CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

Contains fulltext : 229376.pdf (publisher's version ) (Open Access)Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45(-/-) mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module

What works in falls prevention in Asia: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: There is strong research evidence for falls prevention among older people in the community setting, although most is from Western countries. Differences between countries (eg sunlight exposure, diet, environment, exercise preferences) may influence the success of implementing falls prevention approaches in Asian countries that have been shown to be effective elsewhere in the world. The aim of this review is to evaluate the scope and effectiveness of falls prevention randomized controlled trials (RCTs) from the Asian region. METHOD: RCTs investigating falls prevention interventions conducted in Asian countries from (i) the most recent (2012) Cochrane community setting falls prevention review, and (ii) subsequent published RCTs meeting the same criteria were identified, classified and grouped according to the ProFANE intervention classification. Characteristics of included trials were extracted from both the Cochrane review and original publications. Where =2 studies investigated an intervention type in the Asian region, a meta-analysis was performed. RESULTS: Fifteen of 159 RCTs in the Cochrane review were conducted in the Asian region (9%), and a further 11 recent RCTs conducted in Asia were identified (total 26 Asian studies: median 160 participants, mean age:75.1, female:71.9%). Exercise (15 RCTs) and home assessment/modification (n?=?2) were the only single interventions with =2 RCTs. Intervention types with =1 effective RCT in reducing fall outcomes were exercise (6 effective), home modification (1 effective), and medication (vitamin D) (1 effective). One multiple and one multifactorial intervention also had positive falls outcomes. Meta-analysis of exercise interventions identified significant benefit (number of fallers: Odds Ratio 0.43 [0.34,0.53]; number of falls: 0.35 [0.21,0.57]; and number of fallers injured: 0.50 [0.35,0.71]); but multifactorial interventions did not reach significance (number of fallers OR?=?0.57 [0.23,1.44]). CONCLUSION: There is a small but growing research base of falls prevention RCTs from Asian countries, with exercise approaches being most researched and effective. For other interventions shown to be effective elsewhere, consideration of local issues is required to ensure that research and programs implemented in these countries are effective, and relevant to the local context, people, and health system. There is also a need for further high quality, appropriately powered falls prevention trials in Asian countries

Therapeutic potential of venom peptides

Venomous animals have evolved a vast array of peptide toxins for prey capture and defence. These peptides are directed against a wide variety of pharmacological targets, making them an invaluable source of ligands for studying the properties of these targets in different experimental paradigms. A number of these peptides have been used in vivo for proof-of-concept studies, with several having undergone preclinical or clinical development for the treatment of pain, diabetes, multiple sclerosis and cardiovascular diseases. Here we survey the pharmacology of venom peptides and assess their therapeutic prospects

Genome-wide association study of PR interval

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation