Novel pharmacological actions of Trequinsin Hydrochloride improve human sperm cell motility and function

Background and purposeAsthenozoospermia is a leading cause of male infertility, but the development of pharmaceuticals to improve sperm motility has been hindered by the lack of effective screening platforms and knowledge of suitable molecular targets. We have demonstrated that a high throughput screening (HTS) strategy in conjunction with established in vitro tests can identify and characterise the action of compounds that improve sperm motility. The study aimed to apply HTS to identify new compounds from a novel small molecule library that increase intracellular calcium, [Ca2+]I, promote human sperm cell motility and systemically determine the mechanism of action. Experimental approach A validated HTS fluorometric [Ca2+]i assay was used to screen an in-house library of compounds. Trequinsin hydrochloride (a phosphodiesterase 3 inhibitor) was selected for detailed molecular (plate reader assays, electrophysiology and cyclic nucleotide measurement) and functional (motility and acrosome reaction) testing in sperm from healthy volunteer donors and, where possible, patients.   Key resultsThe fluorometric analysis identified Trequinsin as an efficacious agonist of [Ca2+]i, although less potent than progesterone (P4). Functionally, Trequinsin significantly increased cell hyperactivation and penetration into viscous medium in all donor sperm samples and cell hyperactivation in 22/25 (88%) patient sperm samples. The Trequinsin-induced [Ca2+]i response was cross-desensitised consistently by prostaglandin E1 but not with P4. Whole-cell patch clamp electrophysiology confirmed that Trequinsin activates CatSper and partially inhibits potassium channel activity. Trequinsin also increases intracellular cGMP.   Conclusion and Implications Trequinsin exhibits a novel pharmacological profile in human sperm and may be a suitable lead compound for the development of new pharmaceuticals to improve patient sperm function and fertilisation potential

Prevalence of subclinical cardiac abnormalities in patients with metal-on-metal hip replacements

Background Metal-on-metal (MOM) hip prostheses have a higher failure rate than conventional prostheses and leaching of cobalt and chromium has been linked to cardiomyopathy. We screened MOM subjects to evaluate if cobalt and chromium are related to subclinical cardiac dysfunction. Methods A single centre, non-randomised, observational study using echocardiography in 95 patients who had undergone MOM hip prostheses, and 15 age matched controls with non-MOM hip replacement. Serial plasma cobalt and chromium levels were recorded, and data compared by tertiles of cobalt exposure. Results Indexed left ventricular (LV) end-diastolic and end-systolic volumes (EDVi and ESVi) increased with tertile of cobalt (omnibus p = 0.003 for EDVi and ESVi), as did indexed left atrial (LA) volumes (p = 0.003). MOM subjects had 25% larger EDVi than controls, 32% larger ESVi (40 ml vs. 32 ml, and 15 ml vs. 11 ml, p = 0.003 for both) and 28% larger indexed LA (23 ml vs. 18 ml, p = 0.002). There were no differences in LV systolic or diastolic function, including ejection fraction, tissue velocity and mitral E/e′. Estimated glomerular filtration rate was 18% lower in the highest tertile compared with the lowest (p = 0.01) and correlated inversely with LA volume (r = −0.36, p < 0.001) and LV EDV (r = −0.24, p = 0.02). Conclusions No correlations between sensitive measures of systolic or diastolic cardiac function or serum cobalt/chromium levels were observed in this study. However, there was a relationship between increasing left ventricular and left atrial volumes and declining renal function with high cobalt levels which requires further evaluation in MOM patients

What do young athletes implicitly understand about psychological skills?

One reason sport psychologists teach psychological skills is to enhance performance in sport; but the value of psychological skills for young athletes is questionable because of the qualitative and quantitative differences between children and adults in their understanding of abstract concepts such as mental skills. To teach these skills effectively to young athletes, sport psychologists need to appreciate what young athletes implicitly understand about such skills because maturational (e.g., cognitive, social) and environmental (e.g., coaches) factors can influence the progressive development of children and youth. In the present qualitative study, we explored young athletes’ (aged 10–15 years) understanding of four basic psychological skills: goal setting, mental imagery, self-talk, and relaxation. Young athletes (n = 118: 75 males and 43 females) completed an open-ended questionnaire to report their understanding of these four basic psychological skills. Compared with the older youth athletes, the younger youth athletes were less able to explain the meaning of each psychological skill. Goal setting and mental imagery were better understood than self-talk and relaxation. Based on these findings, sport psychologists should consider adapting interventions and psychoeducational programs to match young athletes’ age and developmental level

An ancient Turing-like patterning mechanism regulates skin denticle development in sharks

Vertebrates possess a vast array of epithelial appendages, including scales, feathers and hair. The developmental patterning of these diverse structures can be theoretically explained by Alan Turing’s reaction-diffusion (RD) system. However, the role of this system in epithelial appendage patterning of early diverging lineages (compared to tetrapods), such as the cartilaginous fishes, is poorly understood. We investigate patterning of the unique tooth-like skin denticles of sharks, which closely relates to their hydrodynamic and protective functions. We demonstrate through simulation models that a Turing-like mechanism can explain shark denticle patterning and verify this system using gene expression analysis and gene pathway inhibition experiments. This mechanism bears remarkable similarity to avian feather patterning, suggesting deep homology of the system. We propose that a diverse range of vertebrate appendages, from shark denticles to avian feathers and mammalian hair, utilize this ancient and conserved system, with slight genetic modulation accounting for broad variations in patterning

A corpus-assisted study of the discourse marker well as an indicator of judges' institutional roles in court cases with litigants in person

In this paper, I concentrate on court cases with litigants in person (lay people who act on their own behalf in legal proceedings without a counsel or solicitor) and discuss the challenges of building a corpus of courtroom discourse where it is crucial to distinguish between speakers due to their distinct institutional roles. The corpus incorporates seven sub-corpora of verbatim transcripts from different court cases with litigants in person and comprises over eleven-million tokens. The focus of this paper is on the interplay between the legal and lay discourse types and how judges project their institutional roles through well-initiated turns directed at litigants in person and counsels. As a versatile discourse marker, well provides a good opportunity to explore how judges have to adapt their roles to ensure lay litigants in person receive the necessary support and that their lack of competence does not impede on the fairness of the proceedings. Given the breadth and importance of the topic of litigation in person, I discuss how the tools and approaches of corpus linguistics can be helpful in this multi-disciplinary area where multiple functions and uses of individual linguistic features need to be explored in depth

Observation of non-Hermitian degeneracies in a chaotic exciton-polariton billiard

This research was supported by the Australian Research Council, the ImPACT Program of the Council for Science, Technology and Innovation (Cabinet Office, Government of Japan), the RIKEN iTHES Project, the MURI Center for Dynamic Magneto-Optics, a Grant-in-Aid for Scientific Research (type A), and the State of Bavaria.Exciton-polaritons are hybrid light-matter quasiparticles formed by strongly interacting photons and excitons (electron-hole pairs) in semiconductor microcavities. They have emerged as a robust solid-state platform for next-generation optoelectronic applications as well as for fundamental studies of quantum many-body physics. Importantly, exciton-polaritons are a profoundly open (that is, non-Hermitian) quantum system, which requires constant pumping of energy and continuously decays, releasing coherent radiation. Thus, the exciton-polaritons always exist in a balanced potential landscape of gain and loss. However, the inherent non-Hermitian nature of this potential has so far been largely ignored in exciton-polariton physics. Here we demonstrate that non-Hermiticity dramatically modifies the structure of modes and spectral degeneracies in exciton-polariton systems, and, therefore, will affect their quantum transport, localization and dynamical properties. Using a spatially structured optical pump, we create a chaotic exciton-polariton billiard-a two-dimensional area enclosed by a curved potential barrier. Eigenmodes of this billiard exhibit multiple non-Hermitian spectral degeneracies, known as exceptional points. Such points can cause remarkable wave phenomena, such as unidirectional transport, anomalous lasing/absorption and chiral modes. By varying parameters of the billiard, we observe crossing and anti-crossing of energy levels and reveal the non-trivial topological modal structure exclusive to non-Hermitian systems. We also observe mode switching and a topological Berry phase for a parameter loop encircling the exceptional point. Our findings pave the way to studies of non-Hermitian quantum dynamics of exciton-polaritons, which may uncover novel operating principles for polariton-based devices.PostprintPeer reviewe

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices)

In the European Union (EU), the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, while authorising the placing on the market of medical devices is decentralised to independent 'conformity assessment' organisations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the Medical Device Directive, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre-and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024. Here, we describe how it may contribute to the development of regulatory science in Europe.Orthopaedics, Trauma Surgery and Rehabilitatio

Circumstellar interaction in supernovae in dense environments - an observational perspective

In a supernova explosion, the ejecta interacting with the surrounding circumstellar medium (CSM) give rise to variety of radiation. Since CSM is created from the mass lost from the progenitor star, it carries footprints of the late time evolution of the star. This is one of the unique ways to get a handle on the nature of the progenitor star system. Here, I will focus mainly on the supernovae (SNe) exploding in dense environments, a.k.a. Type IIn SNe. Radio and X-ray emission from this class of SNe have revealed important modifications in their radiation properties, due to the presence of high density CSM. Forward shock dominance of the X-ray emission, internal free-free absorption of the radio emission, episodic or non-steady mass loss rate, asymmetry in the explosion seem to be common properties of this class of SNe.Comment: Fixed minor typos. 31 pages, 9 figures, accepted for publication in Space Science Reviews. Chapter in International Space Science Institute (ISSI) Book on "Supernovae" to be published in Space Science Reviews by Springe

Slow-blue nuclear hypervariables in PanSTARRS-1

We discuss 76 large amplitude transients (Δm > 1.5) occurring in the nuclei of galaxies, nearly all with no previously known active galactic nucleus (AGN). They have been discovered as part of the Pan-STARRS1 (PS1) 3π survey, by comparison with Sloan Digital Sky Survey (SDSS) photometry a decade earlier, and then monitored with the Liverpool Telescope, and studied spectroscopically with the William Herschel Telescope (WHT). Based on colours, light-curve shape, and spectra, these transients fall into four groups. A few are misclassified stars or objects of unknown type. Some are red/fast transients and are known or likely nuclear supernovae. A few are either radio sources or erratic variables and so likely blazars. However the majority (∼66 per cent) are blue and evolve slowly, on a time-scale of years. Spectroscopy shows them to be AGN at z ∼ 0.3 − 1.4, which must have brightened since the SDSS photometry by around an order of magnitude. It is likely that these objects were in fact AGN a decade ago, but too weak to be recognized by SDSS; they could then be classed as ‘hypervariable’ AGN. By searching the SDSS Stripe 82 quasar database, we find 15 similar objects. We discuss several possible explanations for these slow-blue hypervariables – (i) unusually luminous tidal disruption events; (ii) extinction events; (iii) changes in accretion state; and (iv) large amplitude microlensing by stars in foreground galaxies. A mixture of explanations (iii) and (iv) seems most likely. Both hold promise of considerable new insight into the AGN phenomenon