Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network ...analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.
We present GOseq, an application for performing Gene Ontology (GO) analysis on RNA-seq data. GO analysis is widely used to reduce complexity and highlight biological processes in genome-wide ...expression studies, but standard methods give biased results on RNA-seq data due to over-detection of differential expression for long and highly expressed transcripts. Application of GOseq to a prostate cancer data set shows that GOseq dramatically changes the results, highlighting categories more consistent with the known biology.
The human mitochondrial genome is replicated by DNA polymerase γ in concert with key components of the mitochondrial DNA (mtDNA) replication machinery. Defects in mtDNA replication or nucleotide ...metabolism cause deletions, point mutations, or depletion of mtDNA. The resulting loss of cellular respiration ultimately induces mitochondrial genetic diseases, including mtDNA depletion syndromes (MDS) such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. Here we review the current literature regarding human mtDNA replication and heritable disorders caused by genetic changes of the POLG , POLG2 , Twinkle , RNASEH1 , DNA2 , and MGME1 genes. Current Opinion in Genetics & Development 2016, 38 :52–62 This review comes from a themed issue on Molecular and genetic bases of disease Edited by Jason Bielas and Carolyn Suzuki For a complete overview see the Issue and the Editorial Available online 9th April 2016 http://dx.doi.org/10.1016/j.gde.2016.03.005 0959-437X/Published by Elsevier Ltd.
Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The availability of different P2Y12 ...receptor inhibitors (clopidogrel, prasugrel, ticagrelor) with varying levels of potency has enabled physicians to contemplate individualized treatment regimens, which may include escalation or de-escalation of P2Y12-inhibiting therapy. Indeed, individualized and alternative DAPT strategies may be chosen according to the clinical setting (stable coronary artery disease vs. acute coronary syndrome), the stage of the disease (early- vs. long-term treatment), and patient risk for ischemic and bleeding complications. A tailored DAPT approach may be potentially guided by platelet function testing (PFT) or genetic testing. Although the routine use of PFT or genetic testing in percutaneous coronary intervention–treated patients is not recommended, recent data have led to an update in guideline recommendations that allow considering selective use of PFT for DAPT de-escalation. However, guidelines do not expand on when to implement the selective use of such assays into decision making for personalized treatment approaches. Therefore, an international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened. This document updates 2 prior consensus papers on this topic and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention.
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•Different P2Y12 inhibitors have enabled physicians to contemplate individualized treatment regimens.•In selective scenarios, PFT and genotyping may be used as optional tools for guiding treatment.•Further studies on DAPT de-escalation and escalation are needed to refine existing treatment options.
Accurate risk assessment of atherosclerotic cardiovascular disease (ASCVD) is essential to effectively balance the risks and benefits of therapy for primary prevention.
To compare the calibration and ...discrimination of the new American Heart Association (AHA) and American College of Cardiology (ACC) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score.
Prospective epidemiologic study of ASCVD.
MESA (Multi-Ethnic Study of Atherosclerosis), a community-based, sex-balanced, multiethnic cohort.
4227 MESA participants aged 50 to 74 years and without diabetes at baseline.
Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores-and their respective end points-in MESA after a 10.2-year follow-up.
The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37% to 154% in men and 8% to 67% in women. Overestimation was noted throughout the continuum of risk. In contrast, the Reynolds Risk Score overestimated risk by 9% in men but underestimated risk by 21% in women. Aspirin, lipid-lowering or antihypertensive therapy, and interim revascularization did not explain the overestimation.
Comparability of MESA with target populations for primary prevention and possibility of missed events in MESA.
Of the 5 risk scores, 4, including the new AHA-ACC-ASCVD score, showed overestimation of risk (25% to 115%) in a modern, multiethnic cohort without baseline clinical ASCVD. If validated, overestimation of ASCVD risk may have substantial implications for individual patients and the health care system.
National Heart, Lung, and Blood Institute.
Posttraumatic stress disorder (PTSD) is an important mental health issue in terms of the number of people affected and the morbidity and functional impairment associated with the disorder. The ...purpose of this study was to examine the efficacy of all treatments for PTSD.
PubMed, MEDLINE, PILOTS, and PsycINFO databases were searched for randomized controlled clinical trials of any treatment for PTSD in adults published between January 1, 1980, and April 1, 2012, and written in the English language. The following search terms were used: post-traumatic stress disorders, posttraumatic stress disorder, PTSD, combat disorders, and stress disorders, post-traumatic.
Articles selected were those in which all subjects were adults with a diagnosis of PTSD based on DSM criteria and a valid PTSD symptom measure was reported. Other study characteristics were systematically collected. The sample consisted of 137 treatment comparisons drawn from 112 studies.
Effective psychotherapies included cognitive therapy, exposure therapy, and eye movement desensitization and reprocessing (g = 1.63, 1.08, and 1.01, respectively). Effective pharmacotherapies included paroxetine, sertraline, fluoxetine, risperidone, topiramate, and venlafaxine (g = 0.74, 0.41, 0.43, 0.41, 1.20, and 0.48, respectively). For both psychotherapy and medication, studies with more women had larger effects and studies with more veterans had smaller effects. Psychotherapy studies with wait-list controls had larger effects than studies with active control comparisons.
Our findings suggest that patients and providers have a variety of options for choosing an effective treatment for PTSD. Substantial differences in study design and study participant characteristics make identification of a single best treatment difficult. Not all medications or psychotherapies are effective.
Individual host behaviours can drastically impact the spread of infection through a population. Differences in the value individuals place on both socializing with others and avoiding infection have ...been shown to yield emergent homophily in social networks and thereby shape epidemic outcomes. We build on this understanding to explore how individuals who do not conform to their social surroundings contribute to the propagation of infection during outbreaks. We show how non-conforming individuals, even if they do not directly expose a disproportionate number of other individuals themselves, can become functional superspreaders through an emergent social structure that positions them as the functional links by which infection jumps between otherwise separate communities. Our results can help estimate the potential success of real-world interventions that may be compromised by a small number of non-conformists if their impact is not anticipated, and plan for how best to mitigate their effects on intervention success.
The term "environmental flows" describes the quantities, quality, and patterns of water flows required to sustain freshwater and estuarine ecosystems and the ecosystem services they provide. ...Environmental flows may be achieved in a number of different ways, most of which are based on either (1) limiting alterations from the natural flow baseline to maintain biodiversity and ecological integrity or (2) designing flow regimes to achieve specific ecological and ecosystem service outcomes. We argue that the former practice is more applicable to natural and semi-natural rivers where the primary objective and opportunity is ecological conservation. The latter "designer" approach is better suited to modified and managed rivers where return to natural conditions is no longer feasible and the objective is to maximize natural capital as well as support economic growth, recreation, or cultural history. This permits elements of ecosystem design and adaptation to environmental change. In a future characterized by altered climates and intensive regulation, where hybrid and novel aquatic ecosystems predominate, the designer approach may be the only feasible option. This conclusion stems from a lack of natural ecosystems from which to draw analogs and the need to support broader socioeconomic benefits and valuable configurations of natural and social capital.
Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. ...Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.
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•The CDP-ethanolamine pathway was eliminated from muscle•Muscle ECT deficiency altered phospholipid species and increased diacylglycerol•Insulin sensitivity was normal in mice lacking the CDP-ethanolamine pathway•ECT deficiency increased mitochondrial biogenesis and oxidative capacity
Accumulation of diacylglycerol (DAG), a phospholipid precursor, is associated with insulin resistance. Selathurai et al. show that eliminating the CDP-ethanolamine pathway in skeletal muscle causes DAG accumulation and alters membrane phospholipid composition. However, insulin sensitivity remains normal, and muscle mitochondrial content, oxidative capacity, and exercise performance are enhanced.
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