Prediction of elevated groundwater fluoride across India using multi-model approach: insights on the influence of geologic and environmental factors.

Elevated fluoride in groundwater is a severe problem in India due to its extensive occurrence and detrimental health impacts on the large population that thrives on groundwater. Although fluoride is primarily a geogenic pollutant, existing model-based studies lack the amalgamation of the influence of geologic factors, specifically tectonics, for identifying groundwater fluoride distribution. This drawback encourages the present study to investigate the association of the tectonic framework with fluoride in a multi-model approach. We have applied three machine learning models (random forest, boosted regression tree, and logistic regression) to predict elevated groundwater fluoride based on fluoride measurements across India. The random forest model outperformed other models with an accuracy of 93%. Tectonics was found to be one of the most important predictors alongside "depth to water table." Two major areas of high risk identified were the northwest parts and the south-southeast cratonic peninsular region. The random forest model also performed significantly well over the validation dataset. We estimate that nearly 257 million people are exposed to elevated fluoride risk in India. We endeavor that the findings of our study would be an effective tool for identifying the areas at risk of elevated fluoride and also assist in undertaking effective groundwater management strategies.

Regional-scale hydrogeochemical evolution across the arsenic-enriched transboundary aquifers of the Ganges River Delta system, India and Bangladesh.

Arsenic (As) dynamics within the extensively contaminated aquifers of the Ganges River delta have been widely studied over the past few decades, but the hydrogeochemical signatures across the delta aquifers remain to be characterized. Here, we characterize the varied geochemical and isotopic (δ18O, δ2H) signatures of groundwater across the delta and interpret the hydrogeochemical evolution pathways and the driving processes on a regional-scale as a function of the delta hydrostratigraphy. Our hydrostratigraphic model identifies three major aquifer sub-systems across the delta from north-west to south-east: a single continuous unconfined aquifer (Type I); a semiconfined vertically-segregated aquifer sub-system (Type II); and a nearly confined multilayered aquifer sub-system (Type III). The Type I aquifer is dominated by Ca-Mg-HCO3-rich waters, while the aquifers to the south (Type II and Type III) exhibits increasing dominance of Na-Cl hydrogeochemical facies at shallow and intermediate depths and Na-HCO3 hydrogeochemical facies in the deep aquifers. The spatial distribution of As is also found to be heavily dictated by hydrostratigraphy, wherein the Type I aquifer sub-system yields similar concentrations across depths, while the Type II and Type III aquifer sub-systems exhibit a sharp increase in As-safe aquifers with depth. Although dominant reducing conditions occur within the delta groundwater, co-occurrence of redox-sensitive solutes from varying redox stability fields indicates to the development of overlapping redox zones. Stable isotopic signatures of groundwater exhibit a progressive depletion away from the Bay of Bengal. The Type I aquifer exhibits relatively homogenous hydrogeochemical signatures, possibly suggesting deeper infiltration of recharge under higher vertical hydraulic gradients, while the Type II and Type III aquifers exhibit variability across depth, which is possibly a reflection of horizontally stratified groundwater flows, dictated by the spatial geometry of the intervening aquitard layers.

Influence of hydrogeochemical reactions along flow paths on contrasting groundwater arsenic and manganese distribution and dynamics across the Ganges River.

The groundwater within the aquifers of the Ganges River delta exhibits significant spatial variability in concentrations of redox-sensitive solutes [e.g., arsenic (As), iron (Fe), manganese (Mn)]. The groundwater As and Mn concentrations show conspicuous contrasting distribution on the opposite banks of the Bhagirathi-Hooghly (B-H) River, the Indian distributary of the Ganges River. Here, we investigate the differences in hydrostratigraphic framework and groundwater evolutionary pathways across the B-H River that might have resulted in such variations. We developed a hydrostratigraphic model for the region and also used inverse reaction-path modeling along three hypothesized end-member flow paths to understand the dominant processes that might control As and Mn cycling within the aquifers. Our results indicate that the variability of As and Mn across the B-H River is a function of a complex interplay between the aquifer architecture, groundwater chemistry, and redox conditions.

Impact of Covid-19 Lockdown on Availability of Drinking Water in the Arsenic-Affected Ganges River Basin.

The 2020 COVID-19 pandemic has not only resulted in immense loss of human life, but it also rampaged across the global economy and socio-cultural structure. Worldwide, countries imposed stringent mass quarantine and lockdowns to curb the transmission of the pathogen. While the efficacy of such lockdown is debatable, several reports suggest that the reduced human activities provided an inadvertent benefit by briefly improving air and water quality. India observed a 68-days long, nation-wide, stringent lockdown between 24 March and 31 May 2020. Here, we delineate the impact of the lockdown on groundwater and river sourced drinking water sustainability in the arsenic polluted Ganges river basin of India, which is regarded as one of the largest and most polluted river basins in the world. Using groundwater arsenic measurements from drinking water wells and water quality data from river monitoring stations, we have studied ~700 km stretches of the middle and lower reaches of the As (arsenic)-polluted parts of the river for pre-lockdown (January-March 2020), syn-lockdown (April-May), and post-lockdown periods (June-July). We provide the extent of As pollution-free groundwater vis-à-vis river water and examine alleviation from lockdown as an opportunity for sustainable drinking water sources. The overall decrease of biochemical oxygen demand (BOD) and chemical oxygen demand (COD) concentrations and increase of pH suggests a general improvement in Ganges water quality during the lockdown in contrast to pre-and-post lockdown periods, potentially caused by reduced effluent. We also demonstrate that land use (agricultural/industrial) and land cover (urban-periurban/rural) in the vicinity of the river reaches seems to have a strong influence on river pollutants. The observations provide a cautious optimistic scenario for potentially developing sustainable drinking water sources in the arsenic-affected Ganges river basin in the future by using these observations as the basis of proper scientifically prudent, spatially adaptive strategies, and technological interventions.

Occurrence, predictors and hazards of elevated groundwater arsenic across India through field observations and regional-scale AI-based modeling.

Existence of wide spread elevated concentrations of groundwater arsenic (As) across South Asia, including India, has endangered a huge groundwater-based drinking water dependent population. Here, using high-spatial resolution As field-observations (~3 million groundwater sources) across India, we have delineated the regional-scale occurrence of elevated groundwater As (≥10 µg/L), along with the possible geologic-geomorphologic-hydrologic and human-sourced predictors that influence the spatial distribution of the contaminant. Using statistical and machine learning method, we also modeled the groundwater As concentrations probability at 1 Km resolution, along with probabilistic delineation of high As-hazard zones across India. The observed occurrence of groundwater As was found to be most strongly influenced by geology-tectonics, groundwater-fed irrigated area (%) and elevation. Pervasive As contamination is observed in major parts of the Himalayan mega-river Indus-Ganges-Brahmaputra basins, however it also occurs in several more-localized pockets, mostly related to ancient tectonic zones, igneous provinces, aquifers in modern delta and chalcophile mineralized regions. The model results suggest As-hazard potential in yet-undetected areas. Our model performed well in predicting groundwater arsenic, with accuracy: 82% and 84%; area under the curve (AUC): 0.89 and 0.88 for test data and validation datasets. An estimated ~90 million people across India are found to be exposed to high groundwater As from field-observed data, with the five states with highest hazard are West Bengal (28 million), Bihar (21 million), Uttar Pradesh (15 million), Assam (8.6 million) and Punjab (6 million). However it can be much more if the modeled hazard is considered (>250 million). Thus, our study provides a detailed, quantitative assessment of high groundwater As across India, with delineation of possible intrinsic influences and exogenous forcings. The predictive model is helpful in predicting As-hazard zones in the areas with limited measurements.

Modeling regional-scale groundwater arsenic hazard in the transboundary Ganges River Delta, India and Bangladesh: Infusing physically-based model with machine learning.

For the last few decades, toxic levels of arsenic (As) in groundwater from the aquifers of the Ganges River delta, India and Bangladesh, have been known to cause serious public health concerns. Innumerable studies have advocated the control of geomorphologic, geologic, hydrogeologic, biogeochemical, and anthropogenic factors on arsenic mobilization, flow, and distribution patterns within the Ganges River delta. We have developed transboundary regional-scale models for computing the probability of groundwater As concentrations to exceed the WHO permissible thresholds for drinking water of 10 µg/L within the Ganges River delta as a function of the various geomorphologic-(hydro)geologic-hydrostratigraphic-anthropogenic controlling factors, using statistical methods and artificial intelligence (AI) [i.e., machine learning] techniques namely, Random Forest (RF), Boosted Regression Trees (BRT) and Logistic Regression (LR) algorithms, followed by probabilistic delineation the high As-hazard zones within the delta. A "hybrid multi-modeling approach" was adapted for this study, which involved the introduction of hydrostratigraphic parameters (aquifer connectivity and surficial aquitard thickness) derived from a high-resolution transboundary hydrostratigraphic model developed for the Ganges River delta aquifer system, as predictors for modeling groundwater As probabilities within the delta. The RF model outperforms the BRT and LR model in terms of model performance. Model outputs suggest the dominant influence of surficial aquitard thickness and groundwater-fed irrigated area (%) on groundwater As. While, the north-central and southern regions of the Ganges River delta show low As-hazard (<10 µg/L), the western and north-eastern regions demonstrate elevated hazard level (>10 µg/L). An estimated 30.3 million people are found to be exposed to elevated groundwater As within the study area. Thus, our study demonstrates that such hybrid, predictive models are not only helpful in delineating the regional-scale distribution of groundwater As-hazard zones in the areas with limited As data but is also useful in identifying the possible exogenous forcing that may have led to the worst, natural pollution in human history.

Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions.

Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as "undruggable". Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs.

Controls on high and low groundwater arsenic on the opposite banks of the lower reaches of River Ganges, Bengal basin, India.

Understanding the controls on spatial variability of groundwater arsenic (As) is critical for mitigating As contamination. The objective of this study is to determine controls on previously unexplained differences in groundwater As concentrations, which are high along the east bank and low along the west bank of the River Bhagirathi-Hoogly (B-H), the primary Indian distributary of the River Ganges, on the western margin of the Bengal basin. A total of 54 wells were sampled after the monsoon season at four sites (two each east and west of the B-H) in Murshidabad district, West Bengal, for field parameters, major and minor solutes, and stable isotopes of water. An additional four boreholes were drilled for analyses of sediment texture, mineralogy, total organic and inorganic carbon, and total As and other metal(loid)s. Results show that higher As in east-bank groundwater (median 0.031 mg/L) is associated with generally more anoxic conditions (higher median total Fe and lower median EH and NO3-) relative to west-bank groundwater (median As < 0.001 mg/L), consistent with previous studies. In contrast, concentrations of Mn in the study area are highest in west-bank wells near the B-H. Carbonate and silicate weathering appear to be more important in east- and west-bank groundwater, respectively, which may reflect differences in sediment sources. Ranges of total As are similar in east- and west-bank sediments. Relatively depleted values of δ18O and δ2H in the east-bank aquifer and streams appear to reflect focused recharge through paleochannels, while relatively enriched west-bank values suggest diffuse recharge to upland aquifers. We speculate that water infiltrating through erosional, stratigraphic "windows" carries organic matter capable of mobilizing As in east-bank groundwater. This comprehensive evaluation of groundwater chemistry provides a more detailed understanding of controls on As variability within the basin.

A peptide-based synthetic transcription factor selectively down-regulates the proto-oncogene CFOS in tumour cells and inhibits proliferation.

Selectively regulating genes is an important goal in Chemical Biology. We report the development of a peptide-based synthetic transcription factor which binds the targeted DNA sequence with high affinity and single base-pair discrimination capability. When delivered inside a tumor cell, it regulated targeted genes selectively and inhibited cell proliferation.

Differential thermal stability and oxidative vulnerability of the hemoglobin variants, HbA2 and HbE.

Apart from few early biophysical studies, the relative thermal instability of HbE has been only shown by clinical investigations. We have compared in vitro thermal stability of HbE with HbA2 and HbA using optical spectroscopy. From absorption measurements in the soret region, synchronous fluorescence spectroscopy and dynamic light scattering experiments, we have found thermal stability of the three hemoglobin variants following the order HbE11.0 in all the three variants. Under oxidative stress conditions in presence of hydrogen peroxide, HbE has been found to be more vulnerable to aggregation compared to HbA and HbA2. Taken together, these studies have shown thermal and oxidative instability of HbE and points towards the role of HbE in the upregulation of redox regulators and chaperone proteins in erythrocyte proteome of patients suffering from HbEbeta thalassemia.

Triterpenoids from Schleichera oleosa of Darjeeling Foothills and Their Antimicrobial Activity.

Two triterpenoids, taraxerone and tricadenic acid A were isolated from the methanol extract of the outer bark of Schleichera oleosa available in Darjeeling foothills. A preliminary study on their antimicrobial activities was also performed against some fungal and bacterial species. The structure of these compounds was determined by means of chemical characterisation and IR, NMR spectral data.

DNA binding domain of RFX5: interactions with X-box DNA and RFXANK.

Regulatory factor X (RFX) is a heterotrimeric protein complex having RFX5, RFXANK and RFXAP as its three subunits. It is involved in the regulation of the transcription of MHCII molecules in antigen presenting cells. The RFX complex binds to X-box DNA, using the DNA binding domain, present in RFX5. The DNA binding domain (DBD) of RFX5 (12kD) and intact RFXANK (35 kD) were subcloned, expressed and purified. The associations of RFX5DBD with the X-box DNA and between RFX5DBD and RFXANK were measured in this study. The interaction of RFX5DBD and X-box DNA was studied using steady state fluorescence quenching and circular dichroism. The binding dissociation constant (K(d)) of the DNA-protein complex was determined from fluorescence measurements. The van't Hoff plot was linear over the temperature range 10-25 degrees C and the binding was found to be entropy-driven and enthalpy-favorable. The effect of electrolytes in RFX5DBD-DNA association was also studied. Molecular association between RFX5DBD and RFXANK has been observed by fluorescence resonance energy transfer (FRET) measurements, changes in the ratio of the two vibronic intensities of pyrene labeled RFX5DBD in presence of RFXANK and chemical cross-linking followed by tandem mass spectrometry. Results showed that the two proteins could interact in the absence of the third subunit RFXAP, in vitro with an apparent dissociation constant (K(d)) of 128 nM.

Structure and conformational studies on dityrosine formation in the DNA binding domain of RFX5.

The DNA binding protein RFX5 is a subunit of RFX complex involved in transcription regulation of MHCII molecules. The RFX complex binds to the X-box DNA through the DNA binding domain of RFX5. We have examined the formation of intramolecular tyrosine cross linking, dityrosine, in RFX5DBD under oxidative stress, through UV irradiation and enzymatic action of H(2)O(2)/peroxidase by fluorescence spectroscopic studies. Dityrosine (DT) was formed predominantly in alkaline condition showing its intense characteristic fluorescence emission. Homology modeling indicated Y(39) and Y(42) could be the potential tyrosine residues undergoing oxidative cross-linking. Conformational changes in RFX5DBD under oxidative stress were observed by CD measurements. The in vitro association of X-box DNA with RFX5DBD increased DT fluorescence significantly and protected RFX5DBD from UV irradiation as observed in SDS-PAGE followed by mass spectrometric analysis. Results indicate cross protection in both RFX5DBD and DNA under oxidative stress playing important role in protein modification.

Triterpenoids from Psidium guajava with Biocidal Activity.

In continuation of our studies on the phytochemical investigation of medicinal plants available in the foothills of Darjeeling and Teri, we report herein the isolation of two triterpenoids betulinic acid and lupeol from the leaf extract of Psidium guajava and their potential antimicrobial and phytotoxic activities. All the structures of the isolated compounds were confirmed by spectral (IR, NMR) analysis and by comparison with the literature reports.