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

Giant Alcohol: A Worthy Opponent for the Children of the Band of Hope

From its foundation in 1847, the temperance organisation the Band of Hope addressed its young members as consumers, victims, and agents. In the first two roles they encountered the effects of drink of necessity, but in the third role they were encouraged to seek it out, attempting to influence individuals and wider society against 'Giant Alcohol'. With an estimated membership of half the school-age population by the early twentieth century, well over three million, the Band of Hope also acted more directly to influence policy, and encouraged young people to consider issues of policy and politics. With its wide range of activities and material to educate, entertain and empower millions of children, and its radical view of the place of the child, the Band of Hope not only mobilised its child members to lobby for legal change, including prohibition, but took an active part in pointing out the cost of alcohol to society, particularly during the 14-18 war. The organisation began to decline post 1918, and this paper focuses on the address made to children by the Band of Hope in the late nineteenth and early twentieth centuries, at a time when its innovative view of children as able to understand and influence policy decisions reflected developments in the construction of childhood. This article draws on the archive of the British National Temperance League, over 50,000 items located in the Livesey Collection, University of Central Lancashire

Alternative job search strategies in remote rural and peri-urban labour markets: the role of social networks

This paper examines the importance of informal methods (especially social networking) to the job search strategies used by unemployed people. It compares three areas: a small rural town; a larger, more sparsely populated, remote rural area; and a centrally-located, peri-urban labour market. The analysis is based first on survey research undertaken with 490 job seekers across the study areas. Emerging issues were then followed up during a series of twelve focus groups. The survey research showed that job seekers in the rural study areas were significantly more likely to use social networks to look for work. However, those who had experienced repeated or long-term periods out of work, the unskilled and young people were significantly less likely to use such networks. Focus groups confirmed the perceived importance of social networking to the job search process in rural areas, in contrast to the more marginal role such methods appear to play in peri-urban settings. For many rural job seekers, formal job search activities conducted through Jobcentres were seen as largely symbolic, lacking the practical value of social networking. These results suggest that service providers seeking to assist unemployed people in rural areas need to address the problems faced by many disadvantaged job seekers who are currently caught between their lack of social network relations and the absence of local public employment service facilities in more remote communities

Locating current sheets in the solar corona

Current sheets are essential for energy dissipation in the solar corona, in particular by enabling magnetic reconnection. Unfortunately, sufficiently thin current sheets cannot be resolved observationally and the theory of their formation is an unresolved issue as well. We consider two predictors of coronal current concentrations, both based on geometrical or even topological properties of a force free coronal magnetic field. First, there are separatrices related to magnetic nulls. Through separatrices the magnetic connectivity changes discontinuously. Coronal magnetic nulls are, however, very rare. At second, inspired by the concept of generalized magnetic reconnection without nulls, quasi-separatrix layers (QSL) were suggested. Through QSL the magnetic connectivity changes continuously, though strongly. The strength of the connectivity change can be quantified by measuring the squashing of the flux tubes which connect the magnetically conjugated photospheres. We verify the QSL and separatrix concepts by comparing the sites of magnetic nulls and enhanced squashing with the location of current concentrations in the corona. Due to the known difficulties of their direct observation we simulated the coronal current sheets by numerically calculating the response of the corona to energy input from the photosphere heating a simultaneously observed EUV Bright Point. We did not find coronal current sheets not at the separatrices but at several QSL locations. The reason is that although the geometrical properties of force free extrapolated magnetic fields can indeed, hint at possible current concentrations, a necessary condition for current sheet formation is the local energy input into the corona

Loss of the homeostatic protein BPIFA1, leads to exacerbation of otitis media severity in the Junbo mouse model

Otitis Media (OM) is characterized by epithelial abnormalities and defects in innate immunity in the middle ear (ME). Although, BPIFA1, a member of the BPI fold containing family of putative innate defence proteins is abundantly expressed by the ME epithelium and SNPs in Bpifa1 have been associated with OM susceptibility, its role in the ME is not well characterized. We investigated the role of BPIFA1 in protection of the ME and the development of OM using murine models. Loss of Bpifa1 did not lead to OM development. However, deletion of Bpifa1 in Evi1Jbo/+mice, a model of chronic OM, caused significant exacerbation of OM severity, thickening of the ME mucosa and increased collagen deposition, without a significant increase in pro-inflammatory gene expression. Our data suggests that BPIFA1 is involved in maintaining homeostasis within the ME under steady state conditions and its loss in the presence of inflammation, exacerbates epithelial remodelling leading to more severe OM

The 3s Proton Occupancy in 206-Pb

This research was sponsored by the National Science Foundation Grant NSF PHY 87-1440

A Systematic Review Of The Types And Causes Of Prescribing Errors Generated From Using Computerized Provider Order Entry Systems in Primary and Secondary Care

Objective To understand the different types and causes of prescribing errors associated with computerized provider order entry (CPOE) systems, and recommend improvements in these systems. Materials and Methods We conducted a systematic review of the literature published between January 2004 and June 2015 using three large databases: the Cumulative Index to Nursing and Allied Health Literature, Embase, and Medline. Studies that reported qualitative data about the types and causes of these errors were included. A narrative synthesis of all eligible studies was undertaken. Results A total of 1185 publications were identified, of which 34 were included in the review. We identified 8 key themes associated with CPOE-related prescribing errors: computer screen display, drop-down menus and auto-population, wording, default settings, nonintuitive or inflexible ordering, repeat prescriptions and automated processes, users’ work processes, and clinical decision support systems. Displaying an incomplete list of a patient’s medications on the computer screen often contributed to prescribing errors. Lack of system flexibility resulted in users employing error-prone workarounds, such as the addition of contradictory free-text comments. Users’ misinterpretations of how text was presented in CPOE systems were also linked with the occurrence of prescribing errors. Discussion and Conclusions Human factors design is important to reduce error rates. Drop-down menus should be designed with safeguards to decrease the likelihood of selection errors. Development of more sophisticated clinical decision support, which can perform checks on free-text, may also prevent errors. Further research is needed to ensure that systems minimize error likelihood and meet users’ workflow expectations

Test of the DWBA Description of Transfer Reactions at Intermediate Energies by Measuring a Complete Set of Single Nucleon and Elastic Scattering Data

This research was sponsored by the National Science Foundation Grant NSF PHY 87-1440

Test of the DWBA Description of Transfer Reactions at Intermediate Energies by Measuring a Complete Set of Single Nucleon Transfer and Elastic Scattering Data

This research was sponsored by the National Science Foundation Grant NSF PHy 87-1440