The effect of bioenergetic impairment of cytosolic processes in spatio-temporal Ca²⁺ dynamics in a three-dimensional cardiomyocyte model

The heart consumes large amounts of energy with each beat. Mitochondria are the source of over 95% of this energy in the form of ATP and rely on increased Ca²⁺ uptake to stimulate production in times of increased work. Ca²⁺ uptake into the mitochondria primarily occurs within microdomains. Structural remodeling associated with heart failure may disrupt these microdomains leading to impaired mitochondrial Ca²⁺ uptake and energetic impairment. To investigate the effect of structural changes on single cell behavior, a model describing mitochondrial dynamics and energetics production is modified and incorporated into a recently developed three-dimensional model of spatio-temporal calcium handling, which preserves microdomain structure and incorporates stochastic processes in Ca²⁺ handling protein kinetics. Modifications to the mitochondria model included a reformulation of mitochondrial Ca²⁺ uniporter uptake, making it suitable for concentrations in microdomains. With this model we demonstrate the importance of an ordered structure within the cell for normal function. Changes in the arrangement of mitochondria can have a pronounced effect on intracellular Ca²⁺ dynamics through their energetic regulation of SERCA, leading to spatially heterogeneous sarcoplasmic reticulum uptake and loading

Geophysical characterization of derelict coalmine workings and mineshaft detection: a case study from Shrewsbury, United Kingdom

A study site of derelict coalmine workings near Shrewsbury, United Kingdom was the focus for multi‐phase, near‐surface geophysical investigations. Investigation objectives were: 1) site characterization for remaining relict infrastructure foundations, 2) locate an abandoned coalmine shaft, 3) determine if the shaft was open, filled or partially filled and 4) determine if the shaft was capped (and if possible characterize the capping material). Phase one included a desktop study and 3D microgravity modelling of the relict coalmine shaft thought to be on site. In phase two, electrical and electromagnetic surveys to determine site resistivity and conductivity were acquired together with fluxgate gradiometry and an initial microgravity survey. Phase three targeted the phase two geophysical anomalies and acquired high‐resolution self potential and ground penetrating radar datasets. The phased‐survey approach minimised site activity and survey costs. Geophysical results were compared and interpreted to characterize the site, the microgravity models were used to validate interpretations. Relict buildings, railway track remains with associated gravel and a partially filled coalmine shaft were located. Microgravity proved optimal to locate the mineshaft with radar profiles showing ‘side‐swipe’ effects from the mineshaft that did not directly underlie survey lines. Geophysical interpretations were then verified with subsequent geotechnical intrusive investigations. Comparisons of historical map records with intrusive geotechnical site investigations show care must be taken using map data alone, as the latter mineshaft locations was found to be inaccurate

Targeting conservation actions at species threat response thresholds

To improve the status of the world’s biodiversity by 2030, conservation actions must not only seek to halt or slow biodiversity loss, they must increase species’ populations. A better mechanistic understanding of biodiversity loss and of species’ sensitivities to certain intensities of threats is needed to target conservation actions effectively. Moving beyond ordinal space-for-time substitution analyses, towards monitoring concurrent changes in threats and species’ populations over time will help achieve this. We propose a framework to quantify species’ response thresholds along gradients of threat intensity, using a combination of threat-sensitive taxa, biogeographic regions, and biomes. This framework will allow efficient targeting of conservation actions, of relevance to global policy-making

Radical change and dietary conservatism: Mixing model estimates of human diets along the Inner Asia and China’s mountain corridors

Recent research has demonstrated that a series of mountains from the eastern Iranian Plateau to eastern Kazakhstan and to western China played a significant role in trans-Eurasian exchange during the third and second millennia BC. In close association with these mountain corridors, a number of southwestern Asian cereals, notably free threshing wheat and barley, moved eastward, and broomcorn millet, among other plant foods originating in China, moved westward. In this paper, we apply Bayesian stable isotope mixing models to published and newly obtained isotopic data in order to quantitatively estimate the contribution of different food resources to human diets, and we consider the complexity of human food strategies at both ends of these mountain corridors: southern Kazakhstan and the Hexi Corridor in western China. Our results contrast the rapid adoption of wheat and/or barley in the Hexi Corridor with the gradual, incremental adoption of millet in southern Kazakhstan during the second millennium BC.The authors are grateful to European Research Council, under grant 24964 (FOGLIP), Washington University Deanery Office Grant, American Association of University Women (AAUW), International Center for Advanced Renewable Energy and Sustainability (I-CARES) for financial support. We are thankful to Catherine Kneale and James Rolfe from Cambridge for assistance with isotopic analysis. We are also grateful to Pavel Tarasov for helps to the manuscript; and to Professors Mayke Wagner and Pavel Tarasov and Dr Robert Spengler for organizing the workshop, entitled ‘The Introduction and Intensification of Agriculture in Central Eurasia’, Berlin in 2015

Centrifuge modelling of tunnelling with forepoling

Geotechnical centrifuge modelling provides a means by which geotechnical events and processes can be better understood. In particular, the technique has proved invaluable when investigating collapse mechanisms in small scale models that can be related to full scale events. A series of eight plane strain centrifuge model tests investigating the effect of inserting inclusions around the annulus of a single tunnel in over consolidated clay has been conducted using the geotechnical centrifuge at City University London. The model used a compressed air supported circular cavity to simulate the tunnel. Stiff resin inclusions embedded around its periphery were used to represent closely spaced forepoles forming grout umbrella arches. Image processing was used to obtain patterns of displacements at the subsurface and displacement transducers measured vertical settlement at the ground surface level. The investigation focused on how different arrangements of forepoling affected tunnel stability. The influence of forepoling on normally accepted plastic collapse mechanisms is discussed. An optimisation of the forepoling layout is uggested in accordance with the findings

Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.

Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.Molecular Psychiatry advance online publication, 18 October 2016; doi:10.1038/mp.2016.167

Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort

OBJECTIVE: Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. METHOD: We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. RESULTS: Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15-0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10-22) but decreased serum CRP levels (P = 3.5 × 10-5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). CONCLUSIONS: The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples

Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study

BACKGROUND: To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms. METHODS: IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms. RESULTS: Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose-response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68-0.95); that for IL-6 was 1.20 (95% CI, 1.03-1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship. CONCLUSIONS: The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people

Combined palaeolimnological and ecological approach provides added value for understanding the character and drivers of recent environmental change in Flow Country lakes

The Flow Country peatlands receive national and international recognition and protection as a highly valued habitat, and also provide a number of important ecosystem services. While there has been much research on the terrestrial peatland habitat of the Flow Country, the area’s many hundreds of natural water bodies have been largely unstudied. The first part of this study therefore focuses on establishing the contemporary conditions at 18 Flow Country lakes, examining between-lake heterogeneity in terms of physical structure, water chemistry and biological communities. Temporal change in these lakes is then considered by combining contemporary ecological and palaeolimnological approaches. We examine how the diatom and chironomid communities of Flow Country lakes have changed since a time prior to the mid-nineteenth century. Results show that the lake communities today are different to those present pre-1850, containing more taxa tolerant of increased acidity and nutrient availability. General linear modelling (GLM) analysis demonstrated a statistically significant association between the extent of change in diatom communities and both dissolved organic carbon (DOC) and nitrate. Community shifts, though considerable, are shown to be complex and idiosyncratic and no shift between trophic states is indicated. The extent and type of coarse-scale community change we observed points to widespread bottom-up drivers such as land management, afforestation and/or atmospheric deposition rather than more localised management practices such as fish stocking. The benefits of combining approaches is discussed and palaeolimnological methods by which land management, afforestation and atmospheric deposition could be further disentangled are identified