Zooming in on Transcription Preinitiation

AbstractClass II gene transcription commences with the assembly of the Preinitiation Complex (PIC) from a plethora of proteins and protein assemblies in the nucleus, including the General Transcription Factors (GTFs), RNA polymerase II (RNA pol II), co-activators, co-repressors, and more. TFIID, a megadalton-sized multiprotein complex comprising 20 subunits, is among the first GTFs to bind the core promoter. TFIID assists in nucleating PIC formation, completed by binding of further factors in a highly regulated stepwise fashion. Recent results indicate that TFIID itself is built from distinct preformed submodules, which reside in the nucleus but also in the cytosol of cells. Here, we highlight recent insights in transcription factor assembly and the regulation of transcription preinitiation

Hypertensive Cardiotoxicity in Cancer Treatment-Systematic Analysis of Adjunct, Conventional Chemotherapy, and Novel Therapies-Epidemiology, Incidence, and Pathophysiology

Cardiotoxicity is the umbrella term for cardiovascular side effects of cancer therapies. The most widely recognized phenotype is left ventricular dysfunction, but cardiotoxicity can manifest as arrhythmogenic, vascular, myocarditic and hypertensive toxicities. Hypertension has long been regarded as one of the most prevalent and modifiable cardiovascular risk factors in the general population, but its relevance during the cancer treatment journey may be underestimated. Hypertensive cardiotoxicity occurs de novo in a substantial proportion of treated cancer patients. The pathology is incompletely characterized—natriuresis and renin angiotensin system interactions play a role particularly in conventional treatments, but in novel therapies endothelial dysfunction and the interaction between the cancer and cardiac kinome are implicated. There exists a treatment paradox in that a significant hypertensive response not only mandates anti-hypertensive treatment, but in fact, in certain cancer treatment scenarios, hypertension is a predictor of cancer treatment efficacy and response. In this comprehensive review of over 80,000 patients, we explored the epidemiology, incidence, and mechanistic pathophysiology of hypertensive cardiotoxicity in adjunct, conventional chemotherapy, and novel cancer treatments. Conventional chemotherapy, adjunct treatments, and novel targeted therapies collectively caused new onset hypertension in 33–68% of treated patients. The incidence of hypertensive cardiotoxicity across twenty common novel therapies for any grade hypertension ranged from 4% (imatinib) to 68% (lenvatinib), and high grade 3 or 4 hypertension in <1% (imatinib) to 42% (lenvatinib). The weighted average effect was all-grade hypertension in 24% and grade 3 or 4 hypertension in 8%

Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study

KSR and this work are funded by an NIHR Doctoral Fellowship (DRF-2014-07-008

Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide

Nitric oxide (NO) is a vasodilator and independent modulator of cardiac remodelling. Commonly, in cardiac disease (e.g. heart failure) endothelial dysfunction (synonymous with NO-deficiency) has been implicated in increased blood pressure (BP), cardiac hypertrophy and fibrosis. Currently no effective therapies replacing NO have succeeded in the clinic. Inorganic nitrate (NO3 - ), through chemical reduction to nitrite and then NO, exerts potent BP-lowering but whether it might be useful in treating undesirable cardiac remodelling is unknown. In a nested age- and sex-matched case-control study of hypertensive patients +/- left ventricular hypertrophy (NCT03088514) we show that lower plasma nitrite concentration and vascular dysfunction accompany cardiac hypertrophy and fibrosis in patients. In mouse models of cardiac remodelling, we also show that restoration of circulating nitrite levels using dietary nitrate improves endothelial dysfunction through targeting of xanthine oxidoreductase (XOR)-driven H2 O2 and superoxide, and reduces cardiac fibrosis through NO-mediated block of SMAD-phosphorylation leading to improvements in cardiac structure and function. We show that via these mechanisms dietary nitrate offers easily translatable therapeutic options for treatment of cardiac dysfunction

The Relationship Between Availability and Changes to Perceived Workplace Support and Their Impact on the Mental Health, Well-being and Burn-Out of Healthcare Professionals (HCP): Insight and Mitigating Strategies From the CoPE-HCP Cohort Study

AIMS: To examine the relationship between self-reported level of workplace support (WS) and various mental health outcomes in HCPs and non-HCPs at different time-points during the COVID-19 pandemic, and to examine whether improved WS is associated with improved mental health outcomes over time. Lastly, to identify what support healthcare professionals (HCPs) perceive to be most helpful. METHODS: Cohort survey study at baseline (July-September 2020) and follow-up (approximately four months later). Setting HCPs working in primary or secondary care, from UK and other countries, and non-HCP controls from primarily London-based universities. Participants 1574 HCPs and 147 non-HCPs (academic and research staff at London-based universities). The inclusion criteria for the study were: 1) aged 18 or older, 2) electronic consent given, and 3) identified as HCP or non-healthcare academic staff or self-declared non-HCPs. Main outcome measures Presence of generalized anxiety disorder (assessed using the GAD-7), clinical insomnia (ISI), major depressive disorder (PHQ-9), well-being (SWEMWBS), and burnout (emotional exhaustion and depersonalization; EEDP2Q). Qualitative data exploring what support HCPs perceive as most useful was gathered using free-text inputs. RESULTS: At baseline and follow-up, consistently, compared to those who felt unsupported, those who felt supported had significantly reduced risk (odds) of generalized anxiety disorder (baseline: 59% [95% CI of OR, 0.29 to 0.57], follow-up: 41% [0.38 to 0.92]), clinical insomnia (51% [0.34 to 0.69], 66% [0.20 to 0.55]), major depressive disorder (58% [0.31 to 0.58], 54% [0.31 to 0.74]), emotional exhaustion (65% [0.26 to 0.46], 61% [0.27 to 0.56]) and depersonalization (58% [0.28 to 0.61], 68% [0.21 to 0.50]). At follow-up, self-reported improved WS (vs. baseline) was associated with significantly improved GAD-7 (adjusted difference. −1.73 [-2.54 to −0.91]), ISI (-0.96 [-1.88 to −0.04]), PHQ−9 (-1.32 [-2.16 to −0.49]), SWEMWBS (0.97 [0.37 to 1.57]) and EEDP2Q (burnout) (-1.30 [-1.82 to −0.79]) scores, independent of baseline level of support. Five themes were identified constituting WS: ‘managerial support’ was the largest sub-theme. CONCLUSION: A consistent association was observed between level of WS and the mental health of HCPs and non-HCPs. Improved WS was associated with improved mental health scores over a four-month period during the pandemic

Evaluation of computerized health management information system for primary health care in rural India

<p>Abstract</p> <p>Background</p> <p>The Comprehensive Rural Health Services Project Ballabgarh, run by All India Institute of Medical Sciences (AIIMS), New Delhi has a computerized Health Management Information System (HMIS) since 1988. The HMIS at Ballabgarh has undergone evolution and is currently in its third version which uses generic and open source software. This study was conducted to evaluate the effectiveness of a computerized Health Management Information System in rural health system in India.</p> <p>Methods</p> <p>The data for evaluation were collected by in-depth interviews of the stakeholders i.e. program managers (authors) and health workers. Health Workers from AIIMS and Non-AIIMS Primary Health Centers were interviewed to compare the manual with computerized HMIS. A cost comparison between the two methods was carried out based on market costs. The resource utilization for both manual and computerized HMIS was identified based on workers' interviews.</p> <p>Results</p> <p>There have been no major hardware problems in use of computerized HMIS. More than 95% of data was found to be accurate. Health workers acknowledge the usefulness of HMIS in service delivery, data storage, generation of workplans and reports. For program managers, it provides a better tool for monitoring and supervision and data management. The initial cost incurred in computerization of two Primary Health Centers was estimated to be Indian National Rupee (INR) 1674,217 (USD 35,622). Equivalent annual incremental cost of capital items was estimated as INR 198,017 (USD 4213). The annual savings is around INR 894,283 (USD 11,924).</p> <p>Conclusion</p> <p>The major advantage of computerization has been in saving of time of health workers in record keeping and report generation. The initial capital costs of computerization can be recovered within two years of implementation if the system is fully operational. Computerization has enabled implementation of a good system for service delivery, monitoring and supervision.</p

Current perspectives on coronavirus disease 2019 and cardiovascular disease: a white paper by the JAHA editors

Coronavirus Disease 2019 (COVID‐19) has infected more than 3.0 million people worldwide and killed more than 200,000 as of April 27, 2020. In this White Paper, we address the cardiovascular co‐morbidities of COVID‐19 infection; the diagnosis and treatment of standard cardiovascular conditions during the pandemic; and the diagnosis and treatment of the cardiovascular consequences of COVID‐19 infection. In addition, we will also address various issues related to the safety of healthcare workers and the ethical issues related to patient care in this pandemic

Bacterial Transmembrane Proteins that Lack N-Terminal Signal Sequences

Tail-anchored membrane proteins (TAMPs), a class of proteins characterized by their lack of N-terminal signal sequence and Sec-independent membrane targeting, play critical roles in apoptosis, vesicle trafficking and other vital processes in eukaryotic organisms. Until recently, this class of membrane proteins has been unknown in bacteria. Here we present the results of bioinformatic analysis revealing proteins that are superficially similar to eukaryotic TAMPs in the bacterium Streptomyces coelicolor. We demonstrate that at least four of these proteins are bona fide membrane-spanning proteins capable of targeting to the membrane in the absence of their N-terminus and the C-terminal membrane-spanning domain is sufficient for membrane targeting. Several of these proteins, including a serine/threonine kinase and the SecE component of the Sec translocon, are widely conserved in bacteria