316 research outputs found
An EZ Mark to Miss
Ezh2, the methyltransferase within Polycomb Repressive II Complexes, was thought to be essential for all H3K27me3 marks in embryonic stem cells (ESCs). Recently in Molecular Cell, Shen and colleagues (2008) revealed that EZH2 is dispensable for ESC derivation and self-renewal, and that EZH1 may unexpectedly compensate for its loss
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Comprehensive methylome map of lineage commitment from haematopoietic progenitors.
Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions
Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice
(a) Immunoblotting analysis of IRβ in the hippocampus and frontal cortex of 18-month old wildtype and APN-KO mice. (b) Densitometric analysis of the ratio of IRβ. Mean ± S.E.M.; ***p < 0.001, n.s. statistically not significant; Scale bar: 100 μm. (JPG 30 kb
Findings and Guidance for Airborne Infection Resilience
This guidance provides insights into airborne infection risks and proposes mitigation measures to improve airborne infection resilience of indoor and semi-outdoor spaces. In some poorly-ventilated and/or highly occupied spaces, the provision of increased ventilation performance can be the key to reducing airborne infection risk down to 'acceptable' (although currently undefined) levels.This is a complex area of study with many areas of uncertainty that form the basis of ongoing research. That said, the AIRBODS programme, in the context of the global research efforts associated with the COVID-19 pandemic, has generated a sound basis for improving airborne infection resilience. Key aspects of the guide with its many recommendations include:• Experiments carried out in a test chamber showing how screens can improve or, even, worsen airborne infection risk.• Field studies undertaken as part of the Events Research Programme which underpinned the opening up of the UK hospitality sector in summer of 2021. Good practice advice is provided on how to drive high resolution CO2 and microbiological studies and then appropriately interpret results.• Analytical models were developed to understand how infection risk, using a mass balance approach with many different parameters, might be mitigated in some circumstances when compared to reference spaces. These models were then developed into a 'full building' tool which can be downloaded as part of this guidance.• Computational fluid dynamics (CFD) models were developed to provide insights into the physics of droplets or aerosols at microscale. Following completion of a test chamber validation exercise, models were developed to investigate breathing or coughing mannequins at single human moving towards audience or crowd scale.Local ventilation effectiveness and associated airborne infection risk aspects of some real spaces may significantly differ from assumed 'fully-mixed' equivalent spaces. This, along with a number of other issues, will form part of ongoing research activities.• Focus groups were also used to provide some wider context and support some of our recommendations.AIRBODS has produced a repository of data and modelling methods with the mindset of enabling building professionals to inform their design and operation decisions towards improving airborne infection resilience in their buildings
Heart failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings
Aims: Viral-induced cardiac inflammation can induce heart failure with preserved ejection fraction (HFpEF)-like syndromes. COVID-19 can lead to myocardial damage and vascular injury. We hypothesised that COVID-19 patients frequently develop a HFpEF-like syndrome, and designed this study to explore this.
Methods and results: Cardiac function was assessed in 64 consecutive, hospitalized, and clinically stable COVID-19 patients from April-November 2020 with left ventricular ejection fraction (LVEF) ≥50% (age 56 ± 19 years, females: 31%, severe COVID-19 disease: 69%). To investigate likelihood of HFpEF presence, we used the HFA-PEFF score. A low (0-1 points), intermediate (2-4 points), and high (5-6 points) HFA-PEFF score was observed in 42%, 33%, and 25% of patients, respectively. In comparison, 64 subjects of similar age, sex, and comorbidity status without COVID-19 showed these scores in 30%, 66%, and 4%, respectively (between groups: P = 0.0002). High HFA-PEFF scores were more frequent in COVID-19 patients than controls (25% vs. 4%, P = 0.001). In COVID-19 patients, the HFA-PEFF score significantly correlated with age, estimated glomerular filtration rate, high-sensitivity troponin T (hsTnT), haemoglobin, QTc interval, LVEF, mitral E/A ratio, and H2 FPEF score (all P < 0.05). In multivariate, ordinal regression analyses, higher age and hsTnT were significant predictors of increased HFA-PEFF scores. Patients with myocardial injury (hsTnT ≥14 ng/L: 31%) vs. patients without myocardial injury, showed higher HFA-PEFF scores [median 5 (interquartile range 3-6) vs. 1 (0-3), P < 0.001] and more often showed left ventricular diastolic dysfunction (75% vs. 27%, P < 0.001).
Conclusion: Hospitalized COVID-19 patients frequently show high likelihood of presence of HFpEF that is associated with cardiac structural and functional alterations, and myocardial injury. Detailed cardiac assessments including echocardiographic determination of left ventricular diastolic function and biomarkers should become routine in the care of hospitalized COVID-19 patients
Effectiveness of training stop-smoking advisers to deliver cessation support to the UK national proposed standard versus usual care in Malaysia: a two-arm cluster-randomized controlled trial
Aims To assess the effectiveness of training stop smoking services providers in Malaysia to deliver support for smoking
cessation based on the UK National Centre for Smoking Cessation and Training (NCSCT) standard treatment programme
compared with usual care. Design Two-arm cluster-randomized controlled effectiveness trial across 19 sites with followup at 4-week, 3-month, and 6-month. Setting Stop smoking services operating in public hospitals in Malaysia.
Participants Five hundred and two smokers [mean ± standard deviation (SD), age 45.6 (13.4) years; 97.4% male] attending stop smoking services in hospital settings in Malaysia: 330 in 10 hospitals in the intervention condition and 172 in
nine hospitals in the control condition. Intervention and comparator The intervention consisted of training
stop-smoking practitioners to deliver support and follow-up according to the NCSCT Standard Treatment Programme.
The comparator was usual care (brief support and follow-up). Measurements The primary outcome was continuous
tobacco smoking abstinence up to 6 months in smokers who received smoking cessation treatment, verified by
expired-air carbon monoxide (CO) concentration. Secondary outcomes were continuous CO-verified tobacco smoking abstinence up to 4 weeks and 3 months. Results Follow-up rates at 4 weeks, 3 months and 6 months were 80.0, 70.6 and
53.3%, respectively, in the intervention group and 48.8, 30.8 and 23.3%, respectively, in the control group. At 6-month
follow-up, 93 participants in the intervention group and 19 participants in the control group were abstinent from
smoking, representing 28.2 versus 11.0% in an intention-to-treat (ITT) analysis assuming that participants with missing
data had resumed smoking, and 52.8 versus 47.5% in a follow-up-only (FUO) analysis. Unadjusted odds ratios (accounting
for clustering) were 5.04, (95% confidence interval (CI) = 1.22–20.77, P = 0.025) and 1.70, (95% CI = 0.25–11.53,
P = 0.589) in the ITT and FUO analyses, respectively. Abstinence rates at 4 week and 3 month follow-ups were significantly higher in the intervention versus control group in the ITT but not the FUO analysis. Conclusions On an
intention-to-treat analysis with missing-equals-smoking imputation, training Malaysian stop smoking service providers
in the UK National Centre for Smoking Cessation and Training standard treatment programme appeared to increase
6 month continuous abstinence rates in smokers seeking help with stopping compared with usual care. However, the effect
may have been due to increasing follow-up rates
Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis
BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London
Intercellular Transport of Oct4 in Mammalian Cells: A Basic Principle to Expand a Stem Cell Niche?
Background: The octamer-binding transcription factor 4 (Oct4) was originally described as a marker of embryonic stem cells. Recently, the role of Oct4 as a key regulator in pluripotency was shown by its ability to reprogram somatic cells in vitro, either alone or in concert with other factors. While artificial induction of pluripotency using transcription factors is possible in mammalian cell culture, it remains unknown whether a potential natural transfer mechanism might be of functional relevance in vivo. The stem cell based regeneration of deer antlers is a unique model for rapid and complete tissue regeneration in mammals and therefore most suitable to study such mechanisms. Here, the transfer of pluripotency factors from resident stem cell niche cells to differentiated cells could recruit more stem cells and start rapid tissue regeneration. Methodology/Principal Findings: We report on the ability of STRO-1 + deer antlerogenic mesenchymal stem cells (DaMSCs) to transport Oct4 via direct cell-to-cell connections. Upon cultivation in stem cell expansion medium, we observed nuclear Oct4 expression in nearly all cells. A number of these cells exhibit Oct4 expression not only in the nucleus, but also with perinuclear localisation and within far-ranging intercellular connections. Furthermore, many cells showed intercellular connections containing both F-actin and a-tubulin and through which transport could be observed. To proof that intercellular Oct4-transfer has functional consequences in recipient cells we used a co-culture approach with STRO-1 + DaMSCs and a murine embryonic fibroblast indicator cell line (Oct4-GFP MEF). In this cell line a reporter gene (GFP) unde
Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats
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