Strategies for mitigation of pesticides from the environment through alternative approaches: A review of recent developments and future prospects.

Chemical-based peticides are having negative impacts on both the healths of human beings and plants as well. The World Health Organisation (WHO), reported that each year, >25 million individuals in poor nations are having acute pesticide poisoning cases along with 20,000 fatal injuries at global level. Normally, only ∼0.1% of the pesticide reaches to the intended targets, and rest amount is expected to come into the food chain/environment for a longer period of time. Therefore, it is crucial to reduce the amounts of pesticides present in the soil. Physical or chemical treatments are either expensive or incapable to do so. Hence, pesticide detoxification can be achieved through bioremediation/biotechnologies, including nano-based methodologies, integrated approaches etc. These are relatively affordable, efficient and environmentally sound methods. Therefore, alternate strategies like as advanced biotechnological tools like as CRISPR Cas system, RNAi and genetic engineering for development of insects and pest resistant plants which are directly involved in the development of disease- and pest-resistant plants and indirectly reduce the use of pesticides. Omics tools and multi omics approaches like metagenomics, genomics, transcriptomics, proteomics, and metabolomics for the efficient functional gene mining and their validation for bioremediation of pesticides also discussed from the literatures. Overall, the review focuses on the most recent advancements in bioremediation methods to lessen the effects of pesticides along with the role of microorganisms in pesticides elimination. Further, pesticide detection is also a big challenge which can be done by using HPLC, GC, SERS, and LSPR ELISA etc. which have also been described in this review.

Significance of MOF adsorbents in uranium remediation from water.

Uranium is considered as one of the most perilous radioactive contaminants in the aqueous environment. It has shown detrimental effects on both flora and fauna and because of its toxicities on human beings, therefore its exclusion from the aqueous environment is very essential. The utilization of metal-organic frameworks (MOFs) as an adsorbent for the removal of uranium from the aqueous environment could be a good approach. MOFs possess unique properties like high surface area, high porosity, adjustable pore size, etc. This makes them promising adsorbents for the removal of uranium from contaminated water. In this paper, sources of uranium in the water environment, human health disorders, and application of the different types of MOFs as well as the mechanisms of uranium removal have been discussed meticulously.

Comparative assessment of prognostic models in chronic lymphocytic leukemia: evaluation in Indian cohort.

Prognostic indices combining several clinical and laboratory parameters have been proposed for prognostication in chronic lymphocytic leukemia (CLL). Recently, international consortium on CLL proposed an international prognostic index (CLL-IPI) integrating clinical, molecular, and genetic parameters. The present study was designed to evaluate the reproducibility of CLL-IPI in Indian CLL cohort. The prognostic ability of CLL-IPI in terms of overall survival (OS) and time to first treatment (TTFT) was investigated in treatment-naive CLL patients and also compared with other existing prognostic scores. For assigning scores, clinical and laboratory details were obtained from medical records, and IGHV gene mutation status, ß2-microglobulin levels, and copy number variations were determined using c-DNA, ELISA, and multiplex ligation-dependent probe amplification (MLPA), respectively. The scores were generated as per the weighted grades assigned to each variable involved in score categorization. The predictive value of prognostic models was assessed and compared using Harrell's C-index and Akaike's information criterion (AIC). Stratification of patients according to CLL-IPI yielded significant differences in terms of OS and TTFT (p < 0.001). Comparative assessment of scores for OS suggested better performance of CLL-IPI (C = 0.64, AIC = 740) followed by Barcelona-Brno (C = 0.61, AIC = 754) and MDACC score (C = 0.59, AIC = 759). Comparison of predictive value of prognostic scores for TTFT illustrated better performance of CLL-IPI (C = 0.72, AIC = 726) followed by Barcelona-Brno (C = 0.68, AIC = 743), modified GCLLSG (C = 0.66, AIC = 744), and O-CLL1 index (C = 0.55, AIC = 773). The results suggest better performance of CLL-IPI in terms of both OS and TTFT as compared to other available scores in our cohort.

Nucleic acid based risk assessment and staging for clinical practice in multiple myeloma.

The recently introduced Revised International Staging System (R-ISS) for multiple myeloma (MM) integrates albumin, ß2 microglobulin, lactate dehydrogenase (LDH) with high-risk cytogenetic aberrations (CA), i.e., t(4;14) and t(14;16) and del17p using fluorescent in situ hybridization (FISH). We evaluated utility of nucleic acid-based tests of multiplex ligation-based probe amplification (MLPA) and quantitative real-time polymerase chain reaction (qRT-PCR) to define the CA and the R-ISS categories as per this approach were evaluated for their ability to predict outcome in terms of response, progression-free (PFS), and overall survival (OS). In this study (n = 180), 17 (9.4%), 118 (65.6%), and 45 (25%) patients were assigned to R-ISS1, R-ISS2, and R-ISS3 categories with statistically significant differences in median PFS (p = 0.02) and OS (p < 0.001).On univariate analysis, serum creatinine, LDH, 17p deletion, chromosome 1q gain, and response after first induction therapy were associated with statistically significant differences (p < 0.05) in PFS and in addition, age> 65 years and use of triplet therapy with OS. On multivariate analysis, only serum creatinine, LDH, and response after first induction therapy retained significance for predicting PFS and in addition, use of triplet therapy retained significance for the OS. The proposed nucleic acid-based algorithm using qRT-PCR and MLPA for R-ISS is resource-effective in terms of small quantities of sample required; feasibility of batch processing and reduced overall cost for the total number of regions evaluated and retained the prognostic significance of R-ISS, making it suitable for clinical practice for molecular characterization of MM.

Exploring Therapeutic Potential of Phytoconstituents as a Gut Microbiota Modulator in the Management of Neurological and Psychological Disorders.

The functioning of the brain and its impact on behavior, emotions, and cognition can be affected by both neurological and psychiatric disorders that impose a significant burden on global health. Phytochemicals are helpful in the treatment of several neurological and psychological disorders, including anxiety, depression, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD), because they have symptomatic benefits with few adverse reactions. Changes in gut microbiota have been associated with many neurological and psychiatric conditions. This review focuses on the potential efficacy of phytochemicals such as flavonoids, terpenoids, and polyphenols in regulating gut flora and providing symptomatic relief for a range of neurological and psychological conditions. Evidence-based research has shown the medicinal potentials of these phytochemicals, but additional study is required to determine whether altering gut microbiota might slow the advancement of neurological and psychological problems.

Safety and Efficacy of Bendamustine and Rituximab (BR) Regimen in Indian Chronic Lymphocytic Leukaemia Patients.

We investigated the safety and efficacy of bendamustine-rituximab (BR) in previously untreated symptomatic and advanced CLL patients, as there is no data available on BR from the Indian subcontinent.This retrospective study included 120 consecutive treatment naïve patients with CLL without del (17p), who were registered at the Department of Medical Oncology, AIIMS between January 2010 and July 2018. Bendamustine was given at a dose of 90 mg/m2 on days 1 and 2, combined with rituximab 375 mg/m2 rituximab on day 1, every 28 days for up to 6 courses. Event-free survival (EFS) was defined as the date of treatment to date of relapse, disease progression, or death due to any cause.The median age was 57 years (range: 30-75 years). As per the clinical Rai stage, 30 (25%) patients were in stage II, 42 (35%) were in stage III and 48 (40%) were in stage IV. ZAP70 was positive (> 20%) in 50%, CD 38 was positive (> 30%) in 33%, and CD49d was positive (> 30%) in 49% of cases. Beta-2 microglobulin (B2M) was elevated (≥ 3.5 mg/L) in 80% of cases. Fifty-five cases (50%, n = 110) were IGHV mutated. The mean number of cycles was 5 (1-6). The overall response rate (ORR) seen with BR was 90% and complete response was 45%. Median progression-free survival was 24 months with a median follow-up period of 29 months. Haemoglobin (< 10 g/dL), elevated B2 M, unmutated IGHV had a statistically significant adverse impact on EFS on univariate analysis but on multivariate analysis, only IGHV mutation status was found to had significance on EFS. The median EFS was 27 months in IGHV mutated versus 18 months in IGHV unmutated-CLL patients (p = 0.001). Grade 3/4 neutropenia, thrombocytopenia, anemia, and infections were observed in 30.6%, 8%, and 12% respectively. The most common non-hematological toxicity was skin rash which was grade 1/2 in 24 (20%) cases and grade 3/4 in 12 (10%) cases. This is the largest study from India to demonstrate the safety and efficacy of BR in symptomatic CLL patients. BR is an effective and safe regimen in the first-line treatment of CLL. Unmutated-CLL patients have inferior EFS than mutated-CLL patients. Skin toxicity was the most common adverse effect seen in our population which was observed in around one-third of cases.

Graded Depth of Response and Neoplastic Plasma Cell Index as Indicators of Survival Outcomes in Patients With Multiple Myeloma Following Autologous Stem Cell Transplant.

OBJECTIVES: With a substantial number of patients with multiple myeloma (MM) experiencing disease relapse, the quest for more sensitive methods to assess deeper responses indicative of cure continues. METHODS: In this prospective analysis of 170 patients with MM at day 100 after autologous stem cell transplant, we evaluated the predictive value of conventional response, measurable residual disease (MRDTOTAL: the aberrant percentage of plasma cells [PC%] among total bone marrow cells), and neoplastic plasma cell index scores (NPCI: the aberrant PC% of total PCs). RESULTS: Significantly better progression-free survival (PFS) and overall survival (OS) were observed with deepening conventional response. Conventional response-based stratification within the MRD-positive and MRD-negative subgroups showed a significantly higher PFS (hazard ratio [HR], 3.11; P < .005) and OS (HR, 3.08; P = .01) in the conventional response-positive/MRD-positive group compared with the conventional response-negative/MRD-positive group. Using K-adaptive partitioning to find the optimum threshold for MRD, patients achieving less than 0.001% MRDTOTAL had superior PFS (MRDTOTAL 0.001% to <0.1%: HR, 6.66, P < .005; MRDTOTAL ≥0.1%: HR, 11.52, P < .005) and OS (MRDTOTAL 0.001% to <0.1%: HR, 5.3, P < .05; MRDTOTAL ≥0.1%: HR = 9.21, P < .005). The C index and Akaike information criterion metrics demonstrated the superior performance of the NPCI compared with MRDTOTAL in predicting treatment outcome. CONCLUSIONS: Progressive deepening of response, conventional as well as MRD, correlates with superior survival outcomes. The NPCI proved to be a superior determinant of survival and can be explored as a better statistic than MRD.

Phylogeny and evolution of SARS-CoV-2 during Delta and Omicron variant waves in India.

SARS-CoV-2 evolution has continued to generate variants, responsible for new pandemic waves locally and globally. Varying disease presentation and severity has been ascribed to inherent variant characteristics and vaccine immunity. This study analyzed genomic data from 305 whole genome sequences from SARS-CoV-2 patients before and through the third wave in India. Delta variant was reported in patients without comorbidity (97%), while Omicron BA.2 was reported in patients with comorbidity (77%). Tissue adaptation studies brought forth higher propensity of Omicron variants to bronchial tissue than lung, contrary to observation in Delta variants from Delhi. Study of codon usage pattern distinguished the prevalent variants, clustering them separately, Omicron BA.2 isolated in February grouped away from December strains, and all BA.2 after December acquired a new mutation S959P in ORF1b (44.3% of BA.2 in the study) indicating ongoing evolution. Loss of critical spike mutations in Omicron BA.2 and gain of immune evasion mutations including G142D, reported in Delta but absent in BA.1, and S371F instead of S371L in BA.1 could explain very brief period of BA.1 in December 2021, followed by complete replacement by BA.2. Higher propensity of Omicron variants to bronchial tissue, probably ensured increased transmission while Omicron BA.2 became the prevalent variant possibly due to evolutionary trade-off. Virus evolution continues to shape the epidemic and its culmination.Communicated by Ramaswamy H. Sarma.

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

Experimental and simulation studies reveal mechanism of action of human defensin derivatives.

Antimicrobial peptides (AMPs) are naturally occurring promising candidates which can be used as antibiotics against a wide variety of bacteria. The key component for using them as a potent antibiotic is that their mechanism of action is less prone to bacterial resistance. However, the molecular details of their mechanism of action is not yet fully understood. In this study, we try to shed light on the mode of action of AMPs, possible reason behind it, and their interaction with lipid bilayers through experimental as well as molecular dynamics (MD) simulation studies. The focal of our study was Human beta defensin 3 (hBD-3) which is a naturally occurring AMP. We chose three derivatives of hBD-3, namely CHRG01, KSR, and KLR for the detailed analysis presented in this study. These three peptides are evaluated for their antibacterial potency, secondary structure analysis and mechanism of action. The experimental results reveal that these peptides are active against gram positive as well as gram negative bacteria and kill bacteria by forming membrane pores. The MD simulation results correlate well with the antibacterial activity and shed light into the early membrane insertion dynamics. Moreover, the specific amino acids responsible for membrane disruptions are also identified from the MD simulations. Understanding the molecular level interaction of individual amino acids with the lipid bilayer will greatly help in the design of more efficient antimicrobial peptides.

Recent advances in nanomaterial developments for efficient removal of Hg(II) from water.

"Water" contamination by mercury Hg(II) has become the biggest concern due to its severe toxicities on public health. There are different conventional techniques like ion exchange, reverse osmosis, and filtration that have been used for the elimination of Hg(II) from the aqueous solutions. Although, these techniques have some drawbacks during the remediation of Hg(II) present in water. Adsorption could be a better option for the elimination of Hg(II) from the aqueous solutions. "Conventional adsorbents" like zeolite, clay, and activated carbons are inefficient for this purpose. Recently, nanomaterials have attracted attention for the elimination of Hg(II) from the aqueous solutions due to high porosity, better surface properties, and high efficiency. In this review, a thorough discussion has been carried out on the synthesis and characterization of nanomaterials along with mechanisms involved in the elimination of Hg(II) from aqueous solutions.

Site-Specific Stabilization and Destabilization of α Helical Peptides upon Phosphorylation and O-GlcNAcylation.

Helices (α-helix) are the most common type of secondary structure motif present in proteins. In this study, we have investigated the structural influence of phosphorylation and O-GlcNAcylation, common intracellular post-translational modifications (PTMs), on the α-helical conformation. The simulation studies were performed on the Baldwin model α-helical peptide sequence (Ac-AKAAAAKAAAAKAA-NH2). The Baldwin sequences were chosen due to the availability of site-specific experimental post-translational data for cross-validation with the simulations. The influence of PTMs was examined across the span of the α-helix, namely, at the N-terminus, position 10 (interior region), and the C-terminus for both serine and threonine residues placed at these positions. Molecular dynamics (MD) simulations revealed that phosphorylation and O-GlcNAcylation at the N-terminus lead to the stabilization of the helical conformation. PTMs in the interior or the C-terminus were found to disrupt helicity, with the disruption being more pronounced for PTMs in the interior region, in accordance with experimental studies. It was found that phosphorylation-derived destabilization was mainly due to the formation of an intraresidue HN-PO32- electrostatic interaction and interactions between the phosphate group and the side chain of adjacent lysine residues (NH3···PO32-). Hydrophobic and steric clashes were the main causes of destabilization in the case of O-GlcNAcylation. The structural disruptions were found to be more pronounced for PTM at the threonine site when compared to the serine site. The salt-bridge-dependent stability of the α-helix was found to be highly position specific, an i → i + 4 interaction stabilizing the helix, with other placements leading to the destabilization of the helix.

Phosphorylation-Induced Structural Reorganization in Tau-Paired Helical Filaments.

Taupathies involve the deposition of abnormal tau protein into neurofibrillary tangles (NFTs) in the human brain. The abnormally hyperphosphorylated tau dissociates from microtubules and forms insoluble aggregates known as paired helical filaments (PHFs), highlighting the importance of post-translational modifications in taupathies. The present study examines the factors responsible for the structural stability of PHFs in native as well as in phosphorylated and O-GlcNAcylated tau. We carried out molecular dynamics simulations on the R3-R4 repeat domains of the human tau protein to gain atomic insights into the key noncovalent interactions responsible for their unique dimeric C-shaped structure. The structural effects upon post-translational modification were found to be prominent for phosphorylation when compared with O-GlcNAcylation. O-GlcNAcylated tau was found to retain the "C conformation" observed in the native tau PHF, whereas upon phosphorylation, we observed a conformational transition to a more opened "H conformation". We found that this conformational transition is brought about by the loss of a key salt bridge between Lys353 and Asp358 due to the phosphorylation at Ser356 that results in the reorganization of the dimeric interface.

Bioremediation: An effective approach of mercury removal from the aqueous solutions.

Mercury (Hg(II)) is the 16th rarest element present in the earth's crust. Due to rapid industrialization and urban expansions, the mercury concentration has been elevated in the environment. Hg(II) contamination in the aqueous environment has become a great challenge for human beings. The main source of Hg(II) in the aqueous phase is untreated effluent industries (such as the paper industry). Hg(II) is non-biodegradable in nature and even its trace amount in an aqueous environment can pose chronic threats among the humans (damage to the central nervous system, respiratory system, and cardiovascular system, mutation of DNA), animals, and aquatic creatures. Therefore, the removal of mercury from aqueous solutions is an urgent need of the modern era. The conventional techniques such as ion exchange, precipitation, membrane filtrations are costly and also generate byproducts in the environment. Bioremediation is a sustainable, environmentally sound, and cost-effective technique to remove Hg(II) from the aqueous solutions. In this process, naturally occurring microorganisms are utilized to remove the Hg(II) from the aqueous solutions. Lentinus edodes, U. lactuca, and Typha domingensis are found to have great potential to remove mercury from water ranged from ~100 mg g-1 to 337 mg g-1.

Recent Updates on Free Fatty Acid Receptor 1 (GPR-40) Agonists for the Treatment of Type 2 Diabetes Mellitus.

BACKGROUND: The global incidence of type 2 diabetes mellitus (T2DM) has enthused the development of new antidiabetic targets with low toxicity and long-term stability. In this respect, free fatty acid receptor 1 (FFAR1), which is also recognized as a G protein-coupled receptor 40 (GPR40), is a novel target for the treatment of T2DM. FFAR1/GPR40 has a high level of expression in ß-cells of the pancreas, and the requirement of glucose for stimulating insulin release results in immense stimulation to utilise this target in the medication of T2DM. METHODS: The data used for this review is based on the search of several scienctific databases as well as various patent databases. The main search terms used were free fatty acid receptor 1, FFAR1, FFAR1 agonists, diabetes mellitus, G protein-coupled receptor 40 (GPR40), GPR40 agonists, GPR40 ligands, type 2 diabetes mellitus and T2DM. RESULTS: The present review article gives a brief overview of FFAR1, its role in T2DM, recent developments in small molecule FFAR1 (GPR40) agonists reported till now, compounds of natural/plant origin, recent patents published in the last few years, mechanism of FFAR1 activation by the agonists, and clinical status of the FFAR1/GPR40 agonists. CONCLUSION: The agonists of FFAR1/GRP40 showed considerable potential for the therapeutic control of T2DM. Most of the small molecule FFAR1/GPR40 agonists developed were aryl alkanoic acid derivatives (such as phenylpropionic acids, phenylacetic acids, phenoxyacetic acids, and benzofuran acetic acid derivatives) and thiazolidinediones. Some natural/plant-derived compounds, including fatty acids, sesquiterpenes, phenolic compounds, anthocyanins, isoquinoline, and indole alkaloids, were also reported as potent FFAR1 agonists. The clinical investigations of the FFAR1 agonists demonstrated their probable role in the improvement of glucose control. Though, there are some problems still to be resolved in this field as some FFAR1 agonists terminated in the late phase of clinical studies due to "hepatotoxicity." Currently, PBI-4050 is under clinical investigation by Prometic. Further investigation of pharmacophore scaffolds for FFAR1 full agonists as well as multitargeted modulators and corresponding clinical investigations will be anticipated, which can open up new directions in this area.

COVID-19-Associated acute respiratory distress syndrome (CARDS): Mechanistic insights on therapeutic intervention and emerging trends.

AIMS: The novel Coronavirus disease 2019 (COVID-19) has caused great distress worldwide. Acute respiratory distress syndrome (ARDS) is well familiar but when it happens as part of COVID-19 it has discrete features which are unmanageable. Numerous pharmacological treatments have been evaluated in clinical trials to control the clinical effects of CARDS, but there is no assurance of their effectiveness. MATERIALS AND METHODS: A systematic review of the literature of the Medline, Scopus, Bentham, PubMed, and EMBASE (Elsevier) databases was examined to understand the novel therapeutic approaches used in COVID-19-Associated Acute Respiratory Distress Syndrome and their outcomes. KEY FINDINGS: Current therapeutic options may not be enough to manage COVID-19-associated ARDS complications in group of patients and therefore, the current review has discussed the pathophysiological mechanism of COVID-19-associated ARDS, potential pharmacological treatment and the emerging molecular drug targets. SIGNIFICANCE: The rationale of this review is to talk about the pathophysiology of CARDS, potential pharmacological treatment and the emerging molecular drug targets. Currently accessible treatment focuses on modulating immune responses, rendering antiviral effects, anti-thrombosis or anti-coagulant effects. It is expected that considerable number of studies conducting globally may help to discover effective therapies to decrease mortality and morbidity occurring due to CARDS. Attention should be also given on molecular drug targets that possibly will help to develop efficient cure for COVID-19-associated ARDS.

Alcoholic and Non-Alcoholic Liver Diseases: Promising Molecular Drug Targets and their Clinical Development.

Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.