Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

Background/objectivesThe common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson's disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD.MethodsFor immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD.ResultsHomozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses.ConclusionsIn sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression

p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses

Dysfunctional telomeres limit cellular proliferative capacity by activating the p53-p21– and p16INK4a-Rb–dependent DNA damage responses (DDRs). The p16INK4a tumor suppressor accumulates in aging tissues, is a biomarker for cellular senescence, and limits stem cell function in vivo. While the activation of a p53-dependent DDR by dysfunctional telomeres has been well documented in human cells and mouse models, the role for p16INK4a in response to telomere dysfunction remains unclear. Here, we generated protection of telomeres 1b p16–/– mice (Pot1bΔ/Δ;p16–/–) to address the function of p16INK4a in the setting of telomere dysfunction in vivo. We found that deletion of p16INK4a accelerated organ impairment and observed functional defects in highly proliferative organs, including the hematopoietic system, small intestine, and testes. Pot1bΔ/Δ;p16–/– hematopoietic cells exhibited increased telomere loss, increased chromosomal fusions, and telomere replication defects. p16INK4a deletion enhanced the activation of the ATR-dependent DDR in Pot1bΔ/Δ hematopoietic cells, leading to p53 stabilization, increased p21-dependent cell cycle arrest, and elevated p53-dependent apoptosis. In contrast to p16INK4a, deletion of p21 did not activate ATR, rescued proliferative defects in Pot1bΔ/Δ hematopoietic cells, and significantly increased organismal lifespan. Our results provide experimental evidence that p16INK4a exerts protective functions in proliferative cells bearing dysfunctional telomeres

CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145241/1/acel12783.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145241/2/acel12783_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145241/3/acel12783-sup-0001-FigS1-S4.pd

The Effects of Endurance Running Training on Young Adult Bone: Densitometry vs. Biomaterial Properties

Densitometric measurement of bone mineral parameters has been developed in recent decades. Since bone strength is associated with bone mineral density (BMD) and/or bone mineral content (BMC), densitometric measurement is widely accepted and used as one golden standard in clinical settings to determine bone health. Based on this concept, some human studies have suggested that endurance training, such as long distance running, provides no benefit and may even be harmful to bone health or bone mineral accretion during development, since long distance runners often have low BMD and/or BMC and may even exhibit conditions associated with bone loss or osteopenia.1, 2 Conversely, serum bone marker assays in healthy distance runners show normal or positive bone metabolism status.3, 4 Therefore, the definite role of endurance running training (ERT) on bone health remains a controversial issue. It would be valuable to further clarify whether ERT benefits bone health through a pathway other than absolutely increasing BMD or BMC. Clinical observations of human subjects require further basic studies to investigate possible mechanisms. Animal studies can provide unique ways not feasible in studies using human subjects of assessing the effects of endurance running on bone. Generally, previous animal studies further verified benefits of ERT to bone health. However, the limitations of animal studies must be clarified before applying their findings to human beings. The present article reviews the phenomena shown in bone of adolescent or young adult distance runners. Moreover, previous animal studies which adopted growing and young adult rats as subjects are reviewed, and the applicability of the findings to humans is also discussed

THE MYTH OF SELF RELIANCE: Economic Lives Inside a Liberian Refugee Camp. Naohiko Omata. New York: Berghahn Books, 2017

THE MYTH OF SELF RELIANCE: Economic Lives Inside a Liberian Refugee Camp. Naohiko Omata. New York: Berghahn Books, 2017. 194 pages, ISBN 9781785335648 (hardback)

Interventions to improve water quality for preventing diarrhoea

Background Diarrhoea is a major cause of death and disease, especially among young children in low-income countries. In these settings, many infectious agents associated with diarrhoea are spread through water contaminated with faeces. In remote and low-income settings, source-based water quality improvement includes providing protected groundwater (springs, wells, and bore holes), or harvested rainwater as an alternative to surface sources (rivers and lakes). Point-of-use water quality improvement interventions include boiling, chlorination, flocculation, filtration, or solar disinfection, mainly conducted at home. Objectives To assess the effectiveness of interventions to improve water quality for preventing diarrhoea. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register (11 November 2014), CENTRAL (the Cochrane Library, 7 November 2014), MEDLINE (1966 to 10 November 2014), EMBASE (1974 to 10 November 2014), and LILACS (1982 to 7 November 2014). We also handsearched relevant conference proceedings, contacted researchers and organizations working in the field, and checked references from identified studies through 11 November 2014. Selection criteria Randomized controlled trials (RCTs), quasi-RCTs, and controlled before-and-after studies (CBA) comparing interventions aimed at improving the microbiological quality of drinking water with no intervention in children and adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used meta-analyses to estimate pooled measures of effect, where appropriate, and investigated potential sources of heterogeneity using subgroup analyses. We assessed the quality of evidence using the GRADE approach. Main results Forty-five cluster-RCTs, two quasi-RCTs, and eight CBA studies, including over 84,000 participants, met the inclusion criteria. Most included studies were conducted in low- or middle-income countries (LMICs) (50 studies) with unimproved water sources (30 studies) and unimproved or unclear sanitation (34 studies). The primary outcome in most studies was self-reported diarrhoea, which is at high risk of bias due to the lack of blinding in over 80% of the included studies. Source-based water quality improvements There is currently insufficient evidence to know if source-based improvements such as protected wells, communal tap stands, or chlorination/filtration of community sources consistently reduce diarrhoea (one cluster-RCT, five CBA studies, very low quality evidence). We found no studies evaluating reliable piped-in water supplies delivered to households. Point-of-use water quality interventions On average, distributing water disinfection products for use at the household level may reduce diarrhoea by around one quarter (Home chlorination products: RR 0.77, 95% CI 0.65 to 0.91; 14 trials, 30,746 participants, low quality evidence; flocculation and disinfection sachets: RR 0.69, 95% CI 0.58 to 0.82, four trials, 11,788 participants, moderate quality evidence). However, there was substantial heterogeneity in the size of the effect estimates between individual studies. Point-of-use filtration systems probably reduce diarrhoea by around a half (RR 0.48, 95% CI 0.38 to 0.59, 18 trials, 15,582 participants, moderate quality evidence). Important reductions in diarrhoea episodes were shown with ceramic filters, biosand systems and LifeStraw® filters; (Ceramic: RR 0.39, 95% CI 0.28 to 0.53; eight trials, 5763 participants, moderate quality evidence; Biosand: RR 0.47, 95% CI 0.39 to 0.57; four trials, 5504 participants, moderate quality evidence; LifeStraw®: RR 0.69, 95% CI 0.51 to 0.93; three trials, 3259 participants, low quality evidence). Plumbed in filters have only been evaluated in high-income settings (RR 0.81, 95% CI 0.71 to 0.94, three trials, 1056 participants, fixed effects model). In low-income settings, solar water disinfection (SODIS) by distribution of plastic bottles with instructions to leave filled bottles in direct sunlight for at least six hours before drinking probably reduces diarrhoea by around a third (RR 0.62, 95% CI 0.42 to 0.94; four trials, 3460 participants, moderate quality evidence). In subgroup analyses, larger effects were seen in trials with higher adherence, and trials that provided a safe storage container. In most cases, the reduction in diarrhoea shown in the studies was evident in settings with improved and unimproved water sources and sanitation. Authors' conclusions Interventions that address the microbial contamination of water at the point-of-use may be important interim measures to improve drinking water quality until homes can be reached with safe, reliable, piped-in water connections. The average estimates of effect for each individual point-of-use intervention generally show important effects. Comparisons between these estimates do not provide evidence of superiority of one intervention over another, as such comparisons are confounded by the study setting, design, and population. Further studies assessing the effects of household connections and chlorination at the point of delivery will help improve our knowledge base. As evidence suggests effectiveness improves with adherence, studies assessing programmatic approaches to optimising coverage and long-term utilization of these interventions among vulnerable populations could also help strategies to improve health outcomes

Persistent Oscillations of X-ray Speckles: Pt (001) Step Flow

We have performed coherent x-ray scattering experiments on the hexagonally reconstructed Pt (001) surface to study the temperature-dependent surface dynamics. By correlating speckle patterns collected at the (001) anti-Bragg position we are able to measure surface dynamics when the averaged incoherent x-ray scattering appears static. In the temperature range above the rotational epitaxy transition and below the roughening transition (1750 K - 1830 K), we have observed well-defined oscillatory autocorrelations of speckles that persist for tens of minutes, in addition to the expected thermal decorrelation. The observed oscillations indicate surface dynamics due to "step-flow" motion. This is shown with a simple model in which the phase of the scattered x-rays from the steps within the illumination area is retained in the coherent x-ray scattering. This demonstrates a possibility that x-ray speckles can be used to monitor the real-space real-time evolution of surfaces in addition to the traditional decorrelation measurements.Comment: 12 pages, 3 figure

Inverse seesaw and dark matter in models with exotic lepton triplets

We show that models with exotic leptons transforming as E ~ (1,3,-1) under the standard model gauge symmetry are well suited for generating neutrino mass via a radiative inverse seesaw. This approach realizes natural neutrino masses and allows multiple new states to appear at the TeV scale. The exotic leptons are therefore good candidates for new physics that can be probed at the LHC. Furthermore, remnant low-energy symmetries ensure a stable dark matter candidate, providing a link between dark matter and the origins of neutrino mass.Comment: 6 pages, 3 figures (revtex4.1, two-columns

Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance

Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers.Val Skinner FoundationNational Institutes of Health (U.S.) (RC1 CA147961)Rutgers Cancer Institute of New JerseyRutgers Cancer Institute of New Jersey (P30 CA072720)National Institutes of Health (U.S.) (R01 CA163591)National Institutes of Health (U.S.) (R37 CA53370)National Institutes of Health (U.S.) (R01 CA130893