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

Blast Shock Wave Mitigation Using the Hydraulic Energy Redirection and Release Technology

A hydraulic energy redirection and release technology has been developed for mitigating the effects of blast shock waves on protected objects. The technology employs a liquid-filled plastic tubing as a blast overpressure transformer to transfer kinetic energy of blast shock waves into hydraulic energy in the plastic tubings. The hydraulic energy is redirected through the plastic tubings to the openings at the lower ends, and then is quickly released with the liquid flowing out through the openings. The samples of the specifically designed body armor in which the liquid-filled plastic tubings were installed vertically as the outer layer of the body armor were tested. The blast test results demonstrated that blast overpressure behind the body armor samples was remarkably reduced by 97% in 0.2 msec after the liquid flowed out of its appropriate volume through the openings. The results also suggested that a volumetric liquid surge might be created when kinetic energy of blast shock wave was transferred into hydraulic energy to cause a rapid physical movement or displacement of the liquid. The volumetric liquid surge has a strong destructive power, and can cause a noncontact, remote injury in humans (such as blast-induced traumatic brain injury and post-traumatic stress disorder) if it is created in cardiovascular system. The hydraulic energy redirection and release technology can successfully mitigate blast shock waves from the outer surface of the body armor. It should be further explored as an innovative approach to effectively protect against blast threats to civilian and military personnel

Abnormal shortened diastolic time length at increasing heart rates in patients with abnormal exercise-induced increase in pulmonary artery pressure

<p>Abstract</p> <p>Background</p> <p>The degree of pulmonary hypertension is not independently related to the severity of left ventricular systolic dysfunction but is frequently associated with diastolic filling abnormalities. The aim of this study was to assess diastolic times at increasing heart rates in normal and in patients with and without abnormal exercise-induced increase in pulmonary artery pressure (PASP). Methods. We enrolled 109 patients (78 males, age 62 ± 13 years) referred for exercise stress echocardiography and 16 controls. The PASP was derived from the tricuspid Doppler tracing. A cut-off value of PASP ≥ 50 mmHg at peak stress was considered as indicative of abnormal increase in PASP. Diastolic times and the diastolic/systolic time ratio were recorded by a precordial cutaneous force sensor based on a linear accelerometer.</p> <p>Results</p> <p>At baseline, PASP was 30 ± 5 mmHg in patients and 25 ± 4 in controls. At peak stress the PASP was normal in 95 patients (Group 1); 14 patients (Group 2) showed an abnormal increase in PASP (from 35 ± 4 to 62 ± 12 mmHg; P < 0.01). At 100 bpm, an abnormal (< 1) diastolic/systolic time ratio was found in 0/16 (0%) controls, in 12/93 (13%) Group 1 and 7/14 (50%) Group 2 patients (p < 0.05 between groups).</p> <p>Conclusion</p> <p>The first and second heart sound vibrations non-invasively monitored by a force sensor are useful for continuously assessing diastolic time during exercise. Exercise-induced abnormal PASP was associated with reduced diastolic time at heart rates beyond 100 beats per minute.</p

Relationship of EMAST and Microsatellite Instability Among Patients with Rectal Cancer

Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. Among this cohort of patients with rectal cancer (mean age 62.2 ± 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001). EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development

Re-thinking residential mobility: Linking lives through time and space.

This is the final version of the article. It first appeared from SAGE via http://dx.doi.org/10.1177/0309132515575417While researchers are increasingly re-conceptualizing international migration, far less attention has been devoted to re-thinking short-distance residential mobility and immobility. In this paper we harness the life course approach to propose a new conceptual framework for residential mobility research. We contend that residential mobility and immobility should be re-conceptualized as relational practices that link lives through time and space while connecting people to structural conditions. Re-thinking and re-assessing residential mobility by exploiting new developments in longitudinal analysis will allow geographers to understand, critique and address pressing societal challenges.Rory Coulter’s work on this paper was partly supported by an Economic and Social Research Council grant [ES/L009498/1]. Maarten van Ham’s contribution was supported by funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013) / ERC Grant Agreement n. 615159 (ERC Consolidator Grant DEPRIVEDHOODS, Socio-spatial inequality, deprived neighbourhoods, and neighbourhood effects); and from the Marie Curie programme under the European Union’s Seventh Framework Programme (FP/2007–2013) / Career Integration Grant no. PCIG10-GA-2011-303728 (CIG Grant NBHCHOICE, Neighbourhood choice, neighbourhood sorting, and neighbourhood effects). Allan Findlay’s work was supported by an Economic and Social Research Council grant [ES/K007394/1]

The effects of a 6-week strength training on critical velocity, anaerobic running distance, 30-m sprint and yo-yo intermittent running test performances in male soccer players

The objectives of this study were to examine the effects of a moderate intensity strength training on changes in critical velocity (CV), anaerobic running distance (D'), sprint performance and Yo-Yo intermittent running test (Yo-Yo IR1) performances. Methods: two recreational soccer teams were divided in a soccer training only group (SO; n = 13) and a strength and soccer training group (ST; n = 13). Both groups were tested for values of CV, D', Yo-Yo IR1 distance and 30-m sprint time on two separate occasions (pre and post intervention). The ST group performed a concurrent 6-week upper and lower body strength and soccer training, whilst the SO group performed a soccer only training. Results: after the re-test of all variables, the ST demonstrated significant improvements for both, YoYo IR1 distance (p = 0.002) and CV values (p<0.001) with no significant changes in the SO group. 30-m sprint performance were slightly improved in the ST group with significantly decreased performance times identified in the SO group (p<0.001). Values for D' were slightly reduced in both groups (ST -44.5 m, 95% CI = -90.6 to 1.6; SO -42.6 m, 95% CI = -88.7 to 3.5). Conclusions: combining a 6-week moderate strength training with soccer training significantly improves CV, Yo-Yo IR1 whilst moderately improving 30-m sprint performances in non-previously resistance trained male soccer players. Critical Velocity can be recommended to coaches as an additional valid testing tool in soccer

MutSβ exceeds MutSα in dinucleotide loop repair

The target substrates of DNA mismatch recognising factors MutSalpha (MSH2+MSH6) and MutSbeta (MSH2+MSH3) have already been widely researched. However, the extent of their functional redundancy and clinical substance remains unclear. Mismatch repair (MMR)-deficient tumours are strongly associated with microsatellite instability (MSI) and the degree and type of MSI seem to be dependent on the MMR gene affected, and is linked to its substrate specificities. Deficiency in MSH2 and MSH6 is associated with both mononucleotide and dinucleotide repeat instability. Although no pathogenic MSH3 mutations have been reported, its deficiency is also suggested to cause low dinucleotide repeat instability

Vitamin D prevents endothelial progenitor cell dysfunction induced by sera from women with preeclampsia or conditioned media from hypoxic placenta

Context: Placenta-derived circulating factors contribute to the maternal endothelial dysfunction underlying preeclampsia. Endothelial colony forming cells (ECFC), a sub-population of endothelial progenitor cells (EPCs), are thought to be involved in vasculogenesis and endothelial repair. Low vitamin D concentrations are associated with an increased risk for preeclampsia. Objective: We hypothesized that the function of human fetal ECFCs in culture would be suppressed by exposure to preeclampsia-related factors-preeclampsia serum or hypoxic placental conditioned medium- in a fashion reversed by vitamin D. Design, Setting, Patients: ECFCs were isolated from cord blood of uncomplicated pregnancies and expanded in culture. Uncomplicated pregnancy villous placenta in explant culture were exposed to either 2% (hypoxic), 8% (normoxic) or 21% (hyperoxic) O2 for 48 h, after which the conditioned media (CM) was collected. Outcome Measures: ECFC tubule formation (Matrigel assay) and migration were examined in the presence of either maternal serum from preeclampsia cases or uncomplicated pregnancy controls, or pooled CM, in the presence or absence of 1,25(OH)2 vitamin D3. Results: 1,25(OH)2 vitamin D3 reversed the adverse effects of preeclampsia serum or CM from hypoxic placenta on ECFCs capillary-tube formation and migration. Silencing of VDR expression by VDR siRNA, VDR blockade, or VEGF pathway blockade reduced ECFC functional abilities. Effects of VDR or VEGF blockade were partially prevented by vitamin D. Conclusion: Vitamin D promotes the capillary-like tubule formation and migration of ECFCs in culture, minimizing the negative effects of exposure to preeclampsia-related factors. Further evaluation of the role of vitamin D in ECFC regulation and preeclampsia is warranted. © 2014 Brodowski et al

Identification of telomere dysfunction in Friedreich ataxia.

Background: Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker. Results: Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identified similar telomere shortening in FRDA patient autopsy cerebellar tissues. However, FRDA fibroblasts showed significantly longer telomeres at early passage, occurring in the absence of telomerase activity, but with activation of an alternative lengthening of telomeres (ALT)-like mechanism. These cells also showed accelerated telomere shortening as population doubling increases. Furthermore, telomere dysfunction-induced foci (TIF) analysis revealed that FRDA fibroblasts have dysfunctional telomeres. Conclusions: Our finding of dysfunctional telomeres in FRDA cells provides further insight into FRDA molecular disease mechanisms, which may have implications for future FRDA therapy.This work was supported by funding from the European Union Seventh Framework Programme [FP7/2007-2013] under grant agreement number 242193/EFACTS (CS) and the Wellcome Trust [089757] (SA) to MAP. PG is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review

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