Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization.

Vascular endothelial growth factor A (VEGF-A) is a master regulator of angiogenesis, vascular development and function. In this study we investigated the transcriptional regulation of VEGF-A-responsive genes in primary human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) using genome-wide global run-on sequencing (GRO-Seq). We demonstrate that half of VEGF-A-regulated gene promoters are characterized by a transcriptionally competent paused RNA polymerase II (Pol II). We show that transition into productive elongation is a major mechanism of gene activation of virtually all VEGF-regulated genes, whereas only ∼40% of the genes are induced at the level of initiation. In addition, we report a comprehensive chromatin interaction map generated in HUVECs using tethered conformation capture (TCC) and characterize chromatin interactions in relation to transcriptional activity. We demonstrate that sites of active transcription are more likely to engage in chromatin looping and cell type-specific transcriptional activity reflects the boundaries of chromatin interactions. Furthermore, we identify large chromatin compartments with a tendency to be coordinately transcribed upon VEGF-A stimulation. We provide evidence that these compartments are enriched for clusters of regulatory regions such as super-enhancers and for disease-associated single nucleotide polymorphisms (SNPs). Collectively, these findings provide new insights into mechanisms behind VEGF-A-regulated transcriptional programs in endothelial cells

Solar PV - Equipping the Future

The Solar PV team has installed several solar power systems for various partners in the developing world. Most recently, the team installed a solar-powered well pump at the Living Love Ministries Children’s Home in Ol Kalou, Kenya. As is true for all the previous installations, the team gained a wealth of valuable knowledge and experience on the trip to Kenya. A problem the team faces is that a lot of that experience gained leaves when seniors graduate. With the goal of passing on our knowledge and experience to future generations of the Solar PV team, we have been constructing a solar lab at Messiah for experimentation and training. We also are developing a curriculum to teach new team members about solar power and provide a framework for preserving new knowledge the team obtains in the future. Throughout the 2019-2020 year, the solar team has made significant progress towards the completion of these projects.https://mosaic.messiah.edu/engr2020/1011/thumbnail.jp

Hypothesis Article Signatures of a Shadow Biosphere

Abstract Astrobiologists are aware that extraterrestrial life might differ from known life, and considerable thought has been given to possible signatures associated with weird forms of life on other planets. So far, however, very little attention has been paid to the possibility that our own planet might also host communities of weird life. If life arises readily in Earth-like conditions, as many astrobiologists contend, then it may well have formed many times on Earth itself, which raises the question whether one or more shadow biospheres have existed in the past or still exist today. In this paper, we discuss possible signatures of weird life and outline some simple strategies for seeking evidence of a shadow biosphere

Tritium tracers of rapid surface water ingression into arsenic-bearing aquifers in the Lower Mekong Basin, Cambodia

Arsenic (As) contamination of groundwaters in South and Southeast Asia is a major threat to public health in these areas. Understanding the source and age of the groundwaters is critically important to understanding the controls on As mobilization in these aquifers. Using tritium (3H) and noble gas (He and Ne) signatures, model groundwater ages and dominant hydrological controls were identified in a transect oriented broadly parallel to inferred groundwater flowpaths in Kandal Province, Cambodia in the lower Mekong Basin. Apparent 3H-3He ages showed that most groundwaters are modern (< 55 years), indicating relatively fast recharge even in the absence of large-scale groundwater abstraction. The age-depth relationship indicates a strong vertical component of groundwater flow and allows for recharge rates to be estimated. Vertical and horizontal flow velocities are heterogeneous and site-specific. The conceptual framework will be used to better understand As mobilization and subsequent transport with these and similar aquifers

Relative distancing: a grounded theory of how learners negotiate the interprofessional.

A number of extant educational, psychological and sociological theories have been suggested as possessing utility for interprofessional education (IPE). However, there is limited theory proposed that has been derived directly from data. This article adds to the theoretical toolkit by theorizing from data using constructionist grounded theorizing. This article discusses the grounded theorizing of participants' approaches to IPE and describes the social process of relative distancing, a collection of strategies employed by participants to construct their own professional identities and negotiate their way through interprofessional interactions. The categories of relative distancing are conceptualized as (1) integrating the professional and the interprofessional; (2) constellating and maintaining distance; (3) tensioning and manipulating distance and (4) the dimensions of distance. The first, and most theoretically integrative, category will be discussed in detail here. It was found that participants valued certain learning outcomes over others. They favored learning opportunities that were perceived to be of direct relevance to their own professional development and contributed finite personal resources to these. Resources were committed to those interprofessional learning opportunities where relevance was perceived and the conditions of co-presence (with other professions) and a context for interaction were achieved. The discussion draws links between the data and contemporary discourses of economics and identity

High resolution profile of inorganic aqueous geochemistry and key redox zones in an arsenic bearing aquifer in Cambodia

Arsenic contamination of groundwaters in South and Southeast Asia is a major threat to public health. In order to better understand the geochemical controls on the mobility of arsenic in a heavily arsenic-affected aquifer in northern Kandal Province, Cambodia, key changes in inorganic aqueous geochemistry have been monitored at high vertical and lateral resolution along dominant groundwater flow paths along two distinct transects. The two transects are characterized by differing geochemical, hydrological and lithological conditions. Arsenic concentrations in groundwater are highly heterogenous, and are broadly positively associated with iron and negatively associated with sulfate and dissolved oxygen. The observed correlations are generally consistent with arsenic mobilization by reductive-dissolution of iron (hydr)oxides. Key redox zones, as identified using groupings of the PHREEQC model equilibrium electron activity of major redox couples (notably ammonium/nitrite; ammonium/nitrate; nitrite/nitrate; dissolved oxygen/water) have been identified and vary with depth, site and season. Mineral saturation is also characterized. Seasonal changes in groundwater chemistry were observed in areas which were (i) sandy and of high permeability; (ii) in close proximity to rivers; and/or (iii) in close proximity to ponds. Such changes are attributed to monsoonal-driven surface-groundwater interactions and are consistent with the separate provenance of recharge sources as identified using stable isotope mixing models

Resolution extension by image summing in serial femtosecond crystallography of two-dimensional membrane-protein crystals

Previous proof-of-concept measurements on single-layer two-dimensional membrane-protein crystals performed at X-ray free-electron lasers (FELs) have demonstrated that the collection of meaningful diffraction patterns, which is not possible at synchrotrons because of radiation-damage issues, is feasible. Here, the results obtained from the analysis of a thousand single-shot, room-temperature X-ray FEL diffraction images from two-dimensional crystals of a bacteriorhodopsin mutant are reported in detail. The high redundancy in the measurements boosts the intensity signal-to-noise ratio, so that the values of the diffracted intensities can be reliably determined down to the detector-edge resolution of 4 Å. The results show that two-dimensional serial crystallography at X-ray FELs is a suitable method to study membrane proteins to near-atomic length scales at ambient temperature. The method presented here can be extended to pump–probe studies of optically triggered structural changes on submillisecond timescales in two-dimensional crystals, which allow functionally relevant large-scale motions that may be quenched in three-dimensional crystals

Glial Innate Immunity Generated by Non-Aggregated Alpha-Synuclein in Mouse: Differences between Wild-type and Parkinson's Disease-Linked Mutants

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence in the brain of intracellular protein inclusions highly enriched in aggregated alpha-synuclein (alpha-Syn). Although it has been established that progression of the disease is accompanied by sustained activation of microglia, the underlying molecules and factors involved in these immune-triggered mechanisms remain largely unexplored. Lately, accumulating evidence has shown the presence of extracellular alpha-Syn both in its aggregated and monomeric forms in cerebrospinal fluid and blood plasma. However, the effect of extracellular alpha-Syn on cellular activation and immune mediators, as well as the impact of familial PD-linked alpha-Syn mutants on this stimulation, are still largely unknown.Methods and Findings: In this work, we have compared the activation profiles of non-aggregated, extracellular wild-type and PD-linked mutant alpha-Syn variants on primary glial and microglial cell cultures. After stimulation of cells with alpha-Syn, we measured the release of Th1- and Th2-type cytokines as well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1 alpha/CCL3 chemokines. Contrary to what had been observed using cell lines or for the case of aggregated alpha-Syn, we found strong differences in the immune response generated by wild-type alpha-Syn and the familial PD mutants (A30P, E46K and A53T).Conclusions: These findings might contribute to explain the differences in the onset and progression of this highly debilitating disease, which could be of value in the development of rational approaches towards effective control of immune responses that are associated with PD

A foundation model for atomistic materials chemistry

Machine-learned force fields have transformed the atomistic modelling of materials by enabling simulations of ab initio quality on unprecedented time and length scales. However, they are currently limited by: (i) the significant computational and human effort that must go into development and validation of potentials for each particular system of interest; and (ii) a general lack of transferability from one chemical system to the next. Here, using the state-of-the-art MACE architecture we introduce a single general-purpose ML model, trained on a public database of 150k inorganic crystals, that is capable of running stable molecular dynamics on molecules and materials. We demonstrate the power of the MACE-MP-0 model - and its qualitative and at times quantitative accuracy - on a diverse set problems in the physical sciences, including the properties of solids, liquids, gases, chemical reactions, interfaces and even the dynamics of a small protein. The model can be applied out of the box and as a starting or "foundation model" for any atomistic system of interest and is thus a step towards democratising the revolution of ML force fields by lowering the barriers to entry.Comment: 119 pages, 63 figures, 37MB PD

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies