1,057 research outputs found

    Mobile work platform for initial lunar base construction

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    Described is a system of equipment intended for site preparation and construction of a lunar base. The proximate era of lunar exploration and the initial phase of outpost habitation are addressed. Drilling, leveling, trenching, and cargo handling are within the scope of the system's capabilities. The centerpiece is a three-legged mobile work platform, named SKITTER. Using standard interfaces, the system is modular in nature and analogous to the farmer's tractor and implement set. Conceptually somewhat different from their Earthbound counterparts, the implements are designed to take advantage of the lunar environment as well as the capabilities of the work platform. The proposed system is mechanically simple and weight efficient

    Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

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    AbstractCurrent antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.</jats:p

    The influence of cervical and thoracic lymphadenectomy on corneal allograft rejection in inbred rats

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    Aim To investigate the site of alloantigen presentation in the rat following orthotopic corneal transplantation. Methods Adult inbred Fischer 344 rats received penetrating corneal allografts from inbred Wistar Furth donors (n¼17), without lymphadenectomy. A second group (n¼8) underwent bilateral removal of superficial cervical and facial lymph nodes 7 days before transplantation. A third group (n¼9) underwent bilateral removal of superficial cervical, facial, internal jugular and posterior cervical nodes. Graft survival was assessed by corneal clarity and rejection was confirmed histologically. Results All allografts underwent rejection. The median time to rejection for unmodified allografts was day 15, compared with day 14.5 for minimally lymphadenectomised recipients and day 18 for more extensively lymphadenectomised recipients (p>0.05, all comparisons). The median day to rejection for the combined group of lymphadenectomised rats was day 17 (p>0.05 compared with unmodified grafts). The rejection process was similar in all recipients. Conclusions Removal of multiple lymph nodes in the neck and thorax did not significantly influence the incidence, tempo or nature of the corneal allograft response. Sensitisation and clonal expansion of corneal alloantigen-reactive cells cannot occur only in superficial cervical, facial, internal jugular and posterior cervical lymph nodes in the rat.We acknowledge financial support from the Australian National Health and Medical Research Council and the Ophthalmic Research Institute of Australia

    How well does wind speed predict air-sea gas transfer in the sea ice zone? A synthesis of radon deficit profiles in the upper water column of the Arctic Ocean

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    Author Posting. © American Geophysical Union, 2017. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 122 (2017): 3696–3714, doi:10.1002/2016JC012460.We present 34 profiles of radon-deficit from the ice-ocean boundary layer of the Beaufort Sea. Including these 34, there are presently 58 published radon-deficit estimates of air-sea gas transfer velocity (k) in the Arctic Ocean; 52 of these estimates were derived from water covered by 10% sea ice or more. The average value of k collected since 2011 is 4.0 ± 1.2 m d−1. This exceeds the quadratic wind speed prediction of weighted kws = 2.85 m d−1 with mean-weighted wind speed of 6.4 m s−1. We show how ice cover changes the mixed-layer radon budget, and yields an “effective gas transfer velocity.” We use these 58 estimates to statistically evaluate the suitability of a wind speed parameterization for k, when the ocean surface is ice covered. Whereas the six profiles taken from the open ocean indicate a statistically good fit to wind speed parameterizations, the same parameterizations could not reproduce k from the sea ice zone. We conclude that techniques for estimating k in the open ocean cannot be similarly applied to determine k in the presence of sea ice. The magnitude of k through gaps in the ice may reach high values as ice cover increases, possibly as a result of focused turbulence dissipation at openings in the free surface. These 58 profiles are presently the most complete set of estimates of k across seasons and variable ice cover; as dissolved tracer budgets they reflect air-sea gas exchange with no impact from air-ice gas exchange.NSF Arctic Natural Sciences program Grant Number: 12035582017-11-0

    Using the Utah Population Database to assess familial risk of primary open angle glaucoma

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    AbstractPurposePrimary open angle glaucoma (POAG) is a leading cause of irreversible blindness in the elderly. Previous epidemiological studies have identified family history, ethnic origin, age, high intraocular pressure and diabetes mellitus as risk factors. However, it is difficult to assess the extent family history plays in this disease process. The Utah Population Database (UPDB), created by the University of Utah, has recently become a resource for which greater than 9 million records are available for use. The UPDB is divided into two major data sets from which family members can be identified, namely 1.6 million genealogy records and 2 million Utah birth certificates. This study utilizes these resources to assess the familial risk of POAG within the Utah Population.MethodsThe University of Utah’s hospital and clinic records were searched for patients with primary and chronic open angle glaucoma (ICD9 codes 365.04 and 365.11) between the years 1995 and 2005. A case-control analysis was then performed with specialized UPDB software that was modified to constrain the control and pedigree populations to over 1 million University of Utah-UPDB linked records. Controls were matched to cases by gender and birth year (±2.5years) with only one control being used per case. Population-attributable risk (PAR) to familial factors and relative risk (RR) were computed using conditional logistic regression (CLR).ResultsFrom the original 1.5 million medical records, 6198 patients with glaucoma were identified. Of these, 3391 met the inclusion criteria, which required patients to have at least one parent or one child in the UPDB. The PAR in this population was found to be 0.20, indicating 20% of the risk for glaucoma is attributable to genetic factors. CLR computations also showed a significantly increased relative risk (p<0.05) in first cousins (RR=1.45 (95% confidence interval (CI) 1.16–1.8)), second cousins (RR=1.19 (95% CI 1.08–1.32)), siblings (RR=3.76 (95% CI 2.66–5.31)), parents (RR=6.25 (95% CI 3.94–9.9)) and children (RR=6.77 (95% CI 3.39–13.5)).ConclusionsBased on these familial data, there is a significantly higher prevalence of glaucoma in both first and second generation relatives of those affected as compared to relatives in the control group. When compared with other epidemiologic studies, such as an analysis of first-degree relatives of patients from the Rotterdam study, which showed a PAR of 16%, our study actually demonstrates a greater familial contribution to glaucoma. The UPDB is a valuable and unique resource providing a large population from which to analyze the familial risk of glaucoma

    Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?

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    A previous report suggested that 88% of individuals in the general population with total cholesterol (TC)>9.3mmol/L have familial hypercholesterolaemia (FH). We tested this hypothesis in a cohort of 4896 UK civil servants, mean (SD) age 44 (±6) years, using next generation sequencing to achieve a comprehensive genetic diagnosis. 25 (0.5%) participants (mean age 49.2 years) had baseline TC>9.3mmol/L, and overall we found an FH-causing mutation in the LDLR gene in seven (28%) subjects. The detection rate increased to 39% by excluding eight participants with triglyceride levels over 2.3mmol/L, and reached 75% in those with TC>10.4mmol/L. By extrapolation, the detection rate would be ~25% by including all participants with TC>8.6mmol/L (2.5 standard deviations from the mean). Based on the 1/500 FH frequency, 30% of all FH-cases in this cohort would be missed using the 9.3mmol/L cut-off. Given that an overall detection rate of 25% is considered economically acceptable, these data suggest that a diagnostic TC cut-off of 8.6mmol/L, rather than 9.3mmol/L would be clinically useful for FH in the general population

    Establishing the role of rare coding variants in known Parkinson's disease risk loci

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    Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks

    Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease

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    A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis

    Signature for Pain Recovery IN Teens (SPRINT): protocol for a multisite prospective signature study in chronic musculoskeletal pain

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    INTRODUCTION: Current treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches. METHODS AND ANALYSIS: Here we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function. ETHICS AND DISSEMINATION: The study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children's Hospital Medical Center Review Board as the reviewing IRB. Stanford's IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories. TRIAL REGISTRATION NUMBER: NCT04285112
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