Whole Exome Sequencing in Healthy Individuals of Extreme Constitution Types Reveals Differential Disease Risk: A Novel Approach towards Predictive Medicine.

Precision medicine aims to move from traditional reactive medicine to a system where risk groups can be identified before the disease occurs. However, phenotypic heterogeneity amongst the diseased and healthy poses a major challenge for identification markers for risk stratification and early actionable interventions. In Ayurveda, individuals are phenotypically stratified into seven constitution types based on multisystem phenotypes termed "Prakriti". It enables the prediction of health and disease trajectories and the selection of health interventions. We hypothesize that exome sequencing in healthy individuals of phenotypically homogeneous Prakriti types might enable the identification of functional variations associated with the constitution types. Exomes of 144 healthy Prakriti stratified individuals and controls from two genetically homogeneous cohorts (north and western India) revealed differential risk for diseases/traits like metabolic disorders, liver diseases, and body and hematological measurements amongst healthy individuals. These SNPs differ significantly from the Indo-European background control as well. Amongst these we highlight novel SNPs rs304447 (IFIT5) and rs941590 (SERPINA10) that could explain differential trajectories for immune response, bleeding or thrombosis. Our method demonstrates the requirement of a relatively smaller sample size for a well powered study. This study highlights the potential of integrating a unique phenotyping approach for the identification of predictive markers and the at-risk population amongst the healthy.

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes.

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying variants of concern (VOC). Viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host single nucleotide variations (iSNVs). Analysing 1347 samples collected till June 2020, we recorded 16 410 iSNV sites throughout the SARS-CoV-2 genome. We found ∼42% of the iSNV sites to be reported as SNVs by 30 September 2020 in consensus sequences submitted to GISAID, which increased to ∼80% by 30th June 2021. Following this, analysis of another set of 1774 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) lineage-defining variations appeared as iSNVs before getting fixed in the population. Besides, mutations in RdRp as well as RNA-editing by APOBEC and ADAR deaminases seem to contribute to the differential prevalence of iSNVs in hosts. We also observe hyper-variability at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions.

A rigorous framework for detecting SARS-CoV-2 spike protein mutational ensemble from genomic and structural features.

The recent release of SARS-CoV-2 genomic data from several countries has provided clues into the potential antigenic drift of the coronavirus population. In particular, the genomic instability observed in the spike protein necessitates immediate action and further exploration in the context of viral-host interactions. By temporally tracking 527,988 SARS-CoV-2 genomes, we identified invariant and hypervariable regions within the spike protein. We evaluated combination of mutations from SARS-CoV-2 lineages and found that maximum number of lineage-defining mutations were present in the N-terminal domain (NTD). Based on mutant 3D-structural models of known Variants of Concern (VOCs), we found that structural properties such as accessibility, secondary structural type, and intra-protein interactions at local mutation sites are greatly altered. Further, we observed significant differences between intra-protein networks of wild-type and Delta mutant, with the latter showing dense intra-protein contacts. Extensive molecular dynamics simulations of D614G mutant spike structure with hACE2 further revealed dynamic features with 47.7% of mutations mapping on flexible regions of spike protein. Thus, we propose that significant changes within spike protein structure have occurred that may impact SARS-CoV-2 pathogenesis, and repositioning of vaccine candidates is required to contain the spread of COVID-19 pathogen.

Knowledge and Understanding of Personal Protective Equipment Use among Laborer Population of the Nepalese Workforce.

The constructing laborers are mainly unskilled, untrained, migrant, socially backward, and uneducated with low bargaining power. Thus, we assessed the knowledge and prevalence on occupational safety and health (OSH) of laborers working at private constructing sites. A descriptive cross-sectional study of 229 laborers working at private constructing sites selected by 30 cluster sampling methods from the Lalitpur metropolitan city and Mahalaxmi municipality was conducted using a structured questionnaire and observation checklist. EpiData and SPSS were used for data analysis. Most of the laborers (62%) had inadequate knowledge on OSH. The level of knowledge was significantly associated with sex, education, and family type at 95% CI (p value < 0.05). The prevalence of occupational accidents within a year was 19.7% and was significantly associated with the use of Personal Protective Equipment (PPE) at 95% CI (p value < 0.05). About one-fifth of the participants had occupational accidents within a year because of the inadequate knowledge of OSH.

Meta-analysis of genomic variants and gene expression data in schizophrenia suggests the potential need for adjunctive therapeutic interventions for neuropsychiatric disorders.

Schizophrenia (SZ) is a debilitating mental illness with a multigenic aetiology and significant heritability. Despite extensive genetic studies, the molecular aetiology has remained enigmatic. A recent systems biology study suggested a protein-protein interaction network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominant during adolescence, often accompanied by subtle structural abnormalities in multiple regions of the brain. The availability of BrainSpan Atlas data allowed us to re-examine the genes present in the SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and nonpsychiatric Exome Aggregation Consortium database allowed us to identify the variants of criticality. The expression of the SZ candidate genes responsible for cognition and disease onset was studied in different brain regions during particular developmental stages. A subset of novel interactors detected in the network was further validated using gene expression data of post-mortem brains of patients with psychiatric illness. We have narrowed down the list of drug targets proposed by theprevious interactome study to 10 proteins. These proteins belonging to 81 biological pathways are targeted by 34 known Food and Drug Administration-approved drugs that have distinct potential for the treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to celecoxib pharmacodynamics, Gα signalling and cGMP-PKG signalling pathwaysthat are not known to be specific to SZ aetiology.

A review of landfill leachate induced ultraviolet quenching substances: Sources, characteristics, and treatment.

Landfill leachate contains extremely diverse mixtures of pollutants and thus requires appropriate treatment before discharge. Co-treatment of landfill leachate with sewage in wastewater treatment plants is a common approach because of low cost and convenience. However, some recalcitrant organic compounds in leachate can escape biological treatment processes, lower the UV transmittance of waste streams due to their UV-quenching properties, and interfere with the associated disinfection efficacy. Thus, the leachate UV quenching substances (UVQS) must be removed or reduced to a level that UV disinfection is not strongly affected. UVQS consist of three major fractions, humic acids, fulvic acids and hydrophilics, each of which has distinct characteristics and behaviors during treatment. The purpose of this review is to provide a synthesis of the state of the science regarding UVQS and possible treatment approaches. In general, chemical, electrochemical, and physical treatments are more effective than biological treatments, but also costlier. Integration of multiple treatment methods to target the removal of different fractions of UVQS can aid in optimizing treatment. The importance of UVQS effects on wastewater treatment should be better recognized and understood with implemented regulations and improved research and treatment practice.

Two-stage Anaerobic Membrane Bioreactor (AnMBR) system to reduce UV absorbance in landfill leachates.

Landfill leachate typically contains UV-quenching organics, which hinder disinfection at POTWs. This study tested a 2-stage submerged AnMBR for the degradation of UV-absorbing compounds in landfill leachate. Leachate was treated in a thermophilic reactor (55 ±â€¯2 °C) followed by a mesophilic AnMBR (37 ±â€¯1 °C), with HRTs of 25 ±â€¯5 days and 40 ±â€¯5 days respectively. Solids were not wasted, in order to promote biomass accumulation. COD, Organic carbon, and UV254 absorbance were monitored over 13 months of operation. Known UV-quenching compounds, including humic acids, fulvic acids and hydrophilic matter, were reduced by 55%. Molecular weight distribution analyses revealed that the thermophilic reactor hydrolyzed organic carbon >100 KDa into smaller fractions, which were removed in the AnMBR. The system consistently removed 50% of the total UV absorbance. This promising, new enhanced biological process may provide landfills with a feasible pretreatment alternative to expensive chemical oxidation or RO processes before discharging leachate into sewers.

A revisit to prevailing care and challenges of managing diabetes in India: Focus on regional disparities.

An unprecedented rise in diabetes mellitus (DM) prevalence in India is the outcome of lifestyle changes in the background of genetic predisposition. Moreover, there are substantial regional variations in diabetes prevalence and management. The highest prevalence of DM was observed in southern region (Ernakulum, Kerala) and lowest prevalence was observed in North Eastern region (Manipur). Similarly large variations have been evident in overall awareness and diabetes care across the geographies within India. The regional challenges are largely affected by poor disease awareness, socioeconomic disparity and underutilization of the public health-care services. Though government has taken initiatives to address this issue, overall situation demands a collaborative effort from patients, health care professionals and the state. An exhaustive literature search was performed for articles and studies published on electronic databases. Present article assesses the regional disparity of diabetes epidemiology, current management practices and government policies for T2DM in India, identifies policy and research gaps, and suggests corrective measures to address the lacunae in diabetes care.