A comprehensive insight from molecular docking and dynamics with clinical investigation on the impact of direct oral anticoagulants on atheroprotective protein in atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses. METHODS: We focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration. RESULTS: Our computational investigation showed rivaroxaban (-4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (-5.97 kcal/mol) and dabigatran (-9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control. CONCLUSION: Overall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.

Effects of modified sleeper stretch and modified cross-body stretch on upper limb functions and shoulder ROM in tennis players: a randomized trial.

Tennis players often experience posterior shoulder pain due to restricted internal rotation (IR) range of motion (ROM) of the glenohumeral joint. No research has compared the effects of modified sleeper stretch (MSS) versus modified cross-body stretch (MCBS) on tennis players' upper limb functions and IR ROM. The study aimed to compare the efficacy of modified sleeper and cross-body adduction stretch in improving shoulder IR ROM and upper limb functions in tennis players. Thirty male lawn tennis players (aged 20 to 35 years) with more than 15° glenohumeral IR deficiency on the dominant side compared to the non-dominant side were recruited and divided into two groups: Modified sleeper stretch group (MSSG) and modified cross-body stretch group (MCBSG). MSSG received MSS, and MCBSG received MCBS, 3-5 repetitions once daily for 4 weeks. Upper limb functions were measured using the Disability of the Arm, Shoulder, and Hand (DASH) scale, and the IR ROM of the shoulder joint was measured using a universal goniometer. Both groups observed significant (p < 0.05) DASH scores and IR ROM improvements. DASH scores decreased by 85% in MSSG and 79.60% in MCBSG. IR ROM increased by 94.64% in MSSG and 89.52% in MCBSG. No significant differences (p > 0.05) were found in post-intervention DASH scores and IR ROM values between both groups. MSS and MCBS improved upper limb functions and IR ROM of the shoulder joint in the selected sample population of lawn tennis players. No difference was observed between both stretching techniques in improving upper limb functions and IR ROM of the shoulder joint.

Dynamics of TUBB protein with five majorly occurring natural variants: a risk of cortical dysplasia.

Beta-tubulin (TUBB) protein is one of the components of the microtubule cytoskeleton that plays a critical role in the central nervous system. Genetic variants of TUBB cause cortical dysplasia, a developmental brain defect implicated in axonal guidance and the neuron migration. In this study, we assess pathogenic variants (Q15K, Y222F, M299V, V353I, and E401K) of TUBB protein and compared with non-pathogenic variant G235S to determine their impact on protein dynamic to cause cortical dysplasia. Among the analyzed variants, Q15K, Y222F, M299V, and E401K were noticed to have deleterious effect. Then, variant structures were modeled and their affinity with their known cofactor Guanosine-5'-triphosphate (GTP) was assessed which showed diverse binding energies ranged between (-7.436 to -6.950 kcal/mol) for the variants compared to wild-type (-7.428 kcal/mol). Finally, the molecular dynamics simulation of each variant was investigated which showed difference in trajectory between the pathogenic and non-pathogenic variant. Our analysis suggests change in amino acid residue of TUBB structure has notably affects the protein flexibility and their interactions with known cofactor. Overall, our findings provide insight on the relationship between TUBB variants and their structural dynamics that may cause diverse effects leading to cortical dysplasia.

Rheumatoid arthritis treatment with zoledronic acid, a potentialinhibitorofGWAS-derived pharmacogenetics STAT3 and IL2 targets.

Rheumatoid arthritis (RA) is an inflammatory condition that primarily affects the joints and progress to affect other vital organs. Variety of drugs are being recommended to control the disease progression that benefits patients to perform day-to-day activities. Few of these RA drugs have noticeable side effects; therefore, it's crucial to choose the appropriate drug for treating RA with an understanding of the disease's pathophysiology. Herein, we investigated the RA genes from GWAS data to construct protein-protein interaction (PPI) network and to define appropriate drug targets for RA. The predicted drug targets were screened with the known RA drugs based on molecular docking. Further, the molecular dynamics simulations were performed to comprehend the conformational changes and stability of the targets upon binding of the selected top ranked RA drug. As a result, our constructed protein network from GWAS data revealed, STAT3 and IL2 could be potential pharmacogenetics targets that interlink most of the RA genes encoding proteins. These interlinked proteins of both the targets showed involvement in cell signaling, immune response, and TNF signaling pathway. Among the 192 RA drugs investigated, zoledronic acid had the lowest binding energy that inhibit both STAT3 (-6.307 kcal/mol) and IL2 (-6.231 kcal/mol). Additionally, STAT3 and IL2 trajectories on zoledronic acid binding exhibit notable differences in MD simulations as compared to a drug-free environment. Also, the in vitro assessment with the zoledronic acid confirms the outcome of our computational study. Overall, our study identify zoledronic acid could be potential inhibitor against these targets, that will benefits patients with RA. Comparative efficiency assessments between the RA drugs through clinical trials are needed to validate our findings in the treatment of RA.

Asn215Ser, Ala143Thr, and Arg112Cys variants in α-galactosidase A protein confer stability loss in Fabry's disease.

Alpha galactosidase A (α-GalA) gene contains nine exons localized at the q-arm of the X chromosome. Generally, an α-GalA enzyme is involved in the removal of galactosyl moieties from the glycoproteins and glycolipids. Dysregulation results in the accumulation of glycoproteins as well as glycolipids in various organs leading to Fabry disease (FD). In this study, we examine the impact of Asn215Ser, Ala143Thr and Arg112Cys variants on the α-GalA protein structure contributing to functional dynamic changes in FD. The seven computational pathogenicity prediction methods were used to predict the effects of these variants on the α-GalA protein. The three-dimensional structure of α-GalA variants was modeled with the Swiss Model and Robetta server and validated using a variety of tools. Then, molecular dynamics (MD) simulation was performed to understand the stability and dynamic behavior of the wild-type and variants structures. Most of our analyzed pathogenicity prediction tools showed that Asn215Ser, Ala143Thr and Arg112Cys variants cause a deleterious effect on the α-GalA protein. Further, MD trajectory analysis showed the destabilizing effect of variants on α-GalA structure based on the root mean square deviation, root mean square fluctuation, solvent accessible surface area, the radius of gyration, hydrogen bond, cluster analysis and PCA analysis. This concludes that the presence of these variants could potentially affect the protein functional process of galactosyl moieties removal which might lead to Fabry disease.Communicated by Ramaswamy H. Sarma.

Segmentation and Classification of Glaucoma Using U-Net with Deep Learning Model.

Glaucoma is the second most common cause for blindness around the world and the third most common in Europe and the USA. Around 78 million people are presently living with glaucoma (2020). It is expected that 111.8 million people will have glaucoma by the year 2040. 90% of glaucoma is undetected in developing nations. It is essential to develop a glaucoma detection system for early diagnosis. In this research, early prediction of glaucoma using deep learning technique is proposed. In this proposed deep learning model, the ORIGA dataset is used for the evaluation of glaucoma images. The U-Net architecture based on deep learning algorithm is implemented for optic cup segmentation and a pretrained transfer learning model; DenseNet-201 is used for feature extraction along with deep convolution neural network (DCNN). The DCNN approach is used for the classification, where the final results will be representing whether the glaucoma infected or not. The primary objective of this research is to detect the glaucoma using the retinal fundus images, which can be useful to determine if the patient was affected by glaucoma or not. The result of this model can be positive or negative based on the outcome detected as infected by glaucoma or not. The model is evaluated using parameters such as accuracy, precision, recall, specificity, and F-measure. Also, a comparative analysis is conducted for the validation of the model proposed. The output is compared to other current deep learning models used for CNN classification, such as VGG-19, Inception ResNet, ResNet 152v2, and DenseNet-169. The proposed model achieved 98.82% accuracy in training and 96.90% in testing. Overall, the performance of the proposed model is better in all the analysis.

Pilocytic Midbrain Astrocytoma Presenting with Fresh Bleed after Twenty-one-years Survival Following First Surgery: A Unique Case of Longest Brainstem Glioma Survival.

Brainstem glioma usually carries a poor prognosis and prolonged survival is very infrequent. In a detailed Pubmed, Medline search for prolonged survival, authors could got a longest survival only up to seventeen years, reported by Umehara et al, who was subjected to gamma knife therapy and got symptomatic, MRI brain reveled large tumor growth during pregnancy necessitating emergency surgery and histopathological diagnosis was pilocytic astrocytoma. Authors report an interesting case of midbrain glioma diagnosed 21 years back, who underwent gross resection in the year 1993, histopathology was pilocytic astrocytoma, WHO grade I, and received gamma knife surgery for residual subsequently and he presented with sudden onset left sided hemiplegia on the current admission. The cranial MRI imaging revealed an infarct involving right hemi midbrain, contrast MRI brain revealed no residual glioma. To the best knowledge of authors such prolonged survival is not reported with a case of brainstem glioma survived twenty- one years with non residual tumor on the last imaging study represents first case of its kind in the western literature and probably developed hemiplegia due to bleed, highlighting bleed as delayed complication following gamma knife therapy for cranial tumors.

INCIDENCE OF ANTI-SPERM ANTIBODIES IN INFERTILE MALE POPULATION.

The prevalence of anti-sperm antibodies was assessed in 100 patients of male factor infertility. Majority of the patients were in 30-35 years age group. 18% of these patients had anti-sperm antibodies in their seminal fluid and 16% in their serum.