Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo. To address this unmet need, we synthesized and characterized a mitochondria-targeted redox cycler, MitoParaquat (MitoPQ) that comprises a triphenylphosphonium lipophilic cation conjugated to the redox cycler paraquat. MitoPQ accumulates selectively in the mitochondrial matrix driven by the membrane potential. Within the matrix, MitoPQ produces superoxide by redox cycling at the flavin site of complex I, selectively increasing superoxide production within mitochondria. MitoPQ increased mitochondrial superoxide in isolated mitochondria and cells in culture ~a thousand-fold more effectively than untargeted paraquat. MitoPQ was also more toxic than paraquat in the isolated perfused heart and in Drosophila in vivo. MitoPQ enables the selective generation of superoxide within mitochondria and is a useful tool to investigate the many roles of mitochondrial superoxide in pathology and redox signaling in cells and in vivo

The challenge of enterprise/innovation: a case study of a modern university

In the prevailing economic and political climate for Higher Education a greater emphasis has been placed on diversifying the funding base. The present study was undertaken between 2012 and 2014 and addressed the implementation of an approach to the transformation of one academic school in a medium-sized modern university in Wales to a more engaged enterprise culture. A multimethod investigation included a bi-lingual (English and Welsh) online survey of academic staff and yielded a 71% response rate (n = 45). The findings informed a series of in-depth interviews (n = 24) with a representative sample of those involved in enterprise work (support staff, managers, senior managers), and those who were not. The results provided the platform for the ‘S4E model’ for effective engagement with enterprise: (1) Strategic significance for Enterprise, (2) Support for Enterprise, (3) Synergy for Enterprise, and (4) Success for Enterprise. The outcomes of the research and the recommendations from it have potential to inform practice in other academic schools within the university and, in a wider context, within other Schools of Education regionally, nationally and internationally. Its original empirical exploration of enterprise within education studies is a significant contribution to that body of knowledge

Impact of vaccination and non-pharmaceutical interventions on SARS-CoV-2 dynamics in Switzerland

BACKGROUND: As vaccination coverage against SARS-CoV-2 increases amidst the emergence and spread of more infectious and potentially more deadly viral variants, decisions on timing and extent of relaxing effective, but unsustainable, non-pharmaceutical interventions (NPIs) need to be made. METHODS: An individual-based transmission model of SARS-CoV-2 dynamics, OpenCOVID, was developed to compare the impact of various vaccination and NPI strategies on the COVID-19 epidemic in Switzerland. OpenCOVID uses the Oxford Containment Health Index (OCHI) to quantify the stringency of NPIs. RESULTS: Even if NPIs in place in March 2021 were to be maintained and the vaccine campaign rollout rapidly scaled-up, a 'third wave' was predicted. However, we find a cautious phased relaxation can substantially reduce population-level morbidity and mortality. We find that faster vaccination campaign can offset the size of such a wave, allowing more flexibility for NPI to be relaxed sooner. Model outcomes were most sensitive to the level of infectiousness of variants of concern observed in Switzerland. CONCLUSION: A rapid vaccination rollout can allow the sooner relaxation of NPIs, however ongoing surveillance of - and swift responses to - emerging viral variants is of utmost importance for epidemic control

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: A multicenter study

The increase of proinflammatory cytokines in vaginal secretions may serve as a surrogate marker of unwanted inflammatory reaction to microbicide products topically applied for the prevention of sexually transmitted diseases, including HIV-1. Interleukin (IL)-1β and IL-6 have been proposed as indicators of inflammation and increased risk of HIV-1 transmission; however, the lack of information regarding detection platforms optimal for vaginal fluids and interlaboratory variation limit their use for microbicide evaluation and other clinical applications. This study examines fluid matrix variants relevant to vaginal sampling techniques and proposes a model for interlaboratory comparisons across current cytokine detection technologies. IL-1β and IL-6 standards were measured by 12 laboratories in four countries, using 14 immunoassays and four detection platforms based on absorbance, chemiluminescence, electrochemiluminescence, and fluorescence. International reference preparations of cytokines with defined biological activity were spiked into (1) a defined medium simulating the composition of human vaginal fluid at pH 4.5 and 7.2, (2) physiologic salt solutions (phosphate-buffered saline and saline) commonly used for vaginal lavage sampling in clinical studies of cytokines, and (3) human blood serum. Assays were assessed for reproducibility, linearity, accuracy, and significantly detectable fold difference in cytokine level. Factors with significant impact on cytokine recovery were determined by Kruskal−Wallis analysis of variance with Dunn’s multiple comparison test and multiple regression models. All assays showed acceptable intra-assay reproducibility; however, most were associated with significant interlaboratory variation. The smallest reliably detectable cytokine differences (P < 0.05) derived from pooled interlaboratory data varied from 1.5- to 26-fold depending on assay, cytokine, and matrix type. IL-6 but not IL-1β determinations were lower in both saline and phosphate-buffered saline as compared to vaginal fluid matrix, with no significant effect of pH. The (electro)chemiluminescence-based assays were most discriminative and consistently detected <2-fold differences within each matrix type. The Luminex-based assays were less discriminative with lower reproducibility between laboratories. These results suggest the need for uniform vaginal sampling techniques and a better understanding of immunoassay platform differences and cross-validation before the biological significance of cytokine variations can be validated in clinical trials. This investigation provides the first standardized analytic approach for assessing differences in mucosal cytokine levels and may improve strategies for monitoring immune responses at the vaginal mucosal interface

Exercise at Depth Alters Bradycardia and Incidence of Cardiac Anomalies in Deep-Diving Marine Mammals

Unlike their terrestrial ancestors, marine mammals routinely confront extreme physiological and physical challenges while breath-holding and pursuing prey at depth. To determine how cetaceans and pinnipeds accomplish deep-sea chases, we deployed animal-borne instruments that recorded high-resolution electrocardiograms, behaviour and flipper accelerations of bottlenose dolphins (Tursiops truncatus) and Weddell seals (Leptonychotes weddellii) diving from the surface to 4200 m. Here we report that both exercise and depth alter the bradycardia associated with the dive response, with the greatest impacts at depths inducing lung collapse. Unexpectedly, cardiac arrhythmias occurred in 473% of deep, aerobic dives, which we attribute to the interplay between sympathetic and parasympathetic drivers for exercise and diving, respectively. Such marked cardiac variability alters the common view of a stereotypic ‘dive reflex’ in diving mammals. It also suggests the persistence of ancestral terrestrial traits in cardiac function that may help explain the unique sensitivity of some deep-diving marine mammals to anthropogenic disturbances

Regulation of the Cardiac Na+/K+ ATPase by Phospholemman

Hansraj Dhayan, Rajender Kumar, Andreas Kukol, ‘Regulation of the Cardiac Na+/K+ ATPase by Phospholemman’, in Sajal Chakraborti, Naranjan Dhalla, eds., Regulation of Membrane Na+-K+ ATPase, (Switzerland: Springer, 2016), ISBN 978-3-319-24748-9, eISBN 978-3-319-24750-2.Peer reviewe

‘A small town of character’: locating a new Scottish university, 1963-1965

The 1960s are generally regarded as a decisive decade for the postwar expansion of British universities, the process widely associated with the publication of the Robbins Report on Higher Education in October 1963. This period saw significant increases in the number of full-time university students and in the level of public expenditure devoted to higher education. This chapter analyses the debates triggered by the Robbins committee’s recommendation to establish a new university in Scotland, eventually located in the county town of Stirling. Based on previously unexamined documents in the UK National Archives, we argue that the decision to create the new university in Stirling rather than the alternative locations of Ayr, Cumbernauld, Dumfries, Falkirk, Inverness, and Perth arose from the interplay of three somewhat contradictory pressures: the preference of the Robbins committee for new universities in or near to large cities; the prejudices of the academics charged with making this decision for environments that reproduced the perceived creative advantages of the ancient universities where they were educated or employed, specifically Oxford; and the highly successful lobbying campaign in support of Stirling

Autism and nutrition: the role of the gut–brain axis

Autism spectrum disorder (ASD) is characterised by deficits in the ability to socialise, communicate and use imagination, and displays of stereotypical behaviour. It is widely accepted that ASD involves a disorder in brain development. However, the real causes of the neurodevelopmental disorders associated with ASD are not clear. In this respect, it has been found that a majority of children with ASD display gastrointestinal symptoms, and an increased intestinal permeability. Moreover, large differences in microbiotic composition between ASD patients and controls have been reported. Therefore, nutrition-related factors have been hypothesised to play a causal role in the aetiology of ASD and its symptoms. Through a review of the literature, it was found that abnormalities in carbohydrate digestion and absorption could explain some of the gastrointestinal problems observed in a subset of ASD patients, although their role in the neurological and behavioural problems remains uncertain. In addition, the relationship between an improved gut health and a reduction of symptoms in some patients was evaluated. Recent trials involving gluten-free diets, casein-free diets, and pre- and probiotic, and multivitamin supplementation show contradictive but promising results. It can be concluded that nutrition and other environmental influences might trigger an unstable base of genetic predisposition, which may lead to the development of autism, at least in a subset of ASD patients. Clear directions for further research to improve diagnosis and treatment for the different subsets of the disorder are provided