Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While ...significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects. Technological advances and approaches in genomics are critical for the process of disease gene identification. In this review we highlight the impact of various technological developments on male infertility gene discovery as well as functional validation, going from the past to the present and the future. In particular, we draw attention to the use of unbiased genomics approaches, the development of increasingly relevant functional assays and the importance of large-scale international collaboration to advance disease gene identification in male infertility.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum ...states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
We have developed, produced and characterized integrated sensors, actuators and the related read-out and drive electronics that will be used for the control of the Advanced LIGO suspensions. The ...overall system consists of the BOSEMs (a displacement sensor with an integrated electromagnetic actuator), the satellite boxes (the BOSEM readout and interface electronics) and six different types of coil-driver units. In this paper, we present the design of this read-out and control system, we discuss the related performance relevant for the Advanced LIGO suspensions, and we report on the experimental activity finalized at the production of the instruments for the Advanced LIGO detectors.
In metazoans, tissues experiencing proteotoxic stress induce “transcellular chaperone signaling” (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of ...inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ3-42-associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction.
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•PQM-1 is activated in the neurons or gut to induce TCS-mediated hsp-90 expression•Neuron-induced TCS is mediated via PQM-1/CLEC-41 signaling•Intestine-induced TCS is mediated via PQM-1/ASP-12 signaling•TCS via PQM-1 is required for proteostasis and reduces amyloid beta misfolding
O’Brien et al. find that the GATA transcription factor PQM-1 functions as a mediator of transcellular chaperone signaling (TCS). Depending on the sender tissue, PQM-1 activates a neuron-specific or intestine-specific TCS route that triggers hsp-90 expression in remote tissues. TCS-mediated hsp-90 induction reduces amyloid beta oligomerization and toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gravitational wave interferometers achieve their profound sensitivity by combining a Michelson interferometer with optical cavities, suspended masses, and now, squeezed quantum states of light. These ...states modify the measurement process of the LIGO, VIRGO and GEO600 interferometers to reduce the quantum noise that masks astrophysical signals; thus, improvements to squeezing are essential to further expand our gravitational view of the Universe. Further reducing quantum noise will require both lowering decoherence from losses as well more sophisticated manipulations to counter the quantum back-action from radiation pressure. Both tasks require fully understanding the physical interactions between squeezed light and the many components of km-scale interferometers. To this end, data from both LIGO observatories in observing run three are expressed using frequency-dependent metrics to analyze each detector's quantum response to squeezed states. The response metrics are derived and used to concisely describe physical mechanisms behind squeezing's simultaneous interaction with transverse-mode selective optical cavities and the quantum radiation pressure noise of suspended mirrors. These metrics and related analysis are broadly applicable for cavity-enhanced optomechanics experiments that incorporate external squeezing, and-for the first time-give physical descriptions of every feature so far observed in the quantum noise of the LIGO detectors.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Objective To further understand the association between semen quality and cancer risk by means of well defined semen parameters. Design Retrospective cohort study. Setting Not applicable. Patient(s) ...A total of 20,433 men who underwent semen analysis (SA) and a sample of 20,433 fertile control subjects matched by age and birth year. Intervention(s) None. Main Outcome Measure(s) Risk of all cancers as well as site-specific results for prostate cancer, testicular cancer, and melanoma. Result(s) Compared with fertile men, men with SA had an increased risk of testicular cancer (hazard rate HR 3.3). When the characterization of infertility was refined using individual semen parameters, we found that oligozoospermic men had an increased risk of cancer compared with fertile control subjects. This association was particularly strong for testicular cancer, with increased risk in men with oligozoospermia based on concentration (HR 11.9) and on sperm count (HR 10.3). Men in the in the lowest quartile of motility (HR 4.1), viability (HR 6.6), morphology (HR 4.2), or total motile count (HR 6.9) had higher risk of testicular cancer compared with fertile men. Men with sperm concentration and count in the 90th percentiles of the distribution (≥178 and ≥579 × 106 /mL, respectively), as well as total motile count, had an increased risk of melanoma (HRs 2.1, 2.7, and 2.0, respectively). We found no differences in cancer risk between azoospermic and fertile men. Conclusion(s) Men with SA had an increased risk of testicular cancer which varied by semen quality. Unlike earlier work, we did not find an association between azoospermia and increased cancer risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Venous thromboembolism chemoprophylaxis remains underutilized in hospitalized medical patients at high risk for venous thromboembolism. We assessed the effect of a healthcare ...quality improvement initiative comprised of a targeted electronic alert, comparative practitioner metrics, and practitioner-specific continuing medical education on the rate of appropriate venous thromboembolism chemoprophylaxis provided to medical inpatients at high risk for venous thromboembolism. Methods We performed a multicenter prospective observational cohort study in an urban Utah hospital system. All medical patients admitted to one of two participating hospitals from 1 April 2010 to 31 December 2012 were eligible. Patients were members of the “control” (1 April 2010 to 31 December 2010), “intervention” (1 January 2011 to 31 December 2011), or “subsequent year” (1 January 2012 to 31 December 2012) group. The primary outcome was the rate of appropriate chemoprophylaxis among patients at high risk for venous thromboembolism. Secondary outcomes included rates of symptomatic venous thromboembolism, major bleeding, all-cause mortality, heparin-induced thrombocytopenia, physician satisfaction, and alert fatigue. Results The rate of appropriate chemoprophylaxis among patients at high risk for venous thromboembolism increased (66.1% control period vs. 81.0% intervention period vs 88.1% subsequent year; p<0.001 for each comparison). A significant reduction of 90 day symptomatic venous thromboembolism accompanied the quality initiative (9.3% control period, 9.7% intervention period, 6.7% subsequent year; p=0.009); 30 day venous thromboembolism rates also significantly declined. Conclusions A multifaceted intervention was associated with increased appropriate venous thromboembolism chemoprophylaxis among medical inpatients at high risk for venous thromboembolism and reduced symptomatic venous thromboembolism. The effect of the intervention was sustained.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To test the hypothesis that cigarette smoking protects against the development of PD.
Smoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the ...underlying disease process or merely confounding or selection bias remains uncertain.
The authors compared smoking histories in male twin pairs identified from the National Academy of Sciences--National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD.
Detailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic MZ, 50 dizygotic DZ; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs. 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs. 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs. 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease.
Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.
The mechanisms underlying functional mitral regurgitation (MR) and the relation between mechanism and severity of MR have not been evaluated in a large, multicenter, randomized controlled trial. ...Transesophageal echocardiography (TEE) was performed in 215 patients at 17 centers in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Both 2-dimensional (n = 215) and 3-dimensional (n = 81) TEEs were used to assess multiple quantitative measurements of the mechanism and severity of MR. By 2-dimensional TEE, leaflet tenting area, anterior and posterior leaflet angles, mitral annulus diameter, left ventricular (LV) end-systolic volume index, LV ejection fraction (LVEF), and sphericity index (p <0.05 for all) were significantly different across MR grades. By 3-dimensional TEE, mitral annulus area, leaflet tenting area, LV end-systolic volume index, LVEF, and sphericity index (p <0.05 for all) were significantly different across MR grades. A multivariate analysis showed a trend for annulus area (p = 0.069) and LV end-systolic volume index (p = 0.071) to predict effective regurgitant orifice area and for annulus area (p = 0.018) and LV end-systolic volume index (p = 0.073) to predict vena contracta area. In the STICH trial, multiple quantitative parameters of the mechanism of functional MR are related to MR severity. The mechanism of functional MR in ischemic cardiomyopathy is heterogenous, but no single variable stands out as a strong predictor of quantitative severity of MR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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