Low testosterone: Androgen deficiency, endurance exercise training, and competitive performance

Purpose Our intent was to (a) characterize weekly changes in resting testosterone (T), cortisol (C), and the T:C ratio in males during an intensive endurance training program, and (b) determine if clinical androgen deficiency (AD) based upon T-level criteria developed. Methods An 18-week training program in which individual training volume (km/week) increased at 25% increments over baseline (BL) levels observed prior to the study beginning at 4-week intervals throughout the first 12 weeks. After 12 weeks, the volume was reduced to that of the first 4 weeks until the study end (week 18). Competitive performance running tests were assessed at BL and every 4 weeks, while blood T and C were assessed weekly. Results Performance improved from BL at weeks 4–16 (p < 0.01). T was reduced (p < 0.01) from BL at weeks 3, and 5–18. The greatest reduction from BL was at week 13, subsequently T returned toward BL at week 18. C was highly variable, and no significant changes from BL were noted. The T:C ratio at weeks 5, 6, and 8–16 was significantly less than at BL (p < 0.01), the greatest reduction at week 13. The T:C ratio values also returned toward BL by week 18. Finally, ∼50% of the subjects reached T levels to be classified as AD. Conclusions Sports scientists should recognize decreases in T or T:C ratio is not always indicative of compromised competitive performance potential. Clinicians should be aware increased training loads can lead to AD in men

Developing standards for reporting implementation studies of complex interventions (StaRI): a systematic review and e-Delphi

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited

Full Genome Characterization of the Culicoides-Borne Marsupial Orbiviruses: Wallal Virus, Mudjinbarry Virus and Warrego Viruses

Viruses belonging to the species Wallal virus and Warrego virus of the genus Orbivirus were identified as causative agents of blindness in marsupials in Australia during 1994/5. Recent comparisons of nucleotide (nt) and amino acid (aa) sequences have provided a basis for the grouping and classification of orbivirus isolates. However, full-genome sequence data are not available for representatives of all Orbivirus species. We report full-genome sequence data for three additional orbiviruses: Wallal virus (WALV); Mudjinabarry virus (MUDV) and Warrego virus (WARV). Comparisons of conserved polymerase (Pol), sub-core-shell 'T2' and core-surface 'T13' proteins show that these viruses group with other Culicoides borne orbiviruses, clustering with Eubenangee virus (EUBV), another orbivirus infecting marsupials. WARV shares <70% aa identity in all three conserved proteins (Pol, T2 and T13) with other orbiviruses, consistent with its classification within a distinct Orbivirus species. Although WALV and MUDV share <72.86%/67.93% aa/nt identity with other orbiviruses in Pol, T2 and T13, they share >99%/90% aa/nt identities with each other (consistent with membership of the same virus species - Wallal virus). However, WALV and MUDV share <68% aa identity in their larger outer capsid protein VP2(OC1), consistent with membership of different serotypes within the species - WALV-1 and WALV-2 respectively

Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data.

BackgroundAlthough studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.MethodsWe used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo.ResultsIn mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors.ConclusionsWe speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth

Novel pheromone-mediated reproductive behaviour in the stag beetle, Lucanus cervus

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The datasets generated during and/or analysed during the current study are available via the corresponding authors on reasonable request.The iconic European stag beetle (Lucanus cervus) (Coleoptera: Lucanidae) is one of the largest terrestrial beetles in Europe. Due to decreasing population numbers, thought to be a consequence of habitat loss, this beetle has become a near-threatened species across much of Europe, and a reliable monitoring system is required to measure its future population trends. As part of a programme aimed at conserving UK populations, we have investigated the chemical ecology of the beetle, with a view to developing an efficient semiochemical-based monitoring system. Such a scheme will be beneficial not only in the UK but across the European range of the species, where the beetle is of conservation concern. Here, we report on a surprising discovery of a male-produced pheromone, which provokes initial sexual receptivity in females, and which has not been previously identified in the animal kingdom. Furthermore, we assign sex pheromone function to a previously described female-specific compound.Biotechnology and Biological Sciences Research Council (BBSRC)People’s Trust for Endangered SpeciesBritish Ecological Societ

Intravenous Inoculation of a Bat-Associated Rabies Virus Causes Lethal Encephalopathy in Mice through Invasion of the Brain via Neurosecretory Hypothalamic Fibers

The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown whether hematogenous spread has any relevance in RV pathogenesis. To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB. In addition to monitoring the progression of clinical signs of rabies we used immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to follow the spread of the virus from the infection site to the brain. In contrast to i.m. infection where both variants caused a lethal encephalopathy, only i.v. infection with SB resulted in the development of a lethal infection. While qRT-PCR did not reveal major differences in virus loads in spinal cord or brain at different times after i.m. or i.v. infection of SB, immunohistochemical analysis showed that only i.v. administered SB directly infected the forebrain. The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence. Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system. This alternative mode of virus spread has implications for the post exposure prophylaxis of rabies, particularly with silver-haired bat-associated RV

The Structural Features of Trask That Mediate Its Anti-Adhesive Functions

Trask/CDCP1 is a transmembrane protein with a large extracellular and small intracellular domains. The intracellular domain (ICD) undergoes tyrosine phosphorylation by Src kinases during anchorage loss and, when phosphorylated, Trask functions to inhibit cell adhesion. The extracellular domain (ECD) undergoes proteolytic cleavage by serine proteases, although the functional significance of this remains unknown. There is conflicting evidence regarding whether it functions to signal the phosphorylation of the ICD. To better define the structural determinants that mediate the anti-adhesive functions of Trask, we generated a series of deletion mutants of Trask and expressed them in tet-inducible cell models to define the structural elements involved in cell adhesion signaling. We find that the ECD is dispensable for the phosphorylation of the ICD or for the inhibition of cell adhesion. The anti-adhesive functions of Trask are entirely embodied within its ICD and are specifically due to tyrosine phosphorylation of the ICD as this function is completely lost in a phosphorylation-defective tyrosine-phenylalanine mutant. Both full length and cleaved ECDs are fully capable of phosphorylation and undergo phosphorylation during anchorage loss and cleavage is not an upstream signal for ICD phosphorylation. These data establish that the anti-adhesive functions of Trask are mediated entirely through its tyrosine phosphorylation. It remains to be defined what role, if any, the Trask ECD plays in its adhesion functions

Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-β oligomers

The cellular prion protein (PrPC) is a key neuronal receptor for amyloid-β oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrPC shedding and increased AβO binding, which was blocked by the PrPC-specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrPC shedding and decreased AβO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AβO binding to PrPC Besides blocking AβO binding and toxicity, acitretin also increased the non-amyloidogenic processing of APP. However, in the iPSC-derived neurons, Aβ and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrPC in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AβO, revealing a potential therapeutic benefit of ADAM10 activation in AD

DroID: the Drosophila Interactions Database, a comprehensive resource for annotated gene and protein interactions

<p>Abstract</p> <p>Background</p> <p>Charting the interactions among genes and among their protein products is essential for understanding biological systems. A flood of interaction data is emerging from high throughput technologies, computational approaches, and literature mining methods. Quick and efficient access to this data has become a critical issue for biologists. Several excellent multi-organism databases for gene and protein interactions are available, yet most of these have understandable difficulty maintaining comprehensive information for any one organism. No single database, for example, includes all available interactions, integrated gene expression data, and comprehensive and searchable gene information for the important model organism, <it>Drosophila melanogaster</it>.</p> <p>Description</p> <p>DroID, the <it>Drosophila </it>Interactions Database, is a comprehensive interactions database designed specifically for <it>Drosophila</it>. DroID houses published physical protein interactions, genetic interactions, and computationally predicted interactions, including interologs based on data for other model organisms and humans. All interactions are annotated with original experimental data and source information. DroID can be searched and filtered based on interaction information or a comprehensive set of gene attributes from Flybase. DroID also contains gene expression and expression correlation data that can be searched and used to filter datasets, for example, to focus a study on sub-networks of co-expressed genes. To address the inherent noise in interaction data, DroID employs an updatable confidence scoring system that assigns a score to each physical interaction based on the likelihood that it represents a biologically significant link.</p> <p>Conclusion</p> <p>DroID is the most comprehensive interactions database available for <it>Drosophila</it>. To facilitate downstream analyses, interactions are annotated with original experimental information, gene expression data, and confidence scores. All data in DroID are freely available and can be searched, explored, and downloaded through three different interfaces, including a text based web site, a Java applet with dynamic graphing capabilities (IM Browser), and a Cytoscape plug-in. DroID is available at <url>http://www.droidb.org</url>.</p