Furanocoumarins promote proteasomal degradation of viral HBx protein and down-regulate cccDNA transcription and replication of hepatitis B virus.

Nucleot(s)ide analogues, the current antiviral treatments against chronic hepatitis B (CHB) infection, are non-curative due to their inability to eliminate covalently closed circular DNA (cccDNA) from the infected hepatocytes. Preclinical studies have shown that coumarin derivatives can effectively reduce the HBV DNA replication. We evaluated the antiviral efficacy of thirty new coumarin derivatives in cell culture models for studying HBV. Furanocoumarins Fc-20 and Fc-31 suppressed the levels of pre-genomic RNA as well as cccDNA, and reduced the secretion of virions, HBsAg and HBeAg. The antiviral efficacies of Fc-20 and Fc31 improved further when used in combination with the hepatitis B antiviral drug Entecavir. There was a marked reduction in the intracellular HBx level in the presence of these furanocoumarins due to proteasomal degradation resulting in the down-regulation of HBx-dependent viral genes. Importantly, both Fc-20 and Fc-31 were non-cytotoxic to cells even at high concentrations. Further, our molecular docking studies confirmed a moderate to high affinity interaction between furanocoumarins and viral HBx via residues Ala3, Arg26 and Lys140. These data suggest that furanocoumarins could be developed as a new therapeutic for CHB infection.

Deciphering the Drug Delivery Potential of Milk Exosome Nanovesicles for Aminobenzylpenicillin Therapeutic Efficacy against Contagious Staphylococcus Aureus in Bovine Mastitis.

The emergence of antimicrobial resistance and failure of antibiotic treatment are challenging tasks for managing bovine mastitis, which is mainly caused by the contagious Staphylococcus aureus (S. aureus).To overcome these difficulties, there is an urgent need for a novel drug system. In the present study, the aim is to develop next-generation therapeutics against S. aureus by harnessing the drug delivery potential of milk nanovesicles called milk exosomes (mENs). In the present work, a drug system is developed by encapsulating aminobenzylpenicillin (AMP) in mENs (mENs-AMP). Electron microscopy and zeta-sizer results indicate that the size of mENs-AMP ranged from 55.79 ± 2.8 to 85.53 ± 7.4 nm. The AMP loading efficiency in mENs is 88.61% with its sustained release. Fluorescence spectroscopy results indicated that mENs are biocompatible with mammary epithelial cells. In vitro studies show that the antibacterial activity and the minimum inhibitory concentrations of mENs-AMP are eleven times greater and four times lower than that of unencapsulated AMP, respectively. The mENs-AMP exhibit significantly higher therapeutic efficacy than AMP at the same dosage and treatment frequency. Validation of this approach is demonstrated in mastitis-affected animals through an observation in the reduction of somatic cell counts and bacterial loads in the milk of treated animals.

The Arctic Plant Aboveground Biomass Synthesis Dataset.

Plant biomass is a fundamental ecosystem attribute that is sensitive to rapid climatic changes occurring in the Arctic. Nevertheless, measuring plant biomass in the Arctic is logistically challenging and resource intensive. Lack of accessible field data hinders efforts to understand the amount, composition, distribution, and changes in plant biomass in these northern ecosystems. Here, we present The Arctic plant aboveground biomass synthesis dataset, which includes field measurements of lichen, bryophyte, herb, shrub, and/or tree aboveground biomass (g m-2) on 2,327 sample plots from 636 field sites in seven countries. We created the synthesis dataset by assembling and harmonizing 32 individual datasets. Aboveground biomass was primarily quantified by harvesting sample plots during mid- to late-summer, though tree and often tall shrub biomass were quantified using surveys and allometric models. Each biomass measurement is associated with metadata including sample date, location, method, data source, and other information. This unique dataset can be leveraged to monitor, map, and model plant biomass across the rapidly warming Arctic.

Exploring Genetic Diversity within aus Rice Germplasm: Insights into the Variations in Agro-morphological Traits.

The aus (Oryza sativa L.) varietal group comprises of aus, boro, ashina and rayada seasonal and/or field ecotypes, and exhibits unique stress tolerance traits, making it valuable for rice breeding. Despite its importance, the agro-morphological diversity and genetic control of yield traits in aus rice remain poorly understood. To address this knowledge gap, we investigated the genetic structure of 181 aus accessions using 399,115 SNP markers and evaluated them for 11 morpho-agronomic traits. Through genome-wide association studies (GWAS), we aimed to identify key loci controlling yield and plant architectural traits.Our population genetic analysis unveiled six subpopulations with strong geographical patterns. Subpopulation-specific differences were observed in most phenotypic traits. Principal component analysis (PCA) of agronomic traits showed that principal component 1 (PC1) was primarily associated with panicle traits, plant height, and heading date, while PC2 and PC3 were linked to primary grain yield traits. GWAS using PC1 identified OsSAC1 on Chromosome 7 as a significant gene influencing multiple agronomic traits. PC2-based GWAS highlighted the importance of OsGLT1 and OsPUP4/ Big Grain 3 in determining grain yield. Haplotype analysis of these genes in the 3,000 Rice Genome Panel revealed distinct genetic variations in aus rice.In summary, this study offers valuable insights into the genetic structure and phenotypic diversity of aus rice accessions. We have identified significant loci associated with essential agronomic traits, with GLT1, PUP4, and SAC1 genes emerging as key players in yield determination.

Groundwater quality assessment using water quality index and principal component analysis in the Achnera block, Agra district, Uttar Pradesh, Northern India.

The qualitative and quantitative assessment of groundwater is one of the important aspects for determining the suitability of potable water. Therefore, the present study has been performed to evaluate the groundwater quality for Achhnera block in the city of Taj, Agra, India, where groundwater is an important water resource. The groundwater samples, 50 in number were collected and analyzed for major ions along with some important trace element. This study has further investigated for the applicability of groundwater quality index (GWQI), and the principal component analysis (PCA) to mark out the major geochemical solutes responsible for origin and release of geochemical solutes into the groundwater. The results confirm that, majority of the collected groundwater samples were alkaline in nature. The variation of concentration of anions in collected groundwater samples were varied in the sequence as, HCO3- > Cl- > SO42- > F- while in contrast the sequence of cations in the groundwater as Na > Ca > Mg > K. The Piper diagram demonstrated the major hydro chemical facies which were found in groundwater (sodium bicarbonate or calcium chloride type). The plot of Schoellar diagram reconfirmed that the major cations were Na+ and Ca2+ ions, while in contrast; major anions were bicarbonates and chloride. The results showed water quality index mostly ranged between 105 and 185, hence, the study area fell in the category of unsuitable for drinking purpose category. The PCA showed pH, Na+, Ca2+, HCO3- and fluoride with strong loading, which pointed out geogenic source of fluoride contamination. Therefore, it was inferred that the groundwater of the contaminated areas must be treated and made potable before consumption. The outcomes of the present study will be helpful for the regulatory boards and policymaker for defining the actual impact and remediation goal.

Exploring the Role of Non-synonymous and Deleterious Variants Identified in Colorectal Cancer: A Multi-dimensional Computational Scrutiny of Exomes.

Introduction: Colorectal cancers are the world's third most commonly diagnosed type of cancer. Currently, there are several diagnostic and treatment options to combat it. However, a delay in detection of the disease is life-threatening. Additionally, a thorough analysis of the exomes of cancers reveals potential variation data that can be used for early disease prognosis. Methods: By utilizing a comprehensive computational investigation, the present study aimed to reveal mutations that could potentially predispose to colorectal cancer. Ten colorectal cancer exomes were retrieved. Quality control assessments were performed using FastQC and MultiQC, gapped alignment to the human reference genome (hg19) using Bowtie2 and calling the germline variants using Haplotype caller in the GATK pipeline. The variants were filtered and annotated using SIFT and PolyPhen2 successfully categorized the mutations into synonymous, non-synonymous, start loss and stop gain mutations as well as marked them as possibly damaging, probably damaging and benign. This mutational profile helped in shortlisting frequently occurring mutations and associated genes, for which the downstream multi-dimensional expression analyses were carried out. Results: Our work involved prioritizing the non-synonymous, deleterious SNPs since these polymorphisms bring about a functional alteration to the phenotype. The top variations associated with their genes with the highest frequency of occurrence included LGALS8, CTSB, RAD17, CPNE1, OPRM1, SEMA4D, MUC4, PDE4DIP, ELN and ADRA1A. An in-depth multi-dimensional downstream analysis of all these genes in terms of gene expression profiling and analysis and differential gene expression with regard to various cancer types revealed CTSB and CPNE1 as highly expressed and overregulated genes in colorectal cancer. Conclusion: Our work provides insights into the various alterations that might possibly lead to colorectal cancer and suggests the possibility of utilizing the most important genes identified for wet-lab experimentation.

P66Shc Mediates SUMO2-induced Endothelial Dysfunction.

Sumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood. Here, we demonstrate that SUMO2 modifies p66Shc, which impairs endothelial function. Using multiple approaches, we show that p66Shc is a direct target of SUMO2. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36, causing it to translocate to the mitochondria. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. Ingenuity pathway analysis showed that majority of effects of p66Shc SUMO2ylation were mediated via p66ShcK81. Finally, p66ShcK81R knockin mice were resistant to SUMO2-induced endothelial dysfunction. Collectively, our work uncovers a posttranslational modification of redox protein p66Shc and identifies SUMO2-p66Shc signaling as a regulator of vascular endothelial function.

Utilization of Ananas comosus Crown Residue Husk as a Sustainable Strength Additive for EPR/LDPE Blend Composites.

The utilization of waste generated by natural resources is a crucial problem nowadays. The current study describes the utilization of pineapple (Ananas comosus) crown residue husk (PCRh) as a strength additive for low-density polyethylene (LDPE) and ethylene propylene rubber (EPR) composites. The blend composites with 30% husk, 10 wt % EPR, and 60% LDPE content showed much better mechanical properties, such as tensile strength and flexural properties, than pristine LDPE and its binary composite with 10 wt % EPR. The high tensile strength (∼19.28 MPa) and tensile modulus (522.97 MPa) were obtained for the composite consisting of 30 wt % PCRh in the basic polymer matrix. Similarly, the highest flexural strength (∼18.09 MPa) and modulus (∼790.29 MPa) were recorded for the same composition. The incorporation of PCRh with LDPE and EPR was further characterized by attenuated total reflection-Fourier transform infrared, differential scanning calorimetry, field emission scanning electron microscopy, dynamic mechanical analysis, and a universal testing machine to evaluate its impact on various properties.

A screw and wire assisted coronoidectomy procedure: A technical note.

Temporomandibular joint (TMJ) ankylosis and oral submucous fibrosis (OSMF) often exhibit elongated hyperplastic coronoid processes with fibrous attachments to the temporalis muscle. In managing this condition, a vital step involves performing a coronoidotomy or coronoidectomy alongside the primary surgical procedure. While coronoidectomy is preferable due to reattachment issues, its complexity arises from the thickened and elongated coronoid process. Our technical note introduces a screw and wire assisted coronoidectomy method, found to be efficient, replicable, and time-saving.

Manipulating epigenetic diversity in crop plants: Techniques, challenges and opportunities.

Epigenetic modifications act as conductors of inheritable alterations in gene expression, all while keeping the DNA sequence intact, thereby playing a pivotal role in shaping plant growth and development. This review article presents an overview of techniques employed to investigate and manipulate epigenetic diversity in crop plants, focusing on both naturally occurring and artificially induced epialleles. The significance of epigenetic modifications in facilitating adaptive responses is explored through the examination of how various biotic and abiotic stresses impact them. Further, environmental chemicals are explored for their role in inducing epigenetic changes, particularly focusing on inhibitors of DNA methylation like 5-AzaC and zebularine, as well as inhibitors of histone deacetylation including trichostatin A and sodium butyrate. The review delves into various approaches for generating epialleles, including tissue culture techniques, mutagenesis, and grafting, elucidating their potential to induce heritable epigenetic modifications in plants. In addition, the ground breaking CRISPR/Cas is emphasized for its accuracy in targeting specific epigenetic changes. This presents a potent tools for deciphering the intricacies of epigenetic mechanisms. Furthermore, the intricate relationship between epigenetic modifications and non-coding RNA expression, including siRNAs and miRNAs, is investigated. The emerging role of exo-RNAi in epigenetic regulation is also introduced, unveiling its promising potential for future applications. The article concludes by addressing the opportunities and challenges presented by these techniques, emphasizing their implications for crop improvement. Conclusively, this extensive review provides valuable insights into the intricate realm of epigenetic changes, illuminating their significance in phenotypic plasticity and their potential in advancing crop improvement.

Targeted HBx gene editing by CRISPR/Cas9 system effectively reduces epithelial to mesenchymal transition and HBV replication in hepatoma cells.

BACKGROUND AND AIMS: Hepatitis B virus X protein (HBx) play a key role in pathogenesis of HBV-induced hepatocellular carcinoma (HCC) by promoting epithelial to mesenchymal transition (EMT). In this study, we hypothesized that inhibition of HBx is an effective strategy to combat HCC. METHODOLOGY AND RESULTS: We designed and synthesized novel HBx gene specific single guide RNA (sgRNA) with CRISPR/Cas9 system and studied its in vitro effects on tumour properties of HepG2-2.15. Full length HBx gene was excised using HBx-CRISPR that resulted in significant knockdown of HBx expression in hepatoma cells. HBx-CRISPR also decreased levels of HBsAg and HBV cccDNA expression. A decreased expression of mesenchymal markers, proliferation and tumorigenic properties was observed in HBx-CRISPR treated cells as compared to controls in both two- and three- dimensional (2D and 3D) tumour models. Transcriptomics data showed that out of 1159 differentially expressed genes in HBx-CRISPR transfected cells as compared to controls, 70 genes were upregulated while 1089 genes associated with cell proliferation and EMT pathways were downregulated. CONCLUSION: Thus, targeting of HBx by CRISPR/Cas9 gene editing system reduces covalently closed circular DNA (cccDNA) levels, HBsAg production and mesenchymal characteristics of HBV-HCC cells. We envision inhibition of HBx by CRISPR as a novel therapeutic approach for HBV-induced HCC.

Comprehending interaction mechanism of natural actives of Colchicum autumnale L. for rheumatoid arthritis using integrative chemoinformatic approaches.

This research delves into the realm of therapeutic potential within natural compounds derived from Colchicum autumnale L., emphasizing a holistic perspective on medications used in human therapy. Rather than confining the study to their primary actions, the research endeavors to unveil molecular targets for these natural compounds, with a specific focus on their potential applicability in the treatment of rheumatoid arthritis (RA). The study focuses on understanding interactions between specific natural actives that target RA. Fifteen RA target proteins were identified from OMIM, GeneScan and PharmaGKB. Their structures were downloaded from RCSB PDB. Two active components of C. autumnale L. were chosen for mass spectrometry investigation. Ligand characteristics were determined using the ADMETlab and SwissADME software tools. Molecular docking was performed, and the top three complexes were simulated for 200 ns, along with identification of free binding energies. The compounds ß-sitosterol-IL-10 (-6.50 kcal/mol), colchicine-IL-10 (-6.01 kcal/mol), linoleic acid-IL-10 (-7.22 kcal/mol) and linoleic acid-IL-10 (-7.22 kcal/mol) exhibited best binding energies. ß-Sitosterol and colchicine showed the highest stability in simulations, confirmed by molecular mechanics free energy binding calculations. This work provides insights into the molecular interaction of natural compounds against RA targets, offering potential therapeutic anti-RA medications.Communicated by Ramaswamy H. Sarma.

Variability of groundwater fluoride and its proportionate risk quantification via Monte Carlo simulation in rural and urban areas of Agra district, India.

This study quantifies the groundwater fluoride contamination and assesses associated health risks in fluoride-prone areas of the city of Taj Mahal, Agra, India. The United States Environmental Protection Agency (USEPA) risk model and Monte Carlo Simulations were employed for the assessment. Result revealed that, among various rural and urban areas Pachgain Kheda exhibited the highest average fluoride concentration (5.20 mg/L), while Bagda showed the lowest (0.33 mg/L). Similarly, K.K. Nagar recorded 4.38 mg/L, and Dayalbagh had 1.35 mg/L. Both urban and rural areas exceeded the WHO-recommended limit of 1.5 mg/L, signifying significant public health implications. Health risk assessment indicated a notably elevated probability of non-carcinogenic risk from oral groundwater fluoride exposure in the rural Baroli Ahir block. Risk simulations highlighted that children faced the highest health risks, followed by teenagers and adults. Further, Monte Carlo simulation addressed uncertainties, emphasizing escalated risks for for children and teenagers. The Hazard Quotient (HQ) values for the 5th and 95th percentile in rural areas ranged from was 0.28-5.58 for children, 0.15-2.58 for teenager, and 0.05-0.58 for adults. In urban areas, from the range was 0.53 to 5.26 for children, 0.27 to 2.41 for teenagers, and 0.1 to 0.53 for adults. Physiological and exposure variations rendered children and teenagers more susceptible. According to the mathematical model, calculations for the non-cancerous risk of drinking water (HQ-ing), the most significant parameters in all the targeted groups of rural areas were concentration (CW) and Ingestion rate (IR). These findings hold relevance for policymakers and regulatory boards in understanding the actual impact and setting pre-remediation goals.

Association of Facial Wrinkles With Different Facial Forms in the Population of Maharashtra: A Prospective Observational Study.

INTRODUCTION: Wrinkles commonly manifest in various areas of the face as individuals age. This study aimed to assess the association between facial wrinkles and different facial forms. MATERIALS AND METHODS: An observational, prospective study was conducted on the facial photographs of 400 subjects aged 40-60 years, which were divided into four groups of 100 subjects each: Group 1, square facial form; Group 2, ovoid facial form; Group 3, square tapered facial form; and Group 4, tapered facial form. All groups had almost equal distributions of males and females. Six types of facial wrinkles were studied, namely, forehead, glabellar, canthal, nasolabial, wrinkles at the corner of the mouth, and perioral wrinkles. Analysis of variance (ANOVA) was used for intergroup comparison, and an independent Student's t-test was used to assess gender differences in facial wrinkles. RESULTS: Significant gender differences were observed for forehead wrinkles in Groups 1 and 3, canthal wrinkles in Groups 1 and 2, and right perioral wrinkles in Group 1 (p<0.05). There were non-significant gender differences between right and left-side facial wrinkles (p>0.05). Significant differences between the groups were observed for all facial wrinkles between the right and left sides of the face (p<0.05). There was a significant difference between the groups for the presence of glabellar, corner of the mouth, and perioral wrinkles, with the presence of higher wrinkles in ovoid and tapered facial forms compared to square and square tapered facial forms (p<0.05). CONCLUSIONS: Females had more facial wrinkles than males, predominantly in the forehead region. The least prominent wrinkles were observed in the perioral region of the face. Glabellar, corner of the mouth, and perioral wrinkles were predominantly observed in ovoid and tapered facial forms.

Oral manifestations, risk factors and management strategies of COVID-19 associated mucormycosis in tertiary care hospital.

Background: Mucormycosis (black fungus) is an aggressive, life-threatening infectious disease-causing infiltration and by destroying the surrounding bone and soft tissue through vascular thrombosis and subsequent tissue infarction that may reach the brain with fatal complications. Its outbreak has been assessed around the clock during the recent pandemic as post COVID-19 sequelae. Aims: To assess the risk factors, oral signs and symptoms, investigations, treatment and rehabilitation strategies amongst COVID-19 associated mucormycosis patients in a tertiary care hospital. Methods and Material: An observational, pilot study was carried out amongst 30 active or recent COVID-19 associated mucormycosis patients reporting in the Department of Dentistry of a tertiary care hospital in Bhopal over a period of 6 months. Statistical analysis was done using Kolmogorov-Smirnov test using the Statistical Package for Social Sciences, Version 16 software. Results: Study was done on 30 patients (80% males and 20% females) and their median age was 46 years. Predominant risk factor present was diabetes mellitus (90%) and steroid therapy (60%). Prime oral manifestations were toothache (90%), mobile teeth (83%), draining sinus (53%), palatal ulceration (43%) and para-sinusal pain (37%). Conclusions: Mucormycosis can cause serious oro-facial morbidity and mortality in COVID-19 patients. The current management strategy requires early diagnosis, prompt treatment and oral rehabilitation.

Repurposing of known drugs for COVID-19 using molecular docking and simulation analysis.

We selected fifty one drugs already known for their potential disease treatment roles in various studies and subjected to docking and molecular docking simulation (MDS) analyses. Five of them showed promising features that are discussed and suggested as potential candidates for repurposing for COVID-19. These top five compounds were boswellic acid, pimecrolimus, GYY-4137, BMS-345541 and triamcinolone hexacetonide that interacted with the chosen receptors 1R42, 4G3D, 6VW1, 6VXX and 7MEQ, respectively with binding energies of -9.2 kcal/mol, -9.1 kcal/mol, -10.3 kcal/mol, -10.1 kcal/mol and -8.7 kcal/mol, respectively. The MDS studies for the top 5 best complexes revealed binding features for the chosen receptor, human NF-kappa B transcription factor as an important drug target in COVID-19-based drug development strategies.

Botanicals against some important nematodal diseases: Ascariasis and hookworm infections.

Ascariasis and intestinal parasitic nematodes are the leading cause of mass mortality infecting many people across the globe. In light of the various deleterious side effects of modern chemical-based allopathic drugs, our preferences have currently shifted towards the use of traditional plant-based drugs or botanicals for treating diseases. The defensive propensities in the botanicals against parasites have probably evolved during their co-habitation with parasites, humans and plants in nature and hence their combative interference in one another's defensive mechanisms has occurred naturally ultimately being very effective in treating diseases. This article broadly outlines the utility of plant-based compounds or botanicals prepared from various medicinal herbs that have the potential to be developed as effective therapies against the important parasites causing ascariasis and intestinal hookworm infections leading to ascariasis & infections and thereby human mortality, wherein allopathic treatments are less effective and causes enormous side-effects.

Ab initio study of elastic, electronic, and vibrational properties of SnTe and PbTe.

CONTEXT AND RESULTS: The elastic, electronic, and vibrational properties of the ground state of the rocksalt SnTe and PbTe are investigated. The deduced elastic constants, namely, shear modulus, Young's modulus, and Poisson's ratio are in very good agreement with the experimental and other theoretical data. The electronic band structure and density of states are obtained with and without considering the spin-orbit coupling. The bandgaps of SnTe and PbTe with (without) spin-orbit coupling are 0.11 (0.05) eV and 0.01 (0.78) eV, respectively. The bandgaps with spin-orbit interactions are nearer to experimental data. The hybrid functionals give higher values of bandgaps for both the SnTe and PbTe. In both compounds, the bandgap increases with volume. The valence bandwidths, however, decrease with increasing volume. The vibrational frequencies are found in reasonable agreement with the experiment. The frequencies increase with pressure. COMPUTATIONAL METHOD: In this work, the ab initio calculations of SnTe and PbTe crystals are carried out applying plane wave pseudopotential method using the QUANTUM ESPRESSO package. The PBE exchange and correlation functional based on GGA is considered. The fully relativistic norm-conserving pseudopotentials for Sn, Pb, and Te are used. The self-consistent field calculations are performed over a dense MP net of 18 × 18 × 18 k-points. The energy cut-off of 70 Ryd was found sufficient to achieve convergence of 10-6 Ryd in total energy of the crystals.

A geminivirus crosses the monocot-dicot boundary and acts as a viral vector for gene silencing and genome editing.

INTRODUCTION: Members of the family Geminiviridae have been reported to infect either a monocot plant or a dicot plant, but not both. This study reports a geminivirus, Wheat Dwarf India Virus (WDIV), first identified in wheat, that is capable of infecting both monocot and dicot plants and acting as a viral vector. OBJECTIVES: This study was aimed at developing a broad host range viral vector system for reverse genetics and genome editing. METHODS: Here we used a wheat isolate of WDIV and Ageratum yellow leaf curl betasatellite (AYLCB) for infectivity assays and vector development. We performed Agrobacterium-mediated inoculation of WDIV and AYLCB in wheat, oat, barley, corn, soybean, and tobacco. To examine the potential of WDIV to act as a viral vector, we modified the WDIV genome and cloned DNA fragments of the phytoene desaturase (PDS) genes from wheat and tobacco, separately. For gene editing experiments, tobacco lines expressing Cas9 were infiltrated with a WDIV-based vector carrying gRNA targeting the PDS gene. RESULTS: About 80 to 90% of plants inoculated with infectious clones of WDIV alone or WDIV together with AYLCB showed mild symptoms, whereas some plants showed more prominent symptoms. WDIV and AYLCB were detected in the systemically infected leaves of all the plant species. Furthermore, the inoculation of the WDIV vector carrying PDS fragments induced silencing of the PDS gene in both wheat and tobacco plants. We also observed high-efficiency genome editing in the Cas9-expressing tobacco plants that were inoculated with WDIV vector-carrying gRNA. CONCLUSION: Detection of WDIV in naturally infected wheat, barley, and sugarcane in the field and its ability to systemically infect wheat, oat, barley, corn, soybean, and tobacco under laboratory conditions, provides compelling evidence that WDIV is the first geminivirus identified with the capability of infecting both monocot and dicot plant species. The wide host range of WDIV can be exploited for developing a single vector system for high-throughput genome editing in many plant species.

Exploring the Synergistic Mechanism of AP2A2 Transcription Factor Inhibition via Molecular Modeling and Simulations as a Novel Computational Approach for Combating Breast Cancer: In Silico Interpretations.

Studies have shown that transcription factor AP2A2 (activator protein-2 alpha-2) is involved in the expression of DLEC1, a tumor suppressor gene, which, when mutated, will cause breast cancer and is thus an excellent target for breast cancer studies. Therefore, in the present research, a synergistic approach toward combating breast cancer is proposed by blocking AP2A2 factor, and allowing the cancer cells to be sensitive to anti-cancer drugs. The effect of AP2A2 on breast cancer was first understood via gene analysis from cBioPortal. AP2A2 was then modeled using RaptorX and its structure was validated from Ramachandran plots. Using all ligands from MolPort database, molecular docking was performed against AP2A2, from which the top three best docked ligands were studied for toxicity in humans using Protox-II. Once the ligands passed these tests, the best complexes were simulated at 200ns in Desmond Maestro, to comprehend their stabilities, followed by the computations of free energies of binding via Molecular mechanics- Generalized Born Solvent Accessibility method (MM-GBSA). The results showed that molecules MolPort-005-945-556 (sachharolipids), MolPort-001-741-124 (flavonoids), and MolPort-005-944-667 (lignan glycosides) with AP2A2 passed toxicity evaluation and belonged to toxicity classes 6, 5, and 5, respectively, with good docking energies. 200 ns simulations revealed stable complexes with slight conformational changes. Stability of ligands was confirmed via snapshots at every 20 ns of the trajectory. Radial distribution of these molecules against the protein revealed very slight deviation from binding pocket. Additionally, the free binding energies for these complexes were found to be - 54.93 ± 12.982 kcal/mol, - 44.39 ± 14.393 kcal/mol, and - 66.51 ± 13.522 kcal/mol, respectively. A preliminary computational validation of the inability of AP2A2 to bind to DLEC1 in the presence of ligands offers beneficial insights into the potential of these ligands. Therefore, this study sheds light on the potential natural molecules that could stably block AP2A2 with least deviation and act in synergy to aid anti-cancer drugs work on breast cancer cells.