Hybrid model development through the integration of quantitative read-across (qRA) hypothesis with the QSAR framework: An alternative risk assessment of acute inhalation toxicity testing in rats.

Regulatory authorities frequently need information on a chemical's capacity to produce acute systemic toxicity in humans. Due to concerns about animal welfare, human relevance, and reproducibility, numerous international initiatives have centered on finding a substitute for using animals in acute systemic lethality testing. These substitutes include the more current in-silico and in vitro techniques.

Development of hybrid models by the integration of the read-across hypothesis with the QSAR framework for the assessment of developmental and reproductive toxicity (DART) tested according to OECD TG 414.

The governing laws mandate animal testing guidelines (TG) to assess the developmental and reproductive toxicity (DART) potential of new and current chemical compounds for the categorization, hazard identification, and labeling. modeling has evolved as a promising, economical, and animal-friendly technique for assessing a chemical's potential for DART testing. The complexity of the endpoint has presented a problem for Quantitative Structure-Activity Relationship (QSAR) model developers as various facets of the chemical have to be appropriately analyzed to predict the DART.

Development of a read-across-derived classification model for the predictions of mutagenicity data and its comparison with traditional QSAR models and expert systems.

Mutagenicity is considered an important endpoint from the regulatory, environmental and medical points of view. Due to the wide number of compounds that may be of concern and the enormous expenses (in terms of time, money, and animals) associated with rodent mutagenicity bioassays, this endpoint is a major target for the development of alternative approaches for screening and prediction. The majority of old-aged expert systems and quantitative structure-activity relationship (QSAR) models may show reduced performance over time for their application on newer chemical candidates; thus, researchers constantly try to improve the modeling strategies.

Sandwich osteotomy with interpositional grafts for vertical augmentation of the mandible: A meta-analysis.

Sandwich osteotomy is a technique for vertical augmentation based on the principle of a graft being placed between two pedicled native bones. The inherent vascularization helps in graft consolidation. The aim is to review the bone height gained, implant survival and pitfalls with sandwich osteotomy.

QSPR modeling of octanol-water partition coefficient and organic carbon normalized sorption coefficient of diverse organic chemicals using Extended Topochemical Atom (ETA) indices.

Octanol-water partition coefficient (logK) and soil organic carbon content normalized sorption coefficient (logK) values are two important physicochemical properties in the context of bioaccumulation and environmental fate of organic compounds and their environmental risk assessment. Simple, interpretable and easy-to-derive extended topochemical atom (ETA) indices obtained from 2D structural representation of compounds were used for quantitative structure-property relationship (QSPR) modeling of these two endpoints. Linear regression based models developed using only ETA indices show encouraging statistical and validation results.

Exploring QSAR models for assessment of acute fish toxicity of environmental transformation products of pesticides (ETPPs).

Environmental transformation products of pesticides (ETPPs) have a great deal of ecological impact owing to their ability to cause toxicity to the aquatic organisms, which can then be translated to the humans. The limited experimental data on biochemical and toxic effects of ETPPs, the high test costs together with regulatory limitations and the international push to reduce animal testing encourage greater dependence on predictive in silico techniques like quantitative structure-activity relationship (QSAR) models. The aim of the present work was to explore the key structural features, which regulate the toxicity towards fishes, for 85 ETPPs using a partial least squares (PLS) regression based chemometric model developed according to Organisation for Economic Co-operation and Development (OECD) guidelines.

An analysis of deleterious single nucleotide polymorphisms and molecular dynamics simulation of disease linked mutations in genes responsible for neurodegenerative disorder.

Mutation in two genes deglycase gene (DJ-1) and retromer complex component gene (VPS35) are linked with neurodegenerative disorder such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. DJ-1 gene located at 1p36 chromosomal position and involved in PD pathogenesis through many pathways including mitochondrial dysfunction and oxidative injury. VPS35 gene located at 16q13-q21 chromosomal position and the two pathways, the Wnt signaling pathway, and retromer-mediated DMT1 missorting are proposed for basis of VPS35 related PD.

ATP synthase, an essential enzyme in growth and multiplication is modulated by protein tyrosine phosphatase in Mycobacterium tuberculosis H37Ra.

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase (PtpA) has so far been known to control intracellular survival of mycobacteria; whereas the ATP synthase which is essential for mycobacterial growth has recently been contemplated in developing a breakthrough anti-TB drug, diarylquinoline. Since both of these enzymes have been established as validated drug targets; we report a robust and functional relationship between these two enzymes through a series of experiments using Mtb H37Ra. In the present study we report that the mycobacterial ATP synthase alpha subunit is regulated by PtpA.

Mycobacterial protein tyrosine kinase, PtkA phosphorylates PtpA at tyrosine residues and the mechanism is stalled by the novel series of inhibitors.

Phosphorylation and dephosphorylation are the key mechanisms for mycobacterial physiology and play critical roles in mycobacterial survival and in its pathogenesis. Mycobacteria evade host immune mechanism by inhibiting phagosome - lysosome fusion in which mycobacterial protein tyrosine phosphatase A (PtpA;TP) plays an indispensable role. Tyrosine kinase (PtkA;TK) activated by autophosphorylation; phosphorylates TP, which subsequently leads to increase in its phosphatase activity.

Protein kinase C-δ inhibitor, Rottlerin inhibits growth and survival of mycobacteria exclusively through Shikimate kinase.

The molecular bases of disease provide exceptional prospect to translate research findings into new drugs. Nevertheless, to develop new and novel chemical entities takes huge amount of time and efforts, mainly due to the stringent processes. Therefore, drug repurposing is one of such strategies which is being used in recent times to identify new pharmacophores.

Biochemical and functional characterizations of tyrosine phosphatases from pathogenic and nonpathogenic mycobacteria: indication of phenyl cyclopropyl methyl-/phenyl butenyl azoles as tyrosine phosphatase inhibitors.

Tyrosine phosphorylation is one of the most common means of posttranslational modifications which can generate novel recognition motifs for protein interactions and thereafter affecting cellular localization, protein stability, and enzyme activity. Mycobacterium tuberculosis (Mtb) possesses a wide range of signal transduction systems, including two protein tyrosine phosphatases (PtpA and PtpB). Since functional diversities between protein tyrosine phosphatases (PTPases) are illustrated by regulatory domains and subunits, we have characterized the nature of tyrosine phosphatases from slow-grower pathogenic species Mtb and from fast-grower nonpathogenic species Mycobacterium smegmatis (MS).