RNA-Seq data analysis reveals novel nonsense mutations in the NPR3 gene leading to the progression of intellectual disability disorder.

Intellectual disability (ID) is a progressive disorder that affects around 1-3% of the world's population. The heterogeneity of intellectual disability makes it difficult to diagnose as a complete disease. Genetic factors and major mutations play a noticeable role in the development and progression of ID. There is a high need to explore novel variants that may lead to new insights into the progressive aspects of ID. In the current course of study, 31 samples of ID from different studies available on GEO (GSE77742, GSE74263, GSE90682, GSE98476, GSE108887, GSE145710, and PRJEB21964) datasets were taken for the study. These datasets were analyzed for differential gene expression and single nucleotide polymorphism (SNPs). The SNPs of high impact were compared with the differentially expressed genes. Comparison leads to the identification of the priority gene ie NPR3 gene. The identified priority gene further was evaluated for the effect of the mutation using a Mutation Taster. Structure comparison analysis of the wild and mutated proteins of the NPR3 gene was further carried out by UCSF Chimera. Structural analysis reveals the anomalies in protein expression affecting the regulations of the NPR3 gene. These findings identified a novel nonsense mutation (E222*) in the downregulated NPR3 gene that leads to anomalies in the regulation of its protein expression. This missense mutation reveals a major role in causing ID. Our study concludes that the decrease in the expression of the NPR3 gene causes delayed sensory, motor, and physiological functions of the human brain leading to neurodevelopmental delay that causes ID.

Computational framework for identifying and evaluating mutagenic and xenoestrogenic potential of food additives.

Food additives are chemicals incorporated in food to enhance its flavor, color and prevent spoilage. Some of these are associated with substantial health hazards, including developmental disorders, increase cancer risk, and hormone disruption. Hence, this study aimed to comprehend the in-silico toxicology framework for evaluating mutagenic and xenoestrogenic potential of food additives and their association with breast cancer. A total of 2885 food additives were screened for toxicity based on Threshold of Toxicological Concern (TTC), mutagenicity endpoint prediction, and mutagenic structural alerts/toxicophores identification. Ten food additives were identified as having mutagenic potential based on toxicity screening. Furthermore, Protein-Protein Interaction (PPI) analysis identified ESR1, as a key hub gene in breast cancer. KEGG pathway analysis verified that ESR1 plays a significant role in breast cancer pathogenesis. Additionally, competitive interaction studies of the predicted potential mutagenic food additives with the estrogen receptor-α were evaluated at agonist and antagonist binding sites. Indole, Dichloromethane, Trichloroethylene, Quinoline, 6-methyl quinoline, Ethyl nitrite, and 4-methyl quinoline could act as agonists, and Paraldehyde, Azodicarbonamide, and 2-acetylfuranmay as antagonists. The systematic risk assessment framework reported in this study enables the exploration of mutagenic and xenoestrogenic potential associated with food additives for hazard identification and management.

Br - nanoconjugate enhances the antibacterial efficacy of nimboloide against Flavobacterium columnare infection in Labeo rohita: A nanoinformatics approach.

BACKGROUND: The bacterial pathogen, Flavobacterium columnare causes columnaris disease in Labeo rohita globally. Major effects of this bacterial infection include skin rashes and gill necrosis. Nimbolide, the key ingredient of the leaf extract of Azadirachta indica possesses anti-bacterial properties effective against many microorganisms. Nano-informatics plays a promising role in drug development and its delivery against infections caused by multi-drug-resistant bacteria. Currently, studies in the disciplines of dentistry, food safety, bacteriology, mycology, virology, and parasitology are being conducted to learn more about the wide anti-virulence activity of nimbolide. METHODS: The toxicity of nimbolide was predicted to determine its dosage for treating bacterial infection in Labeo rohita. Further, comparative 3-D structure prediction and docking studies are done for nimbolide conjugated nanoparticles with several key target receptors to determine better natural ligands against columnaris disease. The nanoparticle conjugates are being designed using in-silico approaches to study molecular docking interactions with the target receptor. RESULTS: Bromine conjugated nimbolide shows the best molecular interaction with the target receptors of selected species ie L rohita. Nimbolide comes under the class III level of toxic compound so, attempts are made to reduce the dosage of the compound without compromising its efficiency. Further, bromine is also used as a common surfactant and can eliminate heavy metals from wastewater. CONCLUSION: The dosage of bromine-conjugated nimbolide can be reduced to a non-toxic level and thus the efficiency of the Nimbolide can be increased. Moreover, it can be used to synthesize nanoparticle composites which have potent antibacterial activity towards both gram-positive and gram-negative bacteria. This material also forms a good coating on the surface and kills both airborne and waterborne bacteria.

Comparative Transcriptomics Data Profiling Reveals E2F Targets as an Important Biological Pathway Overexpressed in Intellectual Disability Disorder.

Intellectual disability (ID) is an early childhood neurodevelopmental disorder that is characterized by impaired intellectual functioning and adaptive behavior. It is one of the major concerns in the field of neurodevelopmental disorders across the globe. Diversified approaches have been put forward to overcome this problem. Among all these approaches, high throughput transcriptomic analysis has taken an important dimension. The identification of genes causing ID rapidly increased over the past 3 to 5 years owing to the use of sophisticated high throughput sequencing platforms. Early monitoring and preventions are much important for such disorder as their progression occurs during fetal development. This study is an attempt to identify differentially expressed genes (DEGs) and upregulated biological processes involved in development of ID patients through comparative analysis of available transcriptomics data. A total of 7 transcriptomic studies were retrieved from National Center for Biotechnology Information (NCBI) and were subjected to quality check and trimming prior to alignment. The normalization and differential expression analysis were carried out using DESeq2 and EdgeR packages of Rstudio to identify DEGs in ID. In progression of the study, functional enrichment analysis of the results obtained from both DESeq2 and EdgeR was done using gene set enrichment analysis (GSEA) tool to identify major upregulated biological processes involved in ID. Our findings concluded that monitoring the level of E2F targets, estrogen, and genes related to oxidative phosphorylation, DNA repair, and glycolysis during the developmental stage of an individual can help in the early detection of ID disorder.

Molecular docking approaches and its significance in assessing the antioxidant properties in different compounds.

In the last few years, the significance of antioxidant compounds and their properties has attracted great interest from the scientific community. The role of an antioxidant in managing & regulating oxidative stress and also in the protection of the human body from severe adverse effects due to excess release of free radicles or reactive oxygen species (ROS) is remarkable. From aiding protection & combating severe illnesses such as cancer, neurodegeneration, aging, and diabetes to being a vital part of the treatment of SARs-CoV-19 is of great importance. Therefore, the study of anti-oxidants is of great importance in human sustenance. Additionally, molecular docking techniques and their various mathematical features help in understanding the molecular interactions of anti-oxidants based on their lowest binding energy. The evaluation of the binding score between two constituent molecules will provide insight as to the binding process and also suggest possible novel therapeutic targets for the treatment of diseases. In this chapter, we will discuss the significance of molecular docking techniques in the study of antioxidant compounds.

Deciphering the role of precursor miR-12136 and miR-8485 in the progression of intellectual disability (ID).

The short, non-coding RNAs known as miRNA modulate the expression of human protein-coding genes. About 90 % of genes in humans are controlled by the expression of miRNA. The dysfunction of these miRNA target genes leads to many human diseases, including neurodevelopmental disorders as well. Intellectual disability (ID) is a neurodevelopmental disorder that is characterized by adaptive behavior and intellectual functioning which includes logical reasoning, ability in learning, practical intelligence, and verbal skills. Identification of miRNA involved in ID and their associated target genes can help in the identification of diagnostic biomarkers related to ID at a very early age. The present study is an attempt to identify miRNA and their associated target genes that play an important role in the development of intellectual disability patients through the meta-analysis of available transcriptome data. A total of 6 transcriptomic studies were retrieved from NCBI and were subjected to quality check and trimming before alignment. The normalization and identification of differentially expressed miRNA were carried out using the EdgeR package of R studio. Further, the gene targets of downregulated miRNA were identified using miRDB. The system biology approaches were also applied to the study to identify the hub target genes and the diseases associated with main miRNAs.

A molecular dynamics simulation study of the ACE2 receptor with screened natural inhibitors to identify novel drug candidate against COVID-19.

BACKGROUND & OBJECTIVES: The massive outbreak of Novel Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has turned out to be a serious global health issue worldwide. Currently, no drugs or vaccines are available for the treatment of COVID-19. The current computational study was attempted to identify a novel therapeutic inhibitor against novel SARS-CoV-2 using in silico drug discovery pipeline. METHODS: In the present study, the human angiotensin-converting enzyme 2 (ACE2) receptor was the target for the designing of drugs against the deadly virus. The 3D structure of the receptor was modeled & validated using a Swiss-model, Procheck & Errat server. A molecular docking study was performed between a group of natural & synthetic compounds having proven anti-viral activity with ACE2 receptor using Autodock tool 1.5.6. The molecular dynamics simulation study was performed using Desmond v 12 to evaluate the stability and interaction of the ACE2 receptor with a ligand. RESULTS: Based on the lowest binding energy, confirmation, and H-bond interaction, cinnamic acid (-5.20 kcal/mol), thymoquinone (-4.71 kcal/mol), and andrographolide (Kalmegh) (-4.00 kcal/mol) were screened out showing strong binding affinity to the active site of ACE2 receptor. MD simulations suggest that cinnamic acid, thymoquinone, and andrographolide (Kalmegh) could efficiently activate the biological pathway without changing the conformation in the binding site of the ACE2 receptor. The bioactivity and drug-likeness properties of compounds show their better pharmacological property and safer to use. INTERPRETATION & CONCLUSIONS: The study concludes the high potential of cinnamic acid, thymoquinone, and andrographolide against the SARS-CoV-2 ACE2 receptor protein. Thus, the molecular docking and MD simulation study will aid in understanding the molecular interaction between ligand and receptor binding site, thereby leading to novel therapeutic intervention.