Accurate first-derivative nonadiabatic couplings for the H3 system

A conical intersection exists between the ground (1 2 A[prime]) and the first-excited (2 2A[prime]) electronic potential energy surfaces (PESs) of the H3 system for C3v geometries. This intersection induces a geometric phase effect, an important factor in accurate quantum mechanical reactive scattering calculations, which at low energies can be performed using the ground PES only, together with appropriate nuclear motion boundary conditions. At higher energies, however, such calculations require the inclusion of both the 1 2A[prime] and 2 2A[prime] electronic PESs and the corresponding nuclear derivative couplings. Here we present ab initio first-derivative couplings for these states obtained by analytic gradient techniques and a fit to these results. We also present a fit to the corresponding 1 2A[prime] and 2 2A[prime] adiabatic electronic PESs, obtained from the ab initio electronic energies. The first-derivative couplings are compared with their approximate analytical counterparts obtained by Varandas et al. [J. Chem. Phys. 86, 6258 (1987)] using the double many-body expansion method. As expected, the latter are accurate close to conical intersection configurations but not elsewhere. We also present the contour integrals of the ab initio couplings along closed loops around the above-mentioned conical intersection, which contain information about possible interactions between the 2 2A[prime] and 3 2A[prime] states

Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model.

Background & aimsHeavy alcohol drinking is associated with pancreatitis, whereas moderate intake lowers the risk. Mice fed ethanol long term show no pancreas damage unless adaptive/protective responses mediating proteostasis are disrupted. Pancreatic acini synthesize digestive enzymes (largely serine hydrolases) in the endoplasmic reticulum (ER), where perturbations (eg, alcohol consumption) activate adaptive unfolded protein responses orchestrated by spliced X-box binding protein 1 (XBP1). Here, we examined ethanol-induced early structural changes in pancreatic ER proteins.MethodsWild-type and Xbp1+/- mice were fed control and ethanol diets, then tissues were homogenized and fractionated. ER proteins were labeled with a cysteine-reactive probe, isotope-coded affinity tag to obtain a novel pancreatic redox ER proteome. Specific labeling of active serine hydrolases in ER with fluorophosphonate desthiobiotin also was characterized proteomically. Protein structural perturbation by redox changes was evaluated further in molecular dynamic simulations.ResultsEthanol feeding and Xbp1 genetic inhibition altered ER redox balance and destabilized key proteins. Proteomic data and molecular dynamic simulations of Carboxyl ester lipase (Cel), a unique serine hydrolase active within ER, showed an uncoupled disulfide bond involving Cel Cys266, Cel dimerization, ER retention, and complex formation in ethanol-fed, XBP1-deficient mice.ConclusionsResults documented in ethanol-fed mice lacking sufficient spliced XBP1 illustrate consequences of ER stress extended by preventing unfolded protein response from fully restoring pancreatic acinar cell proteostasis during ethanol-induced redox challenge. In this model, orderly protein folding and transport to the secretory pathway were disrupted, and abundant molecules including Cel with perturbed structures were retained in ER, promoting ER stress-related pancreas pathology

Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins

The activation of seven-transmembrane receptors (7TMRs) allows cells to sense their environment and convert extracellular signals (like hormone binding) into intracellular signals (through G protein-coupled and/or β arrestin-coupled pathways). A single 7TMR is capable of transducing a wide spectrum of physiological responses inside a cell by coupling to these pathways. This intracellular pleiotropic action is enabled by multiple conformations exhibited by these receptors. Developments in membrane protein structure determination technologies have led to a rapid increase in crystal structures for many 7TMRs. Majority of these receptors have been crystallized in their inactive conformation and, for some, one of the many active conformations has also been crystallized. Given the topological constraints of a lipid bilayer that results in a single fold of seven almost parallel TM helices connected by mostly unstructured loops, these structures exhibit a diversity of conformations not only across the receptors but also across the different functional forms for receptors with structures for one of the functionally active conformations. Here we present a method to characterize this conformational diversity in terms of transmembrane helix topology (TMHTOP) parameters and how to use these helix orientation parameters to predict functionally-distinct multiple conformations for these receptors. The TMHTOP parameters enable a quantification of the structural changes that underlie 7TMR activation and also sheds a unique mechanistic light on the pleiotropic nature of these receptors. It provides a common language to describe the 7TMR activation mechanisms as well as differences across many receptors in terms of visually intuitive structural parameters. Protein structure prediction methods can use these parameters to describe 7TMR conformational ensembles, which coupled to experimental data can be used to develop testable hypotheses for the structural basis of 7TMR functions

Elucidating glycosaminoglycan–protein–protein interactions using carbohydrate microarray and computational approaches

Glycosaminoglycan polysaccharides play critical roles in many cellular processes, ranging from viral invasion and angiogenesis to spinal cord injury. Their diverse biological activities are derived from an ability to regulate a remarkable number of proteins. However, few methods exist for the rapid identification of glycosaminoglycan–protein interactions and for studying the potential of glycosaminoglycans to assemble multimeric protein complexes. Here, we report a multidisciplinary approach that combines new carbohydrate microarray and computational modeling methodologies to elucidate glycosaminoglycan–protein interactions. The approach was validated through the study of known protein partners for heparan and chondroitin sulfate, including fibroblast growth factor 2 (FGF2) and its receptor FGFR1, the malarial protein VAR2CSA, and tumor necrosis factor-α (TNF-α). We also applied the approach to identify previously undescribed interactions between a specific sulfated epitope on chondroitin sulfate, CS-E, and the neurotrophins, a critical family of growth factors involved in the development, maintenance, and survival of the vertebrate nervous system. Our studies show for the first time that CS is capable of assembling multimeric signaling complexes and modulating neurotrophin signaling pathways. In addition, we identify a contiguous CS-E-binding site by computational modeling that suggests a potential mechanism to explain how CS may promote neurotrophin-tyrosine receptor kinase (Trk) complex formation and neurotrophin signaling. Together, our combined microarray and computational modeling methodologies provide a general, facile means to identify new glycosaminoglycan–protein–protein interactions, as well as a molecular-level understanding of those complexes

On growth and fluctuation of Indian foodgrain production

We have analysed the variation of all-India foodgrain production over the last four decades to assess the typical magnitude of year-to-year fluctuation. This has shown that the magnitude of the variation between the foodgrain production in 1996 and 1997 is by no means unusual for normal monsoon years and such fluctuations should not have a large impact on GDP if the management of the economy allows for this natural fluctuation. Much larger year-to-year changes are expected for years with large anomalies in monsoon rainfall. The problems of sustaining the growth rate in irrigated areas and enhancing that of rainfed areas are addressed. It is suggested that to attain adequate growth rates for sustaining the per capita availability, a genuinely interdisciplinary approach is required with active participation of the farmers in identifying the optimal strategies

Temporary techno-social gatherings? A (hacked) discussion about open practices

This paper is rooted in an experimental inquiry of issue-oriented temporary techno-social gatherings or TTGs, which are typically referred to as hackathons, workshops or pop-ups and employ rapid design and development practices to tackle technical challenges while engaging with social issues. Based on a collaboration between three digital practitioners (a producer, a researcher and a designer), qualitative and creative data was gathered across five different kinds of TTG events in London and in Tartu which were held in partnership with large institutions, including Art:Work at Tate Exchange within Tate Modern, the Mozilla Festival at Ravensbourne College and the 2017 Association of Internet Researchers conference hosted in Tartu. By analysing data using an open and discursive approach manifested in both text and visual formats, we reflect on the dynamic and generative characteristics of TTG gatherings while also arriving at our own conclusions as situated researchers and practitioners who are ourselves engaged in increasingly messy webs where new worlds of theory and practice are built

Behaviour of a Kinetic Energy Projectile on Angular Impact

Experiments of high velocity impact have been carried out with 30 mm armoured piercing projectiles on 55 mm thick hard steel plate. Angle of impact has been varied from 10" to 90". Damage inflicted on target with varying angle of impact has been reported and discussed in this paper. Comparative behaviour with 20 mm APP shot has also been discussed

Clinical and social factors associated with involuntary psychiatric hospitalisation in children and adolescents: a systematic review, meta-analysis, and narrative synthesis.

BACKGROUND: Disparities in involuntary psychiatric hospitalisation between population subgroups have been identified in adults, but little is known about the factors associated with involuntary hospitalisation in children or adolescents. We did a systematic review, meta-analysis, and narrative synthesis to investigate the social and clinical factors associated with involuntary psychiatric hospitalisation among children and adolescents. METHODS: We searched MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials for studies of any type up to July 22, 2020, that compared the characteristics of voluntary and involuntary psychiatric inpatients (mean age of sample ≤18 years). We synthesised results using random effects meta-analysis on unadjusted data and by narrative synthesis. Heterogeneity between studies was calculated using I2. This study is registered on PROSPERO, CRD42020099892. FINDINGS: 23 studies from 11 countries were included in the systematic review and narrative synthesis, of which 19 studies (n=31 212) were included in the meta-analysis. On meta-analysis, involuntary rather than voluntary hospitalisation of minors was associated with a diagnosis of psychosis (eight studies; odds ratio 3·63, 95% CI 2·43-5·44, p<0·0001), substance misuse (five studies; 1·87, 1·05-3·30, p=0·032), or intellectual disability (four studies; 3·33, 1·33-8·34, p=0·010), as well as presenting with a perceived risk of harm to self (eight studies; 2·05, 1·15-3·64, p=0·015) or to others (five studies; 2·37, 1·39-4·03, p=0·0015). Involuntary hospitalisation was also found to be associated with being aged 12 years or older (three studies; 3·57, 1·46-8·73, p=0·0052) and being from a Black rather than a White ethnic group (three studies; 2·72, 1·88-3·95, p<0·0001). There was substantial between-study heterogeneity for most factors included in the meta-analysis (I2 from 51·3% to 92·3%). Narrative synthesis found that more severe illness and poorer global functioning was associated with involuntary hospitalisation. INTERPRETATION: Over-representation of involuntary psychiatric hospitalisation in certain groups might begin in childhood, potentially establishing a cycle of inequality that continues into adulthood. Further research into the systemic factors underlying these health-care inequalities and the barriers to accessing less coercive psychiatric treatment is urgently required, with specific consideration of racial and ethnic factors. FUNDING: UK National Institute for Health Research and Wellcome Trust