for WD, and the accepted method of control is removal of infected fish from the population. We have created a compartmental model of the WD system in order to assess more efficient means of control and management of the disease. Using data gathered from the literature, we used Bayesian model fitting to estimate model parameters and estimated that R0?1.51 (95% CI: 1.39, 1.72), a value which implies that WD can be controlled using available strategies. To this end, we posit several parameters that we expect to be most influential to WD propagation, namely: release of triactinomyxons by T. tubifex, release of spores by salmonids, and infectious particle loads in each respective host. Based on currently available control strategies, approaches targeting the infectious particles and the oligochaete host appear the most effective alternative strategies for management and control of WD.
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Accurate perception of negative emotions predicts functional capacity in schizophrenia.
Psychiatry Res
PUBLISHED: 01-20-2014
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Several studies suggest facial affect perception (FAP) deficits in schizophrenia are linked to poorer social functioning. However, whether reduced functioning is associated with inaccurate perception of specific emotional valence or a global FAP impairment remains unclear. The present study examined whether impairment in the perception of specific emotional valences (positive, negative) and neutrality were uniquely associated with social functioning, using a multimodal social functioning battery. A sample of 59 individuals with schizophrenia and 41 controls completed a computerized FAP task, and measures of functional capacity, social competence, and social attainment. Participants also underwent neuropsychological testing and symptom assessment. Regression analyses revealed that only accurately perceiving negative emotions explained significant variance (7.9%) in functional capacity after accounting for neurocognitive function and symptoms. Partial correlations indicated that accurately perceiving anger, in particular, was positively correlated with functional capacity. FAP for positive, negative, or neutral emotions were not related to social competence or social attainment. Our findings were consistent with prior literature suggesting negative emotions are related to functional capacity in schizophrenia. Furthermore, the observed relationship between perceiving anger and performance of everyday living skills is novel and warrants further exploration.
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Evidence based management for paediatric burn: New approaches and improved scar outcomes.
Burns
PUBLISHED: 01-19-2014
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Little evidence has been produced on the best practice for managing paediatric burns. We set out to develop a formal approach based on the finding that hypertrophic scarring is related to healing-time, with durations under 21 days associated with improved scar outcome. Incorporating new advances in burn care, we compared outcomes under the new approach to a cohort treated previously. Our study was a retrospective cross-sectional case note study, with demographic, treatment and outcome information collected. The management and outcome of each case was assessed and compared against another paediatric burns cohort from 2006. 181 burns presenting across a six month period were analysed (2010 cohort) and compared to 337 children from a previous cohort from 2006. Comparison of patients between cohorts showed an overall shift towards shorter healing-times in the 2010 cohort. A lower overall rate of hypertrophic scarring was seen in the 2010 cohort, and for corresponding healing-times after injury, hypertrophic scarring rates were halved in comparison to the 2006 cohort. We demonstrate that the use of a structured approach for paediatric burns has improved outcomes with regards to healing-time and hypertrophic scarring rate. This approach allows maximisation of healing potential and implements aggressive prophylactic measures.
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Integrated RAS signaling defined by parallel NMR detection of effectors and regulators.
Nat. Chem. Biol.
PUBLISHED: 01-19-2014
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The RAS GTPase directs cell proliferation and survival by selectively relaying signals amid a dynamic network of regulatory enzymes and protein interactions. Oncogenic mutation of RAS alters cell growth by deleteriously controlling output to RAS-binding effectors. Mechanisms underlying multieffector interactions for both wild-type and oncogenic RAS are poorly understood owing to challenges in quantifying outputs to multiple pathways in parallel. Using highly selective NMR probes for wild-type and oncogenic (G12V) RAS, we develop a systematic approach that quantitatively measures RAS output in composite mixtures of GEF, GAP and effector RAS-binding domains (RBDs). We derive effector signaling hierarchies and establish how oscillating concentrations generate effector 'switching'. The G12V mutation highly perturbs this system, specifically altering interactions with RAL GTPase-specific GEFs and RAF kinases. We further reveal that RAS-RBD complexes show extensive feedback to full-length regulatory proteins. Our approach quantifies output from signaling hubs, here providing an integrated view of the RAS network.
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Elacytarabine in relapsed/refractory acute myeloid leukaemia: an evaluation of clinical efficacy, pharmacokinetics, cardiac safety and effects on lipid profile.
Leuk. Res.
PUBLISHED: 01-18-2014
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Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Effects of elacytarabine on QT interval, serum lipid profile and clinical activity were investigated in 43 relapsed/refractory AML patients. Mean maximum increase in corrected QT interval of 24( ± 29)ms occurred 48 h after elacytarabine infusion without associated arrhythmias or clinical symptoms. A non-clinically significant, elacytarabine exposure-dependent increase in cholesterol was caused by a cholesterol rich lipoprotein depleted of apolipoprotein B formed by infused phospholipids complexing cholesterol. Elacytarabine is clinically active in relapsed/refractory AML: overall response rate (CR + CRi) was 44% (16/36 with 7 non-evaluable patients) and adverse events were manageable. Clinical Trials.gov Identifier: NCT01258816.
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From immunotoxicity to nanotherapy: the effects of nanomaterials on the immune system.
Toxicol. Sci.
PUBLISHED: 01-15-2014
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The potential for human exposure to the diverse and ever-changing world of nanoscale materials has raised concerns about their influence on health and disease. The novel physical and chemical properties of these materials, which are associated with their small size, complicate toxicological evaluations. Further, these properties may make engineered nanomaterials (ENMs) a prime target for interaction with the immune system following uptake by phagocytes. Undesired effects on antigen-presenting cells and other phagocytic cells are of concern due to the high likelihood of ENM uptake by these cells. In addition, ENM interactions with lymphocytes and other cell types can contribute to a varied spectrum of possible effects, including inflammation, hypersensitivity, and immunomodulation. Furthermore, the mast cell (a type of immune cell traditionally associated with allergy) appears to contribute to certain inflammatory and toxic effects associated with some ENMs. Although incidental exposure may be undesirable, nanomedicines engineered for various clinical applications provide opportunities to develop therapies that may or may not intentionally target the immune system. The interaction between ENMs and the immune system and the resulting pharmacokinetic and phenotypic responses are critical factors that dictate the balance between toxicity and clinical efficacy of nanotherapeutics.
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Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice.
Food Chem. Toxicol.
PUBLISHED: 01-06-2014
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Interstitial cystitis (IC) is a chronic disorder characterized by bladder discomfort and urinary urgency in the absence of identifiable infection. Despite the expanding use in IC treatment and other chronic conditions, the effects of Elmiron® treatment on immune system remain unknown. Therefore, female B6C3F1/N mice were orally administered Elmiron® daily for 28-days at doses of 63, 125, 250, 500 or 1000mg/kg to evaluate its immunomodulatory effects. Mice treated with Elmiron® had a significant increase in absolute numbers of splenic macrophages (63, 500 and 1000mg/kg) and natural killer (NK) cells (250 and 1000mg/kg). Elmiron® treatment did not affect the humoral immune response or T cell proliferative response. However, innate immune responses such as phagocytosis by liver macrophages (1000mg/kg) and NK cell activity were enhanced (500 and 1000mg/kg). Further analysis using a disease resistance model showed that Elmiron®-treated mice demonstrated significantly increased anti-tumor activity against B16F10 melanoma cells at the 500 and 1000mg/kg doses. Collectively, we conclude that Elmiron® administration stimulates the immune system, increasing numbers of specific cell populations and enhancing macrophage phagocytosis and NK cell activity in female B6C3F1/N mice. This augmentation may have largely contributed to the reduced number of B16F10 melanoma tumors.
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Trifluoroibuprofen inhibits ?-methylacyl coenzyme A racemase (AMACR/P504S), reduces cancer cell proliferation and inhibits in vivo tumor growth in aggressive prostate cancer models.
Anticancer Agents Med Chem
PUBLISHED: 01-02-2014
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?-Methylacyl-CoA racemase (AMACR) participates in the oxidation of branched chain fatty acids and is highly expressed in prostate cancer (PCa). The aims of this study were to verify if the AMACR inhibitor trifluoroibuprofen (TFIP) had anticancer effects and to determine the best route for in vivo administration.
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The scientific impact of nations: journal placement and citation performance.
PLoS ONE
PUBLISHED: 01-01-2014
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International collaboration is becoming increasingly important for the advancement of science. To gain a more precise understanding of how factors such as international collaboration influence publication success, we divide publication success into two categories: journal placement and citation performance. Analyzing all papers published between 1996 and 2012 in eight disciplines, we find that those with more countries in their affiliations performed better in both categories. Furthermore, specific countries vary in their effects both individually and in combination. Finally, we look at the relationship between national output (in papers published) and input (in citations received) over the 17 years, expanding upon prior depictions by also plotting an expected proportion of citations based on Journal Placement. Discrepancies between this expectation and the realized proportion of citations illuminate trends in performance, such as the decline of the Global North in response to rapidly developing countries, especially China. Yet, most countries' show little to no discrepancy, meaning that, in most cases, citation proportion can be predicted by Journal Placement alone. This reveals an extreme asymmetry between the opinions of a few reviewers and the degree to which paper acceptance and citation rates influence career advancement.
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Exserohilum rostratum: Characterization of a Cross-Kingdom Pathogen of Plants and Humans.
PLoS ONE
PUBLISHED: 01-01-2014
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Pathogen host shifts represent a major source of new infectious diseases. There are several examples of cross-genus host jumps that have caused catastrophic epidemics in animal and plant species worldwide. Cross-kingdom jumps are rare, and are often associated with nosocomial infections. Here we provide an example of human-mediated cross-kingdom jumping of Exserohilum rostratum isolated from a patient who had received a corticosteroid injection and died of fungal meningitis in a Florida hospital in 2012. The clinical isolate of E. rostratum was compared with two plant pathogenic isolates of E. rostratum and an isolate of the closely related genus Bipolaris in terms of morphology, phylogeny, and pathogenicity on one C3 grass, Gulf annual rye grass (Lolium multiflorum), and two C4 grasses, Japanese stilt grass (Microstegium vimineum) and bahia grass (Paspalum notatum). Colony growth and color, as well as conidia shape and size were the same for the clinical and plant isolates of E. rostratum, while these characteristics differed slightly for the Bipolaris sp. isolate. The plant pathogenic and clinical isolates of E. rostratum were indistinguishable based on morphology and ITS and 28S rDNA sequence analysis. The clinical isolate was as pathogenic to all grass species tested as the plant pathogenic strains that were originally isolated from plant hosts. The clinical isolate induced more severe symptoms on stilt grass than on rye grass, while this was the reverse for the plant isolates of E. rostratum. The phylogenetic similarity between the clinical and plant-associated E. rostratum isolates and the ability of the clinical isolate to infect plants suggests that a plant pathogenic strain of E. rostratum contaminated the corticosteroid injection fluid and was able to cause systemic disease in the affected patient. This is the first proof that a clinical isolate of E. rostratum is also an effective plant pathogen.
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Multigene molecular phylogeny and biogeographic diversification of the earth tongue fungi in the genera Cudonia and Spathularia (Rhytismatales, Ascomycota).
PLoS ONE
PUBLISHED: 01-01-2014
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The family Cudoniaceae (Rhytismatales, Ascomycota) was erected to accommodate the "earth tongue fungi" in the genera Cudonia and Spathularia. There have been no recent taxonomic studies of these genera, and the evolutionary relationships within and among these fungi are largely unknown. Here we explore the molecular phylogenetic relationships within Cudonia and Spathularia using maximum likelihood and Bayesian inference analyses based on 111 collections from across the Northern Hemisphere. Phylogenies based on the combined data from ITS, nrLSU, rpb2 and tef-1? sequences support the monophyly of three main clades, the /flavida, /velutipes, and /cudonia clades. The genus Cudonia and the family Cudoniaceae are supported as monophyletic groups, while the genus Spathularia is not monophyletic. Although Cudoniaceae is monophyletic, our analyses agree with previous studies that this family is nested within the Rhytismataceae. Our phylogenetic analyses circumscribes 32 species-level clades, including the putative recognition of 23 undescribed phylogenetic species. Our molecular phylogeny also revealed an unexpectedly high species diversity of Cudonia and Spathularia in eastern Asia, with 16 (out of 21) species-level clades of Cudonia and 8 (out of 11) species-level clades of Spathularia. We estimate that the divergence time of the Cudoniaceae was in the Paleogene approximately 28 Million years ago (Mya) and that the ancestral area for this group of fungi was in Eastern Asia based on the current data. We hypothesize that the large-scale geological and climatic events in Oligocene (e.g. the global cooling and the uplift of the Tibetan plateau) may have triggered evolutionary radiations in this group of fungi in East Asia. This work provides a foundation for future studies on the phylogeny, diversity, and evolution of Cudonia and Spathularia and highlights the need for more molecular studies on collections from Europe and North America.
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Targeting and assembly of components of the TOC protein import complex at the chloroplast outer envelope membrane.
Front Plant Sci
PUBLISHED: 01-01-2014
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The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a ?-barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.
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Molecular characterization and expression analysis of chloroplast protein import components in tomato (Solanum lycopersicum).
PLoS ONE
PUBLISHED: 01-01-2014
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The translocon at the outer envelope membrane of chloroplasts (Toc) mediates the recognition and initial import into the organelle of thousands of nucleus-encoded proteins. These proteins are translated in the cytosol as precursor proteins with cleavable amino-terminal targeting sequences called transit peptides. The majority of the known Toc components that mediate chloroplast protein import were originally identified in pea, and more recently have been studied most extensively in Arabidopsis. With the completion of the tomato genome sequencing project, it is now possible to identify putative homologues of the chloroplast import components in tomato. In the work reported here, the Toc GTPase cDNAs from tomato were identified, cloned and analyzed. The analysis revealed that there are four Toc159 homologues (slToc159-1, -2, -3 and -4) and two Toc34 homologues (slToc34-1 and -2) in tomato, and it was shown that tomato Toc159 and Toc34 homologues share high sequence similarity with the comparable import apparatus components from Arabidopsis and pea. Thus, tomato is a valid model for further study of this system. The expression level of Toc complex components was also investigated in different tissues during tomato development. The two tomato Toc34 homologues are expressed at higher levels in non-photosynthetic tissues, whereas, the expression of two tomato Toc159 homologues, slToc159-1 and slToc159-4, were higher in photosynthetic tissues, and the expression patterns of slToc159-2 was not significantly different in photosynthetic and non-photosynthetic tissues, and slToc159-3 expression was limited to a few select tissues.
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A split-ubiquitin yeast two-hybrid screen to examine the substrate specificity of atToc159 and atToc132, two Arabidopsis chloroplast preprotein import receptors.
PLoS ONE
PUBLISHED: 01-01-2014
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Post-translational import of nucleus-encoded chloroplast pre-proteins is critical for chloroplast biogenesis, and the Toc159 family of proteins serve as receptors for the process. Toc159 shares with other members of the family (e.g. Toc132), homologous GTPase (G-) and Membrane (M-) domains, but a highly dissimilar N-terminal acidic (A-) domain. Although there is good evidence that atToc159 and atToc132 from Arabidopsis mediate the initial sorting step, preferentially recognizing photosynthetic and non-photosynthetic preproteins, respectively, relatively few chloroplast preproteins have been assigned as substrates for particular members of the Toc159 family, which has limited the proof for the hypothesis. The current study expands the number of known preprotein substrates for members of the Arabidopsis Toc159 receptor family using a split-ubiquitin membrane-based yeast two-hybrid system using the atToc159 G-domain (Toc159G), atToc132 G-domain (Toc132G) and atToc132 A- plus G-domains (Toc132AG) as baits. cDNA library screening with all three baits followed by pairwise interaction assays involving the 81 chloroplast preproteins identified show that although G-domains of the Toc159 family are sufficient for preprotein recognition, they alone do not confer specificity for preprotein subclasses. The presence of the A-domain fused to atToc132G (Toc132AG) not only positively influences its specificity for non-photosynthetic preproteins, but also negatively regulates the ability of this receptor to interact with a subset of photosynthetic preproteins. Our study not only substantiates the fact that atToc132 can serve as a receptor by directly binding to chloroplast preproteins but also proposes the existence of subsets of preproteins with different but overlapping affinities for more than one member of the Toc159 receptor family.
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Cannabis-Related Working Memory Deficits and Associated Subcortical Morphological Differences in Healthy Individuals and Schizophrenia Subjects.
Schizophr Bull
PUBLISHED: 12-15-2013
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Cannabis use is associated with working memory (WM) impairments; however, the relationship between cannabis use and WM neural circuitry is unclear. We examined whether a cannabis use disorder (CUD) was associated with differences in brain morphology between control subjects with and without a CUD and between schizophrenia subjects with and without a CUD, and whether these differences related to WM and CUD history. Subjects group-matched on demographics included 44 healthy controls, 10 subjects with a CUD history, 28 schizophrenia subjects with no history of substance use disorders, and 15 schizophrenia subjects with a CUD history. Large-deformation high-dimensional brain mapping with magnetic resonance imaging was used to obtain surface-based representations of the striatum, globus pallidus, and thalamus, compared across groups, and correlated with WM and CUD history. Surface maps were generated to visualize morphological differences. There were significant cannabis-related parametric decreases in WM across groups. Similar cannabis-related shape differences were observed in the striatum, globus pallidus, and thalamus in controls and schizophrenia subjects. Cannabis-related striatal and thalamic shape differences correlated with poorer WM and younger age of CUD onset in both groups. Schizophrenia subjects demonstrated cannabis-related neuroanatomical differences that were consistent and exaggerated compared with cannabis-related differences found in controls. The cross-sectional results suggest that both CUD groups were characterized by WM deficits and subcortical neuroanatomical differences. Future longitudinal studies could help determine whether cannabis use contributes to these observed shape differences or whether they are biomarkers of a vulnerability to the effects of cannabis that predate its misuse.
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Characterization of the T-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) in the Göttingen minipig.
J Immunotoxicol
PUBLISHED: 11-12-2013
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Abstract Recently, there has been a renewed interest in the use of the minipig as an alternative to dogs and non-human primates for conducting toxicological assessments in non-rodent species. Since the T-dependent antibody response (TDAR) is one of the most widely-accepted assays used in the assessment of immunocompetence, the present study was undertaken to characterize the primary and secondary TDAR to keyhole limpet hemocyanin (KLH) in the Göttingen Minipig®. Following primary immunization with either 2 or 10?mg KLH, anti-swine IgM and IgG ELISAs were optimized and individual animal responses were evaluated over time. Immunization with 10?mg KLH on Day 0 promoted primary IgM responses that peaked 6-9 days after antigen administration, while primary IgG levels peaked on Day 13 or 14. Secondary IgG antibody levels (following secondary injection with 2?mg KLH on Day 14) plateaued on Days 20-22. Anti-KLH antibody levels were decreased in minipigs treated with cyclophosphamide (CPS), a known immunosuppressant, at doses ranging from 12.5-50?mg/kg/day, while antibody levels in animals treated with 2.5?mg CPS/kg/day were similar to levels in saline-treated swine. These results demonstrate that the Göttingen Minipig® can be a useful alternative non-rodent species to the dog and the non-human primate for evaluating the TDAR to KLH in regulatory assessments of immunotoxicity.
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Expression, Folding, and Proton Transport Activity of Human Uncoupling Protein-1 (UCP1) in Lipid Membranes: EVIDENCE FOR ASSOCIATED FUNCTIONAL FORMS.
J. Biol. Chem.
PUBLISHED: 11-06-2013
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Uncoupling protein-1 (UCP1) is abundantly expressed in the mitochondrial inner membrane of brown adipose tissues and has an important role in heat generation, mediated by its proton transport function. The structure and function of UCP1 are not fully understood, partially due to the difficulty in obtaining native-like folded proteins in vitro. In this study, using the auto-induction method, we have successfully expressed UCP1 in Escherichia coli membranes in high yield. Overexpressed UCP1 in bacterial membranes was extracted using mild detergents and reconstituted into phospholipid bilayers for biochemical studies. UCP1 was folded in octyl glucoside, as indicated by its high helical content and binding to ATP, a known UCP1 proton transport inhibitor. Reconstituted UCP1 in phospholipid vesicles also exhibited highly helical structures and proton transport that is activated by fatty acids and inhibited by purine nucleotides. Self-associated functional forms of UCP1 in lipid membranes were observed for the first time. The self-assembly of UCP1 into tetramers was unambiguously characterized by circular dichroism and fluorescence spectroscopy, analytical ultracentrifugation, and semi-native gel electrophoresis. In addition, the mitochondrial lipid cardiolipin stabilized the structure of associated UCP1 and enhanced the proton transport activity of the protein. The existence of the functional oligomeric states of UCP1 in the lipid membranes has important implications for understanding the structure and proton transport mechanism of this protein in brown adipose tissues as well as structure-function relationships of other mammalian UCPs in other tissues.
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Route-dependent systemic and local immune effects following exposure to solutions prepared from titanium dioxide nanoparticles.
J Immunotoxicol
PUBLISHED: 10-17-2013
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Abstract Nanoparticle titanium dioxide (nano-TiO2) is a white pigment widely used in foods, sunscreens, and other cosmetic products. However, it remains unclear whether exposure to nano-TiO2 results in immunosuppressive effects or induces a contact hypersensitivity response. To address these data gaps, studies were conducted with the hypothesis that nano-TiO2 exposure could alter immune responses. After 28 days of oral gavage, nano-TiO2 (1.25-250?mg/kg in 0.5% methylcellulose) produced no significant effects on innate, humoral, or cell-mediated immune functions in female B6C3F1 mice. Furthermore, there were no effects on the weights of selected organs (spleen, thymus, liver, lung, and kidneys with adrenals). Following dermal exposure on the ears for 3 days, nano-TiO2 (2.5-10% w/v in 4:1 acetone:olive oil) did not affect auricular lymph node cell proliferation, although an irritancy response was observed following treatment with 5% and 10% nano-TiO2. Dermal sensitization (2.5-10%) on the back and subsequent challenge (10%) on the right ear with nano-TiO2 produced no significant effects on percentage ear swelling in the Mouse Ear Swelling Test (MEST). However, when nano-TiO2 was injected subcutaneously along the mid-line on top of the head at 125-250?mg/kg (in 0.5% methylcellulose), significant increases in auricular lymph node cell proliferation resulted. These results demonstrate that immune effects of nano-TiO2 exposure are route-of-exposure dependent, and they suggest that irritancy and/or potential hypersensitivity responses may occur following parenteral exposure or dermal administration of nano-TiO2 to compromised skin.
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ProxiMAX randomization: a new technology for non-degenerate saturation mutagenesis of contiguous codons.
Biochem. Soc. Trans.
PUBLISHED: 09-25-2013
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Back in 2003, we published MAX randomization, a process of non-degenerate saturation mutagenesis using exactly 20 codons (one for each amino acid) or else any required subset of those 20 codons. MAX randomization saturates codons located in isolated positions within a protein, as might be required in enzyme engineering, or else on one face of an ?-helix, as in zinc-finger engineering. Since that time, we have been asked for an equivalent process that can saturate multiple contiguous codons in a non-degenerate manner. We have now developed ProxiMAX randomization, which does just that: generating DNA cassettes for saturation mutagenesis without degeneracy or bias. Offering an alternative to trinucleotide phosphoramidite chemistry, ProxiMAX randomization uses nothing more sophisticated than unmodified oligonucleotides and standard molecular biology reagents. Thus it requires no specialized chemistry, reagents or equipment, and simply relies on a process of saturation cycling comprising ligation, amplification and digestion for each cycle. The process can encode both unbiased representation of selected amino acids or else encode them in predefined ratios. Each saturated position can be defined independently of the others. We demonstrate accurate saturation of up to 11 contiguous codons. As such, ProxiMAX randomization is particularly relevant to antibody engineering.
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Jet fuel kerosene is not immunosuppressive in mice or rats following inhalation for 28 days.
J. Toxicol. Environ. Health Part A
PUBLISHED: 09-14-2013
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Previous reports indicated that inhalation of JP-8 aviation turbine fuel is immunosuppressive. However, in some of those studies, the exposure concentrations were underestimated, and percent of test article as vapor or aerosol was not determined. Furthermore, it is unknown whether the observed effects are attributable to the base hydrocarbon fuel (jet fuel kerosene) or to the various fuel additives in jet fuels. The present studies were conducted, in compliance with Good Laboratory Practice (GLP) regulations, to evaluate the effects of jet fuel kerosene on the immune system, in conjunction with an accurate, quantitative characterization of the aerosol and vapor exposure concentrations. Two female rodent species (B6C3F1 mice and Crl:CD rats) were exposed by nose-only inhalation to jet fuel kerosene at targeted concentrations of 0, 500, 1000, or 2000 mg/m(3) for 6 h daily for 28 d. Humoral, cell-mediated, and innate immune functions were subsequently evaluated. No marked effects were observed in either species on body weights, spleen or thymus weights, the T-dependent antibody-forming cell response (plaque assay), or the delayed-type hypersensitivity (DTH) response. With a few exceptions, spleen cell numbers and phenotypes were also unaffected. Natural killer (NK) cell activity in mice was unaffected, while the NK assessment in rats was not usable due to an unusually low response in all groups. These studies demonstrate that inhalation of jet fuel kerosene for 28 d at levels up to 2000 mg/m(3) did not adversely affect the functional immune responses of female mice and rats.
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Qualitative analysis of factors leading to clinical incidents.
Int J Health Care Qual Assur
PUBLISHED: 09-06-2013
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The purpose of this paper is to evaluate the common themes leading or contributing to clinical incidents in a UK teaching hospital.
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Sentiment analysis on smoking in social networks.
Stud Health Technol Inform
PUBLISHED: 08-08-2013
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Online social networks play a vital role in daily life to share the opinions or behaviors on different topics. The data of social networks can be used to understand health-related behaviors. In this work, we used Twitter status updates to survey of smoking behaviors among the users. We introduce approach to classify the sentiment of smoke-related tweets into positive and negative tweets. The classifier is based on the Support Vector Machines (SVMs) and can achieve high accuracy up to 86%.
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Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-30-2013
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Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human AML cells with a range of genetic lesions. The numbers of normal mouse HSCs were preserved whereas normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs, findings consistent with a differentiation block at the HSC-progenitor transition, rather than displacement. Once removed from the leukemic environment, residual normal hematopoietic cells differentiated normally and outcompeted steady-state hematopoietic cells, indicating that this effect is reversible. We confirmed the clinical significance of this by ex vivo analysis of normal hematopoietic subpopulations from BM of 16 patients with AML. This analysis demonstrated that the numbers of normal CD34(+)CD38(-) stem-progenitor cells were similar in the BM of AML patients and controls, whereas normal CD34(+)CD38(+) progenitors were reduced. Residual normal CD34(+) cells from patients with AML were enriched in long-term culture, initiating cells and repopulating cells compared with controls. In conclusion the data do not support the idea that BM failure in AML is due to HSC depletion. Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition.
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Fertility and sexual function in long-term survivors of haematological malignancy: using patient-reported outcome measures to assess a neglected area of need in the late effects clinic.
Br. J. Haematol.
PUBLISHED: 07-22-2013
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Problems of sexual function and fertility in long-term survivors (?5 years) of haematological malignancy are often neglected in clinic. Our centre carried out a questionnaire study in this population addressing patient-perceived fertility and sexual function. 718 patients responded (56% of those invited; 39% Hodgkin, 45% non-Hodgkin lymphoma, 16% acute leukaemia). Respondent women were more likely to remain childless than a normal control population. Self-reported infertility was more likely in men than women [odds ratio (OR) 1·77, P = 0·001]. Myeloablative therapy increased the likelihood of childlessness (OR 2·48, P = 0·004). Few attended fertility support services (12%). 24% of men banked sperm and 29% of these used the sample, of which 46% resulted in successful pregnancy. Fertility clinic attendance and sperm storage was more likely post-1990 (OR 4·05, P < 0·001; OR 5·05, P < 0·001 respectively). Reporting a negative impact of cancer on sexual function was more common in women than men (OR 2·20, P < 0·001), and increased with current age and age at diagnosis (by 3-4% per year, P ? 0·001) but decreased with longer follow-up (by 2%/year, P = 0·005). Patients on anti-depressants and those reporting cancer-related body change/appearance concerns more frequently reported a negative impact (P < 0·04 and P < 0·03 respectively). These self-reported outcomes confirm literature findings, suggest improvement over time, but highlight a need for involvement of support services.
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A Comparative CEST NMR Study of Slow Conformational Dynamics of Small GTPases Complexed with GTP and GTP Analogues.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 06-24-2013
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Conformational Exchange: Small GTPases, such as Ras and Rheb, exchange between major and minor conformers when bound to GTP, with different functional properties for each state. Two-dimensional (15) N CEST NMR spectroscopy is used to quantify the exchange parameters for both Ras and Rheb complexed with physiological GTP and the analogues GTP?S and GppNHp.
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Characteristics and requirements of basal autophagy in HEK 293 cells.
Autophagy
PUBLISHED: 06-20-2013
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Basal autophagy-here defined as macroautophagic activity during cellular growth in normal medium containing amino acids and serum-appears to be highly active in many cell types and in animal tissues. Here we characterized this pathway in mammalian HEK 293 cells. First, we examined, side by side, three compounds that are widely used to reveal basal autophagy by blocking maturation of autophagosomes: bafilomycin A 1 (BafA1), chloroquine and vinblastine. Only BafA1 appeared to be without complicating side effects. Chloroquine partially inhibited mechanistic target of rapamycin (MTOR) activity, which would induce autophagy induction as well as block autophagosome maturation. Vinblastine caused the distribution of early omegasome components into punctate phagophore assembly sites, and therefore it would also induce autophagy, complicating interpretation. Basal autophagy was significantly sensitive to inhibition by wortmannin, and therefore required formation of phosphatidylinositol 3-phosphate (PtdIns3P), but it was twice as resistant to wortmannin as starvation-induced autophagy. We also determined that basal autophagy was significantly suppressed by MTOR activation brought about by overexpression of RHEB or activated RAGs. Finally we investigated the spatial relationship of nascent autophagosomes to the endoplasmic reticulum (ER) or to mitochondria by live imaging experiments under conditions that reveal basal autophagy (with BafA1 treatment), or upon MTOR inactivation (which would result in autophagy induction). Side-by-side comparison showed that under both basal and induced autophagy, 100% of autophagosomes first appeared in close proximity to ER strands. In parallel measurements, 40% were in close proximity to mitochondria under both conditions. We concluded that in HEK 293 cells, basal autophagy is mechanistically similar to that induced by MTOR inactivation in all aspects examined.
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Predation effects on mean time to extinction under demographic stochasticity.
J. Theor. Biol.
PUBLISHED: 06-03-2013
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Methods for predicting the probability and timing of a species extinction are typically based on single species population dynamics. Assessments of extinction risk often lack effects of interspecific interactions. We study a birth and death process in which the death rate includes an effect of predation. Predation is included via a general nonlinear expression for the functional response of predation to prey density. We investigate the effects of the foraging parameters (e.g. attack rate and handling time) on the mean time to extinction. Mean time to extinction varies by orders of magnitude when we alter the foraging parameters, even when we exclude the effects of these parameters on the equilibrium population size. Conclusions are robust to assumptions about initial conditions and variable predator abundance. These findings clearly show that accounting for the nature of interspecific interactions is likely to be critically important when estimating extinction risk.
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Phylogenetic analysis of the genus Modicella reveals an independent evolutionary origin of sporocarp-forming fungi in the Mortierellales.
Fungal Genet. Biol.
PUBLISHED: 05-24-2013
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Most studies of tissue differentiation and development have focused on animals and plants but many fungi form multi-cellular aggregations of spore-bearing tissue known as fruiting bodies or sporocarps. The ability to form sporocarps has arisen independently in several different evolutionary lineages of fungi. Evolutionary relationships of most sporocarp-forming fungi are well known, but the enigmatic zygomycete genus Modicella contains two species of sporocarp-forming fungi for which the phylogenetic affinities have not been explored based on molecular data. Species of Modicella have an uncertain trophic mode and have alternatively been considered members of the order Endogonales (which contains documented species of sporocarp-forming fungi) or the order Mortierellales (which contains no previously documented species of sporocarp-forming fungi). In this study we perform phylogenetic analyses based on ribosomal DNA of Modicella malleola from the Northern Hemisphere and Modicella reniformis from the Southern Hemisphere to determine the evolutionary affinities of the genus Modicella. Our analyses indicate that Modicella is a monophyletic genus of sporocarp-forming fungi nested within the Mortierellales, a group of microfungi with no previously documented sporocarp-forming species. Because Modicella is distantly related to all other known sporocarp-forming fungi, we infer that this lineage has independently evolved the ability form sporocarps. We conclude that the genus Modicella should be a high priority for comparative genomics studies to further elucidate the process of sporocarp formation in fungi.
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Towards a unified paradigm for sequence-based identification of fungi.
Mol. Ecol.
PUBLISHED: 05-10-2013
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The nuclear ribosomal internal transcribed spacer (ITS) region is the formal fungal barcode and in most cases the marker of choice for the exploration of fungal diversity in environmental samples. Two problems are particularly acute in the pursuit of satisfactory taxonomic assignment of newly generated ITS sequences: (i) the lack of an inclusive, reliable public reference data set and (ii) the lack of means to refer to fungal species, for which no Latin name is available in a standardized stable way. Here, we report on progress in these regards through further development of the UNITE database (http://unite.ut.ee) for molecular identification of fungi. All fungal species represented by at least two ITS sequences in the international nucleotide sequence databases are now given a unique, stable name of the accession number type (e.g. Hymenoscyphus pseudoalbidus|GU586904|SH133781.05FU), and their taxonomic and ecological annotations were corrected as far as possible through a distributed, third-party annotation effort. We introduce the term species hypothesis (SH) for the taxa discovered in clustering on different similarity thresholds (97-99%). An automatically or manually designated sequence is chosen to represent each such SH. These reference sequences are released (http://unite.ut.ee/repository.php) for use by the scientific community in, for example, local sequence similarity searches and in the QIIME pipeline. The system and the data will be updated automatically as the number of public fungal ITS sequences grows. We invite everybody in the position to improve the annotation or metadata associated with their particular fungal lineages of expertise to do so through the new Web-based sequence management system in UNITE.
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Inhibition of Human ?-Methylacyl CoA Racemase (AMACR): a Target for Prostate Cancer.
ChemMedChem
PUBLISHED: 04-23-2013
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The enzyme ?-methylacyl CoA racemase (AMACR) is involved in the metabolism of branched-chain fatty acids and has been identified as a promising therapeutic target for prostate cancer. By using the recently available human AMACR from HEK293 kidney cell cultures, we tested a series of new rationally designed inhibitors to determine the structural requirements in the acyl component. An N-methylthiocarbamate (Ki =98?nM), designed to mimic the proposed enzyme-bound enolate, was found to be the most potent AMACR inhibitor reported to date.
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A comparison of the analytical performance of five commercially available assays for neutrophil gelatinase-associated lipocalin using urine.
Ann. Clin. Biochem.
PUBLISHED: 04-23-2013
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Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for acute kidney injury that is beginning to be used in clinical practice in addition to research studies. The current study describes an independent validation and comparison of five commercially available NGAL assays, focusing on urine samples. This is an essential step in the translation of this marker to clinical use in terms of allowing valid inter-study comparison and generation of robust results.
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Effects of structural connectivity on fine scale population genetic structure of muskrat, Ondatra zibethicus.
Ecol Evol
PUBLISHED: 04-16-2013
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In heterogeneous landscapes, physical barriers and loss of structural connectivity have been shown to reduce gene flow and therefore lead to population structuring. In this study, we assessed the influence of landscape features on population genetic structure and gene flow of a semiaquatic species, the muskrat. A total of 97 muskrats were sampled from three watersheds near Sudbury, Ontario, Canada. We estimated population genetic structure using 11 microsatellite loci and identified a single genetic cluster and no genetic differences were found among the watersheds as a result of high levels of gene flow. At finer scales, we assessed the correlation between individual pairwise genetic distances and Euclidean distance as well as different models of least cost path (LCP). We used a range of cost values for the landscape types in order to build our LCP models. We found a positive relationship between genetic distance and least cost distance when we considered roads as corridors for movements. Open landscapes and urban areas seemed to restrict but not prevent gene flow within the study area. Our study underlines the high-dispersal ability of generalist species in their use of landscape and highlights how landscape features often considered barriers to animal movements are corridors for other species.
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BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes.
Mol. Cell. Biol.
PUBLISHED: 04-15-2013
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RNA polymerase II (Pol II) and the pausing complex, NELF and DSIF, are detected near the transcription start site (TSS) of many active and silent genes. Active transcription starts when the pause release factor P-TEFb is recruited to initiate productive elongation. However, the mechanism of P-TEFb recruitment and regulation of NELF/DSIF during transcription is not fully understood. We investigated this question in interferon (IFN)-stimulated transcription, focusing on BRD4, a BET family protein that interacts with P-TEFb. Besides P-TEFb, BRD4 binds to acetylated histones through the bromodomain. We found that BRD4 and P-TEFb, although not present prior to IFN treatment, were robustly recruited to IFN-stimulated genes (ISGs) after stimulation. Likewise, NELF and DSIF prior to stimulation were hardly detectable on ISGs, which were strongly recruited after IFN treatment. A shRNA-based knockdown assay of NELF revealed that it negatively regulates the passage of Pol II and DSIF across the ISGs during elongation, reducing total ISG transcript output. Analyses with a BRD4 small-molecule inhibitor showed that IFN-induced recruitment of P-TEFb and NELF/DSIF was under the control of BRD4. We suggest a model where BRD4 coordinates both positive and negative regulation of ISG elongation.
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Gender and Racial Differences in Focal and Global Acetabular Version.
J Arthroplasty
PUBLISHED: 04-11-2013
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The purpose of this study was to compare the acetabular version between male and female pelvises. We hypothesized that female acetabula would demonstrate more retroversion because Pincer-type femoroacetabular impingement (FAI) is associated with acetabular retroversion, which is more commonly observed in females. 120 bony pelvic specimens were randomly collected. The version was measured at three different axial sections of each acetabulum: cranial, central, and caudal. Males demonstrated significantly less anteversion than females in every section. The global version (the average of all three measurements) was also significantly different between males and females (16°±7° and 19°±8° respectively, P<0.001). Of the 240 examined acetabuli, 21 demonstrated cranial retroversion (16 males & 5 females). The data showed no significant difference (P=0.353) between global version of African Americans (18°±9°) and Caucasians (17°±7°). The results of this study suggest that symptomatic FAI in the female population likely reflects a complex interplay of femoral and acetabular dysmorphology and cannot be explained by differences in acetabular version alone.
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Selenium segregation in femtosecond-laser hyperdoped silicon revealed by electron tomography.
Microsc. Microanal.
PUBLISHED: 04-10-2013
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Doping of silicon with chalcogens (S, Se, Te) by femtosecond laser irradiation to concentrations well above the solubility limit leads to near-unity optical absorptance in the visible and infrared (IR) range and is a promising route toward silicon-based IR optoelectronics. However, open questions remain about the nature of the IR absorptance and in particular about the impact of the dopant distribution and possible role of dopant diffusion. Here we use electron tomography using a high-angle annular dark-field (HAADF) detector in a scanning transmission electron microscope (STEM) to extract information about the three-dimensional distribution of selenium dopants in silicon and correlate these findings with the optical properties of selenium-doped silicon. We quantify the tomography results to extract information about the size distribution and density of selenium precipitates. Our results show correlation between nanoscale distribution of dopants and the observed sub-band gap optical absorptance and demonstrate the feasibility of HAADF-STEM tomography for the investigation of dopant distribution in highly-doped semiconductors.
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Urinary retention for the neurologist.
Pract Neurol
PUBLISHED: 03-29-2013
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Urinary retention is a common problem, most often due to an anatomical lesion in the urinary tract causing obstruction, such as a urethral stricture or prostate enlargement. However, a subset of patients have no structural urological lesion, and so require neurological evaluation. We present a patient with acute urinary retention who was found to have chronic meningitis, and review the neurological causes for urinary retention.
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Quantifying magnetic exchange in doubly-bridged Cu-X(2)-Cu (X = F, Cl, Br) chains enabled by solid state synthesis of CuF(2)(pyrazine).
Chem. Commun. (Camb.)
PUBLISHED: 03-26-2013
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Solid state techniques involving pressure and temperature have been used to synthesize the fluoride member of the CuX(2)(pyrazine) (X = F, Cl, Br) family of coordination polymers that cannot be crystallized by solution methods. CuF(2)(pyrazine) exhibits unique trans doubly-bridged Cu-F(2)-Cu chains that provide an opportunity to quantify magnetic superexchange in an isostructural Cu-X(2)-Cu series.
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Interface engineering of graphene for universal applications as both anode and cathode in organic photovoltaics.
Sci Rep
PUBLISHED: 03-13-2013
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The high transparency of graphene, together with its good electrical conductivity and mechanical robustness, enable its use as transparent electrodes in optoelectronic devices such as solar cells. While initial demonstrations of graphene-based organic photovoltaics (OPV) have been promising, realization of scalable technologies remains challenging due to their performance and, critically, poor device reproducibility and yield. In this work, we demonstrate by engineering the interface between graphene and organic layers, device performance and yield become close to devices using indium tin oxide. Our study confirms that the key issue leading to the poor performance or irreproducibility in graphene-based OPV originates from the graphene interface, and can be addressed by a simple interface modification method introduced in this work. We also show similar approach allows graphene to be used as cathode in inverted OPV geometry, thereby demonstrating the universal application of graphene as transparent conductors for both the anode and cathode.
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Relationship of scapular neck length to scapular notching after reverse total shoulder arthroplasty by use of plain radiographs.
J Shoulder Elbow Surg
PUBLISHED: 03-11-2013
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Scapular notching in reverse shoulder arthroplasty appears to be a multifactorial problem related to both implant and patient factors. There are well-established guidelines for implant position. Recent cadaveric studies have illustrated anatomic factors that need further consideration. Scapular neck length and inferior glenoid tubercle morphology may be major factors predicting scapular notching.
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Long-term survival with low toxicity after allogeneic transplantation for acute myeloid leukaemia and myelodysplasia using non-myeloablative conditioning without T cell depletion.
Br. J. Haematol.
PUBLISHED: 03-08-2013
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The toxicity burden and long-term anti-leukaemic effect of non-myeloablative (NMA) allogeneic haematopoietic stem-cell transplantation (AHSCT) for acute myeloid leukaemia (AML) and myelodysplasia (MDS) remains undefined. We report the outcome of 56 patients with AML/MDS transplanted from human leucocyte antigen-matched donors using NMA conditioning without T-cell depletion. With a median follow-up of 5 years, treatment-related mortality was 9% and current disease-free survival (CDFS) was 45% (overall) and 55% (patients transplanted in remission). Development of graft-versus-host disease upon withdrawal of post-transplant immunosuppression was associated with less relapse and better CDFS. These data confirm that NMA AHSCT without T-cell depletion is safe and can result in sustained remissions of AML/MDS.
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Towards an expanded definition of value.
Spine J
PUBLISHED: 03-07-2013
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Much of the change being sought in the United States health-care system is predicated on improving value. Value is most simply defined as quality divided by cost, and physicians increasingly rely on the quality-adjusted life year as the numerical measure to justify their services. However, there are many other definitions of value being advocated by various stakeholders in the health-care reform effort. Incentive programs and pilot studies implemented by private and public payers are steering much of the current change. Expanding our understanding of how value is defined by health-care economists and policy makers can help spine providers navigate the evolving health-care landscape.
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The influence of sensitisation to pollens and moulds on seasonal variations in asthma attacks.
Eur. Respir. J.
PUBLISHED: 03-07-2013
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No large study has described the seasonal variation in asthma attacks in population-based asthmatics in whom sensitisation to allergen has been measured. 2,637 young adults with asthma living in 15 countries reported the months in which they usually had attacks of asthma and had skin-prick tests performed. Differences in seasonal patterns by sensitisation status were assessed using generalised estimating equations. Most young adults with asthma reported periods of the year when their asthma attacks were more common (range: 47% in Sweden to 86% in Spain). Seasonal variation in asthma was not modified by sensitisation to house dust mite or cat allergens. Asthmatics sensitised to grass, birch and Alternaria allergens had different seasonal patterns to those not sensitised to each allergen, with some geographical variation. In southern Europe, those sensitised to grass allergens were more likely to report attacks occurred in spring or summer than in winter (OR March/April 2.60, 95% CI 1.70-3.97; OR May/June 4.43, 95% CI 2.34-8.39) and smaller later peaks were observed in northern Europe (OR May/June 1.25, 95% CI 0.60-2.64; OR July/August 1.66, 95% CI 0.89-3.10). Asthmatics reporting hay fever but who were not sensitised to grass showed no seasonal variations. Seasonal variations in asthma attacks in young adults are common and are different depending on sensitisation to outdoor, but not indoor, allergens.
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NMR-based functional profiling of RASopathies and oncogenic RAS mutations.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-04-2013
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Defects in the RAS small G protein or its associated network of regulatory proteins that disrupt GTPase cycling are a major cause of cancer and developmental RASopathy disorders. Lack of robust functional assays has been a major hurdle in RAS pathway-targeted drug development. We used NMR to obtain detailed mechanistic data on RAS cycling defects conferred by oncogenic mutations, or full-length RASopathy-derived regulatory proteins. By monitoring the conformation of wild-type and oncogenic RAS in real-time, we show that opposing properties integrate with regulators to hyperactivate oncogenic RAS mutants. Q61L and G13D exhibited rapid nucleotide exchange and an unexpected susceptibility to GAP-mediated hydrolysis, in direct contrast with G12V, indicating different approaches must be taken to inhibit these oncoproteins. An NMR methodology was established to directly monitor RAS cycling by intact, multidomain proteins encoded by RASopathy genes in mammalian cell extracts. By measuring GAP activity from tumor cells, we demonstrate how loss of neurofibromatosis type 1 (NF1) increases RAS-GTP levels in NF1-derived cells. We further applied this methodology to profile Noonan Syndrome (NS)-derived SOS1 mutants. Combining NMR with cell-based assays allowed us to differentiate defects in catalysis, allosteric regulation, and membrane targeting of individual mutants, while revealing a membrane-dependent compensatory effect that attenuates dramatic increases in RAS activation shown by Y337C, L550P, and I252T. Our NMR method presents a precise and robust measure of RAS activity, providing mechanistic insights that facilitate discovery of therapeutics targeted against the RAS signaling network.
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Laparoscopic simulation for all: two affordable, upgradable, and easy-to-build laparoscopic trainers.
J Surg Educ
PUBLISHED: 02-23-2013
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Laparoscopic surgery has established itself as the approach of choice for a multitude of operations in general, urological, and gynecological surgery. A number of factors make performing laparoscopic surgery technically demanding, and as such it is crucial that surgical trainees hone their skills safely on trainers before operating on patients. These can be highly expensive. Here, we describe a novel and upgradable approach to constructing an affordable laparoscopic trainer.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.