Missing heritability paradox in schizophrenia: hypothesis and plausible clues

Genetic research on schizophrenia, a common psychiatric disease with complex etiology and high (56-80%) heritability, has failed to identify causal genes, variants or causative mechanisms. Given the extensive effort and limited success to date, it is imperative to review potential reasons for this missing heritability. We argue that a successful elucidation of hereditary mechanisms in schizophrenia will likely involve; the identification of discrete endophenotypes; attention to the role of neurodevelopment and cell differentiation; consideration of the genome structure including temporal and spatial patterns, accommodation of environmental effects at the level of gene expression including any sex differences and pattern of mutations including de novo events and the use of analytic techniques that go beyond genome wide association studies. Identification of the heritable component of schizophrenia and sources of “missing heritability” is needed to understand the cause/s of the disorder and to facilitate the development of effective corrective and possibly preventive measures

Insight into Recent Progress and Perspectives in Improvement of Antioxidant Machinery upon PGPR Augmentation in Plants under Drought Stress: A Review

Agriculture has a lot of responsibility as the rise in the world’s population demands more food requirements. However, more than one type of biotic and abiotic stress continually impacts agricultural productivity. Drought stress is a major abiotic stress that significantly affects agricultural productivity every year as the plants undergo several morphological, biochemical, and physiological modifications, such as repressed root and shoot growth, reduced photosynthesis and transpiration rate, excessive production of reactive oxygen species (ROS), osmotic adjustments, and modified leaf senescence regulating and stress signaling pathways. Such modifications may permanently damage the plants; therefore, mitigation strategies must be developed. The use of drought resistant crop cultivars is more expensive and labor-intensive with few advantages. However, exploiting plant growth promoting rhizobacteria (PGPR) is a proven alternative with numerous direct and indirect advantages. The PGPR confers induced systemic tolerance (IST) mechanisms in plants in response to drought stress via multiple mechanisms, including the alteration of root architecture, maintenance of high relative water content, improvement of photosynthesis rate, production of phytohormones, exopolysaccharides, ACC deaminase, carotenoids and volatiles, induction of antioxidant defense system, and alteration in stress-responsive gene expression. The commercial application of PGPR as bioinoculants or biostimulants will remain contingent on more robust strain selection and performance under unfavorable environmental conditions. This review highlights the possible mechanisms of PGPR by activating the plant adaptive defense systems for enhancing drought tolerance and improving overall growth and yield

Exploration of Anti-HIV Phytocompounds against SARS-CoV-2 Main Protease: Structure-Based Screening, Molecular Simulation, ADME Analysis and Conceptual DFT Studies

The ever-expanding pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has gained attention as COVID-19 and caused an emergency in public health to an unmatched level to date. However, the treatments used are the only options; currently, no effective and licensed medications are available to combat disease transmission, necessitating further research. In the present study, an in silico-based virtual screening of anti-HIV bioactive compounds from medicinal plants was carried out through molecular docking against the main protease (Mpro) (PDB: 6LU7) of SARS-CoV-2, which is a key enzyme responsible for virus replication. A total of 16 anti-HIV compounds were found to have a binding affinity greater than −8.9 kcal/mol out of 150 compounds screened. Pseudohypericin had a high affinity with the energy of −10.2 kcal/mol, demonstrating amino acid residual interactions with LEU141, GLU166, ARG188, and GLN192, followed by Hypericin (−10.1 kcal/mol). Moreover, the ADME (Absorption, Distribution, Metabolism and Excretion) analysis of Pseudohypericin and Hypericin recorded a low bioavailability (BA) score of 0.17 and violated Lipinski’s rule of drug-likeness. The docking and molecular simulations indicated that the quinone compound, Pseudohypericin, could be tested in vitro and in vivo as potent molecules against COVID-19 disease prior to clinical trials.This was also supported by the theoretical and computational studies conducted. The global and local descriptors, which are the underpinnings of Conceptual Density FunctionalTheory (CDFT) have beenpredicted through successful model chemistry, hoping that they could be of help in the comprehension of the chemical reactivity properties of the molecular systems considered in this study.Fil: Murali, Mahadevamurthy. University Of Mysore; IndiaFil: Gowtham, Hittanahallikoppal Gajendramurthy. Nrupathunga University; IndiaFil: Shilpa, Natarajamurthy. University Of Mysore; IndiaFil: Krishnappa, Hemanth Kumar Naguvanahalli. University Of Mysore; IndiaFil: Ledesma, Ana Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Centro de Investigación en Biofísica Aplicada y Alimentos. - Universidad Nacional de Santiago del Estero. Centro de Investigación en Biofísica Aplicada y Alimentos; ArgentinaFil: Jain, Anisha S.. University Of Mysore; IndiaFil: Shati, Ali A.. King Khalid University; Arabia SauditaFil: Alfaifi, Mohammad Y.. Vacsera Holding Company; EgiptoFil: Elbehairi, Serag Eldin I.. Jss Academy Of Higher Education And Research; IndiaFil: Achar, Raghu Ram. Pirogov Russian National Research Medical University; RusiaFil: Silina, Ekaterina. Universitat de Les Illesbalears; EspañaFil: Stupin, Victor. Centro de Investigaciónen Materiales Avanzados; MéxicoFil: Ortega Castro, Joaquín. Jss Academy Of Higher Education And Research; IndiaFil: Frau, Juan. Universitat de Les Illesbalears; EspañaFil: Flores Holguín, Norma. Centro de Investigaciónen Materiales Avanzados; MéxicoFil: Amruthesh, Kestur Nagaraj. University Of Mysore; IndiaFil: Shivamallu, Chandan. Jss Academy Of Higher Education And Research; IndiaFil: Kollur, Shiva Prasad. University Of Mysore; IndiaFil: Glossman Mitnik, Daniel. Centro de Investigaciónen Materiales Avanzados; Méxic

Bioinformatics investigation of the effect of volatile and non-volatile compounds of rhizobacteria in inhibiting late embryogenesis abundant protein that induces drought tolerance

Drought is a major problem worldwide for agriculture, horticulture, and forestry. In many cases, major physiological and biochemical changes occur due to drought stress. The plant’s response to drought stress includes a set of systems for intracellular regulation of gene expression and inter-tissue and inter-organ signaling, which ultimately leads to increased stress tolerance. Meanwhile, the role of plant growth-promoting bacteria in improving many harmful consequences of drought stress has been discussed. One of the new ways to increase tolerance to drought stress in plants is drug design using methods based on computer analysis, bioinformatics, pharmacokinetics, and molecular docking. The present study aimed to identify volatile and non-volatile compounds involved in drought tolerance using molecular docking methods. In this research, among the volatile and non-volatile compounds effective in increasing growth and inducing drought tolerance, compounds that have a high affinity for interacting with the active site of late embryogenesis abundant (LEA) protein were identified through molecular docking methods, and it was presented as a suitable inhibitor for this protein. Based on the docking results, the inhibition potentials of the studied compounds differed, and the most vital interaction in the case of LEA 3 protein was related to the gibberellic acid compound, whose energy is equivalent to −7.78 kcal/mol. Due to the basic understanding of many mechanisms operating in the interactions of plants and bacteria, it is expected that the practical use of these compounds will grow significantly in the coming years, relying on pharmacokinetic methods and molecular docking

In silico studies evidenced the role of structurally diverse plant secondary metabolites in reducing SARS-CoV-2 pathogenesis

Plants are endowed with a large pool of structurally diverse small molecules known as secondary metabolites. The present study aims to virtually screen these plant secondary metabolites (PSM) for their possible anti-SARS-CoV-2 properties targeting four proteins/ enzymes which govern viral pathogenesis. Results of molecular docking with 4,704 ligands against four target proteins, and data analysis revealed a unique pattern of structurally similar PSM interacting with the target proteins. Among the top-ranked PSM which recorded lower binding energy (BE), > 50% were triterpenoids which interacted strongly with viral spike protein—receptor binding domain, > 32% molecules which showed better interaction with the active site of human transmembrane serine protease were belongs to flavonoids and their glycosides, > 16% of flavonol glycosides and > 16% anthocyanidins recorded lower BE against active site of viral main protease and > 13% flavonol glycoside strongly interacted with active site of viral RNA-dependent RNA polymerase. The primary concern about these PSM is their bioavailability. However, several PSM recorded higher bioavailability score and found fulfilling most of the drug-likeness characters as per Lipinski's rule (Coagulin K, Kamalachalcone C, Ginkgetin, Isoginkgetin, 3,3′-Biplumbagin, Chrysophanein, Aromoline, etc.). Natural occurrence, bio-transformation, bioavailability of selected PSM and their interaction with the target site of selected proteins were discussed in detail. Present study provides a platform for researchers to explore the possible use of selected PSM to prevent/ cure the COVID-19 by subjecting them for thorough in vitro and in vivo evaluation for the capabilities to interfering with the process of viral host cell recognition, entry and replication

Exploration of CviR-mediated quorum sensing inhibitors from Cladosporium spp. against Chromobacterium violaceum through computational studies

Abstract An opportunistic human pathogenic bacterium, Chromobacterium violaceum resists the potency of most antibiotics by exploiting the quorum sensing system within their community to control virulence factor expression. Therefore, blocking the quorum sensing mechanism could help to treat several infectious caused by this organism. The quorum sensing receptor (CviR) of C. violaceum was used as a model target in the current investigation to identify potentially novel quorum sensing inhibitors from Cladosporium spp. through in silico computational approaches. The molecular docking results confirmed the anti-quorum sensing potential of bioactive compounds from Cladosporium spp. through binding to CviR with varying docking scores between – 5.2 and – 9.5 kcal/mol. Relative to the positive control [Azithromycin (– 7.4 kcal/mol)], the top six metabolites of Cladosporium spp. had higher docking scores and were generally greater than – 8.5 kcal/mol. The thermodynamic stability and binding affinity refinement of top-ranked CviR inhibitors were further studied through a 160 ns molecular dynamic (MD) simulation. The Post-MD simulation analysis confirmed the top-ranked compounds' affinity, stability, and biomolecular interactions with CviR at 50 ns, 100 ns, and 160 ns with Coniochaetone K of the Cladosporium spp. having the highest binding free energy (– 30.87 kcal/mol) and best interactions (two consistent hydrogen bond contact) following the 160 ns simulation. The predicted pharmacokinetics properties of top selected compounds point to their drug likeliness, potentiating their chance as a possible drug candidate. Overall, the top-ranked compounds from Cladosporium spp., especially Coniochaetone K, could be identified as potential C. violaceum CviR inhibitors. The development of these compounds as broad-spectrum antibacterial medicines is thus possible in the future following the completion of further preclinical and clinical research

Insight into Recent Progress and Perspectives in Improvement of Antioxidant Machinery upon PGPR Augmentation in Plants under Drought Stress: A Review

Agriculture has a lot of responsibility as the rise in the world’s population demands more food requirements. However, more than one type of biotic and abiotic stress continually impacts agricultural productivity. Drought stress is a major abiotic stress that significantly affects agricultural productivity every year as the plants undergo several morphological, biochemical, and physiological modifications, such as repressed root and shoot growth, reduced photosynthesis and transpiration rate, excessive production of reactive oxygen species (ROS), osmotic adjustments, and modified leaf senescence regulating and stress signaling pathways. Such modifications may permanently damage the plants; therefore, mitigation strategies must be developed. The use of drought resistant crop cultivars is more expensive and labor-intensive with few advantages. However, exploiting plant growth promoting rhizobacteria (PGPR) is a proven alternative with numerous direct and indirect advantages. The PGPR confers induced systemic tolerance (IST) mechanisms in plants in response to drought stress via multiple mechanisms, including the alteration of root architecture, maintenance of high relative water content, improvement of photosynthesis rate, production of phytohormones, exopolysaccharides, ACC deaminase, carotenoids and volatiles, induction of antioxidant defense system, and alteration in stress-responsive gene expression. The commercial application of PGPR as bioinoculants or biostimulants will remain contingent on more robust strain selection and performance under unfavorable environmental conditions. This review highlights the possible mechanisms of PGPR by activating the plant adaptive defense systems for enhancing drought tolerance and improving overall growth and yield

Repositioning Therapeutics for SARS-CoV-2: Virtual Screening of Plant-based Anti-HIV Compounds as Possible Inhibitors against COVID-19 Viral RdRp

Background: Coronavirus disease 2019 (COVID-19) has caused a global pandemic with a high mortality and morbidity rate worldwide. The COVID-19 vaccines that are currently in development or already approved are expected to provide at least some protection against the emerging variants of the virus, but the mutations may reduce the efficacy of the existing vaccines. Purified phytochemicals from medicinal plants provide a helpful framework for discovering new therapeutic leads as they have long been employed in traditional medicine to treat many disorders. Objective: The objectives of the study are to exploit the anti-HIV bioactive compounds against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) through molecular docking studies and to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of potential compounds. Methods: Molecular docking was performed to study the interaction of ligands with the target sites of RdRp protein (PDB: 6M71) using AutoDock Vina. The ADMET properties of potential compounds were predicted using the pkCSM platform. Results: A total of 151 phytochemicals derived from the medicinal plants with recognized antiviral activity and 18 anti-HIV drugs were virtually screened against COVID-19 viral RdRp to identify putative inhibitors that facilitate the development of potential anti-COVID-19 drug candidates. The computational studies identified 34 compounds and three drugs inhibiting viral RdRp with binding energies ranging from -10.2 to -8.5 kcal/mol. Among them, five compounds, namely Michellamine B, Quercetin 3-O-(2'',6''-digalloyl)-beta-Dgalactopyranoside, Corilagin, Hypericin, and 1,2,3,4,6-Penta-O-galloyl-beta-D-glucose residues, bound efficiently with the binding site of RdRp. Besides, Lopinavir, Maraviroc, and Remdesivir drugs also inhibited SARS-CoV-2 polymerase. In addition, the ADMET properties of top potential compounds were also predicted in comparison to the drugs. Conclusion: The present study suggested that these potential drug candidates can be further subjected to in vitro and in vivo studies that may help develop effective anti-COVID-19 drugs.Fil: Murali, Mahadevamurthy. University of Mysore; IndiaFil: Gowtham, Hittanahallikoppal Gajendramurthy. University of Mysore; IndiaFil: Ansari, Mohammad Azam. Bin Faisal University; Arabia SauditaFil: Alomary, Mohammad N.. King Abdulaziz City for Science and Technology; Arabia SauditaFil: Alghamdi, Saad. Umm Al qura University; Arabia SauditaFil: Almehmadi, Mazen. Taif Universisty; Arabia SauditaFil: Singh, Sudarshana Brijesh. University of Mysore; IndiaFil: Shilpa, Natarajamurthy. University of Mysore; IndiaFil: Aiyaz, Mohammed. University of Mysore; IndiaFil: Kalegowda, Nataraj. University of Mysore; IndiaFil: Ledesma, Ana Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Centro de Investigación en Biofísica Aplicada y Alimentos. - Universidad Nacional de Santiago del Estero. Centro de Investigación en Biofísica Aplicada y Alimentos; ArgentinaFil: Amruthesh, Kestur Nagaraj. University of Mysore; Indi

Cinnamomum verum Bark Extract Mediated Green Synthesis of ZnO Nanoparticles and Their Antibacterial Potentiality

Cinnamomum verum plant extract mediated propellant chemistry route was used for the green synthesis of zinc oxide nanoparticles. Prepared samples were confirmed for their nano regime using advanced characterization techniques such as powder X-ray diffraction and microscopic techniques such as scanning electron microscopy and transmission electron microscopy. The energy band gap of the green synthesized zinc oxide (ZnO)-nanoparticles (NPs) were found between 3.25-3.28 eV. Fourier transmission infrared spectroscopy shows the presence of Zn-O bond within the wave number of 500 cm(-1). SEM images show the specific agglomeration of particles which was also confirmed by TEM studies. The green synthesized ZnO-NPs inhibited the growth of Escherichia coli and Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 125 mu g mL(-1) and 62.5 mu g mL(-1), respectively. The results indicate the prepared ZnO-NPs can be used as a potential antimicrobial agent against harmful pathogens