So depression is an inflammatory disease, but where does the inflammation come from?

BACKGROUND: We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is 'what is the source of this chronic low-grade inflammation?' DISCUSSION: This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. SUMMARY: The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder

CIRCE: Coordinated Ionospheric Reconstruction Cubesat Experiment

The Coordinated Ionospheric Reconstruction Cubesat Experiment (CIRCE) is a collaborative space mission between the UK Defence Science and Technology Laboratory (Dstl), and the US Naval Research Laboratory (NRL) in developing small satellite ionospheric physics capability. CIRCE will characterise space weather effects on a regional scale in the ionosphere/thermosphere system. Properly characterising the dynamic ionosphere is important for a wide range of both civil and defence applications such as GPS, communications, and sensing technology. Consisting of two near-identical 6U (2x3U) CubeSat buses, the CIRCE nanosatellites will fly in a lead-follow tandem configuration in co-planar near-polar orbits at 500km altitude. Provided by Blue Canyon Technologies (BCT), the two buses will use differential drag to achieve and maintain an in-track separation of between 250 and 500km, allowing short time-scale dynamics to be observed in-situ. These nanosatellites each carry a complement of 5 individual scientific instruments, contributed from academic, industrial, and government partners across the UK and US. Scheduled to launch in 2021 via the US Department of Defence Space Test Program, the two CIRCE satellites will provide observations to enable a greater understanding of the driving processes of geophysical phenomena in the ionosphere/thermosphere system, distributed across a wide range of latitudes, and altitudes, as the mission progresses

Climate warming, marine protected areas and the ocean-scale integrity of coral reef ecosystems

Coral reefs have emerged as one of the ecosystems most vulnerable to climate variation and change. While the contribution of a warming climate to the loss of live coral cover has been well documented across large spatial and temporal scales, the associated effects on fish have not. Here, we respond to recent and repeated calls to assess the importance of local management in conserving coral reefs in the context of global climate change. Such information is important, as coral reef fish assemblages are the most species dense vertebrate communities on earth, contributing critical ecosystem functions and providing crucial ecosystem services to human societies in tropical countries. Our assessment of the impacts of the 1998 mass bleaching event on coral cover, reef structural complexity, and reef associated fishes spans 7 countries, 66 sites and 26 degrees of latitude in the Indian Ocean. Using Bayesian meta-analysis we show that changes in the size structure, diversity and trophic composition of the reef fish community have followed coral declines. Although the ocean scale integrity of these coral reef ecosystems has been lost, it is positive to see the effects are spatially variable at multiple scales, with impacts and vulnerability affected by geography but not management regime. Existing no-take marine protected areas still support high biomass of fish, however they had no positive affect on the ecosystem response to large-scale disturbance. This suggests a need for future conservation and management efforts to identify and protect regional refugia, which should be integrated into existing management frameworks and combined with policies to improve system-wide resilience to climate variation and change

Understanding the origin and impact of relativistic cosmic particles with very-high-energy gamma-rays

This white paper briefly summarizes the importance of the study of relativistic cosmic rays, both as a constituent of our Universe, and through their impact on stellar and galactic evolution. The focus is on what can be learned over the coming decade through ground-based gamma-ray observations over the 20 GeV to 300 TeV range

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria

Background: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). Methods: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. Findings: 258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. Interpretation: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. Funding: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication

Boreal forest floor greenhouse gas emissions across a Pleurozium schreberi-dominated, wildfire-disturbed chronosequence

The boreal forest is a globally critical biome for carbon cycling. Its forests are shaped by wildfire events that affect ecosystem properties and climate feedbacks including greenhouse gas (GHG) emissions. Improved understanding of boreal forest floor processes is needed to predict the impacts of anticipated increases in fire frequency, severity, and extent. In this study, we examined relationships between time since last wildfire (TSF), forest floor soil properties, and GHG emissions (CO2, CH4, N2O) along a Pleurozium schreberi-dominated chronosequence in mid- to late succession located in northern Sweden. Over three growing seasons in 2012–2014, GHG flux measurements were made in situ and samples were collected for laboratory analyses. We predicted that P. schreberi-covered forest floor GHG fluxes would be related to distinct trends in the soil properties and microbial community along the wildfire chronosequence. Although we found no overall effect of TSF on GHG emissions, there was evidence that soil C/N, one of the few properties to show a trend with time, was inversely linked to ecosystem respiration. We also found that local microclimatic conditions and site-dependent properties were better predictors of GHG fluxes than TSF. This shows that site-dependent co-variables (that is, forest floor climate and plant-soil properties) need to be considered as well as TSF to predict GHG emissions as wildfires become more frequent, extensive and severe

Blood Pressure and Arterial Stiffness in Kenyan Adolescents With α+Thalassemia.

BACKGROUND: Recent studies have discovered that α-globin is expressed in blood vessel walls where it plays a role in regulating vascular tone. We tested the hypothesis that blood pressure (BP) might differ between normal individuals and those with α+thalassemia, in whom the production of α-globin is reduced. METHODS AND RESULTS: The study was conducted in Nairobi, Kenya, among 938 adolescents aged 11 to 17 years. Twenty-four-hour ambulatory BP monitoring and arterial stiffness measurements were performed using an arteriograph device. We genotyped for α+thalassemia by polymerase chain reaction. Complete data for analysis were available for 623 subjects; 223 (36%) were heterozygous (-α/αα) and 47 (8%) were homozygous (-α/-α) for α+thalassemia whereas the remaining 353 (55%) were normal (αα/αα). Mean 24-hour systolic BP ±SD was 118±12 mm Hg in αα/αα, 117±11 mm Hg in -α/αα, and 118±11 mm Hg in -α/-α subjects, respectively. Mean 24-hour diastolic BP ±SD in these groups was 64±8, 63±7, and 65±8 mm Hg, respectively. Mean pulse wave velocity (PWV)±SD was 7±0.8, 7±0.8, and 7±0.7 ms-1, respectively. No differences were observed in PWV and any of the 24-hour ambulatory BP monitoring-derived measures between those with and without α+thalassemia. CONCLUSIONS: These data suggest that the presence of α+thalassemia does not affect BP and/or arterial stiffness in Kenyan adolescents

Influence of an outpatient multidisciplinary pain management program on the health-related quality of life and the physical fitness of chronic pain patients

BACKGROUND: Approximately 10 to 20 percent of the population is suffering from chronic pain. Since this represents a major contribution to the costs of the health care system, more efficient measures and interventions to treat these patients are sought. RESULTS: The development of general health and physical activity of patients with chronic pain was assessed in an interdisciplinary outpatient pain management program (IOPP). 36 patients with an average age of 48 years were included in the IOPP. Subjective assessment of well-being was performed at five time points (baseline, post intervention and 3, 6, and 12 months thereafter) by using standardized questionnaires. The study focused on the quality of life survey Medical Outcomes Study Short Form-36, which is a validated instrument with established reliability and sensitivity. In addition, the patients participated in physical assessment testing strength, power, endurance, and mobility. Prior to therapy a substantial impairment was found on different levels. Marked improvements in the psychological parameters were obtained by the end of the program. No success was achieved with regard to the physical assessments. CONCLUSION: Although many different studies have evaluated similar programs, only few of them have attained positive results such as improvements of general quality of life or of physical strength. Often no difference from the control group could be detected only some months after the intervention. In the present study no significant persistent improvement of well-being occurred. Possible reasons are either wrong instruments, wrong selection of patients or wrong interventions

Crystal Structure of the PIM2 Kinase in Complex with an Organoruthenium Inhibitor

BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1