Association of epilepsy and neurological impairments with homozygous recessive missense mutations found in the genes responsible for ganglioside biosynthesis (ST3GAL5) and calcium voltage-gated channels (CACNA1H) - insights through molecular dynamic simulations.

With over 2.2 million cases, the incidence rate of epilepsy in Pakistan is far higher than the rest of the world due primarily to the frequent, traditionally imposed cousin marriages. In the present study, comprehensive whole exome sequencing (WES) analyses of a three-generation family with four affected members presenting 'unexplained' childhood absence epilepsy (CAE), seizures and dementia, was performed in a quest to identify heritable, epilepsy-causal gene variants to better aid in carrier screening and genetic counselling. The WES data was generated, analyzed, and validated through Sanger's sequencing, molecular dynamic simulation (MDS) analysis, and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) studies. Two homozygous recessive, missense mutations in ST3GAL5 (c.311A > G, p. His104Arg) and CACNA1H (c.6230G > A, p. Arg2077His) genes, earlier regarded as benign or of uncertain significance, have been identified as a potential etiology. Comparative MDS and free binding energy calculations revealed substantial structural perturbations in mutant forms of ST3GAL5 leading to decreased binding and reduced catalytic activity of the p.His104Arg and two other functional variants (p.Val74Glu and p.Arg288Ter) when compared with wild type. Our findings reinforce that WES analyses may uncover 'hidden', heritable variants and together with MDS and MM/GBSA may provide plausible clues to answer the unexplained causes of epilepsy for an effective management and better patient outcome. Further, revisit of epilepsy-associated mutational landscape in population context is imperative as the variants with 'benign' tags may turn out to be 'non-benign', when exist in combination with other benign.Communicated by Ramaswamy H. Sarma.

The Anisotropic Chemical Reaction Mechanism of 1,3,3-trinitroazetidine (TNAZ) under Different Shock Wave Directions by ReaxFF Reactive Molecular Dynamics Simulations.

1,3,3-Trinitroazetidine (TNAZ) has good thermal stability and low shock sensitivity, among other properties, and it has broad prospects in insensitive ammunition applications. In this study, a molecular dynamics calculation based on the ReaxFF-lg force field and multiscale shock technique (MSST) was used to simulate the shock-induced chemical reaction of TNAZ with different shock wave directions. The results showed that the shock sensitivity of TNAZ was in the order of [100] > [010] > [001]. There were significant differences in molecular arrangements in different shock directions, which affected the reaction rate and reaction path in different directions. The molecular arrangement in the [010] and [001] directions formed a "buffer" effect. The formation and cleavage of bonds, formation of small molecules and growth of clusters were analyzed to show the effect of the "buffer". The polymerization reactions in the [010] and [001] directions appeared later than that in the [100] direction, and the cluster growth in the [010] and [001] directions was slower than that in the [100] direction. In different shock loading directions, the formation and cleavage mechanisms of the N-O bonds of the TNAZ molecules were different, which resulted in differences in the initial reaction path and reaction rate in the three directions

Optimization, in vitro release and toxicity evaluation of novel pH sensitive itaconic acid-g-poly(acrylamide)/sterculia gum semi-interpenetrating networks.

BACKGROUND: In recent era, pH sensitive polymeric carriers that combines the materials engineering and medicine is gaining researcher's attention as they maximizes drug concentration at site of absorption and reduces side effects for e.g. orally administered cetirizine HCl (CTZ HCl) upsets the stomach and furthermore shows high intestinal absorption. Thus, development of pH sensitive hydrogels with sufficient mechanical strength will be good candidate to address this issue. METHODS: Here, we developed pH sensitive itaconic acid-g-poly(acrylamide)/sterculia gum (IA-g-poly(AM)/sterculia gum) semi-interpenetrating network (semi-IPN) by free radical polymerization technique for intestinal delivery of CTZ HCL. RESULTS: Optimized formulation (I5) with 6% w/w IA showed negligible swelling at pH 1.2, and maximum swelling at pH 7.4. Solid state characterization of optimized formulation showed successful development of semi-IPN structure and incorporation of drug without any noticeable drug-carrier interaction. In vitro release study showed biphasic pH dependent release of CTZ HCl, where initial burst release was observed at acidic pH followed by sustained release at basic pH. Acute oral toxicity and histopathological studies confirmed the non-toxic nature of IA-g-poly(AM)/sterculia gum. CONCLUSION: Conclusively, developed biocompatible semi-IPN hydrogels with sufficient pH sensitivity and mechanical strength could serve as a potential carrier for intestinal delivery of CTZ HCL to maximize its absorption and reduce side effects.

Efficient State Management for Scaling Out Stateful Operators in Stream Processing Systems.

Many big data applications require real-time analysis of continuous data streams. Stream Processing Systems (SPSs) are designed to act on real-time streaming data using continuous queries consisting of interconnected operators. The dynamic nature of data streams, for example, fluctuation in data arrival rates and uneven data distribution, can cause an operator to be a bottleneck one. Scalability is an important factor in SPS, but detecting bottleneck operator correctly and scaling it without affecting application execution are challenging. A stateful operator such as aggregation or join makes scaling operation more difficult as it involves state management. Current research does not address the issue of scaling stateful operators efficiently as mostly stop application for handling state, which results in significant overheads to the performance. In this article, the key idea is to detect bottleneck operator correctly using the runtime bottleneck detection approach and then scale out this operator and manage its internal state in a way that we can achieve almost zero latency. During the bottleneck detection process, we have defined alarming_threshold, a parameter for the operators that can be bottleneck operators in the future and scale_out_threshold, when the operator is bottleneck. To scale out, we have presented two techniques, active backup and checkpointing, the former one will start a Secondary Execution (SE) in back end by partitioning state and input streams to multiple nodes at alarming_threshold; this SE will replace primary node at scale_out_threshold. In the latter technique, a State Manager (SM) module will start state checkpointing at alarming_threshold to external store and perform scale out by managing state and input stream at scale_out_threshold. The first approach will help us to achieve almost zero latency goal, while the latter one is a resource efficient technique. Our results show that both techniques are working while providing desired goals of reducing overall latency during scale out and improving resource utilization.