The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and ...re-integration into the host genome. While most ERVs are relics of ancient integration events, “young” proviruses competent for retrotransposition—found in many mammals, but not humans—represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.
Solitary long terminal repeats (LTRs) have been frequently domesticated into gene regulatory elements in mammals. Here, Thompson et al. evaluate the features of LTRs that account for the prevalence of this phenomenon and highlight recent studies providing insight into the molecular mechanisms that influence the exaptation of LTRs.
Objectives The objective of this study was to determine whether colchicine 0.5 mg/day can reduce the risk of cardiovascular events in patients with clinically stable coronary disease. Background The ...presence of activated neutrophils in culprit atherosclerotic plaques of patients with unstable coronary disease raises the possibility that inhibition of neutrophil function with colchicine may reduce the risk of plaque instability and thereby improve clinical outcomes in patients with stable coronary disease. Methods In a clinical trial with a prospective, randomized, observer-blinded endpoint design, 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years. The primary outcome was the composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. The primary analysis was by intention-to-treat. Results The primary outcome occurred in 15 of 282 patients (5.3%) who received colchicine and 40 of 250 patients (16.0%) assigned no colchicine (hazard ratio: 0.33; 95% confidence interval CI 0.18 to 0.59; p < 0.001; number needed to treat: 11). In a pre-specified secondary on-treatment analysis that excluded 32 patients (11%) assigned to colchicine who withdrew within 30 days due to intestinal intolerance and a further 7 patients (2%) who did not start treatment, the primary outcome occurred in 4.5% versus 16.0% (hazard ratio: 0.29; 95% CI: 0.15 to 0.56; p < 0.001). Conclusions Colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.
Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the ...disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP). Senescent beta cells upregulated pro-survival mediator Bcl-2, and treatment of NOD mice with Bcl-2 inhibitors selectively eliminated these cells without altering the abundance of the immune cell types involved in the disease. Significantly, elimination of senescent beta cells halted immune-mediated beta cell destruction and was sufficient to prevent diabetes. Our findings demonstrate that beta cell senescence is a significant component of the pathogenesis of T1D and indicate that clearance of senescent beta cells could be a new therapeutic approach for T1D.
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•Beta cells in NOD mice and human T1D become senescent•Senescent beta cells acquire a senescence-associated secretory phenotype•Senescent beta cells upregulate Bcl-2 and senolytic drugs induce their apoptosis•Clearance of senescent beta cells preserves beta cell mass and prevents diabetes
Pancreatic beta cells are usually thought as passive victims of immune cell attack in type 1 diabetes (T1D). Thompson et al. now demonstrate that a subpopulation of beta cells becomes senescent and actively promotes the immune-mediated destruction process. Clearance of senescent beta cells with small-molecule inhibitors prevents T1D.
Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized in South Africa by large epidemics amongst ruminant livestock at very long, irregular intervals, mainly in the central ...interior. However, the presence and patterns of occurrence of the virus in the eastern parts of the country are poorly known. This study aimed to detect the presence of RVF virus (RVFV) in cattle and goats in far northern KwaZulu-Natal province and to estimate the prevalence of antibodies to the virus and the incidence rate of seroconversion.
Cross-sectional studies were performed in communally farmed cattle (n = 423) and goats (n = 104), followed by longitudinal follow-up of seronegative livestock (n = 253) 14 times over 24 months, representing 160.3 animal-years at risk. Exposure to RVFV was assessed using an IgG sandwich ELISA and a serum neutralization test (SNT) and seroconversion was assessed using SNT. Incidence density was estimated and compared using multivariable Poisson models and hazard of seroconversion was estimated over time.
Initial overall seroprevalence was 34.0% (95%CI: 29.5-38.8%) in cattle and 31.7% (95%CI: 22.9-41.6%) in goats, varying by locality from 18-54%. Seroconversions to RVFV based on SNT were detected throughout the year, with the incidence rate peaking during the high rainfall months of January to March, and differed considerably between years. Overall seroconversion rate in cattle was 0.59 per animal-year (95% CI: 0.46-0.75) and in goats it was 0.41 per animal-year (95% CI: 0.25-0.64), varying significantly over short distances.
The high seroprevalence in all age groups and evidence of year-round viral circulation provide evidence for a hyperendemic situation in the study area. This is the first study to directly estimate infection rate of RVFV in livestock in an endemic area in the absence of reported outbreaks and provides the basis for further investigation of factors affecting viral circulation and mechanisms for virus survival during interepidemic periods.
According to its licence plates, tourist brochures, and commercials, Nova Scotia is Canada's Ocean Playground – an idyllic vacation spot brimming with traditional cultural experiences. Yet this ...picturesque and welcoming ad-friendly façade overlooks the province's history of industrial development, the impact of resource extraction on its landscape, and the effects of its painful and still unfinished period of deindustrialization. Recounting Nova Scotia's struggle to come to terms with its extractive and industrial past, Nights below Foord Street focuses on the spaces ignored by the province's annual Doers and Dreamers tourist guide. Drawing on literary texts by Lynn Coady, Leo McKay, Sarah Mian, and Jonathan Campbell, popular television shows such as Trailer Park Boys, and films including Blackbird, Cottonland, and Poor Boy's Game, Peter Thompson examines the ways in which contemporary authors, filmmakers, and artists explore the lingering consequences of the boom-and-bust cycles of mining and manufacturing. As he demonstrates, these narratives depict a legacy of environmental exploitation, pollution, intermittent disasters, and labour violence left behind by the industrial era, all of which contrast starkly with the romantic and nostalgic portrait of Nova Scotia's industrial heritage promoted in museums, monuments, and tourist sites. As Donald Trump and other populist politicians appeal to working-class nostalgia and international attention converges on environmental racism in northern Nova Scotia, Nights below Foord Street intervenes into debates over the cultural and social effects of the post-industrial economy.According to its licence plates, tourist brochures, and commercials, Nova Scotia is Canada's Ocean Playground – an idyllic vacation spot brimming with traditional cultural experiences. Yet this picturesque and welcoming ad-friendly façade overlooks the province's history of industrial development, the impact of resource extraction on its landscape, and the effects of its painful and still unfinished period of deindustrialization. Recounting Nova Scotia's struggle to come to terms with its extractive and industrial past, Nights below Foord Street focuses on the spaces ignored by the province's annual Doers and Dreamers tourist guide. Drawing on literary texts by Lynn Coady, Leo McKay, Sarah Mian, and Jonathan Campbell, popular television shows such as Trailer Park Boys, and films including Blackbird, Cottonland, and Poor Boy's Game, Peter Thompson examines the ways in which contemporary authors, filmmakers, and artists explore the lingering consequences of the boom-and-bust cycles of mining and manufacturing. As he demonstrates, these narratives depict a legacy of environmental exploitation, pollution, intermittent disasters, and labour violence left behind by the industrial era, all of which contrast starkly with the romantic and nostalgic portrait of Nova Scotia's industrial heritage promoted in museums, monuments, and tourist sites. As Donald Trump and other populist politicians appeal to working-class nostalgia and international attention converges on environmental racism in northern Nova Scotia, Nights below Foord Street intervenes into debates over the cultural and social effects of the post-industrial economy.
Patients with chronic coronary disease were randomly assigned to receive 0.5 mg of colchicine once daily or matching placebo. The incidence of the composite end point of cardiovascular death, ...spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was significantly lower with colchicine than with placebo.
According to Hartung, its first appearance in a pharmacopeia for use in gout was in The London Pharmacopoeia of 1618. During the 1980s, use of colchicine for pericarditis was widespread but ...inconsistent, and it was put on an evidence-based footing with the first report of a randomized trial in 1990.9 The potential for repurposing colchicine for cardiovascular disease was recognized in the accompanying editorial.10 Subsequent explorations of its role in atherosclerosis, pericarditis, and atrial fibrillation reflect a rapidly increasing evidence base on the importance of inflammation in a variety of cardiovascular diseases11 and the challenges in targeting it to improve cardiovascular outcomes.12 This special section of the journal features 5 excellent reviews of the current place of colchicine in cardiovascular medicine, each authored by international leaders in their respective areas of research. The article by Vaidya et al.20 focuses on the potential for colchicine to limit the inflammatory processes that occur during an acute coronary syndrome. Because the pathophysiologic mechanisms of acute coronary syndrome are likely to differ from stable coronary heart disease, they review the inflammatory processes of plaque instability in detail and provide a summary of their own pioneering work on a plaque-stabilizing effect of colchicine on coronary computed tomographic imaging.21 They provide a summary of the key large trials under way in this clinical setting, primarily the 5500-patient Colchicine Cardiovascular Outcomes Trial (COLCOT).22 In a future issue of the Journal, Dr. Massimo Imazio will summarize the series of well-conducted trials led by his research group in Turin, which found that colchicine now has a clear evidence-based role in treatment of acute and recurrent pericarditis but less so in constrictive pericarditis.
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