Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we ...demonstrate that intestine-specific deletion of Hdac3 (Hdac3
) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3
mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.
The aim of this case series is to describe and evaluate our experience of continuous positive airway pressure (CPAP) to treat type 1 respiratory failure in patients with COVID-19. CPAP was delivered ...in negative pressure rooms in the newly repurposed infectious disease unit. We report a cohort of 24 patients with type 1 respiratory failure and COVID-19 admitted to the Royal Liverpool Hospital between 1 April and 30 April 2020. Overall, our results were positive; we were able to safely administer CPAP outside the walls of a critical care or high dependency unit environment and over half of patients (58%) avoided mechanical ventilation and a total of 19 out of 24 (79%) have survived and been discharged from our care.
Successful embryonic development and offspring sex ratios of marine turtles are determined by thermal conditions experienced during incubation, rendering them potentially vulnerable to anthropogenic ...climate change. With the rate of projected temperature rises likely to outpace the adaptive capacity of long‐lived species such as marine turtles, there is growing interest in management interventions aimed at mitigating the effects of climate change at nesting grounds. In this study, we experimentally tested the impacts of artificial nest shading on the incubation temperature, hatching success, and predicted offspring sex ratio of green turtle (Chelonia mydas) clutches at Ascension Island. Clutches (n = 97) were sampled from 2 nesting beaches with naturally contrasting thermal environments (one hot; one cool) and either left as in situ controls or relocated to shaded or unshaded hatcheries on their beach of origin. Compared to unshaded experimental clutches, shading reduced mean incubation temperatures and sex‐determining temperatures (i.e., middle third of embryonic development) by 0.5–0.9°C and 0.5–1.2°C respectively, with the reduction being greater on the hotter beach. Shading also differentially affected hatchling output across the 2 sites: on the hot beach, shading significantly improved hatching success by ~23% but had minimal effects on offspring sex ratio; whereas on the cooler beach, shading did not impact hatching success but resulted in ~12% more male offspring. Interestingly, mean incubation temperatures of in situ controls did not differ significantly from shaded clutches, and were significantly cooler than unshaded experimental clutches, suggesting relocation may have negated some of the benefits of shading. Our results demonstrated that artificial shading may be a viable approach for partially offsetting climate change impacts on nesting marine turtles; however, scalability will be a major challenge in achieving conservation objectives at high‐density nesting sites like Ascension Island.
Successful embryonic development and offspring sex ratios of marine turtles are determined by thermal conditions experienced during incubation, rendering them potentially vulnerable to anthropogenic climate change. Therefore, there is growing interest in management interventions aimed at mitigating the effects of climate change at nesting grounds. In this study, we experimentally tested the impacts of artificial nest shading on the incubation temperature, hatching success and predicted offspring sex ratio of green turtle clutches at Ascension Island. Our results demonstrate that artificial nest shading may be a viable approach for conservation practitioners to partially alleviate the impacts of climate change on nesting marine turtles; however, scalability of such measures will likely be a major challenge at high‐density nesting sites like Ascension Island.
Abstract
Purpose:
Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also ...demonstrated clinical activity in acute myelogenous leukemia, non–small cell lung cancer, and estrogen receptor–positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.
Experimental Design:
Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.
Results:
We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-XL (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-XL, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.
Conclusions:
These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types.
The aim of this article is to provide a detailed description of the Chikwawa lung health cohort which was established in rural Malawi to prospectively determine the prevalence and causes of lung ...disease amongst the general population of adults living in a low-income rural setting in Sub-Saharan Africa.
A total of 1481 participants were randomly identified and recruited in 2014 for the baseline study. We collected data on demographic, socio-economic status, respiratory symptoms and potentially relevant exposures such as smoking, household fuels, environmental exposures, occupational history/exposures, dietary intake, healthcare utilization, cost (medication, outpatient visits and inpatient admissions) and productivity losses. Spirometry was performed to assess lung function. At baseline, 56.9% of the participants were female, mean age was 43.8 (SD:17.8) and mean body mass index (BMI) was 21.6 Kg/m2 (SD: 3.46).
The cohort has reported the prevalence of chronic respiratory symptoms (13.6%, 95% confidence interval CI, 11.9-15.4), spirometric obstruction (8.7%, 95% CI, 7.0-10.7), and spirometric restriction (34.8%, 95% CI, 31.7-38.0). Additionally, an annual decline in forced expiratory volume in one second FEV1 of 30.9mL/year (95% CI: 21.6 to 40.1) and forced vital capacity FVC by 38.3 mL/year (95% CI: 28.5 to 48.1) has been reported.
The ongoing phases of follow-up will determine the annual rate of decline in lung function as measured through spirometry and the development of airflow obstruction and restriction, and relate these to morbidity, mortality and economic cost of airflow obstruction and restriction. Population-based mathematical models will be developed driven by the empirical data from the cohort and national population data for Malawi to assess the effects of interventions and programmes to address the lung burden in Malawi. The present follow-up study started in 2019.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pneumonia remains the leading cause of paediatric infectious mortality globally. Treatment failure, which can result from non-adherence to oral antibiotics, can lead to poor outcomes and therefore ...improving adherence could be a strategy to reduce pneumonia related morbidity and mortality. However, there is little published evidence from low-resource settings for the drivers of non-adherence to oral antibiotics in children.
We aimed to investigate reasons for adherence and non-adherence in children diagnosed and treated in the community with fast-breathing pneumonia in rural Malawi.
We conducted focus group discussions (FGDs) with caregivers of children known to have been diagnosed and treated with oral antibiotics for fast-breathing pneumonia in the community and key informant interviews with community healthcare workers (CHW). FGDs and interviews were conducted within communities in Chichewa, the local language. We used a framework approach to analyze the transcripts.
We conducted 4 FGDs with caregivers and 10 interviews with CHWs. We identified four themes, which were common across caregivers and CHWs: knowledge and understanding, effort, medication perceptions and community influences. Caregivers and CHWs demonstrated good knowledge of pneumonia and types of treatment, but caregivers showed confusion around dosing and treatment durations. Effort was needed to seek care, prepare medication and understand regimens, acting as a barrier to adherence. Perceptions of how well the treatment was working influenced adherence, with both quick recovery and slow recovery leading to non-adherence. Community influences were both supportive, with transport assistance for referrals and home visits to improve adherence, and detrimental, with pressure to share treatments.
Adherence to oral antibiotic treatment for fast-breathing pneumonia was understood to be important, however considerable barriers we described within this rural low-resource setting, such as the effort preparing and administering medication, community pressures to share drugs and potential complexity of regimens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ERK signalling pathway regulates key cell fate decisions in the intestinal epithelium and is frequently dysregulated in colorectal cancers (CRCs). Variations in the dynamics of ERK activation can ...induce different biological outcomes and are regulated by multiple mechanisms, including activation of negative feedback loops involving transcriptional induction of dual-specificity phosphatases (DUSPs). We have found that the nuclear ERK-selective phosphatase DUSP5 is downregulated in colorectal tumours and cell lines, as previously observed in gastric and prostate cancer. The DUSP5 promoter is methylated in a subset of CRC cell lines and primary tumours, particularly those with a CpG island methylator phenotype (CIMP). However, this epigenetic change alone could not account for reduced DUSP5 expression in CRC cells. Functionally, DUSP5 depletion failed to alter ERK signalling or proliferation in CRC cell lines, and its transgenic overexpression in the mouse intestine had minimal impact on normal intestinal homeostasis or tumour development. Our results suggest that DUSP5 plays a limited role in regulating ERK signalling associated with the growth of colorectal tumours, but that methylation the DUSP5 gene promoter can serve as an additional means of identifying CIMP-high colorectal cancers.
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has infected over 150 million people worldwide, with over 3 million deaths as of 6 May 2021 1. In the UK, approximately 15% of individuals ...affected by coronavirus disease 2019 (COVID-19) have required admission to hospital 2 and those with severe disease require advanced respiratory support including invasive mechanical ventilation (IMV) 3. Due to the considerable scale of the pandemic, noninvasive continuous positive airway pressure (CPAP) has been utilised for COVID-19-related type I respiratory failure as a therapeutic strategy to improve patient outcomes 4, 5 and also to preserve IMV capacity during a challenging time for acute healthcare providers. However, its exact role is unclear and is the subject of a UK multicentre trial 6.
An increased incidence of pulmonary barotrauma in patients receiving CPAP for #COVID19 pneumonia was observed during the second peak of infections at this centre in the UK
https://bit.ly/3qeSTp9
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