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

Serum creatine kinase and lactate dehydrogenase activities in patients with thyroid disorders

Background and Objectives: There is the recognition of a pattern of elevations of serum enzymes in hyperthyroid and hypothyroid patients. The aims of this study were to determine the activities of serum creatine kinase (CK) and lactate deydrogenase (LDH) in thyroid disorders, and to evaluate the relationship between CK, LDH and FT4, and TSH levels.Materials and Methods: In this retrospective study, thyroid function tests, serum CK and LDH activities were obtained from the medical records of newly diagnosed hyperthyroid and hypothyroid patients attending the Endocrinology Clinic at the University Hospital of the West Indies from 2005- 2009.Results: Elevation of CK activity was found in 5 patients (28%, 5/18) with overt hypothyroidism and in 12 patients (24.0%, 12/50) with subclinical hypothyroidism. The mean CK activity in subclinical hypothyroid patients was 179.80 ± 125.68 U/L compared with 389.901 ± 381.20 U/L in overt hypothyroid patients. The elevation of LDH activity was found in 6 patients (33.3%, 6/18) with overt hypothyroidism and in 37 patients (74.0%, 37/50) with subclinical hypothyroidism. In the hypothyroid patients, a positive correlation was found between CK activity and TSH (r = 0.292, P = 0.015), and a negative correlation between CK activity and FT4 (r = - 0.325, P = 0.007); and between FT4 and TSH (r = - 0.371, P = 0.002).Conclusion: The significant elevation in serum CK and LDH activities indicates that these can be used as parameters for screening hypothyroid patients but not hyperthyroid patients

Binary companions of nearby supernova remnants found with Gaia

© ESO, 2017. Aims. We search for runaway former companions of the progenitors of nearby Galactic core-collapse supernova remnants (SNRs) in the Tycho-Gaia astrometric solution (TGAS). Methods. We look for candidates among a sample of ten SNRs with distances 2kpc, taking astrometry and G magnitude from TGAS and B,V magnitudes from the AAVSO Photometric All-Sky Survey (APASS). A simple method of tracking back stars and finding the closest point to the SNR centre is shown to have several failings when ranking candidates. In particular, it neglects our expectation that massive stars preferentially have massive companions. We evolve a grid of binary stars to exploit these covariances in the distribution of runaway star properties in colour - magnitude - ejection velocity space. We construct an analytic model which predicts the properties of a runaway star, in which the model paramet ers are the location in the grid of progenitor binaries and the properties of the SNR. Using nested sampling we calculate the Bayesian evidence for each candidate to be the runaway and simultaneously constrain the properties of that runaway and of the SNR itself. Results. We identify four likely runaway companions of the Cygnus Loop (G074.0-08.5), HB 21 (G089.0+ 04.7), S147 (G180.0+ 01.7) and the Monoceros Loop (G205.5+ 00.5). HD 37424 has previously been suggested as the companion of S147, however the other three stars are new candidates. The favoured companion of HB 21 is the Be star BD+50 3188 whose emission-line features could be explained by pre-supernova mass transfer from the primary. There is a small probability that the 2M candidate runaway TYC 2688-1556-1 associated with the Cygnus Loop is a hypervelocity star. If the Monoceros Loop is related to the on-going star formation in the Mon OB2 association, the progenitor of the Monoceros Loop is required to be more massive than 40M which is in tension with the posterior for our candidate runaway star HD 261393.DPB is grateful to the Science and Technology Facilities Council (STFC) for providing Ph.D. funding. M.F. is supported by a Royal Society – Science Foundation Ireland University Research Fellowship. This work was partly supported by the European Union FP7 programme through ERC grant number 320360. RGI thanks the STFC for funding his Rutherford fellowship under grant ST/L003910/1 and Churchill College, Cambridge for his fellowship

Accuracy and computational efficiency of 2D urban surface flood modelling based on cellular automata

There is an emerging abundance freely available of high resolution (one meter or less) LIDAR data due to the advent of remote sensing, which enables wider applications of detailed flood risk modelling and analysis. Digital terrain surface data often comes in raster form, i.e., a square regular grid, and often requires conversion into a specific computational mesh for two-dimensional (2D) flood modelling that adopts triangular irregular meshes. 2D modelling of flood water movement through urban areas requires resolution of complex flow paths around buildings, which requires both high accuracy and computational efficiency. Water distribution and Wastewater systems in the UK contain over 700,000 km of water distribution and sewer pipes, which represents a large risk exposure from flooding caused by sewer surcharging or distribution pipe breaks. This makes it important for utilities to understand and predict where clean or dirty water flows will be directed when they leave the system. In order to establish risk assessment many thousands of simulations may be required calling for the most computational efficient models possible. Cellular Automata (CA) represents a method of running simulations based on a regular square grid, thus saving set-up time of configuring the terrain data into an irregular triangular mesh. It also offers a more uniform memory pattern for very fast modern, highly parallel hardware, such as general purpose graphical processing units (GPGPU). In this paper the performance of the CADDIES, a CA platform and associate flood modelling software caFloodPro, using a square regular grid and Von Neumann neighbourhood, is compared to industry standard software using triangular irregular meshes for similar resolutions. A minimum time step is used to control the computational complexity of the algorithm, which then creates a trade-off between the processing speeds of simulations and the accuracy resulting from the limitations used within the local rule to cope with relatively large time steps. This study shows that using CA based methods on regular square grids offers process speed increases in terms of 5-20 times over that of the industry standard software using irregular triangular meshes, while maintaining 98-99% flooding extent accuracy.This is the final version of the article. Available from Elsevier via the DOI in this record.There is an emerging abundance freely available of high resolution (one meter or less) LIDAR data due to the advent of remote sensing, which enables wider applications of detailed flood risk modelling and analysis. Digital terrain surface data often comes in raster form, i.e., a square regular grid, and often requires conversion into a specific computational mesh for two-dimensional (2D) flood modelling that adopts triangular irregular meshes. 2D modelling of flood water movement through urban areas requires resolution of complex flow paths around buildings, which requires both high accuracy and computational efficiency. Water distribution and Wastewater systems in the UK contain over 700,000 km of water distribution and sewer pipes, which represents a large risk exposure from flooding caused by sewer surcharging or distribution pipe breaks. This makes it important for utilities to understand and predict where clean or dirty water flows will be directed when they leave the system. In order to establish risk assessment many thousands of simulations may be required calling for the most computational efficient models possible. Cellular Automata (CA) represents a method of running simulations based on a regular square grid, thus saving set-up time of configuring the terrain data into an irregular triangular mesh. It also offers a more uniform memory pattern for very fast modern, highly parallel hardware, such as general purpose graphical processing units (GPGPU). In this paper the performance of the CADDIES, a CA platform and associate flood modelling software caFloodPro, using a square regular grid and Von Neumann neighbourhood, is compared to industry standard software using triangular irregular meshes for similar resolutions. A minimum time step is used to control the computational complexity of the algorithm, which then creates a trade-off between the processing speeds of simulations and the accuracy resulting from the limitations used within the local rule to cope with relatively large time steps. This study shows that using CA based methods on regular square grids offers process speed increases in terms of 5-20 times over that of the industry standard software using irregular triangular meshes, while maintaining 98-99% flooding extent accuracy

A frequentist framework of inductive reasoning

Reacting against the limitation of statistics to decision procedures, R. A. Fisher proposed for inductive reasoning the use of the fiducial distribution, a parameter-space distribution of epistemological probability transferred directly from limiting relative frequencies rather than computed according to the Bayes update rule. The proposal is developed as follows using the confidence measure of a scalar parameter of interest. (With the restriction to one-dimensional parameter space, a confidence measure is essentially a fiducial probability distribution free of complications involving ancillary statistics.) A betting game establishes a sense in which confidence measures are the only reliable inferential probability distributions. The equality between the probabilities encoded in a confidence measure and the coverage rates of the corresponding confidence intervals ensures that the measure's rule for assigning confidence levels to hypotheses is uniquely minimax in the game. Although a confidence measure can be computed without any prior distribution, previous knowledge can be incorporated into confidence-based reasoning. To adjust a p-value or confidence interval for prior information, the confidence measure from the observed data can be combined with one or more independent confidence measures representing previous agent opinion. (The former confidence measure may correspond to a posterior distribution with frequentist matching of coverage probabilities.) The representation of subjective knowledge in terms of confidence measures rather than prior probability distributions preserves approximate frequentist validity.Comment: major revisio

A new rhynchocephalian from the late jurassic of Germany with a dentition that is unique amongst tetrapods.

Rhynchocephalians, the sister group of squamates (lizards and snakes), are only represented by the single genus Sphenodon today. This taxon is often considered to represent a very conservative lineage. However, rhynchocephalians were common during the late Triassic to latest Jurassic periods, but rapidly declined afterwards, which is generally attributed to their supposedly adaptive inferiority to squamates and/or Mesozoic mammals, which radiated at that time. New finds of Mesozoic rhynchocephalians can thus provide important new information on the evolutionary history of the group. A new fossil relative of Sphenodon from the latest Jurassic of southern Germany, Oenosaurus muehlheimensis gen. et sp. nov., presents a dentition that is unique amongst tetrapods. The dentition of this taxon consists of massive, continuously growing tooth plates, probably indicating a crushing dentition, thus representing a previously unknown trophic adaptation in rhynchocephalians. The evolution of the extraordinary dentition of Oenosaurus from the already highly specialized Zahnanlage generally present in derived rhynchocephalians demonstrates an unexpected evolutionary plasticity of these animals. Together with other lines of evidence, this seriously casts doubts on the assumption that rhynchocephalians are a conservative and adaptively inferior lineage. Furthermore, the new taxon underlines the high morphological and ecological diversity of rhynchocephalians in the latest Jurassic of Europe, just before the decline of this lineage on this continent. Thus, selection pressure by radiating squamates or Mesozoic mammals alone might not be sufficient to explain the demise of the clade in the Late Mesozoic, and climate change in the course of the fragmentation of the supercontinent of Pangaea might have played a major role

From ‘prison’ to ‘paradise’?:Seeking freedom at the rainforest frontier through urban-rural migration

The lives of the urban poor in the majority world are unfree: blighted by social injustice in its manifold forms, from violence and ill-health to absent economic opportunities. We explore the pursuit of freedom through migration away from the metropole to ramais (colonisation tracks) at the rainforest frontier. Drawing on a case study in Brazilian Amazonia, we reveal urban rural migration as a frontier dynamic driven by the search for a good life. We theorize freedom and the good life using the capabilities approach, starting from the observation that people in the ramais reported feeling better and asking why that is. We find that frontiers provide a safer environment, which fosters individual and collective capabilities. A lower risk of violence reduces fears around bodily integrity, pervasive in Latin American cities. This safety fosters freedom and dignity by reducing worries and anxieties, leading to improvements in emotional wellbeing. We understand this increased sense of freedom as enhanced agency, that is, empowerment. In addition to new forms of political activity and subjectivity, we report a flourishing of senses, imagination and affiliation with others. Inequalities are reduced, positively influencing dignity and self-worth. These new freedoms are threatened by lack of rights provisioning by the State, however. We recommend that the Brazilian state should address social and environmental dimensions of these new forest frontiers. The state should recognize and support these settlements as valid forms of development, because they so clearly contribute to human wellbeing and flourishing. The state should guide and assist livelihood and landscape management toward more ecological approaches such as agroecology and agroforestry, to mitigate deforestation risks typical of forest frontiers