Investigating the utility of satellite-based precipitation products for simulating extreme discharge events: an exhaustive model-driven approach for a tropical river basin in India.

Satellite-based precipitation estimates are a critical source of information for understanding and predicting hydrological processes at regional or global scales. Given the potential variability in the accuracy and reliability of these estimates, comprehensive performance assessments are essential before their application in specific hydrological contexts. In this study, six satellite-based precipitation products (SPPs), namely, CHIRPS, CMORPH, GSMaP, IMERG, MSWEP, and PERSIANN, were evaluated for their utility in hydrological modeling, specifically in simulating streamflow using the Variable Infiltration Capacity (VIC) model. The performance of the VIC model under varying flow conditions and timescales was assessed using statistical indicators, viz., R2, KGE, PBias, RMSE, and RSR. The findings of the study demonstrate the effectiveness of VIC model in simulating hydrological components and its applicability in evaluating the accuracy and reliability of SPPs. The SPPs were shown to be valuable for streamflow simulation at monthly and daily timescales, as confirmed by various performance measures. Moreover, the performance of SPPs for simulating extreme flow events (streamflow above 75%, 90%, and 95%) using the VIC model was assessed and a significant decrease in the performance was observed for high-flow events. Comparative analysis revealed the superiority of IMERG and CMORPH for streamflow simulation at daily timescale and high-flow conditions. In contrast, the performances of CHIRPS and PERSIANN were found to be poor. This study highlights the importance of thoroughly assessing the SPPs in modeling diverse flow conditions.

Evaluation of Immune Exhaustion and Co-Inhibitory Receptor Expression in Mycobacterium avium Subspecies paratuberculosis (MAP) Seropositive Diarrhoeic Bovines.

Mycobacterium avium subspecies paratuberculosis (MAP) infection leads to chronic, persistent granulomatous enteritis, causing prolonged diarrhoea and emaciation. The disease is managed using medications such as antibiotics, live vaccines, mycobacteriophage therapies and other treatments; however, a notable proportion of affected animals do not show improvement with this approach. We hypothesise that immunoinhibitory receptors TIM-3 (T cell immunoglobulin mucin protein-3) and PD-1 (Programmed death receptor 1) may be upregulated on Peripheral blood mononuclear cells (PBMCs) of MAP-seropositive bovines, potentially contributing to immune exhaustion. Samples (blood and faeces) were collected from 32 diarrhoeic bovines suspected of MAP infection; eight apparently healthy buffaloes from the dairy farm at Hisar, Haryana and from 14 cows (suffering from chronic diarrhoea, weakness and emaciation) housed in stray cattle shed. MAP infection was estimated using indigenous ELISA (i-ELISA), faecal IS900 PCR, culture and acid-fast staining. TIM-3 and PD-1 gene expression on PBMCs were determined using qRT-PCR. TIM3 expression was relatively higher (~400-fold, 330-fold, 112-fold, 65-fold and 16-fold) in 5 chronically diarrhoeic PBMCs samples (MAP-seropositive), and higher PD-1 expression (around ~7-fold, 1.75-fold, 2.5-fold, 7.6-fold) was recorded in 4 diarrhoeic MAP-seropositive animals, compared to apparently healthy and other MAP-seronegative diarrhoeic animals. High co-expression of TIM-3 and PD-1 levels was also recorded in chronically diarrhoeic, emaciated stray cattle. Understanding immune responses in field conditions might aid in the therapeutic management of paratuberculosis.

CRISPR/Cas9 as a therapeutic tool for triple negative breast cancer: from bench to clinics.

Clustered regularly interspaced short palindromic repeats (CRISPR) is a third-generation genome editing method that has revolutionized the world with its high throughput results. It has been used in the treatment of various biological diseases and infections. Various bacteria and other prokaryotes such as archaea also have CRISPR/Cas9 systems to guard themselves against bacteriophage. Reportedly, CRISPR/Cas9-based strategy may inhibit the growth and development of triple-negative breast cancer (TNBC) via targeting the potentially altered resistance genes, transcription, and epigenetic regulation. These therapeutic activities could help with the complex issues such as drug resistance which is observed even in TNBC. Currently, various methods have been utilized for the delivery of CRISPR/Cas9 into the targeted cell such as physical (microinjection, electroporation, and hydrodynamic mode), viral (adeno-associated virus and lentivirus), and non-viral (liposomes and lipid nano-particles). Although different models have been developed to investigate the molecular causes of TNBC, but the lack of sensitive and targeted delivery methods for in-vivo genome editing tools limits their clinical application. Therefore, based on the available evidences, this review comprehensively highlighted the advancement, challenges limitations, and prospects of CRISPR/Cas9 for the treatment of TNBC. We also underscored how integrating artificial intelligence and machine learning could improve CRISPR/Cas9 strategies in TNBC therapy.

Identification of small molecule inhibitors of RAD52 for breast cancer therapy: in silico approach.

The breast cancer susceptibility gene 1/2 (BRCA1/2) are the key regulators in maintaining the genomic integrity and mutations in these genes have been associated with development of breast and ovarian cancers. Also, synthetic lethality has been shown in BRCA1/2 deficient cancers, when the RAD52 gene is silenced by shRNA or small molecules aptamers, suggesting a role for RAD52 in the breast cancers pathogenesis. Thus, to find the potential inhibitors of RAD52, a collection of 21,000 compounds from the ChemBridge screening library was screened to conduct molecular docking and molecular dynamics simulation (MD) against RAD52. Further, the results were validated by a density functional theory (DFT) analysis and using post-dynamics free energy calculations. Out of all screened molecules, the docking study revealed five compounds were found to have promising activities against RAD52. Moreover, the catalytic amino acid residues of RAD52 developed stable contacts with compound 8758 and 10593, as anticipated by DFT calculation, MD simulation, and post dynamics MM-GBSA energy calculation. It appears that compound 8758 is the best inhibitor against RAD52 followed by 10593 compared to the other top hits, in terms of the HOMO orbital energy (-1.0966 eV and -1.2136 eV) from DFT and the post dynamics binding free energy calculation (-54.71 and -52.43 Kcal/mol). Furthermore, a drug-like properties of lead molecules (8758 and 10593) were also seen via ADMET analysis. Based on our computational analysis, we hypothesize that a small molecule 8758 and 10593 possess the therapeutic potential in the management for breast cancer patients with a BRCA mutation via targeting RAD52.Communicated by Ramaswamy H. Sarma.

An Extensive Examination of the Warning Signs, Symptoms, Diagnosis, Available Therapies, and Prognosis for Lumpy Skin Disease.

The lumpy skin disease virus (LSDV) infects cattle and buffalo and causes lumpy skin disease (LSD). It affects the lymph nodes of the sick animals, causing them to enlarge and appear as lumps (cutaneous nodules) that are 2-5 cm in diameter on their heads, necks, limbs, udders, genitalia, and perinea. A high temperature, a sharp drop in milk supply, discharge from the eyes and nose, salivation, a loss of appetite, depression, damaged hides, and emaciation are further warning signs and symptoms. As per the Food and Agriculture Organization (FAO), the incubation period, or the time between an infection and symptoms, is approximately 28 days. Infected animals can transfer the virus by direct contact with the vectors, direct virus secretion from mouth or nose, shared feeding and watering troughs, and even artificial insemination. The World Organization for Animal Health (WOAH) and the FAO both warn that the spread of illnesses could lead to serious economic losses. This illness reduces cow's milk production because oral ulcers make the animal weak and lead them to lose their appetite. There are many diagnostics available for LSDV. However, very few tests yield accurate findings. The best methods for preventing and controlling the lumpy skin condition include vaccination and movement restrictions. As a specific cure is not available, the only available treatment for this illness is supportive care for cattle. Recently, India has developed a homologous, live-attenuated vaccine, Lumpi-ProVacInd, which is specifically intended to protect animals against the LSD virus. This study's primary goal is to accumulate data on symptoms, the most accurate method of diagnosis, treatments, and controls to stop infections from spreading as well as to explore future possibilities for the management of LSDV.

Assessment of drought trends and variabilities over the agriculture-dominated Marathwada Region, India.

Drought is considered among the most perilous events with catastrophic consequences, particularly from the agro-economic point of view. These consequences are expected to exacerbate under the increasing meteorological aberrations due to changing climate, which necessitates investigating drought variabilities. This study presents a thorough spatiotemporal assessment of drought trends and variabilities over the agriculture-dominated Marathwada Region, Maharashtra, India. The precipitation data is extracted from the India Meteorological Department (IMD) gridded product, whereas actual evapotranspiration (ET) and Evaporative Stress Index (ESI) are obtained from Global Land Evaporation Amsterdam Model (GLEAM) datasets. Standardized Precipitation Index (SPI) is used to characterize drought occurrences at multiple time frames, whereas non-parametric tests, i.e., modified Mann-Kendall (MMK) and Sen's slope (SS) tests, are employed to detect trends. The results reveal the region to be prone to droughts, and SPI at a longer time frame (i.e., 12-monthly moving frame) can capture drought occurrences better than the shorter time frames, which can be attributed to the lesser randomness in the time series in the longer frame. A mix of positive/negative trends of SPI series are found for the monsoonal months; however, they are relatively more concentrated towards negative ZMMK. Hence, the Marathwada Region can be inferred to have exhibited a relatively increased tendency towards drought occurrences. The seasonal differences in mean values and trends of rainfall, ET, and ESI are discussed in detail. Since the Marathwada Region has a monsoon-dominated climate with high agricultural importance, the information reported in this study will help in devising water management strategies to minimize the repercussions of droughts.

Appraisal of historical trends in maximum and minimum temperature using multiple non-parametric techniques over the agriculture-dominated Narmada Basin, India.

In this study, the long-term trends in climatological parameters, viz., maximum temperature (TMAX) and minimum temperature (TMIN), are determined over 68 years (i.e., June 1951 to May 2019) using the gridded observation datasets (1° × 1° spatial resolution) of India Meteorological Department over the Narmada river basin, India. Multiple non-parametric techniques, viz., modified Mann-Kendall (MMK), Sen's slope (SS), and Spearman's rho (SR) tests, are used to determine monthly, seasonal, and annual trends over individual grids. The trends are also analyzed for the climatic variables spatially averaged over the entire basin to draw general conclusions on historical climate change. The results reveal a significant spatiotemporal variation in trends of TMAX and TMIN over the basin. In general, both the parameters are found to be increasing. Furthermore, the hottest months (April and May) have become hotter, and the coldest month (January) has become colder, implying a higher probability of increasing temperature extremes. Furthermore, the entire duration of 68 years is divided into two epochs of 34 years, i.e., 1951-1984 and 1985-2018, and the trend analysis of TMAX and TMIN is also carried out epoch-wise to better understand/assess the signals of climate change in recent years. In general, a relatively higher warming trend was observed in the latter epoch. As a majority of the basin area is dominated by agricultural lands, the implications of the temperature trends and their impacts on agriculture are succinctly discussed. The information reported in this study will be helpful for proper planning and management of water resources over the basin under the changing climatic conditions.

In silico to In vivo development of a polyherbal against Haemonchus contortus.

Haemonchus contortus is a major constraint in the development of small ruminant subsector due to significant production losses incurred by it. The present study explores the antiparasitic potential of three anthelmintic plants (Butea monosperma, Vitex negundo and Catharanthus roseus (L.) G.Don) against H. contortus taking albendazole as the standard. In silico molecular docking and pharmacokinetic prediction studies were conducted with known bioactive molecules of these plants (palasonin, vinblastine, vincristine, betulinic acid and ursolic acid) against Glutamate Dehydrogenase (GDH) and tubulin molecules of the parasite. Methanolic extracts of these herbs were fractionated (hexane, ethyl acetate, chloroform and methanol) and used in in vitro larvicidal studies. Based on the in vitro data, two herbal prototypes were developed and clinically tested. All the 5 ligand molecules showed better binding affnity for GDH and tubulin protein as compared with albendazole and shared similar binding site in the core of the GDH hexamer with slight variations. Albendazole approximately stacked against GLY190A residue, showing hydrophobic interactions with PRO157A and a Pi-cation electrostatic interaction with ARG390 along with four hydrogen bonds. Vincristine formed 2 pi-anionic electrostatic bonds with ASP158 of B and C subunits alongwith hydrogen bonding and hydrophobic interaction and an additional pi-anion electrostatic interaction at ASP158A for vinblastine. Albendazole bound to α-tubulin next to colchicine site whereas vinblastine is bound at the nearby laulimalide/peloruside site of the dimer. Betulinic acid showed lateral interaction between the H2-H3 loop of one alpha subunit and H10 of the adjacent alpha subunit of two tubulin dimers. Ursolic acid and palasonin bound at the intradimer N site of microtubulin involving the H1-H7 and H1-H2 zone, respectively. The in vitro studies demonstrated good dose dependent anthelmintic potential. Both the prototypes were quite efficacious in clearing the infection, keeping it to a minimal for more than 5 months, probably, through direct anthelmintic effect through GDH, tubulin depolymerization and uncoupling as well as indirectly through immunomodulation along with antioxidant and anti-inflammatory properties.