Salen Mn Complexes Mitigate Radiation Injury in Normal Tissues

Salen Mn complexes, including EUK-134, EUK-189 and a newer cyclized analog EUK-207, are synthetic SOD/catalase mimetics that have beneficial effects in many models of oxidative stress. As oxidative stress is implicated in some forms of delayed radiation injury, we are investigating whether these compounds can mitigate injury to normal tissues caused by ionizing radiation. This review describes some of this research, focusing on several tissues of therapeutic interest, namely kidney, lung, skin, and oral mucosa. These studies have demonstrated suppression of delayed radiation injury in animals treated with EUK-189 and/or EUK-207. While an antioxidant mechanism of action is postulated, it is likely that the mechanisms of radiation mitigation by these compounds in vivo are complex and may differ in the various target tissues. Indicators of oxidative stress are increased in lung and skin radiation injury models, and suppressed by salen Mn complexes. The role of oxidative stress in the renal injury model is unclear, though EUK-207 does mitigate. In certain experimental models, salen Mn complexes have shown “mito-protective” properties, that is, attenuating mitochondrial injury. Consistent with this, EUK-134 suppresses effects of ionizing radiation on mitochondrial function in rat astrocyte cultures. In summary, salen Mn complexes could be useful to mitigate delayed radiation injury to normal tissues following radiation therapy, accidental exposure, or radiological terrorism. Optimization of their mode of delivery and other key pharmaceutical properties, and increasing understanding of their mechanism(s) of action as radiation mitigators, are key issues for future study

Positive psychology interventions in patients with medical illness: What predicts improvement in psychological state?

Positive psychology interventions (PPIs) have been shown to promote wellbeing in individuals with medical illness, although it is still unknown whether certain patient characteristics make participants more likely to benefit from such interventions. The present study tested whether, using individual patient data across five published PPI studies (three single-arm proof-of-concept trials, one non-randomized controlled trial, and one randomized controlled trial) in medically-ill persons, sociodemographic or psychological factors predicted subsequent change in wellbeing. In 208 participants, lower baseline psychological wellbeing and optimism, and higher symptoms of depression and anxiety were associated with greater improvement in psychological symptoms during the PPI. Other factors were unrelated to symptom changes. In a sub-analysis of controlled studies, there were no group differences in the relationship between baseline factors and changes in wellbeing from pre- to post-intervention. Findings suggest that patients with more severe psychiatric and/or medical comorbidity are no less likely to benefit from a PPI compared to those with higher levels of health, even though these programs do not directly target psychological distress. PPIs may be widely applicable to medical patients, with lower psychological wellbeing a potential predictor of increased benefit

North American monsoon and convectively coupled equatorial waves simulated by IPCC AR4 coupled GCMs

This study evaluates the fidelity of North American monsoon and associated intraseasonal variability in the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) coupled general circulation models (CGCMs). Twenty years of monthly precipitation data from each of the 22 models' twentieth-century climate simulations, together with the available daily precipitation data from 12 of them, are analyzed and compared with Global Precipitation Climatology Project (GPCP) monthly and daily precipitation. The authors focus on the seasonal cycle and horizontal pattern of monsoon precipitation in conjunction with the two dominant convectively coupled equatorial wave modes: the eastward-propagating Madden-Julian oscillation (MJO) and the westward-propagating easterly waves. The results show that the IPCC AR4 CGCMs have significant problems and display a wide range of skill in simulating the North American monsoon and associated intraseasonal variability. Most of the models reproduce the monsoon rainbelt, extending from southeast to northwest, and its gradual northward shift in early summer, but overestimate the precipitation over the core monsoon region throughout the seasonal cycle and fail to reproduce the monsoon retreat in the fall. Additionally, most models simulate good westward propagation of the easterly waves, but relatively poor eastward propagation of the MJO and overly weak variances for both the easterly waves and the MJO. There is a tendency for models without undiluted updrafts in their deep convection scheme to produce better MJO propagation.open221

Subseasonal variability associated with Asian summer monsoon simulated by 14 IPCC AR4 coupled GCMs

This study evaluates the subseasonal variability associated with the Asian summer monsoon in 14 coupled general circulation models (GCMs) participating in the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4). Eight years of each model's twentieth-century climate simulation are analyzed. The authors focus on the three major components of Asian summer monsoon: the Indian summer monsoon (ISM), the western North Pacific summer monsoon (WNPSM), and the East Asian summer monsoon (EASM), together with the two dominant subseasonal modes: the eastward- and northward-propagating boreal summer intraseasonal oscillation (BSIO) and the westward-propagating 12-24-day mode. The results show that current state-of-the-art GCMs still have difficulties and display a wide range of skill in simulating the subseasonal variability associated with Asian summer monsoon. During boreal summer (May-October), most of the models produce reasonable seasonal-mean precipitation over the ISM region, but excessive precipitation over the WNPSM region and insufficient precipitation over the EASM region. In other words, models concentrate their rain too close to the equator in the western Pacific. Most of the models simulate overly weak total subseasonal (2-128 day) variance, as well as too little variance for BSIO and the 12-24-day mode. Only 4-5 models produce spectral peaks in the BSIO and 12-24-day frequency bands; instead, most of the models display too red a spectrum, that is, an overly strong persistence of precipitation. For the seven models with three-dimensional data available, five reproduce the preconditioning of moisture in BSIO but often with a too late starting time, and only three simulate the phase lead of low-level convergence. Interestingly, although models often have difficulty in simulating the eastward propagation of BSIO, they tend to simulate well the northward propagation of BSIO, together with the westward propagation of the 12-24-day mode. The northward propagation in these models is thus not simply a NW-SE-tilted tail protruding off of an eastward-moving deep-tropical intraseasonal oscillation.open444

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Monsoons: global energetics and local physics as drivers of past, present and future monsoons

Global constraints on momentum and energy govern the structure of the zonal mean tropical circulation and rainfall. The continental-scale monsoon systems are also facets of a momentum- and energy-constrained global circulation, but their modern and paleo variability deviates substantially from that of the longitudinal mean through mechanisms neither fully understood nor well simulated. A framework grounded in global constraints yet encompassing the complexities of monsoon dynamics is needed to identify the causes of mismatch between theory, models, and observations and, ultimately, improve regional climate projection. In a first step towards this goal, disparate regional processes must be distilled into gross measures of energy flow in and out of continents and from the surface to the tropopause, so that monsoon dynamics may be coherently diagnosed across modern and paleo observations and across idealized and comprehensive simulations. Accounting for zonal asymmetries in the circulation, land/ocean differences in surface fluxes, and the character of convective systems, such a monsoon framework would integrate our understanding at all relevant scales: from the fine details of how moisture and energy are lifted in the updrafts of thunderclouds, up to the global circulations

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe