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101.
Benjamin S. Bleier Richie E. Kohman Rachel E. Feldman Shreshtha Ramanlal Xue Han 《PloS one》2013,8(4)
Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson’s disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS. 相似文献
102.
Allana G. LeBlanc Jean-Philippe Chaput Allison McFarlane Rachel C. Colley David Thivel Stuart J. H. Biddle Ralph Maddison Scott T. Leatherdale Mark S. Tremblay 《PloS one》2013,8(6)
Background
Active video games (AVGs) have gained interest as a way to increase physical activity in children and youth. The effect of AVGs on acute energy expenditure (EE) has previously been reported; however, the influence of AVGs on other health-related lifestyle indicators remains unclear.Objective
This systematic review aimed to explain the relationship between AVGs and nine health and behavioural indicators in the pediatric population (aged 0–17 years).Data sources
Online databases (MEDLINE, EMBASE, psycINFO, SPORTDiscus and Cochrane Central Database) and personal libraries were searched and content experts were consulted for additional material.Data selection
Included articles were required to have a measure of AVG and at least one relevant health or behaviour indicator: EE (both habitual and acute), adherence and appeal (i.e., participation and enjoyment), opportunity cost (both time and financial considerations, and adverse events), adiposity, cardiometabolic health, energy intake, adaptation (effects of continued play), learning and rehabilitation, and video game evolution (i.e., sustainability of AVG technology).Results
51 unique studies, represented in 52 articles were included in the review. Data were available from 1992 participants, aged 3–17 years, from 8 countries, and published from 2006–2012. Overall, AVGs are associated with acute increases in EE, but effects on habitual physical activity are not clear. Further, AVGs show promise when used for learning and rehabilitation within special populations. Evidence related to other indicators was limited and inconclusive.Conclusions
Controlled studies show that AVGs acutely increase light- to moderate-intensity physical activity; however, the findings about if or how AVG lead to increases in habitual physical activity or decreases in sedentary behaviour are less clear. Although AVGs may elicit some health benefits in special populations, there is not sufficient evidence to recommend AVGs as a means of increasing daily physical activity. 相似文献103.
Xiao Li Ran Zhuo Stanley Tiong Francesca Di Cara Kirst King-Jones Sarah C. Hughes Shelagh D. Campbell Rachel Wevrick 《PloS one》2013,8(3)
The SMC5/6 protein complex consists of the Smc5, Smc6 and Non-Smc-Element (Nse) proteins and is important for genome stability in many species. To identify novel components in the DNA repair pathway, we carried out a genetic screen to identify mutations that confer reduced resistance to the genotoxic effects of caffeine, which inhibits the ATM and ATR DNA damage response proteins. This approach identified inactivating mutations in CG5524 and MAGE, homologs of genes encoding Smc6 and Nse3 in yeasts. The fact that Smc5 mutants are also caffeine-sensitive and that Mage physically interacts with Drosophila homologs of Nse proteins suggests that the structure of the Smc5/6 complex is conserved in Drosophila. Although Smc5/6 proteins are required for viability in S. cerevisiae, they are not essential under normal circumstances in Drosophila. However, flies carrying mutations in Smc5, Smc6 and MAGE are hypersensitive to genotoxic agents such as ionizing radiation, camptothecin, hydroxyurea and MMS, consistent with the Smc5/6 complex serving a conserved role in genome stability. We also show that mutant flies are not compromised for pre-mitotic cell cycle checkpoint responses. Rather, caffeine-induced apoptosis in these mutants is exacerbated by inhibition of ATM or ATR checkpoint kinases but suppressed by Rad51 depletion, suggesting a functional interaction involving homologous DNA repair pathways that deserves further scrutiny. Our insights into the SMC5/6 complex provide new challenges for understanding the role of this enigmatic chromatin factor in multi-cellular organisms. 相似文献
104.
Kathryn Whetten Kristen Shirey Brian Wells Pence Jia Yao Nathan Thielman Rachel Whetten Julie Adams Bernard Agala Jan Ostermann Karen O'Donnell Amy Hobbie Venance Maro Dafrosa Itemba Elizabeth Reddy for the CHAT Research Team 《PloS one》2013,8(10)
Background
As antiretroviral therapy (ART) for HIV becomes increasingly available in low and middle income countries (LMICs), understanding reasons for lack of adherence is critical to stemming the tide of infections and improving health. Understanding the effect of psychosocial experiences and mental health symptomatology on ART adherence can help maximize the benefit of expanded ART programs by indicating types of services, which could be offered in combination with HIV care.Methodology
The Coping with HIV/AIDS in Tanzania (CHAT) study is a longitudinal cohort study in the Kilimanjaro Region that included randomly selected HIV-infected (HIV+) participants from two local hospital-based HIV clinics and four free-standing voluntary HIV counselling and testing sites. Baseline data were collected in 2008 and 2009; this paper used data from 36 month follow-up interviews (N = 468). Regression analyses were used to predict factors associated with incomplete self-reported adherence to ART.Results
Incomplete ART adherence was significantly more likely to be reported amongst participants who experienced a greater number of childhood traumatic events: sexual abuse prior to puberty and the death in childhood of an immediate family member not from suicide or homicide were significantly more likely in the non-adherent group and other negative childhood events trended toward being more likely. Those with incomplete adherence had higher depressive symptom severity and post-traumatic stress disorder (PTSD). In multivariable analyses, childhood trauma, depression, and financial sacrifice remained associated with incomplete adherence.Discussion
This is the first study to examine the effect of childhood trauma, depression and PTSD on HIV medication adherence in a low income country facing a significant burden of HIV. Allocating spending on HIV/AIDS toward integrating mental health services with HIV care is essential to the creation of systems that enhance medication adherence and maximize the potential of expanded antiretroviral access to improve health and reduce new infections. 相似文献105.
Jan F. Kamler Khamtai Thatdokkham Susana Rostro-García Anita Bousa Anthony Caragiulo Rachel Crouthers Visattha In Chen Pay Chanratana Pin Sovanna Prum Chantavy Vongkhamheng Arlyne Johnson David W. Macdonald 《The Journal of wildlife management》2020,84(7):1396-1405
Endangered dholes (Cuon alpinus) are restricted to small and declining populations in Southeast Asia, and little is known about how their ecology differs within the region. We used DNA-confirmed scats and prey surveys to determine the seasonal diet and prey selection of dholes in 2 different landscapes that dominate Southeast Asia: closed evergreen forests in hilly terrain in northern Laos, and open deciduous forests in relatively flat terrain in eastern Cambodia. On both sites, muntjac (Muntiacus spp.; 20–28 kg) was the dominant prey item and was selectively consumed over other ungulates in all seasons. Our findings differ from previous conclusions, based largely on studies from India, that the preferred prey weight range of dholes was either 40–60 kg or 130–190 kg. Other important prey were sambar (Rusa unicolor) in Laos, and wild pig (Sus scrofa) and banteng (Bos javanicus) in Cambodia. Seasonal differences in overall diet occurred in Laos, but not Cambodia, primarily because of an increase in livestock consumption. The mean number of dhole scats in group defecation sites was higher in Cambodia (5.9 ± 0.5 [SE]) than Laos (2.4 ± 0.2), suggesting pack sizes were larger in Cambodia. Our results suggest that regardless of land cover type, prey diversity, or pack size, the management of muntjac will be important for conserving dhole populations in Southeast Asia. In Laos, we recommend that local villagers remove livestock from the protected area during the hot-dry season to reduce livestock predation by dholes. © 2020 The Authors. The Journal of Wildlife Management published by Wiley Periodicals LLC on behalf of The Wildlife Society. 相似文献
106.
Pupo Amaury Ayers Michael C. Sherman Zachary N. Vance Rachel J. Cumming Jonathan R. Gallagher Jennifer E. G. 《Biological trace element research》2020,195(1):260-271
Biological Trace Element Research - While drugs and other industrial chemicals are routinely studied to assess risks, many widely used chemicals have not been thoroughly evaluated. One such... 相似文献
107.
Rachel Heyard Jean-François Timsit Leonhard Held COMBACTE-MAGNET consortium 《Biometrical journal. Biometrische Zeitschrift》2020,62(3):643-657
Clinical prediction models play a key role in risk stratification, therapy assignment and many other fields of medical decision making. Before they can enter clinical practice, their usefulness has to be demonstrated using systematic validation. Methods to assess their predictive performance have been proposed for continuous, binary, and time-to-event outcomes, but the literature on validation methods for discrete time-to-event models with competing risks is sparse. The present paper tries to fill this gap and proposes new methodology to quantify discrimination, calibration, and prediction error (PE) for discrete time-to-event outcomes in the presence of competing risks. In our case study, the goal was to predict the risk of ventilator-associated pneumonia (VAP) attributed to Pseudomonas aeruginosa in intensive care units (ICUs). Competing events are extubation, death, and VAP due to other bacteria. The aim of this application is to validate complex prediction models developed in previous work on more recently available validation data. 相似文献
108.
109.
Noushin Niknafs Dewey Kim RyangGuk Kim Mark Diekhans Michael Ryan Peter D. Stenson David N. Cooper Rachel Karchin 《Human genetics》2013,132(11):1235-1243
Mutation position imaging toolbox (MuPIT) interactive is a browser-based application for single-nucleotide variants (SNVs), which automatically maps the genomic coordinates of SNVs onto the coordinates of available three-dimensional (3D) protein structures. The application is designed for interactive browser-based visualization of the putative functional relevance of SNVs by biologists who are not necessarily experts either in bioinformatics or protein structure. Users may submit batches of several thousand SNVs and review all protein structures that cover the SNVs, including available functional annotations such as binding sites, mutagenesis experiments, and common polymorphisms. Multiple SNVs may be mapped onto each structure, enabling 3D visualization of SNV clusters and their relationship to functionally annotated positions. We illustrate the utility of MuPIT interactive in rationalizing the impact of selected polymorphisms in the PharmGKB database, somatic mutations identified in the Cancer Genome Atlas study of invasive breast carcinomas, and rare variants identified in the exome sequencing project. MuPIT interactive is freely available for non-profit use at http://mupit.icm.jhu.edu. 相似文献
110.
Rachel Lescasse Sabrina Pobiega Isabelle Callebaut Stéphane Marcand 《The EMBO journal》2013,32(6):805-815
In eukaryotes, permanent inhibition of the non‐homologous end joining (NHEJ) repair pathway at telomeres ensures that chromosome ends do not fuse. In budding yeast, binding of Rap1 to telomere repeats establishes NHEJ inhibition. Here, we show that the Uls1 protein is required for the maintenance of NHEJ inhibition at telomeres. Uls1 protein is a non‐essential Swi2/Snf2‐related translocase and a Small Ubiquitin‐related Modifier (SUMO)‐Targeted Ubiquitin Ligase (STUbL) with unknown targets. Loss of Uls1 results in telomere–telomere fusions. Uls1 requirement is alleviated by the absence of poly‐SUMO chains and by rap1 alleles lacking SUMOylation sites. Furthermore, Uls1 limits the accumulation of Rap1 poly‐SUMO conjugates. We propose that one of Uls1 functions is to clear non‐functional poly‐SUMOylated Rap1 molecules from telomeres to ensure the continuous efficiency of NHEJ inhibition. Since Uls1 is the only known STUbL with a translocase activity, it can be the general molecular sweeper for the clearance of poly‐SUMOylated proteins on DNA in eukaryotes. 相似文献