The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.

Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals.

How does the sexual, physical and mental health of young adults not in education, employment or training (NEET) compare to workers and students?

BACKGROUND: Syndemic theory highlights the potential for health problems to interact synergistically, compounding impact. Young adults not in education, employment or training (NEET) are more likely to experience disadvantage and poorer general health outcomes. However, there is little research on their sexual health, or the extent to which this clusters with mental and physical health outcomes. METHODS: Analysis of data from 16 to 24 year olds (1729 men, 2140 women) interviewed 2010-12 for Britain's third National Survey of Sexual Attitudes and Lifestyles. Natsal-3 is a national probability sample survey using computer-assisted personal interviewing with computer-assisted self-interviewing. Participants were classified as workers, students or NEET. We used multivariable logistic regression to examine associations between being NEET (relative to worker or student) and risk behaviours and outcomes in physical, sexual and mental health domains. We then examined how risk behaviours and poor health outcomes cluster within and across domains. RESULTS: 15% men and 20% women were NEET; 36% men and 32% women were workers; and 49% men and 48% women were students. Young people who were NEET were more likely to report smoking and drug use (men) than other young people. There were few differences in sexual health, although NEETs were more likely to report condomless sex, and NEET women, unplanned pregnancy (past year). Risk behaviours clustered more within and across domains for NEET men. Among NEET women, poor health outcomes clustered across mental, physical and sexual health domains. CONCLUSIONS: Harmful health behaviours (men) and poor health outcomes (women) clustered more in those who are NEET. This points to a possible syndemic effect of NEET status on general ill health, especially for women. Our paper is novel in highlighting that elevated risk pertains to sexual as well as mental and physical health.

Myostatin-like proteins regulate synaptic function and neuronal morphology.

Growth factors of the TGFß superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner. Both myostatin and GDF11 affected synapse formation in isolated rat cortical neuron cultures, suggesting an effect on synaptogenesis beyond neuromuscular junctions. We also show that MYO acts in vivo to inhibit synaptic transmission between neurons in the escape response neural circuit of adult flies. Thus, these anti-myogenic proteins act as important inhibitors of synapse function and neuronal growth.

Finding sexual partners online: prevalence and associations with sexual behaviour, STI diagnoses and other sexual health outcomes in the British population.

OBJECTIVES: Online venues might facilitate sexual encounters, but the extent to which finding partners online is associated with sexual risk behaviour and sexual health outcomes is unclear. We describe use of the internet to find sexual partners in a representative sample in Britain. METHODS: The third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) was a cross-sectional probability survey of 15 162 adults (aged 16-74 years) undertaken 2010-2012. We estimated prevalence of, and identified factors associated with, finding sexual partners online among those reporting ≥1 new sexual partners in the past year. RESULTS: Finding sexual partners online in the past year was reported by 17.6% (95% CI 15.6 to 19.9) of men and 10.1% (8.5-11.9) of women, and most common among those aged 35-44 years. After age-adjustment, those reporting a non-heterosexual identity were more likely to report this. Finding partners online was also associated with reporting sexual risk behaviours: condomless sex with ≥2 partners (adjusted OR (aOR) men: 1.52 (1.03 to 2.23); women: 1.62 (1.06 to 2.49)), concurrent partnerships (aOR men: 2.33 (1.62 to 3.35); women: 2.41 (1.49 to 3.87)) and higher partner numbers (reporting ≥5 partners aOR men: 5.95 (3.78 to 9.36); women: 7.00 (3.77 to 13.00)) (all past year). STI diagnoses and HIV testing were more common among men reporting finding partners online (adjusted for age, partner numbers, same-sex partnerships), but not women. CONCLUSIONS: Finding partners online was associated with markers of sexual risk, which might be important for clinical risk assessment, but this was not matched by uptake of sexual health services. Online opportunities to find partners have increased, so these data might underestimate the importance of this social phenomenon for public health and STI control.

Establishing risk factors and outcomes for congenital hypothyroidism with gland in situ using population-based data linkage methods: study protocol.

INTRODUCTION: There has been an increase in the birth prevalence of congenital hypothyroidism (CH) since the introduction of newborn screening, both globally and in the UK. This increase can be accounted for by an increase in CH with gland in situ (CH-GIS). It is not known why CH-GIS is becoming more common, nor how it affects the health, development and learning of children over the long term. Our study will use linked administrative health, education and clinical data to determine risk factors for CH-GIS and describe long-term health and education outcomes for affected children. METHODS AND ANALYSIS: We will construct a birth cohort study based on linked, administrative data to determine what factors have contributed to the increase in the birth prevalence of CH-GIS in the UK. We will also set up a follow-up study of cases and controls to determine the health and education outcomes of children with and without CH-GIS. We will use logistic/multinomial regression models to establish risk factors for CH-GIS. Changes in the prevalence of risk factors over time will help to explain the increase in birth prevalence of CH-GIS. Multivariable generalised linear models or Cox proportional hazards regression models will be used to assess the association between type of CH and school performance or health outcomes. ETHICS AND DISSEMINATION: This study has been approved by the London Queen Square Research Ethics Committee and the Health Research Authority's Confidentiality Advisory Group CAG. Approvals are also being sought from each data provider. Obtaining approvals from CAG, data providers and information governance bodies have caused considerable delays to the project. Our methods and findings will be published in peer-reviewed journals and presented at academic conferences.

Equity considerations in outcome measures of the HIV pre-exposure prophylaxis care continuum in high-income countries: a systematic review protocol.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP) is an effective intervention to reduce acquisition of HIV. PrEP provision has increased in recent years, however, it is not known whether PrEP implementation has been equitably implemented across all risk groups, particularly groups experiencing high levels of health inequity. A PrEP care continuum (PCC) has been proposed to evaluate the success of PrEP implementation programmes, but the extent to which health equity characteristics are currently taken into account in the PCC has not been described. The objectives of this proposed systematic review are to (i) identify and collate outcome measure definitions for the main stages of the PCC (awareness, acceptability, uptake, adherence and retention), (ii) describe how equity characteristics are considered in outcome definitions of the PCC and (iii) describe data sources for capturing equity characteristics. METHODS AND ANALYSIS: Quantitative studies published between 1 January 2012 and 3 March 2020 will be included. Five databases (MEDLINE, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Applied Social Sciences Index and Abstracts) will be searched to identify English language publications that include an outcome measure definition of at least one of the five main stages of the PCC. Risk of bias will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Data on outcome measure definitions and equity characteristics will be extracted. Results will be presented in a narrative synthesis and all findings will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required. The results will be disseminated via submission for publication to a peer-reviewed journal when complete. The review findings will have relevance to healthcare professionals, policymakers and commissioners in informing how to best evaluate PrEP implementation programmes and inform new implementation strategies for vulnerable and less advantaged populations. PROSPERO REGISTRATION NUMBER: CRD42020169779.

Approaches for combining primary care electronic health record data from multiple sources: a systematic review of observational studies.

OBJECTIVE: To identify observational studies which used data from more than one primary care electronic health record (EHR) database, and summarise key characteristics including: objective and rationale for using multiple data sources; methods used to manage, analyse and (where applicable) combine data; and approaches used to assess and report heterogeneity between data sources. DESIGN: A systematic review of published studies. DATA SOURCES: Pubmed and Embase databases were searched using list of named primary care EHR databases; supplementary hand searches of reference list of studies were retained after initial screening. STUDY SELECTION: Observational studies published between January 2000 and May 2018 were selected, which included at least two different primary care EHR databases. RESULTS: 6054 studies were identified from database and hand searches, and 109 were included in the final review, the majority published between 2014 and 2018. Included studies used 38 different primary care EHR data sources. Forty-seven studies (44%) were descriptive or methodological. Of 62 analytical studies, 22 (36%) presented separate results from each database, with no attempt to combine them; 29 (48%) combined individual patient data in a one-stage meta-analysis and 21 (34%) combined estimates from each database using two-stage meta-analysis. Discussion and exploration of heterogeneity was inconsistent across studies. CONCLUSIONS: Comparing patterns and trends in different populations, or in different primary care EHR databases from the same populations, is important and a common objective for multi-database studies. When combining results from several databases using meta-analysis, provision of separate results from each database is helpful for interpretation. We found that these were often missing, particularly for studies using one-stage approaches, which also often lacked details of any statistical adjustment for heterogeneity and/or clustering. For two-stage meta-analysis, a clear rationale should be provided for choice of fixed effect and/or random effects or other models.

Increased Glucose Transport into Neurons Rescues Aß Toxicity in Drosophila.

Glucose hypometabolism is a prominent feature of the brains of patients with Alzheimer's disease (AD). Disease progression is associated with a reduction in glucose transporters in both neurons and endothelial cells of the blood-brain barrier. However, whether increasing glucose transport into either of these cell types offers therapeutic potential remains unknown. Using an adult-onset Drosophila model of Aß (amyloid beta) toxicity, we show that genetic overexpression of a glucose transporter, specifically in neurons, rescues lifespan, behavioral phenotypes, and neuronal morphology. This amelioration of Aß toxicity is associated with a reduction in the protein levels of the unfolded protein response (UPR) negative master regulator Grp78 and an increase in the UPR. We further demonstrate that genetic downregulation of Grp78 activity also protects against Aß toxicity, confirming a causal effect of its alteration on AD-related pathology. Metformin, a drug that stimulates glucose uptake in cells, mimicked these effects, with a concomitant reduction in Grp78 levels and rescue of the shortened lifespan and climbing defects of Aß-expressing flies. Our findings demonstrate a protective effect of increased neuronal uptake of glucose against Aß toxicity and highlight Grp78 as a novel therapeutic target for the treatment of AD.

Lithium suppresses Aß pathology by inhibiting translation in an adult Drosophila model of Alzheimer's disease.

The greatest risk factor for Alzheimer's disease (AD) is age, and changes in the ageing nervous system are likely contributors to AD pathology. Amyloid beta (Aß) accumulation, which occurs as a result of the amyloidogenic processing of amyloid precursor protein (APP), is thought to initiate the pathogenesis of AD, eventually leading to neuronal cell death. Previously, we developed an adult-onset Drosophila model of AD. Mutant Aß42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aß42 protein, but not mRNA, and was able to rescue Aß42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aß42 protein levels and Aß42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aß42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aß42, but it rescued lifespan only at lower doses, suggesting that long-term, high-dose lithium treatment may have induced toxicity. Lithium also down-regulated translation in the fission yeast Schizosaccharomyces pombe associated with increased chronological lifespan. Our data highlight a role for lithium and reduced protein synthesis as potential therapeutic targets for AD pathogenesis.

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted "RNA-only" repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.

Biological effects of the anti-parasitic chemotherapeutant emamectin benzoate on a non-target crustacean, the spot prawn (Pandalus platyceros Brandt, 1851) under laboratory conditions.

The potential impact of commercial salmon aquaculture along the coast of British Columbia on the health of non-target marine wildlife is of growing concern. In the current initiative, the biological effects on gene expression within spot prawn (Pandalus platyceros) exposed to the sea lice controlling agent, emamectin benzoate (EB; 0.1-4.8 mg/kg sediment), were investigated. A mean sediment/water partitioning coefficient (K(p)) was determined to be 21.81 and significant levels of EB were detected in the tail muscle tissue in all exposed animals. Animals selected for the experiment did not have eggs and were of similar weight. Significant mortality was observed within 8 days of EB treatment at concentrations between 0.1 and 0.8 mg/kg and there was no effect of EB on molting. Twelve spot prawn cDNA sequences were isolated from the tail muscle either by directed cloning or subtractive hybridization of control versus EB exposed tissues. Three of the transcripts most affected by EB exposure matched sequences encoding the 60S ribosomal protein L22, spliceosome RNA helicase WM6/UAP56, and the intracellular signal mediator histidine triad nucleotide binding protein 1 suggesting that translation, transcription regulation, and apoptosis pathways were impacted. The mRNA encoding the molting enzyme, ß-N-acetylglucosaminidase, was not affected by EB treatment. However, the expression of this transcript was extremely variable making it unsuitable for effects assessment. The results suggest that short-term exposure to EB can impact biological processes within this non-target crustacean.