Feasible mitigation actions in developing countries

Energy use is not only crucial for economic development, but is also the main driver of greenhouse-gas emissions. Developing countries can reduce emissions and thrive only if economic growth is disentangled from energy-related emissions. Although possible in theory, the required energy-system transformation would impose considerable costs on developing nations. Developed countries could bear those costs fully, but policy design should avoid a possible 'climate rent curse', that is, a negative impact of financial inflows on recipients' economies. Mitigation measures could meet further resistance because of adverse distributional impacts as well as political economy reasons. Hence, drastically re-orienting development paths towards low-carbon growth in developing countries is not very realistic. Efforts should rather focus on 'feasible mitigation actions' such as fossil-fuel subsidy reform, decentralized modern energy and fuel switching in the power sector

Transcranial Magnetic Stimulation Intensities in Cognitive Paradigms

BACKGROUND: Transcranial magnetic stimulation (TMS) has become an important experimental tool for exploring the brain's functional anatomy. As TMS interferes with neural activity, the hypothetical function of the stimulated area can thus be tested. One unresolved methodological issue in TMS experiments is the question of how to adequately calibrate stimulation intensities. The motor threshold (MT) is often taken as a reference for individually adapted stimulation intensities in TMS experiments, even if they do not involve the motor system. The aim of the present study was to evaluate whether it is reasonable to adjust stimulation intensities in each subject to the individual MT if prefrontal regions are stimulated prior to the performance of a cognitive paradigm. METHODS AND FINDINGS: Repetitive TMS (rTMS) was applied prior to a working memory task, either at the 'fixed' intensity of 40% maximum stimulator output (MSO), or individually adapted at 90% of the subject's MT. Stimulation was applied to a target region in the left posterior middle frontal gyrus (pMFG), as indicated by a functional magnetic resonance imaging (fMRI) localizer acquired beforehand, or to a control site (vertex). Results show that MT predicted the effect size after stimulating subjects with the fixed intensity (i.e., subjects with a low MT showed a greater behavioral effect). Nevertheless, the individual adaptation of intensities did not lead to stable effects. CONCLUSION: Therefore, we suggest assessing MT and account for it as a measure for general cortical TMS susceptibility, even if TMS is applied outside the motor domain

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Prospects of Genetics and Epigenetics of Alcohol Use Disorder

Purpose of Review: In this study, we illustrate recent findings regarding the genetics and epigenetics of alcohol use disorder (AUD). We further outline the future direction of genetic and epigenetic research in AUD. Recent Findings: Recent genome- and epigenome-wide studies allow new insight into genetic and epigenetic variation associated with AUD. The largest EWAS of AUD so far/to date found evidence for altered glucocorticoid receptor regulation. Longitudinal studies provide insight into the dynamics of the disease. Analyses of postmortem brain tissue reveal the impact of chronic alcohol consumption on DNA methylation in the brain. Summary: Genetic and environmental factors-mediated via epigenetic mechanisms-play an important role in AUD. Although knowledge of the biological underpinnings of AUD is still limited, ongoing research will ultimately lead to the development of biomarkers for disease classification, course of disease, and treatment response to support personalized medicine in the future

Suicide risk with selective serotonin reuptake inhibitors and other new-generation antidepressants in adults: a systematic review and meta-analysis of observational studies

Background: There is ongoing controversy whether antidepressant use alters suicide risk in adults with depression and other treatment indications. Methods: Systematic review of observational studies, searching MEDLINE, PsycINFO, Web of Science, PsycARTICLES and SCOPUS for case–control and cohort studies. We included studies on depression and various indications unspecified (including off-label use) reporting risk of suicide and/or suicide attempt for adult patients using selective serotonin reuptake inhibitors (SSRI) and other new-generation antidepressants relative to non-users. Effects were meta-analytically aggregated with random-effects models, reporting relative risk (RR) estimates with 95% CIs. Publication bias was assessed via funnel-plot asymmetry and trim-and-fill method. Financial conflict of interest (fCOI) was defined present when lead authors’ professorship was industry-sponsored, they received industry-payments, or when the study was industry-sponsored. Results: We included 27 studies, 19 on depression and 8 on various indications unspecified (n=1.45 million subjects). SSRI were not definitely related to suicide risk (suicide and suicide attempt combined) in depression (RR=1.03, 0.70–1.51) and all indications (RR=1.19, 0.88–1.60). Any new-generation antidepressant was associated with higher suicide risk in depression (RR=1.29, 1.06–1.57) and all indications (RR=1.45, 1.2–1.70). Studies with fCOI reported significantly lower risk estimates than studies without fCOI. Funnel-plots were asymmetrical and imputation of missing studies with trim-and-fill method produced considerably higher risk estimates. Conclusions: Exposure to new-generation antidepressants is associated with higher suicide risk in adult routine-care patients with depression and other treatment indications. Publication bias and fCOI likely contribute to systematic underestimation of risk in the published literature

The homeostasis of Plasmodium falciparum-infected red blood cells.

The asexual reproduction cycle of Plasmodium falciparum, the parasite responsible for severe malaria, occurs within red blood cells. A merozoite invades a red cell in the circulation, develops and multiplies, and after about 48 hours ruptures the host cell, releasing 15-32 merozoites ready to invade new red blood cells. During this cycle, the parasite increases the host cell permeability so much that when similar permeabilization was simulated on uninfected red cells, lysis occurred before approximately 48 h. So how could infected cells, with a growing parasite inside, prevent lysis before the parasite has completed its developmental cycle? A mathematical model of the homeostasis of infected red cells suggested that it is the wasteful consumption of host cell hemoglobin that prevents early lysis by the progressive reduction in the colloid-osmotic pressure within the host (the colloid-osmotic hypothesis). However, two critical model predictions, that infected cells would swell to near prelytic sphericity and that the hemoglobin concentration would become progressively reduced, remained controversial. In this paper, we are able for the first time to correlate model predictions with recent experimental data in the literature and explore the fine details of the homeostasis of infected red blood cells during five model-defined periods of parasite development. The conclusions suggest that infected red cells do reach proximity to lytic rupture regardless of their actual volume, thus requiring a progressive reduction in their hemoglobin concentration to prevent premature lysis

Coordinates and Z value maximum of individual pMFG target regions.

<p>Note that images were not normalized prior to fitting to the Talairach coordinate system provided by Brainsight; compatibility between subjects is therefore limited. Reference point for the origin of the underlying coordinate system is the anterior commissure (AC: 0 0 0) with the axial plane through anterior and posterior commissures (AC-PC) and the z-axis orthogonal to this plane. Values are like in the standard coordinate systems in mm with −x - left, +x - right, −y - posterior, +y - anterior, −z - inferior, +z - superior.</p

Motor thresholds and SCD.

<p>Motor threshold is expressed as % of MSO; note that SCD in pMFG was measured at the target stimulation site and the SCD in the M1 was measured on the anatomical area of the representation of the hand (handknob).</p