Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis

Ca2+ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP3R) serve to discharge Ca2+ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP3R isoforms and protect cells from apoptosis, reducing ER Ca2+ release. However, it has not been elucidated which IP3R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP3R I, strongly suppresses IP3-mediated Ca2+ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca2+ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca2+ release. Moreover, regulating Ca2+ flux to mitochondria, Akt maintains the mitochondrial integrity and delays the trigger of apoptosis, in a type III-dependent mechanism. These results demonstrate a specific activity of Akt on IP3R III, leading to diminished Ca2+ transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

Background The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders

Modelling the impact of a time‐varying wave angle on the nonlinear evolution of sand bars in the surf zone

Sandy beaches are often characterized by the presence of sand bars, whose characteristics (growth, migration speed, etc.) strongly depend on offshore wave conditions, such as wave height and angle of wave incidence. This study addresses the impact of a sinusoidally time-varying wave angle of incidence with different time-means on the saturation height, migration speed and longshore spacing of sand bars. Model results show that shore-transverse sand bars (so-called TBR bars) eventually develop under a time-varying wave angle. Depending on the time-mean, amplitude and period of the varying angle of wave incidence, the mean heights and mean migration speeds of the bars can be larger or smaller than their corresponding values in the case of time-invariant angles. Bars might not even form when the wave angle varies around a too large oblique mean value, whereas bars exist in the case of a time-invariant wave angle. The oscillations in both bar height and migration speed are large if the period of the time-varying wave angle is close to the adjustment timescale of the system and if large differences in the local growth and migration rates of the bars occur during one oscillation period. The oscillations in bar height are a combination of harmonics with the principal period and half the period of the time-varying wave angle, whereas those of migration speed contain only the principal period. Bars that are subject to time-varying wave angles have larger longshore crest-to-crest spacings than those which form under fixed wave angles. Physical explanations for these findings are given

Engaging with Faith Councils to Develop Stoma-specific Fatawās: A Novel Approach to the Healthcare Needs of Muslim Colorectal Patients.

Intestinal stomas are common. Muslims report significantly lower quality of life following stoma surgery compared to non-Muslims. A fatwā is a ruling on a point of Islamic law according to a recognised religious authority. The use of fatawās to guide health-related decision-making has becoming an increasingly popular practice amongst Muslims, regardless of geographic location. This project aimed to improve the quality of life of Muslim ostomates by addressing faith-specific stoma concerns. Through close collaboration with Muslim ostomates, a series of 10 faith-related questions were generated, which were posed to invited local faith leaders during a stoma educational event. Faith leaders received education concerning the realities of stoma care before generating their fatawās. The event lead to the formulation of a series of stoma-specific fatawās representing Hanafi and Salafi scholarship, providing faith-based guidance for Muslim ostomates and their carers. Enhanced communication between healthcare providers and Islamic faith leaders allows for the delivery of informed fatawās that directly benefit Muslim patients and may represent an efficient method of improving health outcomes in this faith group

Novel classes of antibiotics or more of the same?

The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant bacteria until 10–20 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance, particularly among gram-negative bacteria. This review examines the existing systemic antibiotic pipeline in the public domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20 classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this effort. The alternative is Medicine without effective antibiotics