Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN- response pathway activation and senescence in differentiated microglia; an early life stress model

One form of early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in later life. Increasingly, the importance of microglia in these disorders is recognized. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-exposure of human iPS-microglia to GCs during primitive hematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia, using RNA-seq analyses and functional assays. The iPS-microglia predominantly expressed glucocorticoid receptors over mineralocorticoid receptors, and in particular, the GR-α splice variant. Chronic GCs exposure during primitive hematopoiesis was able to recapitulate in vivo ELS effects. Thus, pre-exposure to prolonged GCs resulted in increased type I interferon signaling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, cellular senescence and reduced proliferation in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC- mediated ELS-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autism spectrum disorder

Large Variations in Volcanic Aerosol Forcing Efficiency Due to Eruption Source Parameters and Rapid Adjustments

The relationship between volcanic stratospheric aerosol optical depth (SAOD) and volcanic radiative forcing is key to quantify volcanic climate impacts. In their fifth assessment report, the Intergovernmental Panel on Climate Change used one scaling factor between volcanic SAOD and volcanic forcing based on climate model simulations of the 1991 Mt. Pinatubo eruption, which may not be appropriate for all eruptions. Using a large-ensemble of aerosol-chemistry-climate simulations of eruptions with different sulfur dioxide emissions, latitudes, emission altitudes and seasons, we find that the effective radiative forcing (ERF) is on average 20% less than the instantaneous radiative forcing, predominantly due to a positive shortwave cloud adjustment. In our model, the volcanic SAOD-ERF relationship is non-unique and varies widely depending on time since an eruption, eruption latitude and season due to differences in aerosol dispersion and incoming solar radiation. Our revised SAOD-ERF relationships suggest that volcanic forcing has been previously overestimated

A systematic approach towards the identification and protection of vulnerable marine ecosystems

Author Posting. © The Author(s), 2013. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Marine Policy 49 (2014):146-154, doi:10.1016/j.marpol.2013.11.017.The United Nations General Assembly in 2006 and 2009 adopted resolutions that call for the identification and protection of vulnerable marine ecosystems (VMEs) from significant adverse impacts of bottom fishing. While general criteria have been produced, there are no guidelines or protocols that elaborate on the process from initial identification through to the protection of VMEs. Here, based upon an expert review of existing practices, a 10-step framework is proposed: 1) Comparatively assess potential VME indicator taxa and habitats in a region; 2) determine VME thresholds; 3) consider areas already known for their ecological importance; 4) compile information on the distributions of likely VME taxa and habitats, as well as related environmental data; 5) develop predictive distribution models for VME indicator taxa and habitats; 6) compile known or likely fishing impacts; 7) produce a predicted VME naturalness distribution (areas of low cumulative impacts); 8) identify areas of higher value to user groups; 9) conduct management strategy evaluations to produce trade-off scenarios; 10) review and re-iterate, until spatial management scenarios are developed that fulfil international obligations and regional conservation and management objectives. To date, regional progress has been piecemeal and incremental. The proposed 10-step framework combines these various experiences into a systematic approach.The New Zealand Ministry of Science and Innovation (now known as the Ministry of Business, Innovation and Employment) provided funding for the worksho

Alzheimer's disease-associated R47H TREM2 increases, but wild-type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss

Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated on the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for the R47H variant of TREM2 have greatly increased risk of developing AD. We examined the effects of wild-type (WT), R47H and knock-out (KO) of human TREM2 expression in three microglial cell systems. Addition of mouse BV-2 microglia expressing R47H TREM2 to primary mouse neuronal cultures caused neuronal loss, not observed with WT TREM2. Neuronal loss was prevented by using annexin V to block exposed phosphatidylserine, an eat-me signal and ligand of TREM2, suggesting loss was mediated by microglial phagocytosis of neurons exposing phosphatidylserine. Addition of human CHME-3 microglia expressing R47H TREM2 to LUHMES neuronal-like cells also caused loss compared to WT TREM2. Expression of R47H TREM2 in BV-2 and CHME-3 microglia increased their uptake of phosphatidylserine-beads and synaptosomes versus WT TREM2. Human iPSC-derived microglia with heterozygous R47H TREM2 had increased phagocytosis of synaptosomes vs common-variant TREM2. Additionally, phosphatidylserine liposomes increased activation of human iPSC-derived microglia expressing homozygous R47H TREM2 versus common-variant TREM2. Finally, overexpression of TREM2 in CHME-3 microglia caused increased expression of cystatin F, a cysteine protease inhibitor, and knock-down of cystatin F increased CHME-3 uptake of phosphatidylserine-beads. Together, these data suggest that R47H TREM2 may increase AD risk by increasing phagocytosis of synapses and neurons via greater activation by phosphatidylserine and that WT TREM2 may decrease microglial phagocytosis of synapses and neurons via cystatin F

Earth Virtualization Engines -- A Technical Perspective

Participants of the Berlin Summit on Earth Virtualization Engines (EVEs) discussed ideas and concepts to improve our ability to cope with climate change. EVEs aim to provide interactive and accessible climate simulations and data for a wide range of users. They combine high-resolution physics-based models with machine learning techniques to improve the fidelity, efficiency, and interpretability of climate projections. At their core, EVEs offer a federated data layer that enables simple and fast access to exabyte-sized climate data through simple interfaces. In this article, we summarize the technical challenges and opportunities for developing EVEs, and argue that they are essential for addressing the consequences of climate change

Postsynaptic p47phox regulates long-term depression in the hippocampus

Abstract It is well documented that reactive oxygen species (ROS) affects neurodegeneration in the brain. Several studies also implicate ROS in the regulation of synapse function and learning and memory processes, although the precise source of ROS generation within these contexts remains to be further explored. Here we show that postsynaptic superoxide generation through PKCζ-activated NADPH oxidase 2 (NOX2) is critical for long-term depression (LTD) of synaptic transmission in the CA1–Shaffer collateral synapse of the rat hippocampus. Specifically, PKCζ-dependent phosphorylation of p47phox at serine 316, a NOX2 regulatory subunit, is required for LTD but is not necessary for long-term potentiation (LTP). Our data suggest that postsynaptic p47phox phosphorylation at serine 316 is a key upstream determinant for LTD and synapse weakening

Increased water vapour lifetime due to global warming

Water vapour in the atmosphere is the source of a major climate feedback mechanism and potential increases in the availability of water vapour could have important consequences for mean and extreme precipitation. Future precipitation changes further depend on how the hydrological cycle responds to drivers of climate change, such as greenhouse gases and aerosols. Currently, neither the total anthropogenic influence on the hydrological cycle, nor those from individual drivers, are constrained sufficiently to make solid projections. We investigate how integrated water vapour (IWV) responds to different drivers of climate change. Results from 11 global climate models have been used, based on simulations where CO2, methane, solar irradiance, black carbon (BC), and sulphate have been perturbed separately. While the global-mean IWV is usually assumed to increase by ~7% per degree K surface temperature change, we find that the feedback response of IWV differs somewhat between drivers. Fast responses, which include the initial radiative effect and rapid adjustments to an external forcing, amplify these differences. The resulting net changes in IWV range from 6.4±0.9%/K for sulphate to 9.8±2%/K for BC. We further calculate the relationship between global changes in IWV and precipitation, which can be characterized by quantifying changes in atmospheric water vapour lifetime. Global climate models simulate a substantial increase in the lifetime, from 8.2±0.5 to 9.9±0.7 days between 1986-2005 and 2081-2100 under a high emission scenario, and we discuss to what extent the water vapour lifetime provides additional information compared to analysis of IWV and precipitation separately. We conclude that water vapour lifetime changes are an important indicator of changes in precipitation patterns and that BC is particularly efficient in prolonging the distance between evaporation and precipitation

Study Protocol - Accurate assessment of kidney function in Indigenous Australians: aims and methods of the eGFR Study

Background: There is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function. However, differences in body build and body composition between Indigenous and non-Indigenous Australians suggest that creatinine-based estimates of glomerular filtration rate derived for European populations may not be appropriate for Indigenous Australians. The burden of kidney disease is borne disproportionately by Indigenous Australians in central and northern Australia, and there is significant heterogeneity in body build and composition within and amongst these groups. This heterogeneity might differentially affect the accuracy of estimation of glomerular filtration rate between different Indigenous groups. By assessing kidney function in Indigenous Australians from Northern Queensland, Northern Territory and Western Australia, we aim to determine a validated and practical measure of glomerular filtration rate suitable for use in all Indigenous Australians

Moral Distress Amongst American Physician Trainees Regarding Futile Treatments at the End of Life: A Qualitative Study.

BACKGROUND: Ethical challenges are common in end of life care; the uncertainty of prognosis and the ethically permissible boundaries of treatment create confusion and conflict about the balance between benefits and burdens experienced by patients. OBJECTIVE: We asked physician trainees in internal medicine how they reacted and responded to ethical challenges arising in the context of perceived futile treatments at the end of life and how these challenges contribute to moral distress. DESIGN: Semi-structured in-depth qualitative interviews. PARTICIPANTS: Twenty-two internal medicine residents and fellows across three American academic medical centers. APPROACH: This study uses systematic qualitative methods of data gathering, analysis and interpretation. KEY RESULTS: Physician trainees experienced significant moral distress when they felt obligated to provide treatments at or near the end of life that they believed to be futile. Some trainees developed detached and dehumanizing attitudes towards patients as a coping mechanism, which may contribute to a loss of empathy. Successful coping strategies included formal and informal conversations with colleagues and superiors about the emotional and ethical challenges of providing care at the end of life. CONCLUSIONS: Moral distress amongst physician trainees may occur when they feel obligated to provide treatments at the end of life that they believe to be futile or harmful.This study was funded by the Health Resources and Service Administration T32 HP10025-20 Training Grant, the Gates Cambridge Scholarship, Society of General Internal Medicine Founders Grant, and the Ho-Chiang Palliative Care Research Fellowship at the Johns Hopkins School of Medicine.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11606-015-3505-

Protein-protein interaction based on pairwise similarity

<p>Abstract</p> <p>Background</p> <p>Protein-protein interaction (PPI) is essential to most biological processes. Abnormal interactions may have implications in a number of neurological syndromes. Given that the association and dissociation of protein molecules is crucial, computational tools capable of effectively identifying PPI are desirable. In this paper, we propose a simple yet effective method to detect PPI based on pairwise similarity and using only the primary structure of the protein. The PPI based on Pairwise Similarity (PPI-PS) method consists of a representation of each protein sequence by a vector of pairwise similarities against large subsequences of amino acids created by a shifting window which passes over concatenated protein training sequences. Each coordinate of this vector is typically the E-value of the Smith-Waterman score. These vectors are then used to compute the kernel matrix which will be exploited in conjunction with support vector machines.</p> <p>Results</p> <p>To assess the ability of the proposed method to recognize the difference between "<it>interacted</it>" and "<it>non-interacted</it>" proteins pairs, we applied it on different datasets from the available yeast <it>saccharomyces cerevisiae </it>protein interaction. The proposed method achieved reasonable improvement over the existing state-of-the-art methods for PPI prediction.</p> <p>Conclusion</p> <p>Pairwise similarity score provides a relevant measure of similarity between protein sequences. This similarity incorporates biological knowledge about proteins and it is extremely powerful when combined with support vector machine to predict PPI.</p