Aortic aneurysms are a common vascular disease in Western populations that can involve virtually any portion of the aorta. Abdominal aortic aneurysms are much more common than thoracic aortic ...aneurysms and combined they account for >25 000 deaths in the United States annually. Although thoracic and abdominal aortic aneurysms share some common characteristics, including the gross anatomic appearance, alterations in extracellular matrix, and loss of smooth muscle cells, they are distinct diseases. In recent years, advances in genetic analysis, robust molecular tools, and increased availability of animal models have greatly enhanced our knowledge of the pathophysiology of aortic aneurysms. This review examines the various proposed cellular mechanisms responsible for aortic aneurysm formation and identifies opportunities for future studies.
The gut microbiome and intestinal dysfunction have emerged as potential contributors to the development of cardiovascular disease (CVD). Alterations in gut microbiome are well documented in ...hypertension, atherosclerosis, and heart failure and have been investigated as a therapeutic target. However, a perhaps underappreciated but related role for intestinal barrier function has become evident. Increased intestinal permeability is observed in patients and mouse models of CVD. This increased intestinal permeability can enhance systemic inflammation, alter gut immune function, and has been demonstrated as predictive of adverse cardiovascular outcomes. The goal of this review is to examine the evidence supporting a role for intestinal barrier function in cardiovascular disease and its prospect as a novel therapeutic target. We outline key studies that have investigated intestinal permeability in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction. We highlight the central mechanisms involved in the breakdown of barrier function and look at emerging evidence for restored barrier function as a contributor to promising treatment strategies such as short chain fatty acid, probiotic, and renin angiotensin system-targeted therapeutics. Recent studies of more selective targeting of the intestinal barrier to improve disease outcomes are also examined. We suggest that although current data supporting a contribution of intestinal permeability to CVD pathogenesis are largely associative, it appears to be a promising avenue for further investigation. Additional studies of the mechanisms of barrier restoration in CVD and testing of intestinal barrier-targeted compounds will be required to confirm their potential as a new class of CVD therapeutic.
Mitochondrial diseases are among the most common and most complex of all inherited genetic diseases. The involvement of both the mitochondrial and nuclear genome presents unique challenges, but ...despite this there have been some remarkable advances in our knowledge of mitochondrial diseases over the past few years. A greater understanding of mitochondrial genetics has led to improved diagnosis as well as novel ways to prevent transmission of severe mitochondrial disease. These and other advances have had a major impact on patient care, but considerable challenges remain, particularly in the areas of therapies for those patients manifesting clinical symptoms associated with mitochondrial dysfunction and the tissue specificity seen in many mitochondrial disorders. This review highlights some important recent advances in mitochondrial disease but also stresses the areas where progress is essential.
In an application of the social cognitive model of career self-management (Lent & Brown, 2013), we assessed the primary experiential sources of self-efficacy and outcome expectations relative to ...career exploration and decision-making activities. These sources included personal mastery, verbal persuasion, vicarious learning, and affect (both positive and negative) experienced in relation to career exploration and decision-making. Participants were 324 college students, who completed an experiential sources measure along with domain-correspondent measures of self-efficacy, outcome expectations, goals, and level of career decidedness. A confirmatory factor analysis offered support for a 5-factor representation of the experiential sources, though the personal mastery and verbal persuasion sources were substantially interrelated. As a set, the source variables accounted for a larger portion of the variance in self-efficacy than outcome expectations, with much of their relation to outcome expectations being mediated by self-efficacy. Good support was also found for a path model including the source variables in the prediction of career exploration goals and level of career decidedness. Though the sources were generally linked to goals indirectly, mastery and positive affect both produced significant direct paths to level of decidedness. The findings are interpreted in light of social cognitive career theory and their implications for further research and practice are discussed.
•Extended a social cognitive model to career exploration and decision-making•Developed a measure of the sources of self-efficacy and outcome expectations•The measure produced adequate reliability and validity estimates.•Used the measure in a test of the social cognitive model of career self-management•The self-management model fit the data well, especially with slight modification.
Knots are topological structures describing how a looped thread can be arranged in space. Although most familiar as knotted material filaments, it is also possible to create knots in singular ...structures within three-dimensional physical fields such as fluid vortices1 and the nulls of optical fields2–4. Here we produce, in the transverse polarization profile of optical beams, knotted lines of circular transverse polarization. We generate and observe both simple torus knots and links as well as the topologically more complicated figure-eight knot. The presence of these knotted polarization singularities endows a nontrivial topological structure on the entire three-dimensional propagating wavefield. In particular, the contours of constant polarization azimuth form Seifert surfaces of high genus5, which we are able to resolve experimentally in a process we call seifertometry. This analysis reveals a level of topological complexity, present in all experimentally generated polarization fields, that goes beyond the conventional reconstruction of polarization singularity lines.
Sponges (phylum Porifera) are early-diverging metazoa renowned for establishing complex microbial symbioses. Here we present a global Porifera microbiome survey, set out to establish the ecological ...and evolutionary drivers of these host-microbe interactions. We show that sponges are a reservoir of exceptional microbial diversity and major contributors to the total microbial diversity of the world's oceans. Little commonality in species composition or structure is evident across the phylum, although symbiont communities are characterized by specialists and generalists rather than opportunists. Core sponge microbiomes are stable and characterized by generalist symbionts exhibiting amensal and/or commensal interactions. Symbionts that are phylogenetically unique to sponges do not disproportionally contribute to the core microbiome, and host phylogeny impacts complexity rather than composition of the symbiont community. Our findings support a model of independent assembly and evolution in symbiont communities across the entire host phylum, with convergent forces resulting in analogous community organization and interactions.
The assembly of mitochondrial oxidative phosphorylation (OXPHOS) complexes is an intricate process, which-given their dual-genetic control-requires tight co-regulation of two evolutionarily distinct ...gene expression machineries. Moreover, fine-tuning protein synthesis to the nascent assembly of OXPHOS complexes requires regulatory mechanisms such as translational plasticity and translational activators that can coordinate mitochondrial translation with the import of nuclear-encoded mitochondrial proteins. The intricacy of OXPHOS complex biogenesis is further evidenced by the requirement of many tightly orchestrated steps and ancillary factors. Early-stage ancillary chaperones have essential roles in coordinating OXPHOS assembly, whilst late-stage assembly factors-also known as the LYRM (leucine-tyrosine-arginine motif) proteins-together with the mitochondrial acyl carrier protein (ACP)-regulate the incorporation and activation of late-incorporating OXPHOS subunits and/or co-factors. In this review, we describe recent discoveries providing insights into the mechanisms required for optimal OXPHOS biogenesis, including the coordination of mitochondrial gene expression with the availability of nuclear-encoded factors entering via mitochondrial protein import systems.
Recent Advances in Mitochondrial Disease Craven, Lyndsey; Alston, Charlotte L; Taylor, Robert W ...
Annual review of genomics and human genetics,
08/2017, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different ...symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.
Objective
The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease ...has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial DNA (mtDNA) rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA.
Methods
Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the midyear period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondrial diseases.
Results
The minimum prevalence rate for mtDNA mutations was 1 in 5,000 (20 per 100,000), comparable with our previously published prevalence rates. In this population, nuclear mutations were responsible for clinically overt adult mitochondrial disease in 2.9 per 100,000 adults.
Interpretation
Combined, our data confirm that the total prevalence of adult mitochondrial disease, including pathogenic mutations of both the mitochondrial and nuclear genomes (≈1 in 4,300), is among the commonest adult forms of inherited neurological disorders. These figures hold important implications for the evaluation of interventions, provision of evidence‐based health policies, and planning of future services. Ann Neurol 2015 Ann Neurol 2015;77:753–759
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