Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

A systematic review of mental disorder, suicide, and deliberate self harm in lesbian, gay and bisexual people

Background: Lesbian, gay and bisexual (LGB) people may be at higher risk of mental disorders than heterosexual people.Method: We conducted a systematic review and meta-analysis of the prevalence of mental disorder, substance misuse, suicide, suicidal ideation and deliberate self harm in LGB people. We searched Medline, Embase, PsycInfo, Cinahl, the Cochrane Library Database, the Web of Knowledge, the Applied Social Sciences Index and Abstracts, the International Bibliography of the Social Sciences, Sociological Abstracts, the Campbell Collaboration and grey literature databases for articles published January 1966 to April 2005. We also used Google and Google Scholar and contacted authors where necessary. We searched all terms related to homosexual, lesbian and bisexual people and all terms related to mental disorders, suicide, and deliberate self harm. We included papers on population based studies which contained concurrent heterosexual comparison groups and valid definition of sexual orientation and mental health outcomes.Results: Of 13706 papers identified, 476 were initially selected and 28 (25 studies) met inclusion criteria. Only one study met all our four quality criteria and seven met three of these criteria. Data was extracted on 214,344 heterosexual and 11,971 non heterosexual people. Meta-analyses revealed a two fold excess in suicide attempts in lesbian, gay and bisexual people [ pooled risk ratio for lifetime risk 2.47 (CI 1.87, 3.28)]. The risk for depression and anxiety disorders (over a period of 12 months or a lifetime) on meta-analyses were at least 1.5 times higher in lesbian, gay and bisexual people (RR range 1.54-2.58) and alcohol and other substance dependence over 12 months was also 1.5 times higher (RR range 1.51-4.00). Results were similar in both sexes but meta analyses revealed that lesbian and bisexual women were particularly at risk of substance dependence (alcohol 12 months: RR 4.00, CI 2.85, 5.61; drug dependence: RR 3.50, CI 1.87, 6.53; any substance use disorder RR 3.42, CI 1.97-5.92), while lifetime prevalence of suicide attempt was especially high in gay and bisexual men (RR 4.28, CI 2.32, 7.88).Conclusion: LGB people are at higher risk of mental disorder, suicidal ideation, substance misuse, and deliberate self harm than heterosexual people

The Association of the COVID-19 Pandemic on Male Sexual Function in the United States: A Survey Study of Male Cannabis Users

Introduction: International studies have suggested that social disruptions caused by the COVID-19 pandemic have led to sexual dysfunction, but the impact on males in the United States is less defined. Aim: To examine changes in male sexual function during the COVID-19 pandemic and to evaluate associated demographic variables. Methods: Prepandemic survey data was collected between October 20, 2019 and March 1, 2020 on adult males in the United States. Follow-up survey data collected for comparison during the COVID-19 pandemic between August 1, 2020 and October 10, 2020 included International Index of Erectile Function (IIEF) scores, Patient Health Questionnaire for Depression and Anxiety with 4 items (PHQ-4) scores, and questions regarding sexual frequency. Questions were also asked about mask-wearing habits, job loss, relationship changes, and proximity to individuals who tested positive for COVID-19. Main Outcome Measures: Differences in prepandemic and pandemic male sexual function assessed by self-reported IIEF domain scores and sexual frequency Results: Seventy six men completed both prepandemic and pandemic surveys with a mean age of 48.3 years. Overall, there were no differences in either overall IIEF score or any subdomain score when comparing men's pre-pandemic and pandemic survey data. There was an increase in sexual frequency during the pandemic with 45% of men reporting sex ten or more times per month during the pandemic compared to only 25% of men prior to the pandemic (P = .03). Among the subgroup of 36 men who reported a decrease in IIEF, the decrease was an average of 3.97, and significantly associated with higher PHQ-4 depression subscale scores (1.78 vs 1.03, P = .02). Conclusion: The COVID-19 pandemic is associated with increased sexual frequency and no change in overall sexual function in males in the United States. Interventions intended to promote male sexual health during the COVID-19 pandemic should include a focus on mental health. Chen T, Bhambhvani HP, Kasman AM, et al. The Association of the COVID-19 Pandemic on Male Sexual Function in the United States: A Survey Study of Male Cannabis Users. J Sex Med 2021;9:100340

Association of Bicycle-Related Genital Numbness and Female Sexual Dysfunction: Results From a Large, Multinational, Cross-Sectional Study

ABSTRACT: Introduction: Cycling can lead to microtrauma due to increased perineal pressure, possibly contributing to genital numbness and sexual dysfunction in female cyclists. Aim: We aim to explore the associations between cycling characteristics, female genital numbness, and female sexual dysfunction. Methods: We conducted a cross-sectional study on female cyclists and sexual wellness. Participants were recruited through Facebook® advertisements and online outreach at athletic clubs. Participants were asked about their cycling characteristics, genital numbness, and female sexual function using the Female Sexual Function Index (FSFI). Univariate and multivariable linear and logistic regression were used to assess risk factors for genital numbness and the association between genital numbness and the FSFI. Outcome Measures: The outcome measures were cycling characteristics, questions regarding numbness (intensity, duration, location), and the FSFI score. Results: Eight-hundred and seventy-five women were included in the study. Total lifetime miles cycled, biking duration, frequency, distance, speed, and biking surface were not significantly associated with genital numbness. Higher handlebar height was associated with less numbness. The prevalence of sexual dysfunction in the cohort was 52%. Genital numbness was significantly associated with sexual dysfunction (OR: 1.43, 95% CI: 1.05 – 1.95). Sub-group analysis for location of numbness demonstrated significant increase in risk for sexual dysfunction in cyclists who described numbness aro`und the perineum (OR: 2.72, 95% CI: 1.05 – 7.02) and the vulva (OR: 1.55, 95% CI: 1.13 – 2.13). There was also a significant increase in the risk of sexual dysfunction in cyclists who reported a longer duration of numbness (OR: 6.58, 95% CI: 2.27 – 19.07). Conclusions: Genital numbness is common in women who cycle and is associated with increased risk of FSD and lower average sexual response scores on FSFI. Lui H, Mmonu N, Awad MA, et al. Association of Bicycle-Related Genital Numbness and Female Sexual Dysfunction: Results From a Large, Multinational, Cross-Sectional Study. Sex Med 2021;9:100365

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the 247DLIIKGISVHI257 segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs. These associations include seven distinct interfaces displaying five different symmetry classes of steric zippers. Additionally, we find that this segment can adopt three different backbone conformations that contribute to its polymorphic capabilities. The polymorphic nature of this segment illustrates at the molecular level how amyloid proteins can form diverse fibril structures

A benchmark for RNA-seq quantification pipelines

Obtaining RNA-seq measurements involves a complex data analytical process with a large number of competing algorithms as options. There is much debate about which of these methods provides the best approach. Unfortunately, it is currently difficult to evaluate their performance due in part to a lack of sensitive assessment metrics. We present a series of statistical summaries and plots to evaluate the performance in terms of specificity and sensitivity, available as a R/Bioconductor package (http://bioconductor.org/packages/rnaseqcomp). Using two independent datasets, we assessed seven competing pipelines. Performance was generally poor, with two methods clearly underperforming and RSEM slightly outperforming the rest