MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Four models of HIV counseling and testing: utilization and test results in South Africa.

BACKGROUND: HIV Counseling and Testing (HCT) is the point-of-entry for pathways of HIV care and prevention. However, HCT is not reaching many who are HIV infected and this may be related to the HCT provision model. We describe HCT utilization and HIV diagnosis using four models of HCT delivery: clinic-based, urban mobile, rural mobile, and stand-alone. METHODS: Using cross-sectional data from routine HCT provided in South Africa, we described client characteristics and HIV test results from information collected during service delivery between January 2009 and June 2012. RESULTS: 118,358 clients received services at clinic-based units, 18,597; stand-alone, 28,937; urban mobile, 38,840; and rural mobile, 31,984. By unit, clients were similar in terms of median age (range 28-31), but differed in sex distribution, employment status, prior testing, and perceived HIV risk. Urban mobile units had the highest proportion of male clients (52%). Rural mobile units reached the highest proportion of clients with no prior HCT (61%) and reporting no perceived HIV risk (64%). Overall, 10,862 clients (9.3%) tested HIV-positive. CONCLUSIONS: Client characteristics varied by HCT model. Importantly, rural and urban mobile units reached more men, first-time testers, and clients who considered themselves to be at low risk for HIV

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells:Comparison with human bone marrow and adipose-derived mesenchymal stem cells

We have investigated and compared the neurotrophic activity of human dental pulp stem cells (hDPSC), human bone marrow-derived mesenchymal stem cells (hBMSC) and human adipose-derived stem cells (hAMSC) on axotomised adult rat retinal ganglion cells (RGC) in vitro in order to evaluate their therapeutic potential for neurodegenerative conditions of RGC. Using the transwell system, RGC survival and length/number of neurites were quantified in coculture with stem cells in the presence or absence of specific Fc-receptor inhibitors to determine the role of NGF, BDNF, NT-3, VEGF, GDNF, PDGF-AA and PDGF-AB/BB in stem cell-mediated RGC neuroprotection and neuritogenesis. Conditioned media, collected from cultured hDPSC/hBMSC/hAMSC, were assayed for the secreted growth factors detailed above using ELISA. PCR array determined the hDPSC, hBMSC and hAMSC expression of genes encoding 84 growth factors and receptors. The results demonstrated that hDPSC promoted significantly more neuroprotection and neuritogenesis of axotomised RGC than either hBMSC or hAMSC, an effect that was neutralized after the addition of specific Fc-receptor inhibitors. hDPSC secreted greater levels of various growth factors including NGF, BDNF and VEGF compared with hBMSC/hAMSC. The PCR array confirmed these findings and identified VGF as a novel potentially therapeutic hDPSC-derived neurotrophic factor (NTF) with significant RGC neuroprotective properties after coculture with axotomised RGC. In conclusion, hDPSC promoted significant multi-factorial paracrine-mediated RGC survival and neurite outgrowth and may be considered a potent and advantageous cell therapy for retinal nerve repair

Voluntary HIV counselling and testing among men in rural western Uganda: Implications for HIV prevention

<p>Abstract</p> <p>Background</p> <p>Voluntary HIV counselling and testing (VCT) is one of the key strategies in the prevention and control of HIV/AIDS in Uganda. However, the utilization of VCT services particularly among men is low in Kasese district. We therefore conducted a study to determine the prevalence and factors associated with VCT use among men in Bukonzo West health sub-district, Kasese district.</p> <p>Methods</p> <p>A population-based cross-sectional study employing both quantitative and qualitative techniques of data collection was conducted between January and April 2005. Using cluster sampling, 780 men aged 18 years and above, residing in Bukonzo West health sub-district, were sampled from 38 randomly selected clusters. Data was collected on VCT use and independent variables. Focus group discussions (4) and key informant interviews (10) were also conducted. Binary logistic regression was performed to determine the predictors of VCT use among men.</p> <p>Results</p> <p>Overall VCT use among men was 23.3% (95% CI 17.2–29.4). Forty six percent (95% CI 40.8–51.2) had pre-test counselling and 25.9% (95%CI 19.9–31.9) had HIV testing. Of those who tested, 96% returned for post-test counselling and received HIV results. VCT use was higher among men aged 35 years and below (OR = 2.69, 95%CI 1.77–4.07), the non-subsistence farmers (OR = 2.37, 95%CI 2.37), the couple testing (OR = 2.37, 95%CI 1.02–8.83) and men with intention to disclose HIV test results to sexual partners (OR = 1.64, 95%CI 1.04–2.60). The major barriers to VCT use among men were poor utilization of VCT services due to poor access, stigma and confidentiality of services.</p> <p>Conclusion</p> <p>VCT use among men in Bukonzo West, Kasese district was low. In order to increase VCT use among men, the VCT programme needs to address HIV stigma and improve access and confidentiality of VCT services. Among the more promising interventions are the use of routine counselling and testing for HIV of patients seeking health care in health units, home based VCT programmes, and mainstreaming of HIV counselling and testing services in community development programmes.</p

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014–2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V

Extreme enrichment of Se, Te, PGE and Au in Cu sulfide microdroplets: evidence from LA-ICP-MS analysis of sulfides in the Skaergaard Intrusion, east Greenland

The Platinova Reef, in the Skaergaard Intrusion, east Greenland, is an example of a magmatic Cu–PGE–Au sulfide deposit formed in the latter stages of magmatic differentiation. As is characteristic with such deposits, it contains a low volume of sulfide, displays peak metal offsets and is Cu rich but Ni poor. However, even for such deposits, the Platinova Reef contains extremely low volumes of sulfide and the highest Pd and Au tenor sulfides of any magmatic ore deposit. Here, we present the first LA-ICP-MS analyses of sulfide microdroplets from the Platinova Reef, which show that they have the highest Se concentrations (up to 1200 ppm) and lowest S/Se ratios (190–700) of any known magmatic sulfide deposit and have significant Te enrichment. In addition, where sulfide volume increases, there is a change from high Pd-tenor microdroplets trapped in situ to larger, low tenor sulfides. The transition between these two sulfide regimes is marked by sharp peaks in Au, and then Te concentration, followed by a wider peak in Se, which gradually decreases with height. Mineralogical evidence implies that there is no significant post-magmatic hydrothermal S loss and that the metal profiles are essentially a function of magmatic processes. We propose that to generate these extreme precious and semimetal contents, the sulfides must have formed from an anomalously metal-rich package of magma, possibly formed via the dissolution of a previously PGE-enriched sulfide. Other processes such as kinetic diffusion may have also occurred alongside this to produce the ultra-high tenors. The characteristic metal offset pattern observed is largely controlled by partitioning effects, producing offset peaks in the order Pt+Pd>Au>Te>Se>Cu that are entirely consistent with published D values. This study confirms that extreme enrichment in sulfide droplets can occur in closed-system layered intrusions in situ, but this will characteristically form ore deposits that are so low in sulfide that they do not conform to conventional deposit models for Cu–Ni–PGE sulfides which require very high R factors, and settling of sulfide liquids