Tweek, an Evolutionarily Conserved Protein, Is Required for Synaptic Vesicle Recycling

SummarySynaptic vesicle endocytosis is critical for maintaining synaptic communication during intense stimulation. Here we describe Tweek, a conserved protein that is required for synaptic vesicle recycling. tweek mutants show reduced FM1-43 uptake, cannot maintain release during intense stimulation, and harbor larger than normal synaptic vesicles, implicating it in vesicle recycling at the synapse. Interestingly, the levels of a fluorescent PI(4,5)P2 reporter are reduced at tweek mutant synapses, and the probe is aberrantly localized during stimulation. In addition, various endocytic adaptors known to bind PI(4,5)P2 are mislocalized and the defects in FM1-43 dye uptake and adaptor localization are partially suppressed by removing one copy of the phosphoinositide phosphatase synaptojanin, suggesting a role for Tweek in maintaining proper phosphoinositide levels at synapses. Our data implicate Tweek in regulating synaptic vesicle recycling via an action mediated at least in part by the regulation of PI(4,5)P2 levels or availability at the synapse

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Age-specific population centiles for androgen status in men

AimThe age-specific population profiles in men of circulating testosterone and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described.ObjectiveOur objective was to deduce smoothed age-specific centiles of circulating testosterone, DHT, and E2 in men using pooled data from population-based studies in three Australian cities from liquid chromatography-mass spectrometry steroid measurements in a single laboratory.Design, setting, and participantsWe pooled data of 10 904 serum samples (serum testosterone, DHT, E2, age, height, and weight) from observational population-based studies in three major cities across Australia.Main outcome measuresAge-specific smoothed centiles for serum testosterone, DHT, and E2 in men aged 35-100 years were deduced by large sample data analysis methods.ResultsWe found that serum testosterone, DHT, and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, BMI, and body surface area as well as shorter stature are associated with reduced serum testosterone, DHT, and E2.ConclusionsAmong Australian men, there is a gradual progressive population-wide decline in androgen status during male aging until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.D J Handelsman, B B Yeap, L Flicker, S Martin, G A Wittert and Lam P L

Recovery of Male Reproductive Function After Ceasing Prolonged Testosterone Undecanoate Injections

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.Objective: The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.Materials and Methods: Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later.Results: In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since the last injection.Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn G A Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Witter