Physiologically based pharmacokinetic (PBPK) modeling and simulation in drug discovery and development

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic or physiology based mathematical modeling technique which integrates the knowledge from both drug-based properties including physiochemical and biopharmaceutical properties and system based or physiological properties to generate a model for predicting the absorption, distribution, metabolism and excretion (ADME) properties of a drug as well as pharmacokinetic behavior of a drug in preclinical species and humans

FACTORS AFFECTING INVESTOR’S DECISION-MAKING IN SMALL AND MEDIUM ENTERPRISES IN PAKISTAN

ABSTRACT   Purpose - The purpose of this study is to examine the impact of financial literacy on the investment decisions of the SME’s investors in Pakistan

Towards Delay-sensitive Routing in Underwater Wireless Sensor Networks

AbstractIn Underwater Acoustic Sensor Networks (UASNs), fundamental difference between operational methodologies of routing schemes arises due to the requirement of time-critical applications therefore, there is a need for the design of delay-sensitive techniques. In this paper, Delay-Sensitive Depth-Based Routing (DSDBR), Delay-Sensitive Energy Efficient Depth-Based Routing (DSEEDBR) and Delay-Sensitive Adaptive Mobility of Courier nodes in Threshold-optimized Depth-based routing (DSAMCTD) protocols are proposed to empower the depth-based routing schemes. The proposed approaches formulate delay-efficient Priority Factors (PF) and Delay-Sensitive Holding time (DS HT) to minimize end-to-end delay with a small decrease in network throughput. These schemes also employ an optimal weight function WF for the computation of transmission loss and speed of received signal. Furthermore, solution for delay lies in efficient data forwarding, minimal relative transmissions in low-depth region and better forwarder selection. Simulations are performed to assess the proposed protocols and the results indicate that the three schemes largely minimize end-to-end delay of network

Selenium and Salt Interactions in Black Gram (Vigna mungo L.): Ion Uptake, Antioxidant Defense System, and Photochemistry Efficiency

Salinity is a major abiotic stress which limits crop production, especially under rainfed conditions. Selenium (Se), as an important micronutrient, plays a vital role in mitigating detrimental effects of different abiotic stresses. The objective of this research was to examine the effect of Se fertilization on black gram (Vigna mungo) under salt stress. Our results showed that salt stress (100 mM NaCl) in leaves significantly induced oxidative damage and caused a decline in relative water content, chlorophyll (Chl), stomatal conductance (gs), photochemical efficiency (Fv/Fm), sucrose, and reducing sugars. A low dose of Se (1.5 ppm) significantly reduced hydrogen peroxide content, malondialdehyde formation, cell membrane damage, and also improved antioxidative enzyme activities, including superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase, and glutathione peroxidase under salt stress. Se-treated plants exhibited higher Chl, gs, Fv/Fm, sucrose, and reducing sugars than untreated plants in response to salt stress. In addition, Se application enhanced Se uptake and reduced Na+ uptake, but Cl remained unaffected. Our results indicated that a low dose of Se effectively alleviated salt damage via inhibition of Na+ uptake and enhanced antioxidant defense resulting in a significant decrease in oxidative damage, and maintained gaseous exchange and PS II function for sucrose and reducing sugars accumulation in black gram

Potential degradation of norfloxacin using UV-C/Fe2+/peroxides-based oxidative pathways

The removal of norfloxacin (NOR), a widely used pharmaceutical and emerging water pollutant, was studied using UV-C and Fe2+ catalyzed peroxides-based oxidative processes (e.g., UV-C/Fe2+/H2O2, UV-C/Fe2+/S2O8 2− and UV-C/Fe2+/HSO5 −) and compared with UV-C and UV-C/Fe2+. The UV-C and UV-C/Fe2+ degraded NOR to 38 and 55%. However, use of peroxides, i.e., H2O2, S2O8 2−, HSO5 − with UV-C and UV-C/Fe2+ promoted NOR %degradation to 75, 83, and 90% using [peroxides]0 = 50 mg/L, [Fe2+]0 = 1 mg/L, and [NOR]0 = 10 mg/L, respectively. The significant impact of peroxides on NOR degradation was due to their decomposition into ●OH and SO4 ●− which showed high activity towards NOR degradation. The ●OH and SO4 ●− formation from peroxides decomposition and their contribution in NOR degradation was verified by different scavenger studies. Among the UV-C/Fe2+/peroxides processes, UV-C/Fe2+/HSO5 − showed better performance. The changing concentrations of peroxides, Fe2+, and NOR affected degradation of NOR. The use of different pH and inorganic anions also influenced NOR degradation. The degradation pathways of NOR were established and analyzed acute as well as chronic toxicities of NOR and its DPs

Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability

Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32–p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

BackgroundCohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.MethodsClinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.ResultsWe identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.ConclusionWe suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup