Multicomponent Amorphous Solid Forms of Telmisartan: Insights into Mechanochemical Activation and Physicochemical Attributes.

The present work aims to explore the new solid forms of telmisartan (TEL) with alpha-ketoglutaric acid (KGA) and glutamic acid (GA) as potential coformers using mechanochemical approach and their role in augmentation in physicochemical parameters over pure crystalline TEL. Mechanochemical synthesis was performed using 1:1 stoichiometric ratio of TEL and the selected coformers in the presence of catalytic amount of ethanol for 1 h. The ground product was characterized by PXRD, DSC, and FTIR. The new solid forms were evaluated for apparent solubility, intrinsic dissolution, and physical stability. Preliminary characterization revealed the amorphization of the mechanochemical product as an alternate outcome of cocrystallization screening. Mechanistic understanding of the amorphous phase highlights the formation of amorphous-mediated cocrystallization that involves three steps, viz., molecular recognition, intermediate amorphous phase, and product nucleation. The solubility curves of both multicomponent amorphous solid forms (TEL-KGA and TEL-GA) showed the spring-parachute effect and revealed significant augmentation in apparent solubility (8-10-folds), and intrinsic dissolution release (6-9-folds) as compared to the pure drug. Besides, surface anisotropy and differential elemental distributions in intrinsic dissolution compacts of both solid forms were confirmed by FESEM and EDX mapping. Therefore, amorphous phases prepared from mechanochemical synthesis can serve as a potential solid form for the investigation of a cocrystal through amorphous-mediated cocrystallization. This has greater implications in solubility kinetics wherein the rapid precipitation of the amorphous phase can be prevented by the metastable cocrystal phase and contribute to the significant augmentation in the physicochemical parameters.

Boron Facilitates Amelioration of Hepatic Injury by the Osmolyte Glycine and Resolves Injury by Improving the Tissue Redox Homeostasis.

Background: Glycine is a conditional non-essential amino acid in human and other mammals. It is abundant in the liver and is known for a wide spectrum of characteristics including the antioxidant, antiinflammatory, immunomodulatory, and cryoprotective effects. The amino acid is a naturally occurring osmolyte compatible with protein surface interactions and has been reported in literature as a potent therapeutic immuno-nutrient for liver diseases such as alcoholic liver disease. Oral glycine administration protects ethanol-induced liver injury, improves serum and tissue lipid profile, and alleviates hepatic injury in various conditions. In recent years, sodium salt of boron (borax) has been reported for its beneficial effects on cellular stress, including the effects on cell survival, immunity, and tissue redox state. Incidentally both glycine and boron prevent apoptosis and promote cell survival under stress. Objective: This study investigates the beneficial effect of borax on liver protection by glycine. Methods: Briefly, liver toxicity was induced in rats by a single intraperitoneal injection of thioacetamide (400 mg/kg b. wt.). Results: Significant changes in oxidative stress and liver function test parameters, the molybdenum Fe-S flavin hydroxylase activity, nitric oxide and tissue histopathology were observed in thioacetamide treated positive control group. The changes were ameliorated both by glycine as well as borax, but the combinatorial treatment yielded a better response indicating the impact of boron supplementation on glycine mediated protection of liver injury in experimental animal model. Conclusions: The study has clinical implications as the hepatotoxicity caused by thioacetamide mimics features of hepatitis C infection in human.

Fluoride in Raw Rice (Oryza sativa): a Global Systematic Review and Probabilistic Health Risk Assessment.

Rice (Oryza sativa) is one of the essential staple foods highly consumed globally, with nearly 40% to 45% of the global population estimated to consume rice. Therefore, consumable rice should have low levels of harmful elements. This study investigates fluoride (F¯) content in raw rice (uncooked rice) and evaluates Probabilistic Health Risk Assessment (PHRA) through Monte Carlo simulation (MCS) due to the consumption of F¯ enriched rice. The literature review reveals that limited studies have been conducted on the investigation of F¯ in raw rice. The fluoride (F¯) concentration in raw rice varies across the studied countries, indicating the need for additional studies to facilitate a more accurate comparison. The F¯ content in raw rice varied among the studied countries, making it difficult to definitively state that the concentration of F¯ in one country is higher. However, the concentration of F¯ in raw rice in India is notably elevated. This study also highlighted the importance of investigating the F¯ content in raw rice. The study will be highly helpful for policymakers to formulate guidelines for water used for irrigation.

Hydrogeochemical evaluation with emphasis on nitrate and fluoride in urban and rural drinking water resources in western Isfahan province, central Iran.

Nitrate (NO3-) and fluoride (F-) are two major potential contaminants found in the groundwater of Iran. These contaminants are highly dangerous to humans if consumed more than the safe limit prescribed by the WHO. Therefore, in this study, the urban and rural drinking water resources of Isfahan province (central Iran) were investigated to evaluate the quality of groundwater from the perspective of NO3- and F-. The calculated saturation index (SI) shows that the majority of samples are mainly undersaturated or in equilibrium with respect to potential minerals. The most likely interpretation for undersaturation with respect to most minerals is either that the minerals are not present if they are reactive or if they are present, then they are not reactive. This study reveals that the majority of the groundwater samples belong to the Ca-Mg-HCO3 water type. Further, in this study, potential physicochemical variables have been used to calculate entropy weighted water quality index (EWQI). The EWQI reveals that the majority of the groundwater in the area is of good quality. Results show that the water chemistry in the area is largely governed by the water-rock interaction. This study based on large data sets reveals that the majority of drinking water resources are uncontaminated by F-. However, the groundwater is found to be largely contaminated by NO3-. The bivariate plot suggests that the unscientific farming practices and overuse of manures and fertilizers are largely responsible for high content of NO3-. Therefore, emphasis should be given on the cost-effective environmentally friendly fertilizers. The findings from this study will aid the governing authorities and concerned stakeholders to understand the hydrogeochemical evolution of groundwater in this region. The results will help formulate policies in the area for sustainable water supply.

On Optimal and Quantum Code Construction from Cyclic Codes over FqPQ with Applications.

The key objective of this paper is to study the cyclic codes over mixed alphabets on the structure of FqPQ, where P=Fq[v]⟨v3-α22v⟩ and Q=Fq[u,v]⟨u2-α12,v3-α22v⟩ are nonchain finite rings and αi is in Fq/{0} for i∈{1,2}, where q=pm with m≥1 is a positive integer and p is an odd prime. Moreover, with the applications, we obtain better and new quantum error-correcting (QEC) codes. For another application over the ring P, we obtain several optimal codes with the help of the Gray image of cyclic codes.

Uptake of lead by bacteria isolated from industrial effluents and their potential use in bioremediation of wastewater.

Due to rising populations and human activities, heavy metals (HM) toxicity has become a serious problem for all life forms. The present study deals with isolating and identifying lead-resistant bacteria from contaminated wastewater of tanneries effluents. Two isolated strains were identified as Bacillus cereus (ID1), and Bacillus sp. (ID3), and both strains resisted a 25 mM concentration of Lead nitrate (Pb (NO3)2). After four days of treatment, Bacillus cereus (ID1) showed 80% lead uptake, and Bacillus sp. (ID3) showed 88%. Lead uptake was confirmed by Energy dispersive X-Ray (EDX) analysis. Fourier transform infrared spectroscopy (FTIR) showed that structural alterations had occurred in functional groups of the treated samples compared to the controls. Our research indicates that these Bacillus strains may be useful in bioremediating heavy metals from polluted environments. Further investigation into the processes involved in the uptake and homeostasis of heavy metals by these strains is required, as is the identification of the genes and enzymes responsible for Pb-bioremediation.

Hydrogeochemical and isotopic evolution of groundwater in shallow and deep aquifers of the Kabul Plain, Afghanistan.

Groundwater from shallow and deep aquifers are widely used for drinking, agricultural and industrial use in Kabul, the capital of Afghanistan. However, unplanned urbanization and rapid population growth has led to the installation of numerous unlicensed wells to meet the public demand. This has caused to extraction of huge amounts of groundwater from the subsurface and further deterioration of groundwater quality. Therefore, understanding the hydrogeochemical characteristics of groundwater in shallow aquifers and deep aquifers is imperative for sustainable management of the groundwater resource in Kabul Plain. Thus, in this study, we used a multi-parameter approach, involving hydrochemical and environmental isotopes to understand the geochemical evolution of entire groundwater system of the Kabul Plain including river and dam water. The results of this study show that shallow and deep aquifers are dominantly of Mg-(Ca)-HCO3 and Na-Cl water type, respectively. We observed that (1) water-rock interaction is the major contributing factor to the chemical compositions of groundwater in the Kabul Plain; (2) groundwater in deep aquifer is mainly influenced by silicate weathering, and dissolution of evaporitic and carbonate minerals and reverse cation exchange; (3) dissolution of carbonates and silicate weathering plays a pivotal role in the groundwater chemistry of shallow aquifer; (4) the stable isotopes of groundwater display that the shallow aquifer is principally recharged by river water and local precipitation; (5) the tritium analysis exhibited that groundwater of shallow aquifer was primarily recharged recently, whereas groundwater of deep aquifer is the mixture of pre 1953 with post 1953 groundwater. This study revealed that there are hydraulic interactions between the two aquifers and the deep aquifer is recharged through shallow aquifer. The findings of this study would be useful for Afghanistan's water authorities to develop an effective strategy for sustainable water resources management in the Kabul Basin.

Investigating the link between miR-34a-5p and TLR6 signaling in sepsis-induced ARDS.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6 and an antagonizing effect on STAT6 to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03700-1.

Role of non-coding RNAs against salinity stress in Oryza species: Strategies and challenges in analyzing miRNAs, tRFs and circRNAs.

Salinity is an imbalanced concentration of mineral salts in the soil or water that causes yield loss in salt-sensitive crops. Rice plant is vulnerable to soil salinity stress at seedling and reproductive stages. Different non-coding RNAs (ncRNAs) post-transcriptionally regulate different sets of genes during different developmental stages under varying salinity tolerance levels. While microRNAs (miRNAs) are well known small endogenous ncRNAs, tRNA-derived RNA fragments (tRFs) are an emerging class of small ncRNAs derived from tRNA genes with a demonstrated regulatory role, like miRNAs, in humans but unexplored in plants. Circular RNA (circRNA), another ncRNA produced by back-splicing events, acts as target mimics by preventing miRNAs from binding with their target mRNAs, thereby reducing the miRNA's action upon its target. Same may hold true between circRNAs and tRFs. Hence, the work done on these ncRNAs was reviewed and no reports were found for circRNAs and tRFs under salinity stress in rice, either at seedling or reproductive stages. Even the reports on miRNAs are restricted to seedling stage only, in spite of severe effects on rice crop production due to salt stress during reproductive stage. Moreover, this review sheds light on strategies to predict and analyze these ncRNAs in an effective manner.

Correction: Gupta et al. Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease. Nutrients 2022, 14, 2965.

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Characterization of plastic degrading bacteria isolated from sewage wastewater.

Plastic is a fundamental polymer used in routine life and disposed of in sewage. It leads to microplastic pollution in aquatic organisms, introducing it into the food chain and affecting human health. In the present study, samples were collected from sewage wastewater to isolate the bacteria that could potentially reduce plastic. The six samples were incubated with plastic pieces in minimal salt media for 120 days. After 120 days, the weight loss experiment showed that samples SH5B and SH6B degraded 25% plastic. After chemical and molecular characterization, these strains were identified as Pseudomonas sp. SH5B and Pseudomonas aeruginosa SH6B. The Fourier-transform infrared spectroscopy (FTIR) analysis showed peaks shifting, indicating bond stretching, bond bending, and new bond formation. The Gas Chromatography-Mass Spectrometry (GC-MS) analysis revealed various new compounds produced during plastic degradation by these bacterial strains. The plastic biodegradation potential makes these bacteria an impending foundation for green chemistry to eradicate tough pollutants from the environment.

Call for biotechnological approach to degrade plastic in the era of COVID-19 pandemic.

Plastic pollution is a global issue and has become a major concern since Coronavirus disease (COVID)-19. In developing nations, landfilling and illegal waste disposal are typical ways to dispose of COVID-19-infected material. These technologies worsen plastic pollution and other human and animal health problems. Plastic degrades in light and heat, generating hazardous primary and secondary micro-plastic. Certain bacteria can degrade artificial polymers using genes, enzymes, and metabolic pathways. Microorganisms including bacteria degrade petrochemical plastics slowly. High molecular weight, strong chemical bonds, and excessive hydrophobicity reduce plastic biodegradation. There is not enough study on genes, enzymes, and bacteria-plastic interactions. Synthetic biology, metabolic engineering, and bioinformatics methods have been created to biodegrade synthetic polymers. This review will focus on how microorganisms' degrading capacity can be increased using recent biotechnological techniques.

Pyrazoline scaffold: hit identification to lead synthesis and biological evaluation as antidiabetic agents.

Background: Mining of novel scaffolds as potential DPP-IV inhibitors for future development of potential candidates as antidiabetic agents to address global issues. Methodology: The identified hit KB-10 from a previously reported study was taken as a lead for designing a library of analogues and screened initially based on in silico parameters and docking score. A series of selected (2[4-(1-acetyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy]-1-phenylethanone derivatives were synthesized and evaluated through in vitro studies. Compounds KB-23, KB-22 and KB-06 were found to be as potent, with IC50 values of 0.10 µM, 0.12 µM and 0.35 µM, respectively. They also showed promising antihyperglycemic potential in in vivo studies (oral glucose tolerance tests) in Wistar rats. Conclusion: This work establishes pyrazoline analogues KB-23, KB-22 and KB-06 as promising starting points for the development of potential antidiabetic agents.

Genetic polymorphism of fatty acid binding protein-2 in hyperlipidemic Asian Indians in North India.

BACKGROUND: Fatty acid binding protein-2 (FABP-2) is involved in the metabolism of lipids in the intestine. FABP-2 Ala54Thr polymorphism involves a transition of G to A at codon 54 of FABP-2, resulting in an amino acid substitution Ala54 to Thr54 and is associated with elevated fasting triglycerides in some hyperlipidemic populations. In current genome builds and gene databases the variant of the Ala54Thr FABP-2 (rs 1 799 883) is annotated as c.163A>G (p. Thr55Ala). AIM AND OBJECTIVE: The status of this polymorphism in hyperlipidemic Asian Indians from North India has not been investigated. This study was aimed to evaluate the distribution of the polymorphic variants of the Ala54Thr FABP-2 and their association with lipids in hyperlipidemic subjects. METHODS: Ala54Thr FABP-2 polymorphism in both hyperlipidemic (n = 210) and normolipidemic (n = 342) subjects was assessed by PCR-RFLP. RESULTS: Ala54Thr genotypes and alleles distribution did not differ between the hyperlipidemic and normolipidemic groups. The heterozygous genotype FABP-2 Ala/Thr was significantly associated with higher levels of triglycerides and very low-density lipoproteins as compared to the homozygous variant (Thr/Thr) genotype and the wild type homozygous (Ala/Ala) genotype. CONCLUSIONS: The heterozygous genotype FABP-2 Ala54Thr is a risk factor for the development of hypertriglyceridemia and increased levels of VLDL-c in Asian Indians from North India.

Dual role of an essential HtrA2/Omi protease in the human malaria parasite: Maintenance of mitochondrial homeostasis and induction of apoptosis-like cell death under cellular stress.

Members of the HtrA family of serine proteases are known to play roles in mitochondrial homeostasis as well as in programmed cell death. Mitochondrial homeostasis and metabolism are crucial for the survival and propagation of the malaria parasite within the host. Here we have functionally characterized a Plasmodium falciparum HtrA2 (PfHtrA2) protein, which harbours trypsin-like protease activity that can be inhibited by its specific inhibitor, ucf-101. A transgenic parasite line was generated, using the HA-glmS C-terminal tagging approach, for localization as well as for inducible knock-down of PfHtrA2. The PfHtrA2 was localized in the parasite mitochondrion during the asexual life cycle. Genetic ablation of PfHtrA2 caused significant parasite growth inhibition, decreased replication of mtDNA, increased mitochondrial ROS production, caused mitochondrial fission/fragmentation, and hindered parasite development. However, the ucf-101 treatment did not affect the parasite growth, suggesting the non-protease/chaperone role of PfHtrA2 in the parasite. Under cellular stress conditions, inhibition of PfHtrA2 by ucf-101 reduced activation of the caspase-like protease as well as parasite cell death, suggesting the involvement of protease activity of PfHtrA2 in apoptosis-like cell death in the parasite. Under these cellular stress conditions, the PfHtrA2 gets processed but remains localized in the mitochondrion, suggesting that it acts within the mitochondrion by cleaving intra-mitochondrial substrate(s). This was further supported by trans-expression of PfHtrA2 protease domain in the parasite cytosol, which was unable to induce any cell death in the parasite. Overall, we show the specific roles of PfHtrA2 in maintaining mitochondrial homeostasis as well as in regulating stress-induced cell death.

Long COVID-19 prevalence among a sample of infected people in Erbil city.

BACKGROUND: Long-term effects of the disease were founded and described as post-COVID-19 syndrome post-COVID syndrome are the symptoms that develop and last for four weeks or even months and cannot be explained by an alternative diagnosis; symptoms may remain for >3 months. The cause of persistent symptoms is unclear. Objectives: This study aimed to Estimate the prevalence of residual symptoms among a sample of people infected with COVID-19 who survived and recovered in Erbil city and to find out the relation between the severity of the disease and post-COVID-19 syndrome. And to know the incidence of post-COVID-19 syndrome in chronic disease patients. PATIENTS AND METHODS: This cross-sectional study was conducted in 6 primary health care centers in 6 municipalities in Erbil city, Kurdistan region, Iraq. A convenience sample of randomly selected 300 patients was involved in the study depending on inclusion criteria. For one year, starting from March 1, 2021, until the end of February 2022. RESULTS: The prevalence of post-COVID syndrome among the 300 cases was 54.67%. Of these cases, 11.7% had one symptom, 26% had two signs, and 17% had with three or more symptoms. There was a significant statistical association between persistent symptoms and the severity of COVID-19. Also, there was a substantial statistical association between persistent symptoms and chronic disease, most (67.9%) respondents with post-COVID-19 syndromes suffered from chronic disease, and the p-value was 0.001. There was a significant statistical association between persistent symptoms and disease duration; most (73%) of cases with post-COVID-19 syndrome got the disease from 7 to 14 days, while 54.5% of them struggled with COVID-19 for >14 days. CONCLUSION: Most people who have recovered from COVID-19 have many long-lasting symptoms that make it hard to go about their daily lives. This is now called a post-COVID syndrome. Getting to this status could have been caused by several things. Age, gender, whether a person has a chronic disease, disease severity, and duration are all things to consider, Even though all COVID-19 victims should be kept an eye on for long-term evaluation and treatment of post-COVID symptoms.

Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease.

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD.

Latent Tuberculosis Infection Diagnosis among Household Contacts in a High Tuberculosis-Burden Area: a Comparison between Transcript Signature and Interferon Gamma Release Assay.

Diagnosis of latent tuberculosis infection (LTBI) using biomarkers in order to identify the risk of progressing to active TB and therefore predicting a preventive therapy has been the main bottleneck in eradication of tuberculosis. We compared two assays for the diagnosis of LTBI: transcript signatures and interferon gamma release assay (IGRA), among household contacts (HHCs) in a high tuberculosis-burden population. HHCs of active TB cases were recruited for our study; these were confirmed to be clinically negative for active TB disease. Eighty HHCs were screened by IGRA using QuantiFERON-TB Gold Plus (QFT-Plus) to identify LTBI and uninfected cohorts; further, quantitative levels of transcript for selected six genes (TNFRSF10C, ASUN, NEMF, FCGR1B, GBP1, and GBP5) were determined. Machine learning (ML) was used to construct models of different gene combinations, with a view to identify hidden but significant underlying patterns of their transcript levels. Forty-three HHCs were found to be IGRA positive (LTBI) and thirty-seven were IGRA negative (uninfected). FCGR1B, GBP1, and GBP5 transcripts differentiated LTBI from uninfected among HHCs using Livak method. ML and ROC (Receiver Operator Characteristic) analysis validated this transcript signature to have a specificity of 72.7%. In this study, we compared a quantitative transcript signature with IGRA to assess the diagnostic ability of the two, for detection of LTBI cases among HHCs of a high-TB burden population; we concluded that a three gene (FCGR1B, GBP1, and GBP5) transcript signature can be used as a biomarker for rapid screening. IMPORTANCE The study compares potential of transcript signature and IGRA to diagnose LTBI. It is first of its kind study to screen household contacts (HHCs) in high TB burden area of India. A transcript signature (FCGR1B, GBP1, & GBP5) is identified as potential biomarker for LTBI. These results can lead to development of point-of-care (POC) like device for LTBI screening in a high TB burdened area.

Xanthone glucoside 2-ß-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one binds to the ATP-binding pocket of glycogen synthase kinase 3ß and inhibits its activity: implications in prostate cancer and associated cardiovascular disease risk.

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase which in the presence of ATP in its ATP-binding pocket transfers a phosphate to a primed substrate. GSK3ß is an isoform of GSK3 which has been projected as a potent therapeutic target in human diseases including cancers and metabolic syndrome. Incidentally, cardiovascular disease is a common cause of non-cancer related deaths in prostate cancer (PCa) patients, mainly due to the effects of androgen-deprivation therapy (ADT), a mainstay for PCa treatment. Several small molecular inhibitors of GSK3 are either ATP-competitive (bind to the ATP-binding pocket), or non-ATP-competitive inhibitors (binding to the substrate-binding site of the enzyme). In this study, 2-ß-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one (ßDGT), a natural xanthonoid present in many plant species, is reported to bind to the ATP-binding pocket of GSK3ß and inhibit its activity, as demonstrated by the molecular docking and molecular dynamics simulation analysis and experimental validation in vitro. A comparison of the binding affinities with five known ATP-competitive inhibitors of GSK3ß suggested similarity in binding site residues in the ATP-binding pocket of the enzyme. The optimum inhibitory concentration of the xanthonoid as determined by the luminescent kinase assay was 200 µM. The study envisages the use of ßDGT as a natural ATP-competitive inhibitor of GSK3ß and implicates its use in PCa patients on ADT, a cardiovascular disease risk, and other pathological conditions where GSK3 inhibition may be clinically important. HighlightsGSK3ß is a multifaceted kinase known for its role in cancers, cardiovascular, and other diseases.In this study, ßDGT, a xanthonoid, is reported to bind to the ATP-binding pocket of GSK3ß.A comparison of ßDGT binding with 5 known ATP-competitive inhibitors of GSK3ß suggested the involvement of residues at the ATP binding site.The binding site analysis suggested an ATP-competitive mechanism of enzyme inhibition.Study envisages the use of ßDGT as a natural ATP-competitive inhibitor of GSK3ß and implicates its use in prostate cancer patients on androgen-deprivation therapy, a cardiovascular disease risk, and other pathological conditions.Communicated by Ramaswamy H. Sarma.

miRPreM and tiRPreM: Improved methodologies for the prediction of miRNAs and tRNA-induced small non-coding RNAs for model and non-model organisms.

In recent years, microRNAs (miRNAs) and tRNA-derived RNA fragments (tRFs) have been reported extensively following different approaches of identification and analysis. Comprehensively analyzing the present approaches to overcome the existing variations, we developed a benchmarking methodology each for the identification of miRNAs and tRFs, termed as miRNA Prediction Methodology (miRPreM) and tRNA-induced small non-coding RNA Prediction Methodology (tiRPreM), respectively. We emphasized the use of respective genome of organism under study for mapping reads, sample data with at least two biological replicates, normalized read count support and novel miRNA prediction by two standard tools with multiple runs. The performance of these methodologies was evaluated by using Oryza coarctata, a wild rice species as a case study for model and non-model organisms. With organism-specific reference genome approach, 98 miRNAs and 60 tRFs were exclusively found. We observed high accuracy (13 out of 15) when tested these genome-specific miRNAs in support of analyzing the data with respective organism. Such a strong impact of miRPreM, we have predicted more than double number of miRNAs (186) as compared with the traditional approaches (79) and with tiRPreM, we have predicted all known classes of tRFs within the same small RNA data. Moreover, the methodologies presented here are in standard form in order to extend its applicability to different organisms rather than restricting to plants. Hence, miRPreM and tiRPreM can fulfill the need of a comprehensive methodology for miRNA prediction and tRF identification, respectively, for model and non-model organisms.