Genetic landscape of common epilepsies: advancing towards precision in treatment

Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy like childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizure on awakening and focal epilepsy like temporal lobe epilepsy and cryptogenic focal epilepsy. In 70% of the epilepsy cases, genetic factors are responsible either as single genetic variant in rare epilepsies or multiple genetic variants acting along with different environmental factors as in common epilepsies. Genetic testing and precision treatment have been developed for a few rare epilepsies and is lacking for common epilepsies due to their complex nature of inheritance. Precision medicine for common epilepsies require a panoramic approach that incorporates polygenic background and other non-genetic factors like microbiome, diet, age at disease onset, optimal time for treatment and other lifestyle factors which influence seizure threshold. This review aims to comprehensively present a state-of-art review of all the genes and their genetic variants that are associated with all common epilepsy subtypes. It also encompasses the basis of these genes in the epileptogenesis. Here, we discussed the current status of the common epilepsy genetics and address the clinical application so far on evidence-based markers in prognosis, diagnosis, and treatment management. In addition, we assessed the diagnostic predictability of a few genetic markers used for disease risk prediction in individuals. A combination of deeper endo-phenotyping including pharmaco-response data, electro-clinical imaging, and other clinical measurements along with genetics may be used to diagnose common epilepsies and this marks a step ahead in precision medicine in common epilepsies management

Symbolic math for computation of radiation shielding

787-789Radiation transport calculations for shielding studies in the field of accelerator technology often involve intensive numerical computations. Traditionally, radiation transport equation is solved using finite difference scheme or advanced finite element method with respect to specific initial and boundary conditions suitable for the geometry of the problem. All these computations need CPU intensive computer codes for accurate calculation of scalar and angular fluxes. Computation using symbols of the analytical expression representing the transport equation as objects is an enhanced numerical technique in which the computation is completely algorithm and data oriented. Algorithm on the basis of symbolic math architecture is developed using Symbolic math toolbox of MATLAB software. Present paper describes the symbolic math algorithm and its application as a case study in which shielding calculation of rectangular slab geometry is studied for a line source of specific activity. Study of application of symbolic math in this domain evolves a new paradigm compared to the existing computer code such as DORT

A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease

Abstract Background PD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common molecular link with disease susceptibility. A systematic review for LR was conducted for ADR, and drug efficacy, independently. All included articles were assessed for methodological quality on 14 parameters. GWAS of PD were also reviewed. Protein-protein interaction (PPI) analysis using STRING and functional enrichment using WebGestalt was performed to explore the common link between LR and PD. Results From 37 candidate studies on levodopa toxicity, 18 genes were found associated, of which, CAn STR 13, 14 (DRD2) was most significantly associated with dyskinesia, followed by rs1801133 (MTHFR) with hyper-homocysteinemia, and rs474559 (HOMER1) with hallucination. Similarly, 8 studies on efficacy resulted in 4 genes in which rs28363170, rs3836790 (SLC6A3) and rs4680 (COMT), were significant. To establish the molecular connection between LR with PD, we identified 35 genes significantly associated with PD. With 19 proteins associated with LR and 35 with PD, two independent PPI networks were constructed. Among the 67 nodes (263 edges) in LR, and 62 nodes (190 edges) in PD pathophysiology, UBC, SNCA, FYN, SRC, CAMK2A, and SLC6A3 were identified as common potential candidates. Conclusion Our study revealed the genetically significant polymorphism concerning the ADRs and levodopa efficacy. The six common genes may be used as predictive markers for therapy optimization and as putative drug target candidates

Amino terminus of Plasmodium falciparum acidic basic repeat antigen interacts with the erythrocyte membrane through band 3 protein

The acidic basic repeat antigen (ABRA) of Plasmodium falciparum is localised in the parasitophorous vacuole, and associates with the merozoite surface at the time of schizont rupture. By virtue of its protease-like activity, it is implicated in the process of merozoite invasion and schizont rupture, and therefore, possibly interacts with erythrocyte membrane proteins to execute its function during these events. In this study, using Escherichia coli expressed recombinant fragments of ABRA, we have demonstrated that ABRA interacts with red blood cells through its N-terminus. Out of the four human erythrocyte proteins tested, namely, band 3, glycophorin A and B and spectrin, ABRA showed dose-dependent and saturable binding with the band 3 protein. This binding was lost on chymotrypsin treatment of erythrocytes or their membrane extract. Studies with the deletion constructs of the N-terminus revealed that the binding domain lies in the cysteine-rich N-proximal region of ABRA. In addition to the recombinant fragments, native ABRA derived from the P. falciparum-infected erythrocytes also showed binding to band 3 protein. Sequencing of the cysteine-rich 528 bp region, amplified from fifteen field isolates of P. falciparum, showed that not only the five cysteines of mature ABRA but also the whole sequence is fully conserved, even at the nucleotide level. This sequence conservation of the N-terminus and its role in RBC binding suggests that this region may be crucial for any putative function of ABRA, therefore emphasising its importance as a vaccine/drug target