Ablation of the dystrophin Dp71f alternative C-terminal variant increases sarcoma tumour cell aggressiveness.

Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells. Dp71f ablation induced major transcriptomic alterations, particularly affecting the expression of genes involved in calcium signalling and ECM-receptor interaction pathways. The genome-scale metabolic analysis identified significant downregulation of glucose transport via membrane vesicle reaction (GLCter) and downregulated glycolysis/gluconeogenesis pathway. Functionally, these molecular changes corresponded with, increased calcium responses, cell adhesion, proliferation, survival under serum starvation and chemotherapeutic resistance. Knockout cells showed reduced GLUT1 protein expression, survival without attachment and their migration and invasion in vitro and in vivo were unaltered, despite increased matrix metalloproteinases release. Our findings emphasise the importance of alternative splicing of dystrophin transcripts and underscore the role of the Dp71f variant, which appears to govern distinct cellular processes frequently dysregulated in tumour cells. The loss of this regulatory mechanism promotes sarcoma cell survival and treatment resistance. Thus, Dp71f is a target for future investigations exploring the intricate functions of specific DMD transcripts in physiology and across malignancies.

Mechanism-aware and multimodal AI: beyond model-agnostic interpretation.

Artificial intelligence (AI) is widely used for exploiting multimodal biomedical data, with increasingly accurate predictions and model-agnostic interpretations, which are however also agnostic to biological mechanisms. Combining metabolic modelling, 'omics, and imaging data via multimodal AI can generate predictions that can be interpreted mechanistically and transparently, therefore with significantly higher therapeutic potential.

Stabilizing Polar Domains in MAPbBr3 via the Hydrostatic Pressure-Induced Liquid Crystal-like Transition.

Pressure-induced phases of MAPbBr3 were investigated at room temperature in the range of 0-2.8 GPa by ab initio molecular dynamics. Two structural transitions at 0.7 GPa (cubic → cubic) and 1.1 GPa (cubic → tetragonal) involved both the inorganic host (lead bromide) and the organic guest (MA). MA dipoles behave like a liquid crystal undergoing isotropic → isotropic and isotropic → oblate nematic transitions as pressure confines their orientational fluctuations to a crystal plane. Beyond 1.1 GPa, the MA ions lie alternately along two orthogonal directions in the plane forming stacks perpendicular to it. However, the molecular dipoles are statically disordered, leading to stable polar and antipolar MA domains in each stack. H-Bond interactions, which primarily mediate host-guest coupling, facilitate the static disordering of MA dipoles. Interestingly, high pressures suppress CH3 torsional motion, emphasizing the role of C-H···Br bonds in the transitions.

A comparative study of sexual behavior, dysfunction, satisfaction, relationship, and sexual quality of life amongst treatment-naïve and abstinent men (buprenorphine-maintained) with Opioid (heroin) dependence syndrome.

Background: Association between opioid use and sexual functioning is well-known. However, data evaluating the influence of treatment on different aspects of sexuality are lacking. Aim: To compare sexual behavior, functioning, relationship, satisfaction, and sexual quality of life (sQoL) among treatment naïve patients (GROUP-I) with Opioid (heroin) dependence syndrome (ODS-H) with those maintained on buprenorphine (GROUP-II). Methods: Married adult males diagnosed with ODS-H, currently sexually active, and living with their partner were recruited. They were assessed for their sexual practices and high-risk sexual behavior (HRSB) through a semi-structured questionnaire and sexual functioning, relationships, satisfaction, and sQoL through structured questionnaires. Results: A total of 112 individuals (GROUP-I: 63; GROUP-II: 49) were recruited from the outpatient settings. Mean age and employment in GROUP-II were higher (p < 0.05) than in GROUP-I (37 vs 32 years; 94% vs 70%, respectively). Other sociodemographic variables and the age of onset of heroin use were comparable. The current practice of HRSB (e.g., engaging in casual partner sex, sex with commercial sex workers, and sex under intoxication) was higher in GROUP-I while almost no differences were seen in lifetime HRSB. The frequency of erectile dysfunction and premature ejaculation in the two groups were: 78% vs 39% (p < 0.001), and 30% vs 6% (p = 0.001), respectively. GROUP-II had significantly higher scores in all the scales (p < 0.05) as compared to GROUP-I, indicating better sexual satisfaction, quality of life, and sexual relationship. Conclusion: Heroin use is associated with HRSB, poorer sexual functioning, overall satisfaction, and sQoL. Maintenance of Buprenorphine helps with improvement in all these parameters. Comprehensive management for substance use should target sexual problems as well.

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts.

Duchenne muscular dystrophy (DMD) affects myofibers and muscle stem cells, causing progressive muscle degeneration and repair defects. It was unknown whether dystrophic myoblasts-the effector cells of muscle growth and regeneration-are affected. Using transcriptomic, genome-scale metabolic modelling and functional analyses, we demonstrate, for the first time, convergent abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx myoblasts lacking full-length dystrophin, the expression of 170 genes was significantly altered. Myod1 and key genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signalling and fibrosis genes) were significantly downregulated. Gene ontology analysis indicated enrichment in genes involved in muscle development and function. Functionally, we found increased myoblast proliferation, reduced chemotaxis and accelerated differentiation, which are all essential for myoregeneration. The defects were caused by the loss of expression of full-length dystrophin, as similar and not exacerbated alterations were observed in dystrophin-null Dmdmdx-ßgeo myoblasts. Corresponding abnormalities were identified in human DMD primary myoblasts and a dystrophic mouse muscle cell line, confirming the cross-species and cell-autonomous nature of these defects. The genome-scale metabolic analysis in human DMD myoblasts showed alterations in the rate of glycolysis/gluconeogenesis, leukotriene metabolism, and mitochondrial beta-oxidation of various fatty acids. These results reveal the disease continuum: DMD defects in satellite cells, the myoblast dysfunction affecting muscle regeneration, which is insufficient to counteract muscle loss due to myofiber instability. Contrary to the established belief, our data demonstrate that DMD abnormalities occur in myoblasts, making these cells a novel therapeutic target for the treatment of this lethal disease.

Hand, Foot, and Mouth Disease in Thailand: A Comprehensive Modelling of Epidemic Dynamics.

Hand, foot, and mouth disease (HFMD) is a highly contagious disease with several outbreaks in Asian-Pacific countries, including Thailand. With such epidemic characteristics and potential economic impact, HFMD is a significant public health issue in Thailand. Generally, contagious/infectious diseases' transmission dynamics vary across geolocations due to different socioeconomic situations, demography, and lifestyles. Hence, a nationwide comprehensive model of the disease's epidemic dynamics can provide information to understand better and predict a potential outbreak of this disease and efficiently and effectively manage its impact. However, there is no nationwide and comprehensive (i.e., the inclusion of reinfections in the model) model of HFDM dynamics for Thailand. This paper has endeavoured to promote nationwide comprehensive modelling of HFMD's epidemic dynamics and comprehend the reinfection cases. We have formulated the SEIRS epidemiological model with dynamic vitals, including reinfections, to explore this disease's prevalence. We also introduced periodic seasonality to reproduce the seasonal effect. The pattern of spread of this disease is uneven across the provinces in Thailand, so we used K-means clustering algorithm to cluster those provinces into three groups (i.e., highly, moderately, and least affected levels). We also analysed health records collected from district hospitals, which suggest significant reinfection cases. For example, we found that 11% (approximately) of infectious patients return for repeat treatment within the study period. We also performed sensitivity analysis which indicates that the basic reproduction number (R 0) is sensitive to the rate of transmission (ß) and the rate at which infected people recover (γ). By fitting the model with HFMD confirmed data for the provinces in each cluster, the basic reproduction number (R 0) was estimated to be 2.643, 1.91, and 3.246 which are greater than 1. Based on this high R 0, this study recommends that this disease will persist in the coming years under identical cultural and environmental conditions.

Sexual relationship, self-esteem, dysfunction, and sexual satisfaction in treatment naïve men with heroin dependence.

Heroin use, a prevalent and disabling condition, affects sexual functioning and the sexual quality of life. While there is adequate literature on sexual dysfunction with heroin use, the literature is scarce on the emotional aspects of sex, like the perception of sexual relationship, self-esteem, and satisfaction amongst heroin users. The study assessed these parameters among treatment-naïve, sexually active, married, male patients with heroin dependence. We interviewed 63 treatment-naïve men seeking treatment for heroin dependence using Self-esteem and Relationship Questionnaire (SEAR), New Sexual Satisfaction Scale-Short form (NSSS-S), Sexual Quality of Life Questionnaire-Male (SQoL-M), Index of Premature Ejaculation (IPE), and International Index of Erectile Function (IIEF). Overall scores in SEAR, NSSS-S, SQoL-M, IIEF, and IPE were low, suggesting poor self-esteem and relationship, poor sexual quality of life and sexual satisfaction, higher premature ejaculation, and erectile dysfunction. Injecting drug use was associated with lower scores on confidence domain of SEAR, partner activity focused domain of NSSS-S, intercourse-satisfaction, and overall sexual quality of life. Sexual dysfunctions, poor sexual relationship, and sexual quality of life are common among men seeking treatment for heroin dependence. Treatment strategies must not lose focus on this dimension of health during the treatment process.

Pharmacophore, 3D-QSAR Models and Dynamic Simulation of 1,4-Benzothiazines for Colorectal Cancer Treatment.

AIM AND OBJECTIVE: Interleukin-6 has become an attractive protein target. This is found in the progression of colon cancer. It performs various functions in the colon cancer cells such as inflammation, activates various cell types signaling and also promotes proliferation in colon cancer cells. It is a valid target to develop anticolon cancer drug. The purpose of our study is to develop the Three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models, pharmacophore modeling and docking study as well as MD simulation to find out the novel potent inhibitors that bind with Interleukin-6 in colon cancer treatment. MATERIAL AND METHODS: In this study, common pharmacophore models and atom-based 3D-QSAR studies were carried out by using 1,4-benzothiazine derivatives with their experiential GI50values towards HT-29 human colon cancer cell line. RESULTS: The common pharmacophore model (ADHR26) was developed and the survival score was found to be 3.828. The generated pharmacophore-based alignment was used to develop a predictive atom-based 3D-QSAR model by using Partial Least Square (PLS) method. Phase predictable activity and LogGI50 also exhibited the most significant atomic position in the backbone structure of ligands for anticolon cancer activity. Molecular dynamic and docking studies for the IL-6 target provide key framework of ligand for the anticolon cancer activity. CONCLUSION: Finally, results generated from the work data, that exhibited the pharmacophore models and 3D-QSAR hypothesis might be a path of milestone in the area of medicinal chemistry to researchers for further design of new and potent IL-6 inhibitors.

Molecular Docking, Pharmacophore, and 3D-QSAR Approach: Can Adenine Derivatives Exhibit Significant Inhibitor Towards Ebola Virus?

INTRODUCTION: Ebola Virus Disease (EVD) is caused by Ebola virus, which is often accompanied by fatal hemorrhagic fever upon infection in humans. This virus has caused the majority of deaths in human. There are no proper vaccinations and medications available for EVD. It is pivoting the attraction of scientist to develop the potent vaccination or novel lead to inhibit Ebola virus. METHODS & MATERIALS: In the present study, we developed 3D-QSAR and the pharmacophoric model from the previous reported potent compounds for the Ebola virus. RESULTS & DISCUSSION: Results & Discussion: The pharmacophoric model AAAP.116 was generated with better survival value and selectivity. Moreover, the 3D-QSAR model also showed the best r2 value 0.99 using PLS factor. Thereby, we found the higher F value, which demonstrated the statistical significance of both the models. Furthermore, homological modeling and molecular docking study were performed to analyze the affinity of the potent lead. This showed the best binding energy and bond formation with targeted protein. CONCLUSION: Finally, all the results of this study concluded that 3D-QSAR and Pharmacophore models may be helpful to search potent lead for EVD treatment in future.

Synthesis and in vitro antimicrobial activity of novel N-(6-chlorobenzo[d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class.

In this study, a series of novel 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole (6a-g) and 1,3,4-oxadiazole (7a-g, 8) were synthesized from N-(6-chlorobenzo[d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class. Antimicrobial properties of the title compound derivatives were investigated against one Gram (+) bacteria (Staphylococcus aureus), three Gram (-) bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and five fungi (Candida albicans, Aspergillus niger, Aspergillus flavus, Monascus purpureus and Penicillium citrinum) using serial plate dilution method. The investigation of antibacterial and antifungal screening data revealed that all the tested compounds showed moderate to good inhibition at 12.5-100 µg/mL in DMSO. It has been observed that triazolo-thiadiazole derivatives are found to be more active than 1,3,4-oxadiazole derivatives against all pathogenic bacterial and fungal strains.

Antihypertensive activity of newer 1,4-dihydro-5-pyrimidine carboxamides: synthesis and pharmacological evaluation.

A number of 5-(4-substituted phenyl)-2-(substituted benzylsulfanyl)-4-(substituted phenyl)-6-methyl-1,4-dihydro-5-pyrimidine carboxamides (1-30) were designed and synthesized keeping in view the structural requirements as suggested in the pharmacophore model for antihypertensive activity. All the synthesized compounds were tested for antihypertensive activity by non-invasive blood pressure (NIBP) measurements (tail-cuff method) in rats. Almost all the tested compounds displayed considerable decrease in the blood pressure as compared to control. Thirteen compounds showed significant antihypertensive activity comparable to the standard drug nifedipine.