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Find video protocols related to scientific articles indexed in Pubmed.
Combined inhibition of PI3K? and PI3K? reduces fat mass by enhancing ?-MSH-dependent sympathetic drive.
Sci Signal
PUBLISHED: 11-20-2014
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Obesity is defined as an abnormal increase in white adipose tissue and has become a major medical burden worldwide. Signals from the brain control not only appetite but also energy expenditure, both of which contribute to body weight. We showed that genetic or pharmacological inhibition of two phosphatidylinositol 3-kinases (PI3K? and PI3K?) in mice reduced fat mass by promoting increased energy expenditure. This effect was accompanied by stimulation of lipolysis and the acquisition of the energy-burning characteristics of brown adipocytes by white adipocytes, a process referred to as "browning." The browning of the white adipocytes involved increased norepinephrine release from the sympathetic nervous system. We found that PI3K? and PI3K? together promoted a negative feedback loop downstream of the melanocortin 4 receptor in the central nervous system, which controls appetite and energy expenditure in the periphery. Analysis of mice with drug-induced sympathetic denervation suggested that these kinases controlled the sympathetic drive in the brain. Administration of inhibitors of both PI3K? and PI3K? to mice by intracerebroventricular delivery induced a 10% reduction in fat mass as quickly as 10 days. These results suggest that combined inhibition of PI3K? and PI3K? might represent a promising treatment for obesity.
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Eccentric training as a new approach for rotator cuff tendinopathy: Review and perspectives.
World J Orthop
PUBLISHED: 11-18-2014
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Excessive mechanical loading is considered the major cause of rotator cuff tendinopathy. Although tendon problems are very common, they are not always easy to treat. Eccentric training has been proposed as an effective conservative treatment for the Achilles and patellar tendinopathies, but less evidence exists about its effectiveness for the rotator cuff tendinopathy. The mechanotransduction process associated with an adequate dose of mechanical load might explain the beneficial results of applying the eccentric training to the tendons. An adequate load increases healing and an inadequate (over or underuse) load can deteriorate the tendon structure. Different eccentric training protocols have been used in the few studies conducted for people with rotator cuff tendinopathy. Further, the effects of the eccentric training for rotator cuff tendinopathy were only evaluated on pain, function and strength. Future studies should assess the effects of the eccentric training also on shoulder kinematics and muscle activity. Individualization of the exercise prescription, comprehension and motivation of the patients, and the establishment of specific goals, practice and efforts should all be considered when prescribing the eccentric training. In conclusion, eccentric training should be used aiming improvement of the tendon degeneration, but more evidence is necessary to establish the adequate dose-response and to determine long-term follow-up effects.
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Geographic variation in thermal physiological performance of the intertidal crab Petrolisthes violaceus along a latitudinal gradient.
J. Exp. Biol.
PUBLISHED: 11-15-2014
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Environmental temperature has profound implications on the biological performance and biogeographical distribution of ectothermic species. Variation of this abiotic factor across geographic gradients is expected to produces physiological differentiation and local adaptation of natural populations depending on their thermal tolerances and physiological sensitivities. Here, we have studied geographic variation in whole-organism thermal physiology of seven populations of the porcelain crab Petrolisthes violaceus across a latitudinal gradient of 3000 km, characterized by a cline of thermal conditions. Our study found that populations of P. violaceus exhibit a lack of differences in the limits of their thermal performance curves and a negative correlation of their optimal temperatures with latitude. Additionally, our findings showed that high latitude populations of P. violaceus exhibited broader thermal tolerances, which is consistent with the Climatic Variability Hypothesis. Interestingly, under a future scenario of warming oceans, the thermal safety margins of P. violaceus indicate that lower latitude populations can physiologically tolerate the ocean warming scenarios projected by the IPCC for the end of the twenty-first century.
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Bartonella clarridgeiae bacteremia detected in an asymptomatic blood donor.
J. Clin. Microbiol.
PUBLISHED: 11-14-2014
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Human exposure to Bartonella clarridgeiae has only been reported on the basis of antibody detection. We report for the first time an asymptomatic human blood donor infected with B. clarridgeiae, as documented by enrichment blood culture, PCR and DNA sequencing.
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TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA.
EMBO J.
PUBLISHED: 11-14-2014
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Caenorhabditis elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA-binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: (1) preferentially alters the accumulation of RNAs with inherent double-stranded structure (dsRNA); (2) increases the accumulation of nuclear dsRNA foci; (3) enhances the frequency of adenosine-to-inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA, indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function.
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Finding the 'who' in whooping cough: vaccinated siblings are important pertussis sources in infants 6 months of age and under.
Commun Dis Intell Q Rep
PUBLISHED: 11-14-2014
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To describe the epidemiology of pertussis, and to identify changes in the source of pertussis in infants 6 months of age and under, during the 2008-2012 epidemic in south metropolitan Perth.
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The vaginal microbiota and susceptibility to HIV.
AIDS
PUBLISHED: 11-13-2014
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There is some evidence that the risk of HIV infection per heterosexual act is higher in low-income countries than in high-income countries. We hypothesize that variations in per sex-act transmission probability of HIV may in part be attributed to differences in the composition and function of the vaginal microbiota between different populations. This paper presents data that are in support of this hypothesis. Experimental and clinical studies have provided evidence that the normal vaginal microbiota plays a protective role against acquisition of HIV and other sexually transmitted infections. Epidemiological studies have convincingly shown that disturbances of the vaginal microbiome, namely intermediate flora and bacterial vaginosis, increase the risk of acquisition of HIV infection. A review of the literature found large differences in prevalence of bacterial vaginosis between different populations, with the highest prevalence rates found in black populations. Possible explanations for these differences are presented including data suggesting that there are ethnic differences in the composition of the normal vaginal microbiota. Lastly, interventions are discussed to restore and maintain a healthy vaginal environment.
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Petunia x hybrida floral scent production is negatively affected by high-temperature growth conditions.
Plant Cell Environ.
PUBLISHED: 11-05-2014
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Increasing temperatures due to changing global climate are interfering with plant-pollinator mutualism, an interaction facilitated mainly by floral color and scent. Gas chromatography-mass spectroscopy analyses revealed that increasing ambient temperature leads to a decrease in phenylpropanoid-based floral scent production in two Petunia x hybrida varieties, P720 and Blue Spark, acclimated at 22/16°C or 28/22°C (day/night). This decrease could be attributed to down-regulation of scent-related structural genes' expression from both phenylpropanoid and shikimate pathways, and up-regulation of a negative regulator of scent production, EMISSION OF BENZENOIDS V (EOBV). To test whether the negative effect of increased temperature on scent production can be reduced in flowers with enhanced metabolic flow in the phenylpropanoid pathway, we analyzed floral volatile production by transgenic 'Blue Spark' plants over-expressing CaMV 35S-driven Arabidopsis thaliana PRODUCTION OF ANTHOCYANIN PIGMENTS 1 (PAP1) under elevated vs. standard temperature conditions. Flowers of 35S:PAP1-transgenic plants produced the same or even higher levels of volatiles when exposed to a long-term high-temperature regime. This phenotype was also evident when analyzing relevant gene expression, as inferred from sequencing the transcriptome of 35S:PAP1-transgenic flowers under the two temperature regimes. Thus, up-regulation of transcription might negate the adverse effects of temperature on scent production.
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Golgi N-glycan branching N-acetylglucosaminyltransferases I, V and VI promote nutrient uptake and metabolism.
Glycobiology
PUBLISHED: 10-01-2014
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Nutrient transporters are critical gate-keepers of extracellular metabolite entry into the cell. As integral membrane proteins, most transporters are N-glycosylated, and the N-glycans are remodeled in the Golgi apparatus. The Golgi branching enzymes N-acetylglucosaminyltransferases I, II, IV, V and avian VI (encoded by Mgat1, Mgat2, Mgat4a/b/c Mgat5 and Mgat6), each catalyze the addition of acetylglucosamine (GlcNAc) in N-glycans. Here, we asked whether N-glycan branching promotes nutrient transport and metabolism in immortal human HeLa carcinoma and non-malignant HEK293 embryonic kidney cells. Mgat6 is absent in mammals, but ectopic expression can be expected to add an additional ?1,4-linked branch to N-glycans, and may provide evidence for functional redundancy of the N-glycan branches. Tetracycline (tet)-induced overexpression of Mgat1, Mgat5 and Mgat6 resulted in increased enzyme activity and increased N-glycan branching concordant with the known specificities of these enzymes. Tet-induced Mgat1, Mgat5 and Mgat6 combined with stimulation of hexosamine biosynthesis pathway (HBP) to UDP-GlcNAc, increased cellular metabolite levels, lactate and oxidative metabolism in an additive manner. We then tested the hypothesis that N-glycan branching alone might promote nutrient uptake when glucose (Glc) and glutamine are limiting. In low glutamine and Glc medium, tet-induced Mgat5 alone increased amino acids uptake, intracellular levels of glycolytic and TCA intermediates, as well as HEK293 cell growth. More specifically, tet-induced Mgat5 and HBP elevated the import rate of glutamine, although transport of other metabolites may be regulated in parallel. Our results suggest that N-glycan branching cooperates with HBP to regulate metabolite import in a cell autonomous manner, and can enhance cell growth in low-nutrient environments.
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Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance.
J. Antimicrob. Chemother.
PUBLISHED: 09-28-2014
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In ?10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo.
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Ultrasmall NHC-coated gold nanoparticles obtained through solvent free thermolysis of organometallic Au(i) complexes.
Dalton Trans
PUBLISHED: 09-24-2014
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Ultrasmall gold nanoparticles (Au UNPs) represent a unique class of nanomaterials making them very attractive for certain applications. Herein, we developed an organometallic approach to the synthesis of Au UNPs stabilized with the C18H37-NHC ligand by the solvent free thermolysis of [RMIM][Au(C6F5)2] () or [Au(C6F5)(RNHC)] () (with R = C18H37-), by controlling the reactivity of pentafluorophenyl ligands as deprotonating or reductive elimination agents; Au UNPs can be achieved by solvent free thermolysis. Pentafluorophenyl Au(i) complexes and are synthesized from the corresponding ionic and neutral precursors. The presence of long alkyl chain imidazolium or carbene species in the complexes makes them to behave as isotropic liquids at moderate temperatures. The use of multinuclear NMR allows the description of the mechanism of formation of the UNPs as well as the surface state of the UNPs.
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Investigation of genetic factors underlying typical orofacial clefts: mutational screening and copy number variation.
J. Hum. Genet.
PUBLISHED: 09-01-2014
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Typical orofacial clefts (OFCs) comprise cleft lip, cleft palate and cleft lip and palate. The complex etiology has been postulated to involve chromosome rearrangements, gene mutations and environmental factors. A group of genes including IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, MSX1 and FGF has been implicated in the etiology of OFCs. Recently, the role of the copy number variations (CNVs) has been studied in genetic defects and diseases. CNVs act by modifying gene expression, disrupting gene sequence or altering gene dosage. The aims of this study were to screen the above-mentioned genes and to investigate CNVs in patients with OFCs. The sample was composed of 23 unrelated individuals who were grouped according to phenotype (associated with other anomalies or isolated) and familial recurrence. New sequence variants in GLI2, MSX1 and FGF8 were detected in patients, but not in their parents, as well as in 200 control chromosomes, indicating that these were rare variants. CNV screening identified new genes that can influence OFC pathogenesis, particularly highlighting TCEB3 and KIF7, that could be further analyzed. The findings of the present study suggest that the mechanism underlying CNV associated with sequence variants may play a role in the etiology of OFC.Journal of Human Genetics advance online publication, 13 November 2014; doi:10.1038/jhg.2014.96.
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Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress.
Acta Neuropathol.
PUBLISHED: 08-31-2014
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The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the "c9RAN proteins" thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.
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Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398.
Int J Pharm
PUBLISHED: 08-28-2014
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The purpose of this work was to design and evaluate a vaginal film delivery system for UAMC01398, a novel non-nucleoside reverse transcriptase inhibitor currently under investigation for use as an anti-HIV microbicide. UAMC01398 (1mg) films consisting of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol 400 (PEG400) in different ratios were prepared by solvent evaporation. Based on its flexibility, softness and translucent appearance, the 30% PEG400 and 70% HPMC containing film was selected for further assessment. The vaginal film formulation was fast-dissolving (<10min in 1mL of vaginal fluid simulant), stable up to at least one month and safe toward epithelial cells and lactobacilli. Furthermore, formulating UAMC01398 into the film dosage form did not influence its antiviral activity. Powder X-ray diffraction revealed the amorphous nature of the UAMC01398 film, resulting in enhanced compound permeation across the epithelial HEC-1A cell layer, presumably owing to the induction of supersaturation. The in vivo vaginal tissue uptake of UAMC01398 in rabbits, as measured by systemic concentrations, was increased compared to the previously established non-solubilizing gel (significant difference) and sulfobutyl ether-?-cyclodextrin (5%) containing gel. To conclude, we identified a film formulation suitable for the vaginal delivery of UAMC01398.
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The vaginal microbiota: what have we learned after a decade of molecular characterization?
PLoS ONE
PUBLISHED: 08-22-2014
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We conducted a systematic review of the Medline database (U.S. National Library of Medicine, National Institutes of Health, Bethesda, MD, U.S.A) to determine if consistent molecular vaginal microbiota (VMB) composition patterns can be discerned after a decade of molecular testing, and to evaluate demographic, behavioral and clinical determinants of VMB compositions. Studies were eligible when published between 1 January 2008 and 15 November 2013, and if at least one molecular technique (sequencing, PCR, DNA fingerprinting, or DNA hybridization) was used to characterize the VMB. Sixty three eligible studies were identified. These studies have now conclusively shown that lactobacilli-dominated VMB are associated with a healthy vaginal micro-environment and that bacterial vaginosis (BV) is best described as a polybacterial dysbiosis. The extent of dysbiosis correlates well with Nugent score and vaginal pH but not with the other Amsel criteria. Lactobacillus crispatus is more beneficial than L. iners. Longitudinal studies have shown that a L. crispatus-dominated VMB is more likely to shift to a L. iners-dominated or mixed lactobacilli VMB than to full dysbiosis. Data on VMB determinants are scarce and inconsistent, but dysbiosis is consistently associated with HIV, human papillomavirus (HPV), and Trichomonas vaginalis infection. In contrast, vaginal colonization with Candida spp. is more common in women with a lactobacilli-dominated VMB than in women with dysbiosis. Cervicovaginal mucosal immune responses to molecular VMB compositions have not yet been properly characterized. Molecular techniques have now become more affordable, and we make a case for incorporating them into larger epidemiological studies to address knowledge gaps in etiology and pathogenesis of dysbiosis, associations of different dysbiotic states with clinical outcomes, and to evaluate interventions aimed at restoring and maintaining a lactobacilli-dominated VMB.
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Changes in protein expression of pacific oyster Crassostrea gigas exposed in situ to urban sewage.
Environ Sci Pollut Res Int
PUBLISHED: 08-15-2014
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The composition and concentration of substances in urban effluents are complex and difficult to measure. These contaminants elicit biological responses in the exposed organisms. Proteomic analysis is a powerful tool in environmental toxicology by evidencing alterations in protein expression due to exposure to contaminants and by providing a useful framework for the development of new potential biomarkers. The aim of this study was to determine changes in protein expression signatures (PES) in the digestive gland of oysters Crassostrea gigas transplanted to two farming areas (LIS and RIB) and to one area contaminated by sanitary sewage (BUC) after 14 days of exposure. This species is one of the most cultivated molluscs in the world. The identified proteins are related to the cytoskeleton (CKAP5 and ACT2), ubiquitination pathway conjugation (UBE3C), G protein-coupled receptor and signal transduction (SVEP1), and cell cycle/division (CCNB3). CKAP5 showed higher expression in oysters kept at BUC in comparison with those kept at the farming areas, while ACT2, UBE3C, SVEP1, and CCNB3 were suppressed. The results suggest that these changes might lead to DNA damage, apoptosis, and interference with the immune system in oyster C. gigas exposed to sewage and give initial information on PES of C. gigas exposed to sanitary sewage, which can subsequently be useful in the development of more sensitive tools for biomonitoring coastal areas, particularly those devoted mainly to oyster farming activities.
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Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS.
Neuron
PUBLISHED: 08-14-2014
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A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins." Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.
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Immunocytotoxicity, cytogenotoxicity and genotoxicity of cadmium-based quantum dots in the marine mussel Mytilus galloprovincialis.
Mar. Environ. Res.
PUBLISHED: 08-04-2014
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There is an increased use of Quantum Dot (QDs) in biological and biomedical applications, but little is known about their marine ecotoxicology. So, the aim of this study was to investigate the possible immunocytotoxic, cytogenotoxic and genotoxic effects of cadmium telluride QDs (CdTe QDs) on the marine mussel Mytilus galloprovincialis. Mussels were exposed to 10 ?g L(-1) of CdTe QDs or to soluble Cd [Cd(NO3)2] for 14 days and Cd accumulation, immunocytotoxicity [hemocyte density, cell viability, lysosomal membrane stability (LMS), differential cell counts (DCC)], cytogenotoxicity (micronucleus test and nuclear abnormalities assay) and genotoxicity (comet assay) were analyzed. Results show that in vivo exposure to QDs, Cd is accumulated in mussel soft tissues and hemolymph and induce immunotoxic effects mediated by a decrease in LMS, changes in DCC, as well as genotoxicity (DNA damage). However, QDs do not induce significant changes in hemocytes density, cell viability and cytogenetic parameters in opposition to Cd(2+). Soluble Cd is the most cytotoxic and cytogenotoxic form on Mytilus hemocytes due to a higher accumulation of Cd in tissues. Results indicate that immunotoxicity and genotoxicity of CdTe QDs and Cd(2+) are mediated by different modes of action and show that Mytilus hemocytes are important targets for in vivo QDs toxicity.
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Morphology of the reproductive tract and acquisition of sexual maturity in males of Potamotrygon magdalenae (Elasmobranchii: Potamotrygonidae).
J. Morphol.
PUBLISHED: 07-09-2014
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The purpose of this study was to describe the structure of the reproductive tract of males of Potamotrygon magdalenae before, during, and after they acquire sexual maturity, and to establish the first maturity scale for males within the family Potamotrygonidae. The male reproductive tract of P. magdalenae is composed of testes, efferent ducts, epididymides, deferent ducts, seminal vesicles, Leydig, alkaline, and clasper glands, and claspers, all of which are paired and functional. Four sexual maturity stages were established: immature, maturing, reproductively active, and resting. The degree of claspers calcification is also a good indicator of sexual maturity in this species. The testes are lobulated, each lobe contains numerous spermatocysts which are organized in zones and are displaced radially from germinal papillae to the spermatozoa zone where individual spermatozoa are conveyed to the efferent ducts. The epididymis can be regionalized in head, body, and tail; these regions are distinguished by external pigmentation and by the epithelium lining configuration. The tail of the epididymis is connected with the deferent duct and this, in turn, with the seminal vesicle. The spermatozoa are organized in spermatozeugmata which begin to form in the deferent duct; this latter organ is attached laterally at the Leydig gland that is composed by simple glandular units. Irregular and vesicular secretions can be found in the genital ducts. These secretions might be associated with the maturation of the spermatozoa and formation of spermatozeugmata. The male reproductive tract of P. magdalenae is similar to other elasmobranchs; however, two types of primary spermatogonia, an epididymis internally regionalized, and the presence and structure of spermatozeugmata are specific features not yet described in freshwater stingrays. Most of the year, the males were reproductively active, however, few resting adult males occurred during one of the months of the lowest waters. J. Morphol., 2014. © 2014 Wiley Periodicals, Inc.
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Impact of Domestication in the Production of the Class II Lanthipeptide Lichenicidin by Bacillus licheniformis I89.
Curr. Microbiol.
PUBLISHED: 07-01-2014
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Investigation on lantibiotics biosynthesis constitutes an emergent field, since these molecules have demonstrated a great potential to replace the so-called "traditional antibiotics". The adaptation of bacteria to laboratory conditions (domestication) is an unpredictable phenomenon, which sometimes is associated with the loss of important biotechnological properties. In this study, the domestication of Bacillus licheniformis was associated with the production of the lantibiotic lichenicidin, a two-peptide lantibiotic with activity against several Gram-positive bacteria.
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Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes.
Prostate
PUBLISHED: 06-20-2014
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LIGHT, a ligand for lymphotoxin-? receptor (LT?R) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LT?R signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LT?R has been previously shown to activate immune cells and result in tumor regression in a virally-induced tumor model, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration toward an anti-tumoral milieu, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors.
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Transcription mediated insulation and interference direct gene cluster expression switches.
Elife
PUBLISHED: 06-08-2014
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In yeast, many tandemly arranged genes show peak expression in different phases of the metabolic cycle (YMC) or in different carbon sources, indicative of regulation by a bi-modal switch, but it is not clear how these switches are controlled. Using native elongating transcript analysis (NET-seq), we show that transcription itself is a component of bi-modal switches, facilitating reciprocal expression in gene clusters. HMS2, encoding a growth-regulated transcription factor, switches between sense- or antisense-dominant states that also coordinate up- and down-regulation of transcription at neighbouring genes. Engineering HMS2 reveals alternative mono-, di- or tri-cistronic and antisense transcription units (TUs), using different promoter and terminator combinations, that underlie state-switching. Promoters or terminators are excluded from functional TUs by read-through transcriptional interference, while antisense TUs insulate downstream genes from interference. We propose that the balance of transcriptional insulation and interference at gene clusters facilitates gene expression switches during intracellular and extracellular environmental change.
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Hybrid 2D-0D MoS2 -PbS Quantum Dot Photodetectors.
Adv. Mater. Weinheim
PUBLISHED: 06-03-2014
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A hybrid phototransistor consisting of colloidal PbS quantum dots and few layers of MoS2 (?2 layers) is demonstrated. The hybrid benefits from tailored light absorption in the quantum dots throughout the visible/near infrared region, efficient charge carrier separation at the p-n interface, and fast carrier transport through the MoS2 channel. It shows responsivity of up to 10(6) A W(-1) and backgate dependent sensitivity.
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Predictors for multiple sclerosis relapses after switching from natalizumab to fingolimod.
Mult. Scler.
PUBLISHED: 05-19-2014
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Risks of natalizumab (NAT) therapy have to be weighed against disease recurrence after stopping NAT.
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Natalizumab use during the third trimester of pregnancy.
JAMA Neurol
PUBLISHED: 05-14-2014
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Natalizumab reduces multiple sclerosis relapses very effectively; however, severe disease activity may return once natalizumab treatment is withdrawn, as recommended during pregnancy. Sometimes restarting natalizumab treatment may be the best option for the mother, but the consequences for the infant are unknown. Except for a few single case reports, to our knowledge, comprehensive data about third-trimester natalizumab exposure are scant.
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Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.
Oncotarget
PUBLISHED: 05-10-2014
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The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
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MicroRNA-133 modulates the ?1-adrenergic receptor transduction cascade.
Circ. Res.
PUBLISHED: 05-07-2014
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The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate ?-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of ?-adrenergic receptors leads to impaired cardiac function, and ?-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability.
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Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy.
J. Clin. Invest.
PUBLISHED: 05-01-2014
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Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.
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Effects of silver nanoparticles exposure in the mussel Mytilus galloprovincialis.
Mar. Environ. Res.
PUBLISHED: 04-08-2014
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Silver nanoparticles (Ag NPs) have emerged as one of the most commonly used NPs in a wide range of industrial and commercial applications. This has caused increasing concern about their fate in the environment as well as uptake and potential toxicity towards aquatic organisms. Accordingly, mussels Mytilus galloprovincialis were exposed to 10 ?g L(-1) of Ag NPs and ionic silver (Ag(+)) for 15 days, and biomarkers of oxidative stress and metal accumulation were determined. Accumulation results show that both Ag NPs and Ag(+) accumulated in both gills and digestive glands. Antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) were activated by Ag NPs and Ag(+), showing different antioxidant patterns in both gills and digestive glands. Moreover, metallothionein was inducted in gills, directly related to Ag accumulation, while in the digestive glands only a small fraction of Ag seems to be associated with this protein. Lipid peroxidation was higher in gills exposed to Ag NPs, whereas in the digestive glands only Ag(+) induced lipid peroxidation. Ag NPs and Ag(+) cause oxidative stress with distinct modes of action and it's not clear if for Ag NPs the observed effects are attributed to free Ag(+) ions associated with the nanoparticle effect.
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Cerebrospinal Fluid JC Virus Antibody Index for Diagnosis of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy.
Ann. Neurol.
PUBLISHED: 03-16-2014
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Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy, is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging. Our objective was to assess the complementary value of a CSF JCV antibody index (AIJCV ) in the diagnosis of natalizumab-associated PML.
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Hypothalamo-pituitary-adrenal axis activity evolves differentially in untreated versus treated multiple sclerosis.
Psychoneuroendocrinology
PUBLISHED: 03-05-2014
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Heterogeneous hypothalamo-pituitary-adrenal (HPA) system dysregulation has been shown in multiple sclerosis (MS), and cross-sectional studies suggested increasing hyperactivity with longer, progressing disease. Longitudinal studies to confirm this hypothesis and to study the impact of disease modifying treatment (DMT) have not been performed.
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Serum Zn levels in dysphagic patients who underwent endoscopic gastrostomy for long term enteral nutrition.
Nutr Hosp
PUBLISHED: 02-18-2014
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Dysphagic patients who underwent endoscopic gastrostomy (PEG) usually present protein-energy malnutrition, but little is known about micronutrient malnutrition. The aim of the present study was the evaluation of serum zinc in patients who underwent endoscopic gastrostomy and its relationship with serum proteins, whole blood zinc, and the nature of underlying disorder.
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Proteomic response of mussels Mytilus galloprovincialis exposed to CuO NPs and Cu²?: an exploratory biomarker discovery.
Aquat. Toxicol.
PUBLISHED: 02-13-2014
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CuO NPs are one of the most used metal nanomaterials nowadays with several industrial and other commercial applications. Nevertheless, less is known about the mechanisms by which these NPs inflict toxicity in mussels and to what extent it differs from Cu(2+). The aim of this study was to investigate changes in protein expression profiles in mussels Mytilus galloprovincialis exposed for 15 days to CuO NPs and Cu(2+) (10 ?g L(-1)) using a proteomic approach. Results demonstrate that CuO NPs and Cu(2+) induced major changes in protein expression in mussels' showing several tissue and metal-dependent responses. CuO NPs showed a higher tendency to up-regulate proteins in the gills and down-regulate in the digestive gland, while Cu(2+) showed the opposite tendency. Distinctive sets of differentially expressed proteins were found, either common or specific to each Cu form and tissue, reflecting different mechanisms involved in their toxicity. Fifteen of the differentially expressed proteins from both tissues were identified by MALDI-TOF-TOF. Identified proteins indicate common response mechanisms induced by CuO NPs and Cu(2+), namely in cytoskeleton and cell structure (actin, ?-tubulin, paramyosin), stress response (heat shock cognate 71, putative C1q domain containing protein), transcription regulation (zinc-finger BED domain-containing protein 1, nuclear receptor subfamily 1G) and energy metabolism (ATP synthase F0 subunit 6). CuO NPs alone also had a marked effect on other biological processes, namely oxidative stress (GST), proteolysis (cathepsin L) and apoptosis (caspase 3/7-1). On the other hand, Cu(2+) affected a protein associated with adhesion and mobility, precollagen-D that is associated with the detoxification mechanism of Cu(2+). Protein identification clearly showed that the toxicity of CuO NPs is not solely due to Cu(2+) dissolution and can result in mitochondrial and nucleus stress-induced cell signalling cascades that can lead to apoptosis. While the absence of the mussel genome precluded the identification of other proteins relevant to clarify the effects of CuO NPs in mussels' tissues, proteomics analysis provided additional knowledge of their potential effects at the protein level that after confirmation and validation can be used as putative new biomarkers in nanotoxicology.
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Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis.
Neurogenetics
PUBLISHED: 02-11-2014
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Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2)?=?0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio ?=?1.15, P?=?3.48?×?10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.
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What carers and family said about music therapy on behaviours of older people with dementia in residential aged care.
Int J Older People Nurs
PUBLISHED: 01-21-2014
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This study sought to evaluate the effectiveness of group music therapy (MT) intervention on behaviours of older people with dementia.
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Remote trap passivation in colloidal quantum dot bulk nano-heterojunctions and its effect in solution-processed solar cells.
Adv. Mater. Weinheim
PUBLISHED: 01-20-2014
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More-efficient charge collection and suppressed trap recombination in colloidal quantum dot (CQD) solar cells is achieved by means of a bulk nano-heterojunction (BNH) structure, in which p-type and n-type materials are blended on the nanometer scale. The improved performance of the BNH devices, compared with that of bilayer devices, is displayed in higher photocurrents and higher open-circuit voltages (resulting from a trap passivation mechanism).
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Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients.
Brain Res.
PUBLISHED: 01-16-2014
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A significant number of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two diseases commonly seen in comorbidity, carry an expanded noncoding hexanucleotide repeat in the C9orf72 gene, a condition collectively referred to as c9FTD/ALS. Repeat expansions, also present in other neurodegenerative diseases, have been shown to alter epigenetic mechanisms and consequently lead to decreased gene expression, while also leading to toxic RNA gain-of-function. As expression of multiple C9orf72 transcript variants is known to be reduced in c9FTD/ALS cases, our group and others have sought to uncover the mechanisms causing this reduction. We recently demonstrated that histones H3 and H4 undergo trimethylation at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) in all pathogenic repeat carrier brain samples, confirming the role of altered histone methylation in disease. It was also reported that about 40% of c9ALS cases show hypermethylation of the CpG island located at the 5' end of the repeat expansion in blood, frontal cortex, and spinal cord. To determine whether the same CpG island is hypermethylated in the cerebella of cases in whom aberrant histone methylation has been identified, we bisulfite-modified the extracted DNA and PCR-amplified 26 CpG sites within the C9orf72 promoter region. Among the ten c9FTD/ALS (4 c9ALS, 6 c9FTD), nine FTD/ALS, and eight disease control samples evaluated, only one c9FTD sample was found to be hypermethylated within the C9orf72 promoter region. This study is the first to report cerebellar hypermethylation in c9FTD/ALS, and the first to identify a c9FTD patient with aberrant DNA methylation. Future studies will need to evaluate hypermethylation of the C9orf72 promoter in a larger cohort of c9FTD patients, and to assess whether DNA methylation variation across brain regions reflects disease phenotype.
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Mechanisms of toxicity in C9FTLD/ALS.
Acta Neuropathol.
PUBLISHED: 01-07-2014
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A hexanucleotide repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation causative of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Elucidating how this bidirectionally transcribed G4C2·C4G2 expanded repeat causes "C9FTLD/ALS" has since become an important goal of the field. Likely pathogenic mechanisms include toxicity induced by repeat-containing RNAs, and loss of C9orf72 function due to epigenetic changes resulting in decreased C9ORF72 mRNA expression. With regards to the former, sense and antisense transcripts of the expanded repeat aberrantly interact with various RNA-binding proteins and form discrete nuclear structures, termed RNA foci. These foci have the capacity to sequester select RNA-binding proteins, thereby impairing their function. (G4C2)exp and (C4G2)exp transcripts also succumb to an alternative fate: repeat-associated non-ATG (RAN) translation. This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the abnormal production of poly(GA), poly(GP), poly(GR), poly(PR) and poly(PA) peptides, collectively referred to as C9RAN proteins. C9RAN proteins form neuronal inclusions throughout the central nervous system of C9FTLD/ALS patients and may contribute to disease pathogenesis. This review aims to summarize the important findings from studies examining mechanisms of disease in C9FTLD/ALS, and will also highlight some of the many questions in need of further investigation.
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PTB Binds to the 3' Untranslated Region of the Human Astrovirus Type 8: A Possible Role in Viral Replication.
PLoS ONE
PUBLISHED: 01-01-2014
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The 3' untranslated region (3'UTR) of human astroviruses (HAstV) consists of two hairpin structures (helix I and II) joined by a linker harboring a conserved PTB/hnRNP1 binding site. The identification and characterization of cellular proteins that interact with the 3'UTR of HAstV-8 virus will help to uncover cellular requirements for viral functions. To this end, mobility shift assays and UV cross-linking were performed with uninfected and HAstV-8-infected cell extracts and HAstV-8 3'UTR probes. Two RNA-protein complexes (CI and CII) were recruited into the 3'UTR. Complex CII formation was compromised with cold homologous RNA, and seven proteins of 35, 40, 45, 50, 52, 57/60 and 75 kDa were cross-linked to the 3'UTR. Supermobility shift assays indicated that PTB/hnRNP1 is part of this complex, and 3'UTR-crosslinked PTB/hnRNP1 was immunoprecipitated from HAstV-8 infected cell-membrane extracts. Also, immunofluorescence analyses revealed that PTB/hnRNP1 is distributed in the nucleus and cytoplasm of uninfected cells, but it is mainly localized perinuclearly in the cytoplasm of HAstV-8 infected cells. Furthermore, the minimal 3'UTR sequences recognized by recombinant PTB are those conforming helix I, and an intact PTB/hnRNP1-binding site. Finally, small interfering RNA-mediated PTB/hnRNP1 silencing reduced synthesis viral genome and virus yield in CaCo2 cells, suggesting that PTB/hnRNP1 is required for HAstV replication. In conclusion, PTB/hnRNP1 binds to the 3'UTR HAstV-8 and is required or participates in viral replication.
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Regulator of G-Protein Signaling 18 Controls Both Platelet Generation and Function.
PLoS ONE
PUBLISHED: 01-01-2014
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RGS18 is a myeloerythroid lineage-specific regulator of G-protein signaling, highly expressed in megakaryocytes (MKs) and platelets. In the present study, we describe the first generation of a RGS18 knockout mouse model (RGS18-/-). Interesting phenotypic differences between RGS18-/- and wild-type (WT) mice were identified, and show that RGS18 plays a significant role in both platelet generation and function. RGS18 deficiency produced a gain of function phenotype in platelets. In resting platelets, the level of CD62P expression was increased in RGS18-/- mice. This increase correlated with a higher level of plasmatic serotonin concentration. RGS18-/- platelets displayed a higher sensitivity to activation in vitro. RGS18 deficiency markedly increased thrombus formation in vivo. In addition, RGS18-/- mice presented a mild thrombocytopenia, accompanied with a marked deficit in MK number in the bone marrow. Analysis of MK maturation in vitro and in vivo revealed a defective megakaryopoiesis in RGS18-/- mice, with a lower bone marrow content of only the most committed MK precursors. Finally, RGS18 deficiency was correlated to a defect of platelet recovery in vivo under acute conditions of thrombocytopenia. Thus, we highlight a role for RGS18 in platelet generation and function, and provide additional insights into the physiology of RGS18.
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Testosterone response to competition in males is unrelated to opponent familiarity or threat appraisal.
Front Psychol
PUBLISHED: 01-01-2014
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It has been proposed in the literature that the testosterone (T) response to competition in humans may be modulated by cognitive variables. In a previous experiment with a female sample we have reported that opponent familiarity and threat appraisal moderated the T response to competition in women. With this experiment we aim to investigate if these variables have the same impact on males T response to competition, extending the previous findings in our lab. Forty male participants (20 dyads) were recruited to engage in a same sex, face to face competition using the Number Tracking Test as a competitive task. Levels of T, cortisol (C) and dehydroepiandrosterone (DHEA) were measured before and 20 min after the competition. Results show that losers report higher levels of threat than winners and increased their T levels after the competition, however this T change was not predicted by opponent familiarity or threat appraisal. No variation was detected for C and DHEA levels. These findings suggest that there could be sex differences for the moderators/mediators of the T response to competition in humans.
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Uptake of Genital Mucosal Sampling in HVTN 097, a Phase 1b HIV Vaccine Trial in South Africa.
PLoS ONE
PUBLISHED: 01-01-2014
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Because sexual transmission of HIV occurs across mucosal membranes, understanding the immune responses of the genital mucosa to vaccines may contribute knowledge to finding an effective candidate HIV vaccine. We describe the uptake of rectal secretion, cervical secretion and seminal mucosal secretion sampling amongst volunteers in a Phase 1b HIV vaccine trial. Age at screening, gender, study site and the designation of the person conducting the informed consent procedure were collected for volunteers who screened for the HVTN 097 study. A total of 211 volunteers (54% female) were screened at three sites in South Africa: Soweto (n?=?70, 33%), Cape Town (n?=?68, 32%) and Klerksdorp (n?=?73, 35%). Overall uptake of optional mucosal sampling amongst trial volunteers was 71% (n?=?149). Compared to Cape Town, volunteers from Soweto and Klerksdorp were less likely to consent to sampling (Soweto OR 0.08 CI: 0.03-0.25 p<0.001 and Klerksdorp OR 0.13 CI: 0.04-0.41 p?=?0.001). In contrast, volunteers over 25 years of age were 2.39 times more likely to consent than younger volunteers (CI: 1.13-5.08, p?=?0.02). Further studies are required to better understand the cultural, demographic and sociobehavioral factors which influence willingness to participate in mucosal sampling in HIV prevention studies.
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A cultural side effect: learning to read interferes with identity processing of familiar objects.
Front Psychol
PUBLISHED: 01-01-2014
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Based on the neuronal recycling hypothesis (Dehaene and Cohen, 2007), we examined whether reading acquisition has a cost for the recognition of non-linguistic visual materials. More specifically, we checked whether the ability to discriminate between mirror images, which develops through literacy acquisition, interferes with object identity judgments, and whether interference strength varies as a function of the nature of the non-linguistic material. To these aims we presented illiterate, late literate (who learned to read at adult age), and early literate adults with an orientation-independent, identity-based same-different comparison task in which they had to respond "same" to both physically identical and mirrored or plane-rotated images of pictures of familiar objects (Experiment 1) or of geometric shapes (Experiment 2). Interference from irrelevant orientation variations was stronger with plane rotations than with mirror images, and stronger with geometric shapes than with objects. Illiterates were the only participants almost immune to mirror variations, but only for familiar objects. Thus, the process of unlearning mirror-image generalization, necessary to acquire literacy in the Latin alphabet, has a cost for a basic function of the visual ventral object recognition stream, i.e., identification of familiar objects. This demonstrates that neural recycling is not just an adaptation to multi-use but a process of at least partial exaptation.
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Use of dolutegravir in two INI-experienced patients with multiclass resistance resulted in excellent virological and immunological responses.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Dolutegravir is a second generation integrase inhibitor with a proposed high genetic barrier to resistance. However, in clinical trials, decreased virological response was seen in a subset of patients with prior exposure to raltegravir and multiple integrase resistance mutations.
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Role of recurrent hypoxia-ischemia in preterm white matter injury severity.
PLoS ONE
PUBLISHED: 01-01-2014
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Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI.
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Residual Viremia Is Preceding Viral Blips and Persistent Low-Level Viremia in Treated HIV-1 Patients.
PLoS ONE
PUBLISHED: 01-01-2014
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It has been suggested that low-level viremia or blips in HIV-infected patients on antiretroviral treatment are related to assay variation and/or increased sensitivity of new commercial assays. The 50-copy cut-off for virologic failure is, therefore, under debate.
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Prevalence and correlates of bacterial vaginosis in different sub-populations of women in sub-saharan Africa: a cross-sectional study.
PLoS ONE
PUBLISHED: 01-01-2014
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Clinical development of vaginally applied products aimed at reducing the transmission of HIV and other sexually transmitted infections, has highlighted the need for a better characterisation of the vaginal environment. We set out to characterise the vaginal environment in women in different settings in sub-Saharan Africa.
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Complexities in understanding attentional functioning among children with fetal alcohol spectrum disorder.
Front Hum Neurosci
PUBLISHED: 01-01-2014
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Parental reports of attention problems and clinical symptomatology of ADHD among children with fetal alcohol syndrome disorder (FASD) were assessed in relation to performance on standardized subtests of attentional control/shifting and selective attention from the Test of Everyday Attention for Children (TEA-Ch; Manly etal., 1998). The participants included 14 children with FASD with a mean chronological age (CA) of 11.7 years and a mean mental age (MA) of 9.7 years, and 14 typically developing (TD) children with no reported history of prenatal exposure to alcohol or attention problems with a mean CA of 8.4 years and a mean MA of 9.6 years. The children with FASD were rated by their caregivers as having clinically significant attention difficulties for their developmental age. The reported symptomatology for the majority of the children with FASD were consistent with a diagnosis of ADHD, combined type, and only one child had a score within the average range. These reports are consistent with the finding that the children with FASD demonstrated difficulties with attentional control/shifting, but inconsistent with the finding that they outperformed the TD children on a test assessing selective attention. These findings are considered within the context of the complexity in understanding attentional functioning among children with FASD and discrepancies across sources of information and components of attention.
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Intermediate vaginal flora and bacterial vaginosis are associated with the same factors: findings from an exploratory analysis among female sex workers in Africa and India.
Sex Transm Infect
PUBLISHED: 11-13-2013
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Several recent studies suggest that intermediate vaginal flora (IVF) is associated with similar adverse health outcomes as bacterial vaginosis (BV). Yet, it is still unknown if IVF and BV share the same correlates. We conducted a cross-sectional and exploratory analysis of data from women screened prior to enrolment in a microbicide trial to estimate BV and IVF prevalence and examine their respective correlates.
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Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency.
Hum. Mol. Genet.
PUBLISHED: 10-26-2013
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Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRNs interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.
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Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS).
J. Neurol.
PUBLISHED: 09-24-2013
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Neuromyelitis optica (NMO, Devics syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.
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Tomato fruits expressing a bacterial feedback-insensitive 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase of the shikimate pathway possess enhanced levels of multiple specialized metabolites and upgraded aroma.
J. Exp. Bot.
PUBLISHED: 09-04-2013
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Tomato (Solanum lycopersicum) fruit contains significant amounts of bioactive compounds, particularly multiple classes of specialized metabolites. Enhancing the synthesis and accumulation of these substances, specifically in fruits, are central for improving tomato fruit quality (e.g. flavour and aroma) and could aid in elucidate pathways of specialized metabolism. To promote the production of specialized metabolites in tomato fruit, this work expressed under a fruit ripening-specific promoter, E8, a bacterial AroG gene encoding a 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAHPS), which is feedback-insensitive to phenylalanine inhibition. DAHPS, the first enzyme of the shikimate pathway, links between the primary and specialized metabolism derived from aromatic amino acids. AroG expression influenced the levels of number of primary metabolites, such as shikimic acid and aromatic amino acids, as well as multiple volatile and non-volatile phenylpropanoids specialized metabolites and carotenoids. An organoleptic test, performed by trained panellists, suggested that the ripe AroG-expressing tomato fruits had a preferred floral aroma compare with fruits of the wild-type line. These results imply that fruit-specific manipulation of the conversion of primary to specialized metabolism is an attractive approach for improving fruit aroma and flavour qualities as well as discovering novel fruit-specialized metabolites.
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Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS.
Acta Neuropathol.
PUBLISHED: 08-28-2013
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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. A hexanucleotide (GGGGCC) repeat expansion in a non-coding region of C9ORF72 is the major genetic cause of both diseases. The mechanisms by which this repeat expansion causes "c9FTD/ALS" are not definitively known, but RNA-mediated toxicity is a likely culprit. RNA transcripts of the expanded GGGGCC repeat form nuclear foci in c9FTD/ALS, and also undergo repeat-associated non-ATG (RAN) translation resulting in the production of three aggregation-prone proteins. The goal of this study was to examine whether antisense transcripts resulting from bidirectional transcription of the expanded repeat behave in a similar manner. We show that ectopic expression of (CCCCGG)66 in cultured cells results in foci formation. Using novel polyclonal antibodies for the detection of possible (CCCCGG)exp RAN proteins [poly(PR), poly(GP) and poly(PA)], we validated that (CCCCGG)66 is also subject to RAN translation in transfected cells. Of importance, foci composed of antisense transcripts are observed in the frontal cortex, spinal cord and cerebellum of c9FTD/ALS cases, and neuronal inclusions of poly(PR), poly(GP) and poly(PA) are present in various brain tissues in c9FTD/ALS, but not in other neurodegenerative diseases, including CAG repeat disorders. Of note, RNA foci and poly(GP) inclusions infrequently co-occur in the same cell, suggesting these events represent two distinct ways in which the C9ORF72 repeat expansion may evoke neurotoxic effects. These findings provide mechanistic insight into the pathogenesis of c9FTD/ALS, and have significant implications for therapeutic strategies.
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Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.
Hum. Mol. Genet.
PUBLISHED: 08-19-2013
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The accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is a neuropathological hallmark of tauopathies, including Alzheimers disease (AD) and chronic traumatic encephalopathy, but effective therapies directly targeting the tau protein are currently lacking. Herein, we describe a novel mechanism in which the acetylation of tau on KXGS motifs inhibits phosphorylation on this same motif, and also prevents tau aggregation. Using a site-specific antibody to detect acetylation of KXGS motifs, we demonstrate that these sites are hypoacetylated in patients with AD, as well as a mouse model of tauopathy, suggesting that loss of acetylation on KXGS motifs renders tau vulnerable to pathogenic insults. Furthermore, we identify histone deacetylase 6 (HDAC6) as the enzyme responsible for the deacetylation of these residues, and provide proof of concept that acute treatment with a selective and blood-brain barrier-permeable HDAC6 inhibitor enhances acetylation and decreases phosphorylation on taus KXGS motifs in vivo. As such, we have uncovered a novel therapeutic pathway that can be manipulated to block the formation of pathogenic tau species in disease.
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Imprinted Electrodes for Enhanced Light Trapping in Solution Processed Solar Cells.
Adv. Mater. Weinheim
PUBLISHED: 08-07-2013
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A simple approach is demonstrated to combine a light trapping scheme and a conductive substrate for solution processed solar cells. By means of soft lithography, a new light trapping architecture can be integrated as bottom electrode for emerging thin film solar cell technologies without added costs, fully compatible with low temperature processes, and yielding an enhancement in the photocurrent without altering the rest of the electrical performance of the device.
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Effect of seated thoracic manipulation on changes in scapular kinematics and scapulohumeral rhythm in young asymptomatic participants: a randomized study.
J Manipulative Physiol Ther
PUBLISHED: 07-23-2013
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The purpose of this study was to evaluate the immediate effects of seated thoracic manipulation on scapulothoracic kinematics and scapulohumeral rhythm during arm flexion in young asymptomatic participants.
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c9RAN translation: a potential therapeutic target for the treatment of amyotrophic lateral sclerosis and frontotemporal dementia.
Expert Opin. Ther. Targets
PUBLISHED: 07-12-2013
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A hexanucleotide (GGGGCC) repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation associated with both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Elucidating how these expanded repeats (GGGGCCexp) cause c9FTD/ALS has since become an important goal of the FTD/ALS field. GGGGCCexp transcripts aggregate into discrete nuclear structures, termed RNA foci. This phenomenon, observed in various repeat expansion disorders, is associated with RNA-binding protein sequestration. Of note, recent findings show that GGGGCCexp transcripts also succumb to an alternative fate: repeat-associated non-ATG translation (RAN translation). This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the production of polyGA, polyGP and polyGR peptides. Antibodies generated against these peptides detect high molecular weight, insoluble material in brain homogenates, as well as neuronal inclusions throughout the central nervous system of c9FTD/ALS cases. Given that both foci formation and RAN translation in c9FTD/ALS require the synthesis of GGGGCCexp RNA, therapeutic strategies that target these transcripts and result in their neutralization or degradation could effectively block these two potential pathogenic mechanisms and provide a much needed treatment for c9FTD/ALS.
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Heterometallic gold(I)-thallium(I) compounds with crown thioethers.
Dalton Trans
PUBLISHED: 07-09-2013
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The polymeric Au/Tl compounds [{Au(C6X5)2}Tl]n (X = Cl, F) react with the crown thioethers 1,4,7-trithiacyclononane ([9]aneS3), 1,5,8,11-tetrathiacyclotetradecane ([14]aneS4), and 1,4,7,10,13,16,19,22-octathiacyclotetracosane ([24]aneS8) in an appropriate molar ratio to afford [{Au(C6X5)2}Tl(L)]2 [L = [9]aneS3, X = Cl (1), F (4); L = [14]aneS4, X = Cl (2), F (5)], [{Au(C6Cl5)2}2Tl2([24]aneS8)]n (3) or [{Au(C6F5)2}2Tl2([24]aneS8)] (6). X-ray diffraction studies of 3, 4 and 6 reveal polymeric (3) or tetranuclear (4, 6) structures formed via Tl-S bonds and AuTl or AuTl and AuAu contacts. All the complexes are luminescent in the solid state, but not in solution, where the metal-metal interactions, which are responsible for the luminescence, are no longer present. DFT calculations on representative model systems of complexes 3, 4 and 6 have also been carried out in order to determine the origin of the electronic transitions responsible for their optical properties.
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Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood.
Acta Neuropathol.
PUBLISHED: 07-01-2013
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Individuals carrying (GGGGCC) expanded repeats in the C9orf72 gene represent a significant portion of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Elucidating how these expanded repeats cause "c9FTD/ALS" has since become an important goal of the field. Toward this end, we sought to investigate whether epigenetic changes are responsible for the decrease in C9orf72 expression levels observed in c9FTD/ALS patients. We obtained brain tissue from ten c9FTD/ALS individuals, nine FTD/ALS cases without a C9orf72 repeat expansion, and nine disease control participants, and generated fibroblastoid cell lines from seven C9orf72 expanded repeat carriers and seven participants carrying normal alleles. Chromatin immunoprecipitation using antibodies for histone H3 and H4 trimethylated at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) revealed that these trimethylated residues bind strongly to C9orf72 expanded repeats in brain tissue, but not to non-pathogenic repeats. Our finding that C9orf72 mRNA levels are reduced in the frontal cortices and cerebella of c9FTD/ALS patients is consistent with trimethylation of these histone residues, an event known to repress gene expression. Moreover, treating repeat carrier-derived fibroblasts with 5-aza-2-deoxycytidine, a DNA and histone demethylating agent, not only decreased C9orf72 binding to trimethylated histone residues, but also increased C9orf72 mRNA expression. Our results provide compelling evidence that trimethylation of lysine residues within histones H3 and H4 is a novel mechanism involved in reducing C9orf72 mRNA expression in expanded repeat carriers. Of importance, we show that mutant C9orf72 binding to trimethylated H3K9 and H3K27 is detectable in blood of c9FTD/ALS patients. Confirming these exciting results using blood from a larger cohort of patients may establish this novel epigenetic event as a biomarker for c9FTD/ALS.
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Reliability of isokinetic evaluation in passive mode for knee flexors and extensors in healthy children.
Braz J Phys Ther
PUBLISHED: 06-20-2013
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The isokinetic dynamometer has been considered the gold-standard measurement of muscle performance. However, the reliability for the passive mode in children has not been reported to date.
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Quadriceps muscle atrophy after anterior cruciate ligament transection involves increased mRNA levels of atrogin-1, muscle ring finger 1, and myostatin.
Am J Phys Med Rehabil
PUBLISHED: 06-20-2013
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The aim of this study was to assess the mRNA levels of atrogin-1, muscle ring finger 1, and myostatin in rat quadriceps after anterior cruciate ligament (ACL) transection.
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The deficit of letter processing in developmental dyslexia: combining evidence from dyslexics, typical readers and illiterate adults.
Dev Sci
PUBLISHED: 06-10-2013
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To clarify the link between anomalous letter processing and developmental dyslexia, we examined the impact of surrounding contours on letter vs. pseudo-letter processing by three groups of children - phonological dyslexics and two controls, one matched for chronological age, the other for reading level - and three groups of adults differing by schooling and literacy - unschooled illiterates and ex-illiterates, and schooled literates. For pseudo-letters, all groups showed congruence effects (CE: better performance for targets surrounded by a congruent than by an incongruent shape). In contrast, for letters, only dyslexics exhibited a CE, strongly related to their phonological recoding abilities even after partialling out working memory, whereas the reverse held true for the pseudo-letter CE. In illiterate adults, the higher letter knowledge, the smaller their letter CE; their letter processing was immune (to some extent) to inference from surrounding information. The absence of a letter CE in illiterates and the positive CE in dyslexics have their origin in different aspects of the same ability, i.e. phonological recoding.
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Effect of tibiotarsal joint inflammation on gene expression and cross-sectional area in rat soleus muscle.
Braz J Phys Ther
PUBLISHED: 06-07-2013
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Joint inflammation is a common clinical problem in patients treated by physical therapists. The hypothesis of this study is that joint inflammation induces molecular and structural changes in the soleus muscle, which is composed mainly of slow-twitch muscle fibers.
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MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.
Brain
PUBLISHED: 06-07-2013
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A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ? 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.
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Central precocious puberty caused by mutations in the imprinted gene MKRN3.
N. Engl. J. Med.
PUBLISHED: 06-05-2013
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The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified.
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Literacy acquisition reduces the influence of automatic holistic processing of faces and houses.
Neurosci. Lett.
PUBLISHED: 05-28-2013
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Writing was invented too recently to have influenced the human genome. Consequently, reading acquisition must rely on partial recycling of pre-existing brain systems. Prior fMRI evidence showed that in literates a left-hemispheric visual region increases its activation to written strings relative to illiterates and reduces its response to faces. Increasing literacy also leads to a stronger right-hemispheric lateralization for faces. Here, we evaluated whether this reorganization of the brains face system has behavioral consequences for the processing of non-linguistic visual stimuli. Three groups of adult illiterates, ex-illiterates and literates were tested with the sequential composite face paradigm that evaluates the automaticity with which faces are processed as wholes. Illiterates were consistently more holistic than participants with reading experience in dealing with faces. A second experiment replicated this effect with both faces and houses. Brain reorganization induced by literacy seems to reduce the influence of automatic holistic processing of faces and houses by enabling the use of a more analytic and flexible processing strategy, at least when holistic processing is detrimental to the task.
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Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors.
Neuropharmacology
PUBLISHED: 05-22-2013
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Mammalian RF-amide peptides are encoded by five different genes and act through five different G protein-coupled receptors. RF-amide-related peptides-1 and -3, neuropeptides AF and FF, Prolactin releasing peptides, Kisspeptins and RFa peptides are currently considered endogenous peptides for NPFF1, NPFF2, GPR10, GPR54 and GPR103 receptors, respectively. However, several studies suggest that the selectivity of these peptides for their receptors is low and indicate that expression patterns for receptors and their corresponding ligands only partially overlap. In this study, we took advantage of the cloning of the five human RF-amide receptors to systematically examine their affinity for and their activation by all human RF-amide peptides. Binding experiments, performed on membranes from CHO cells expressing GPR10, GPR54 and GPR103 receptors, confirmed their high affinity and remarkable selectivity for their cognate ligands. Conversely, NPFF1 and NPFF2 receptors displayed high affinity for all RF-amide peptides. Moreover, GTP?S and cAMP experiments showed that almost all RF-amide peptides efficiently activate NPFF1 and NPFF2 receptors. As NPFF is known to modulate morphine analgesia, we undertook a systematic analysis in mice of the hyperalgesic and anti morphine-induced analgesic effects of a representative set of endogenous RF-amide peptides. All of them induced hyperalgesia and/or prevented morphine analgesia following intracerebroventricular administration. Importantly, these effects were prevented by administration of RF9, a highly selective NPFF1/NPFF2 antagonist. Altogether, our results show that all endogenous RF-amide peptides display pain-modulating properties and point to NPFF receptors as essential players for these effects.
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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.

How does it work?

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

Video X seems to be unrelated to Abstract Y...

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.