Genetically Encoded Photo-cross-linkers Map the Binding Site of an Allosteric Drug on a G Protein-Coupled Receptor

G protein-coupled receptors (GPCRs) are dynamic membrane proteins that bind extracellular molecules to transduce signals. Although GPCRs represent the largest class of therapeutic targets, only a small percentage of their ligand-binding sites are precisely defined. Here we describe the novel application of targeted photo-cross-linking using unnatural amino acids to obtain structural information about the allosteric binding site of a small molecule drug, the CCR5-targeted HIV-1 co-receptor blocker maraviroc

A perspective on reactive nitrogen in a global, Asian and Indian context

Reactive nitrogen (Nr) includes the inorganic (NH3, NH+4 , NOx, HNO3, N2O, NO-3) and organic forms (urea, amines, proteins, nucleic acids) that readily participate in various reactions of the global N cycle. Over the last half a century, anthropogenic perturbations of the natural N cycle have led to the increasing accumulation of inorganic Nr in the soil, water and air, intentionally through agriculture and unintentionally through fossil-fuel consumption and other activities, adversely affecting human health, biodiversity, environment and climate change. One of the major emerging challenges of this century will be to ensure adequate availability of Nr inputs for agriculture and other activities, while preventing their unwanted accumulation. This article provides an overall perspective of the emerging issues related to Nr in the global, Asian and Indian contexts

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

Regional nitrogen cycle: an Indian perspective

During the past century through food and energy production, human activities have altered the world's nitrogen cycle by accelerating the rate of reactive nitrogen creation. India has made impressive strides in the agricultural front, in which N fertilizer plays a major role. There has been a marked change in the supply and use of land, water, fertilizers, seeds and livestock, but the N use efficiency remained at a low level. Exploring the nature of these changes and quantification of the impacts on the N cycle has become essential. Hence we have presented data on various N pools and fluxes based on a conceptual N model. In India, efforts should focus on understanding the fate and consequences of the applied N and to increase the efficiency of N use

Are nitrate concentrations in leafy vegetables within safe limits?

Leafy vegetables are an important source of nutrition in the human diet. Estimation of nitrate concentration in samples of leafy vegetables collected from the local markets of Delhi has revealed that a significant number of spinach and chenopodium samples contained nitrate in concentrations higher than the Acceptable Daily Intake (ADI) limit for an average 60 kg person (if consumed @ 100 g/day). However, nitrate concentration in fenugreek, coriander and sowa samples was well within the safe limits for consumption. On the basis of our findings with market samples, extensive studies were conducted in nine genotypes of spinach (Spinacia oleracea L.) grown under greenhouse conditions. The genotypes varied markedly in their nitrate concentration as well as nitrate reductase activity. At the threeweek stage of plant growth, one genotype, and at the six-week stage, six of the nine genotypes under investigation exceeded the ADI limit. Petioles possessed several times higher level of nitrate than the leaf laminae in market samples as well as in the genotypes. All the genotypes showed diurnal variation in nitrate accumulation with minimum concentration at noon. These findings warrant thorough investigation of nitrate levels in other leafy vegetables consumed regularly and the ways and means to control them

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

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

Background &amp; 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

Improvement in nitrogen use efficiency: physiological and molecular approacheses

Nitrogen deficiency in agricultural systems is a world-wide problem. It is true of the Indian scenario as well. The utilization efficiency of nitrogenous fertilizers under field conditions is poor. This results in loss of a costly input and accentuates the environmental degradation. In this paper, the present status of our knowledge on physiological and molecular approaches to improve nitrogen utilization efficiency at the level of its uptake, assimilation and relationship to photosynthesis, a major factor determining biomass and grain yield, is discussed. The work done in the authors' laboratory for over a decade is summarized. It is hoped that better understanding will help to apply the tools of molecular biology to genetically manipulate the crop plants so as to enhance yields at low inputs of nitrogen