Fundamental genomic unity of ethnic India is revealed by analysis of mitochondrial DNA

Mitochondrial DNA (mtDNA) profiles of 23 ethnic populations of India drawn from diverse cultural, linguistic and geographical backgrounds are presented. There is extensive sharing of a small number of mtDNA haplotypes, reconstructed on the basis of restriction fragment length polymorphisms, among the populations. This indicates that Indian populations were founded by a small number of females, possibly arriving on one of the early waves of out-of-Africa migration of modern humans; ethnic differentiation occurred subsequently through demographic expansions and geographic dispersal. The Asian-specific haplogroup M is in high frequency in most populations, especially tribal populations and Dravidian populations of southern India. Populations in which the frequencies of haplogroup M are relatively lower show higher frequencies of haplogroup U; such populations are primarily caste populations of northern India. This finding is indicative of a higher Caucasoid admixture in northern Indian populations. By examining the sharing of haplotypes between Indian and south-east Asian populations, we have provided evidence that south-east Asia was peopled by two waves of migration, one originating in India and the other originating in southern China. These findings have been examined and interpreted in the light of inferences derived from previous genomic and historical studies

DNA sequence variation and haplotype structure of the ICAM1 and TNF genes in 12 ethnic groups of India reveal patterns of importance in designing association studies

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies

Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancementRamon y Cajal program RYC2014-15784, RETOS-MINECO SAF2016-76565-R, ERANET-Neuron JTC 2019 ISCIII AC19/00077 FEDER funds (to R.A.); RETOS-MINECO SAF2017-87928-R (to A.B.); an NIH grant (NS76637) and UTHSC College of Medicine funds (to S.J.T.); and NARSAD Independent Investigator Award and grants from the MINECO (CSD2008-00005, SAF2013-48983R, SAF2016-80895-R), Generalitat Valenciana (PROMETEO 2019/020)(to I.P.O.) and Severo-Ochoa Excellence Awards (SEV-2013-0317, SEV-2017-0723)Peer reviewe

Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement

Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS)

Background Sepsis is a major contributor to neonatal mortality, particularly in low-income and middle-income countries (LMICs). WHO advocates ampicillin–gentamicin as first-line therapy for the management of neonatal sepsis. In the BARNARDS observational cohort study of neonatal sepsis and antimicrobial resistance in LMICs, common sepsis pathogens were characterised via whole genome sequencing (WGS) and antimicrobial resistance profiles. In this substudy of BARNARDS, we aimed to assess the use and efficacy of empirical antibiotic therapies commonly used in LMICs for neonatal sepsis. Methods In BARNARDS, consenting mother–neonates aged 0–60 days dyads were enrolled on delivery or neonatal presentation with suspected sepsis at 12 BARNARDS clinical sites in Bangladesh, Ethiopia, India, Pakistan, Nigeria, Rwanda, and South Africa. Stillborn babies were excluded from the study. Blood samples were collected from neonates presenting with clinical signs of sepsis, and WGS and minimum inhibitory concentrations for antibiotic treatment were determined for bacterial isolates from culture-confirmed sepsis. Neonatal outcome data were collected following enrolment until 60 days of life. Antibiotic usage and neonatal outcome data were assessed. Survival analyses were adjusted to take into account potential clinical confounding variables related to the birth and pathogen. Additionally, resistance profiles, pharmacokinetic–pharmacodynamic probability of target attainment, and frequency of resistance (ie, resistance defined by in-vitro growth of isolates when challenged by antibiotics) were assessed. Questionnaires on health structures and antibiotic costs evaluated accessibility and affordability. Findings Between Nov 12, 2015, and Feb 1, 2018, 36 285 neonates were enrolled into the main BARNARDS study, of whom 9874 had clinically diagnosed sepsis and 5749 had available antibiotic data. The four most commonly prescribed antibiotic combinations given to 4451 neonates (77·42%) of 5749 were ampicillin–gentamicin, ceftazidime–amikacin, piperacillin–tazobactam–amikacin, and amoxicillin clavulanate–amikacin. This dataset assessed 476 prescriptions for 442 neonates treated with one of these antibiotic combinations with WGS data (all BARNARDS countries were represented in this subset except India). Multiple pathogens were isolated, totalling 457 isolates. Reported mortality was lower for neonates treated with ceftazidime–amikacin than for neonates treated with ampicillin–gentamicin (hazard ratio [adjusted for clinical variables considered potential confounders to outcomes] 0·32, 95% CI 0·14–0·72; p=0·0060). Of 390 Gram-negative isolates, 379 (97·2%) were resistant to ampicillin and 274 (70·3%) were resistant to gentamicin. Susceptibility of Gram-negative isolates to at least one antibiotic in a treatment combination was noted in 111 (28·5%) to ampicillin–gentamicin; 286 (73·3%) to amoxicillin clavulanate–amikacin; 301 (77·2%) to ceftazidime–amikacin; and 312 (80·0%) to piperacillin–tazobactam–amikacin. A probability of target attainment of 80% or more was noted in 26 neonates (33·7% [SD 0·59]) of 78 with ampicillin–gentamicin; 15 (68·0% [3·84]) of 27 with amoxicillin clavulanate–amikacin; 93 (92·7% [0·24]) of 109 with ceftazidime–amikacin; and 70 (85·3% [0·47]) of 76 with piperacillin–tazobactam–amikacin. However, antibiotic and country effects could not be distinguished. Frequency of resistance was recorded most frequently with fosfomycin (in 78 isolates [68·4%] of 114), followed by colistin (55 isolates [57·3%] of 96), and gentamicin (62 isolates [53·0%] of 117). Sites in six of the seven countries (excluding South Africa) stated that the cost of antibiotics would influence treatment of neonatal sepsis

Strength development in fine-grained paddy field soil by lime addition

Due to high population density, the people of Bangladesh are building houses and the government is establishing infrastructure (such as roads, flyovers, bridges) on agricultural land that pose significant settlement issues. Consequently, such development works require prior improvement of the soft soil or improvement during construction to restrict post-construction failures. Soil stabilization, a conventionally used ground improvement method, is often utilized to alter engineering properties of fine-grained soil such as strength, stability, permeability, weathering resistance, etc. to maintain the required construction criteria. Moreover, the addition of lime in the soil is demonstrated to markedly reduce the hydraulic conductivity, which will prevent the vertical movement of pore water. With this in mind, in the current study an attempt has been undertaken to increase the strength of fine-grained soil of agricultural land by adding commercially available hydrated lime, which may in the future be used as foundation material. For this purpose, lime was added at various percentages (0–12%) by weight to soil collected from a paddy field. The study noted the collected soils as being inorganic silts of high plasticity or organic clays of medium to high plasticity. Unconfined compression tests were conducted on cylindrical mold prepared specimens with clayey soil in the presence of lime, and all specimens were cured for 3–90 days for strength development. The study revealed 7% added lime as the optimum content, with the corresponding unconfined compressive strength (UCS) observed to be 344 kPa and 356 kPa at the end of 28 days and 90 days, respectively. The evolution of unconfined compressive strength was higher in hotter and more alkaline environments

[In Press] Does greenwashing obstruct sustainable environmental technologies and green financing from promoting environmental sustainability? : analytical evidence from the Indian economy

This study aims at assessing the impacts of green growth, in the form of adopting sustainable energy technologies and financing green projects, on environmental conditions in India. Thus, this study is important from the point of view of India's efforts in formulating strategies linked with achieving the environmental development targets enlisted under United Nations SDG-13 declaration. In this regard, it is assumed that strategies targeted at establishing green growth in India can fail in the presence of greenwashing. To test this hypothesis, a newly introduced econometric technique, namely the Augmented-ARDL techniques of estimation is used. Accordingly, the results obtained firstly suggest the existence of long-run and cointegrated relationship exists between the variables of choice. Secondly, it is very much striking to find out that the the there is an inverse relationship between use of sustainable environmental technologies and environmental sustainability across India. Hence, this particular finding points to the possibility of stimulating geenwashing in the context of technology adoption in order to improve the state of the environment in India. Lastly, financing of green projects is seen to promote environmental sustainability which, in turn, affirms the absence of greenwashing in the context of green financing initiatives

Figure 1-fig suppl 1

Values used in fig1 - fig supplement

Figure 3 - fig suppl 1

Values used in figure 3 - fig supplement