Comparative efficacy of different surgical techniques for pediatric urolithiasis-a systematic review and meta-analysis.

Background: Prior research has assessed a range of surgical treatments for pediatric urolithiasis, emphasizing the necessity of tailor-made therapeutic approaches. These studies also show the adaptability of percutaneous nephrolithotomy (PCNL), retrograde intrarenal surgery (RIRS), and shock wave lithotripsy (SWL) in managing diverse stone dimensions. The goal of this research was to examine the effectiveness of these varying surgical methods in treating pediatric urolithiasis. Methods: Seven digital databases were explored to gather pertinent studies, following the guidelines established by the PRISMA protocol. The retrieved studies were subsequently scrutinized to draw comparisons between the stone-free rate (SFR) and the rate of complications associated with PCNL, RIRS, and SWL. Results: The SFR evaluation revealed no notable disparity between PCNL and RIRS [odds ratio (OR) 1.43, 95% confidence interval (CI): 0.67-3.05, P=0.36]. However, it was observed that both PCNL and RIRS outperformed SWL in terms of effectiveness (OR 2.51, 95% CI: 1.19-5.29, P=0.02 and OR 2.42, 95% CI: 1.41-4.14, P=0.001 respectively). Regarding the complication rates, no significant differences were observed among the three surgical methods (OR 0.67, 95% CI: 0.49-1.59, P=0.05), albeit with various forms of complications being reported. Certain studies associated PCNL with an elevated rate of complications, specifically urinary tract infections (UTIs) and severe hematuria. Conclusions: Though PCNL and RIRS demonstrated higher effectiveness than SWL in achieving SFR, there was no significant disparity in the rates of complications across all three procedures. The study underscores the significance of personalized treatment plans, taking into account aspects such as the dimension and location of the stone, along with patient-specific characteristics.

Identification of Novel Antileishmanial Chemotypes By High-Throughput Virtual and In Vitro Screening.

BACKGROUND: Leishmaniasis is a deadly protozoan parasitic disease and a significant health problem in underdeveloped and developing countries. The global spread of the parasite, coupled with the emergence of drug resistance and severe side effects associated with existing treatments, has necessitated the identification of new and potential drugs. OBJECTIVE: This study aimed to identify promising compounds for the treatment of leishmaniasis by targeting two essential enzymes of Leishmania donovani: trypanothione reductase (Try-R) and trypanothione synthetase (Try-S). METHODS: High-throughput virtual and in vitro screening of in-house and commercial databases was conducted. A pharmacophore model with seven features was developed and validated using the Guner-Henery method. The pharmacophore-based virtual screening yielded 690 hits, which were further filtered through Lipinski's rule, ADMET analysis, and molecular docking against Try-R and Try-S. Molecular dynamics studies were performed on selected compounds, and in vitro experiments were conducted to evaluate their activity against the promastigote and amastigote forms of L. donovani. RESULTS: The virtual screening and subsequent analysis identified 33 promising compounds. Molecular dynamics studies of two compounds (comp-1 and comp-2) demonstrated stable binding interactions with the target enzymes and high affinity. In vitro experiments revealed that 13 compounds exhibited moderate activity against both the promastigote (IC50, 41 µM-76 µM) and the amastigote (IC50, 44 µM-72 µM) forms of L. donovani. Compounds 1 and 2 showed the highest percent inhibition and the lowest IC50 values. CONCLUSION: The identified compounds demonstrated significant inhibitory activity against Leishmania donovani and stable interactions with target enzymes. These findings suggest that the compounds could serve as promising leads for developing new treatments for leishmaniasis.

Systemic immune-inflammation index and its relation to blood pressure and dyslipidemia in adults: A retrospective study.

High blood pressure (BP) and dyslipidemia are major risk factors for cardiovascular disease mortality. The systemic immune-inflammation index (SII) has been suggested as a predictive tool to identify those at risk for chronic diseases, however, its use for predicting high BP and dyslipidemia has not been thoroughly investigated. This study aimed to examine the association between SII and high BP as well as lipid markers. Retrospective hospital data from a large cohort (n = 3895) of Saudi adults aged ≥18 years were analyzed. Lipid markers (cholesterol, high-density lipoprotein, low-density lipoprotein [LDL]), systolic BP, and diastolic BP measures were extracted. When the sample was divided into quartiles of SII, cholesterol, triglycerides, and LDL were higher in those with a higher SII than in those with a lower SII (P < .01). After adjusting for potential confounders, higher SII was significantly associated with higher odds of hypertension (odds ratio: 1.12, 95% confidence interval: 1.04-1.21) and elevated LDL (odds ratio: 1.07, 95% CI: 1.02-1.14), but not with elevated cholesterol. Across quartiles of SII, there was a significant trend between higher SII and the odds of hypertension in people with diabetes and those aged ≥65 years. The SII could be an economical predictive measure for identifying individuals at risk of hypertension and some aspects of dyslipidemia. Longitudinal studies are needed to confirm this relationship.

Designing a multiepitope mRNA-based vaccine against enterotoxigenic Escherichia coli infection in calves: Immunoinformatics and molecular modeling approach.

Background: Escherichia coli is one of the serious pathogens causing various infections in the animal field, such as neonatal calf diarrhea, which is responsible for mortality associated with diarrhea during the first days of life. Aim: Current work is aimed at designing an effective and safe multiepitope vaccine candidate against E. coli infection in calves based on the fimbrial protein K99 of Enterotoxigenic E. coli (ETEC) and Immuno-informatics. Methods: A conserved sequence of K99 protein was generated, and then highly antigenic, nonallergic, and overlapped epitopes were used to construct a multiepitope vaccine. Five THL, six MHC II, and four beta cell epitopes were targeted to create the candidate. The candidate vaccine was produced utilizing 15 epitopes and three types of linkers, two types of untranslated region (UTR) human hemoglobin subunit beta (HBB), UTR beta-globin (Rabb), and RpfE protein as an immunomodulation adjuvant. Results: Immuno-informatics analysis of the constructed protein showed that the protein was antigenic (antigenic score of 0.8841), stable, nonallergen, and soluble. Furthermore, the Immuno-informatics and physiochemical analysis of the constructed protein showed a stable, nonallergic, soluble, hydrophilic, and acidic PI (isoelectric point). of 9.34. Docking of the candidate vaccine with the toll-like receptor TLR3 was performed, and results showed a strong interaction between the immune receptor and the vaccine. Finally, the expression efficiency of the construct in E. coli was estimated via computational cloning of the vaccine sequence into Pet28a. Conclusion: Results of immunoinformatics and in silico approaches reveal that the designed vaccine is antigenic, stable, and able to bind to the immune cell receptors. Our results interpret the proposed multiepitope mRNA vaccine as a good preventive option against E. coli infection in calves.

Investigating mechanistic insights of curcumin in blocking the Interleukin-8 signaling pathway associated with Breast Cancer: An in-silico approach.

Interleukin-8 (IL-8) is a chemokine, a type of signaling molecule that has a role in immunological responses and inflammation. In recent years, IL-8 is additionally related to cancer growth and recurrence. Breast cancer growth, progression, and metastatic development are all linked to IL-8. Breast cancer cells are known to develop faster when IL-8 stimulates their proliferation and survival. It can also cause angiogenesis, or the creation of new blood vessels, which is necessary for tumor nutrition and growth. IL-8 and curcumin have been subjects of interest in drug design, particularly in the context of inflammation-related disorders and cancer. This study aims to give an overview of the role of IL-8. Inhibitor-based treatment approaches were being used to target IL-8 with curcumin. Molecular docking method was employed to find a potential interaction to supress competitive inhibition of IL-8 with curcumin. PASS analysis and ADMET characteristics were also being carried out. In the end, IL-8 complexed with curcumin is chosen for MD simulations. Overall, our results showed that during the simulation, the complex stayed comparatively stable. It is also possible to investigate curcumin further as a possible treatment option. The combined results imply that IL-8 and their genetic alterations can be studied in precision cancer therapeutic treatments, utilizing target-driven therapy and early diagnosis.

Knowledge of Undergraduate Students About Chronic Obstructive Pulmonary Disease in King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

Aims Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. This study assesses the level of knowledge about COPD among undergraduate students that makes it different from other respiratory illnesses. Methods A cross-sectional study was conducted among undergraduate students at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS). The Bristol Chronic obstructive pulmonary disease Knowledge Questionnaire (BCKQ) was used to evaluate the knowledge about COPD, epidemiology, symptoms, exercise, smoking, and breathlessness domains. The questionnaire was distributed among the different male colleges. Results There were 304 respondents from five colleges. The overall BCKQ mean score was 15.16±4.52 (maximum 30). The mean score was highest for the Colleges of Pharmacy (18.89±2.17) and Medicine (18.00±3.84), and the College of Science and Health Professions had the lowest score (11.56±5.58). The highest overall means for the different domains (max=5) were for smoking (2.19±1.2), and epidemiology (2.83±1.27), while symptoms of COPD (2.23±1.06) and breathlessness (1.96±1.13) were the lowest among the domains. Conclusions There was a low level of understanding among undergraduate students in general, but the Colleges of Medicine and Pharmacy had better knowledge. On the other hand, the College of Science and Health Professions had a lower score. This indicates some areas for improvement in the education program. Appropriate development in the education program is recommended, such as increasing the awareness of symptoms of COPD and other aspects of the disease.

Varicella-zoster virus-related neurological complications: From infection to immunomodulatory therapies.

The Varicella-zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV-associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune-mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune-mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV-induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV-related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV-induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections.

Competitiveness of citrus export and its determinants: a two-way fixed effect panel data model approach.

Pakistan has a conducive condition for the development of a wide range of scrumptious fruits. As a result, the country grows a diverse assortment of tropical and subtropical fruits; the most prized and top-ranked fruit among all fruits grown in Pakistan is citrus. Citrus is the principal fruit that contributes significantly to Pakistan's export earnings and national income. In this study, the cross-border determinants influencing Pakistan's citrus exports to its topmost 22 trading partners are examined using a gravity model technique. This is the first large study from Pakistan by using gravity model to check the impact of various cross-border factors on citrus fruit export. The analysis is based on a panel dataset covering the years 2003 to 2021. To estimate the results, the study used fixed effect regression with time and country fixed effects. The results signify that per capita income, population, and some regional dummies are positively associated with citrus exports from Pakistan. Citrus price, distance, exchange rate, and other regional dummies are observed to have an adverse effect on citrus exports. Trade agreements between Pakistan and trade partners such as free trade agreements, preferential trade agreements, and SAFTA, have been observed as important determinants of citrus exports. Citrus exporters in Pakistan can also benefit from understanding the factors that influence export markets. By addressing the challenges identified in this study, Pakistan can enhance its citrus exports and boost its agricultural sector.

Green synthesized silver nanoparticles of Terminalia bellirica leaves extract: synthesis, characterization, in-silico studies, and antimalarial activity.

Malaria is a mosquito-borne infectious disease that is caused by the Plasmodium parasite. Most of the available medication are losing their efficacy. Therefore, it is crucial to create fresh leads to combat malaria. Green silver nanoparticles (AgNPs) have recently attracted a lot of attention in biomedical research. As a result, green mediated AgNPs from leaves of Terminalia bellirica, a medicinal plant with purported antimalarial effects, were used in this investigation. Initially, cysteine-rich proteins from Plasmodium species were studied in silico as potential therapeutic targets. With docking scores between -9.93 and -11.25 kcal/mol, four leaf constituents of Terminalia bellirica were identified. The green mediated silver nanoparticles were afterward produced using leaf extract and were further examined using UV-vis spectrophotometer, DLS, Zeta potential, FTIR, XRD, and FESEM. The size of synthesized TBL-AgNPs was validated by the FESEM results; the average size of TBL-AgNPs was around 44.05 nm. The zeta potential study also supported green mediated AgNPs stability. Additionally, Plasmodium falciparum (3D7) cultures were used to assess the antimalarial efficacy, and green mediated AgNPs could effectively inhibit the parasitized red blood cells (pRBCs). In conclusion, this novel class of AgNPs may be used as a potential therapeutic replacement for the treatment of malaria.

Exploring Zingiber officinale bioactive compounds for inhibitory effects on Streptococcus pneumoniae capsular polysaccharide biosynthesis proteins: In silico study.

The capsule is a major virulence factor for Streptococcus pneumoniae which causes global morbidity and mortality. It is already known that there are few conserved genes in the capsular biosynthesis pathway, which are common among all known serotypes, called CpsA, CpsB, CpsC and CpsD. Inhibiting capsular synthesis can render S. pneumoniae defenseless and vulnerable to phagocytosis. The Inhibitory potential of active Zingiber officinale compounds was investigated against the 3D (3-dimensional) structural products of Cps genes using in silico techniques. A 3D compound repository was created and screened for drug-likeness and the qualified compounds were used for molecular docking and dynamic simulation-based experiments using gallic acid for outcome comparison. Cavity-based docking revealed five different cavities in the CpsA, CpsB and CpsD proteins, with gallic acid and selected compounds of Zingiber in a binding affinity range of -6.8 to -8.8 kcal/mol. Gingerenone A, gingerenone B, isogingerenone B and gingerenone C showed the highest binding affinities for CpsA, CpsB and CpsD, respectively. Through the Molegro Virtual Docker re-docking strategy, the highest binding energies (-126.5 kcal/mol) were computed for CpsB with gingerenone A and CpsD with gingerenone B. These findings suggest that gingerenone A, B and C are potential inhibitors of S. pneumoniae-conserved capsule-synthesizing proteins.

In silico identification of phytochemical inhibitors for multidrug-resistant tuberculosis based on novel pharmacophore generation and molecular dynamics simulation studies.

BACKGROUND: Multidrug-resistant tuberculosis (particularly resistant to pyrazinoic acid) is a life-threatening chronic pulmonary disease. Running a marketed regime specifically targets the ribosomal protein subunit-1 (RpsA) and stops trans-translation in the non-mutant bacterium, responsible for the lysis of bacterial cells. However, in the strains of mutant bacteria, this regime has failed in curing TB and killing pathogens, which may only because of the ala438 deletion, which inhibit the binding of pyrazinoic acid to the RpsA active site. Therefore, such cases of tuberculosis need an immediate and effective regime. OBJECTIVE: This study has tried to determine and design such chemotypes that are able to bind to the mutant RpsA protein. METHODS: For these purposes, two phytochemical databases, i.e., NPASS and SANCDB, were virtually screened by a pharmacophore model using an online virtual screening server Pharmit. RESULTS: The model of pharmacophore was developed using the potential inhibitor (zr115) for the mutant of RpsA. Pharmacophore-based virtual screening results into 154 hits from the NPASS database, and 22 hits from the SANCDB database. All the predicted hits were docked in the binding pocket of the mutant RpsA protein. Top-ranked five and two compounds were selected from the NPASS and SANCDB databases respectively. On the basis of binding energies and binding affinities of the compounds, three compounds were selected from the NPASS database and one from the SANCDB database. All compounds were found to be non-toxic and highly active against the mutant pathogen. To further validate the docking results and check the stability of hits, molecular dynamic simulation of three compounds were performed. The MD simulation results showed that all these finally selected compounds have stronger binding interactions, lesser deviation or fluctuations, with greater compactness compared to the reference compound. CONCLUSION: These findings indicate that these compounds could be effective inhibitors for mutant RpsA.

Prevalence and Risk Factors of Voice Disorders Among Teachers in Saudi Arabia.

Introduction Voice is a crucial tool for communication, and voice problems are more likely to occur in professionals who frequently use their voice for work. Teachers, whose profession requires sustained vocal use, are particularly susceptible to occupation-related voice disorders. This study aimed to quantify the prevalence of voice disorders among teachers in Saudi Arabia, with the general population serving as a control group, and to identify associated risk factors. Methods A cross-sectional study was conducted utilizing an online self-administered questionnaire, which was completed by both teachers and the general population in Saudi Arabia. The latter group acted as a control. The questionnaire included sections on sociodemographic data, teaching patterns, symptoms of voice issues, and the Voice Handicap Index-10 (VHI-10) for assessing voice disorders among participants. Results The study included 640 participants, with 438 (68.4%) being teachers, the majority of whom were females (N = 406; 63.4%). The most common voice-related symptoms reported by teachers were hoarseness (N = 210; 37.9%) and dry throat (N = 147; 26.9%). Voice disorders, as determined by the VHI, affected 355 (55.5%) of the teachers. A high VHI score was associated with a diagnosis of voice disorders and GERD. There was no significant difference in the VHI scores between teachers and the general population (p > 0.05). Conclusion Teachers in Saudi Arabia exhibited a higher prevalence of voice disorders compared to the general population. Risk factors, such as smoking, longer teaching experience, and more teaching hours per week, were more common among teachers with voice disorders. Further investigative studies are warranted to elucidate the causal relationships between these variables and voice disorders.

Prospective virtual screening combined with bio-molecular simulation enabled identification of new inhibitors for the KRAS drug target.

Lung cancer is a disease with a high mortality rate and it is the number one cause of cancer death globally. Approximately 12-14% of non-small cell lung cancers are caused by mutations in KRASG12C. The KRASG12C is one of the most prevalent mutants in lung cancer patients. KRAS was first considered undruggable. The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. Drug development is a challenging, expensive, and time-consuming process. Recently, machine-learning-based virtual screening are used for the development of new drugs. In this study, we performed machine-learning-based virtual screening followed by molecular docking, all atoms molecular dynamics simulation, and binding energy calculations for the identifications of new inhibitors against the KRASG12C mutant. In this study, four machine learning models including, random forest, k-nearest neighbors, Gaussian naïve Bayes, and support vector machine were used. By using an external dataset and 5-fold cross-validation, the developed models were validated. Among all the models the performance of the random forest (RF) model was best on the train/test dataset and external dataset. The random forest model was further used for the virtual screening of the ZINC15 database, in-house database, Pakistani phytochemicals, and South African Natural Products database. A total of 100 ns MD simulation was performed for the four best docking score complexes as well as the standard compound in complex with KRASG12C. Furthermore, the top four hits revealed greater stability and greater binding affinities for KRASG12C compared to the standard drug. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at ( https://github.com/Amar-Ajmal/Datasets-for-KRAS ).

Structure-based investigation of pyruvate dehydrogenase kinase-3 inhibitory potential of thymoquinone, targeting lung cancer therapy.

Protein kinases are an attractive therapeutic target for cardiovascular, cancer and neurodegenerative diseases. Cancer cells demand energy generation through aerobic glycolysis, surpassing "oxidative phosphorylation" (OXPHOS) in mitochondria. The pyruvate dehydrogenase kinases (PDKs) have many regulatory roles in energy generation balance by controlling the pyruvate dehydrogenase complex. Overexpression of PDKs is associated with the overall survival of cancer. PDK3, an isoform of PDK is highly expressed in various cancer types, is targeted for inhibition in this study. PDK3 has been shown to binds strongly with a natural compound, thymoquinone (TQ), which is known to exhibit anti-cancer potential. Detailed interaction between the PDK3 and TQ was carried out using spectroscopic and docking methods. The overall changes in the protein's structures after TQ binding were estimated by UV-Vis spectroscopy, circular dichroism and fluorescence binding studies. The kinase activity assay was also carried out to see the kinase inhibitory potential of TQ. The enzyme inhibition assay suggested an excellent inhibitory potential of TQ towards PDK3 (IC50 = 5.49 µM). We observed that TQ forms a stable complex with PDK3 without altering its structure and can be a potent PDK3 inhibitor which may be implicated in cancer therapy after desired clinical validation.

Rural households' livelihood adaptation strategies in the face of changing climate: A case study from Pakistan.

Rural and agricultural communities' adaptation to climate change has gained significant attention owing to many countries' vulnerability to climate change risks. A similar trend has been witnessed in South Asia, a highly climate-vulnerable region, where research has grown dramatically considering the agriculture sector's vulnerability to climate-induced disasters. However, little attention has been paid to the adaptation of the livelihoods of rural households. This research, therefore, takes the case of Pakistan to explore livelihood adaptation strategies of rural households to climate change and investigate the factors that expedite or halt the adoption of livelihood diversification strategies. A multistage sampling design is used in this research, where 480 rural households from the Punjab province of Pakistan were selected and interviewed using stratified and random sampling approaches. A multivariate probit (MVP) regression model is employed to analyze the factors affecting households' adoption of livelihood adaptation strategies. The results show that besides adaptation of agronomic operations (agricultural adaptation strategies), rural households in the study area employed a wide range of strategies to adapt their livelihoods to climate change. These strategies include poultry and livestock farming, value addition of farm produce, trading of animals and farm commodities, small businesses (shops, etc.), daily wage labor, horticultural crop farming, and non-farming jobs. The estimates of the MVP model revealed that respondents' education, household size, income, access to a credit facility, access to farm advisory services, and access to climate forecasts have significantly influenced the choice of livelihood adaptation strategies. Based on these findings, this research recommends that the authorities should make efforts to improve farmers' understanding of the adaptation of climate change risks and educate them to adopt multiple livelihood options to improve the resilience of their livelihoods to climate-induced risks. This research has important policy implications for other countries with similar socio-economic features.

Identification of potential therapeutic targets for COVID-19 through a structural-based similarity approach between SARS-CoV-2 and its human host proteins.

Background: The COVID-19 pandemic caused by SARS-CoV-2 has led to millions of deaths worldwide, and vaccination efficacy has been decreasing with each lineage, necessitating the need for alternative antiviral therapies. Predicting host-virus protein-protein interactions (HV-PPIs) is essential for identifying potential host-targeting drug targets against SARS-CoV-2 infection. Objective: This study aims to identify therapeutic target proteins in humans that could act as virus-host-targeting drug targets against SARS-CoV-2 and study their interaction against antiviral inhibitors. Methods: A structure-based similarity approach was used to predict human proteins similar to SARS-CoV-2 ("hCoV-2"), followed by identifying PPIs between hCoV-2 and its target human proteins. Overlapping genes were identified between the protein-coding genes of the target and COVID-19-infected patient's mRNA expression data. Pathway and Gene Ontology (GO) term analyses, the construction of PPI networks, and the detection of hub gene modules were performed. Structure-based virtual screening with antiviral compounds was performed to identify potential hits against target gene-encoded protein. Results: This study predicted 19,051 unique target human proteins that interact with hCoV-2, and compared to the microarray dataset, 1,120 target and infected group differentially expressed genes (TIG-DEGs) were identified. The significant pathway and GO enrichment analyses revealed the involvement of these genes in several biological processes and molecular functions. PPI network analysis identified a significant hub gene with maximum neighboring partners. Virtual screening analysis identified three potential antiviral compounds against the target gene-encoded protein. Conclusion: This study provides potential targets for host-targeting drug development against SARS-CoV-2 infection, and further experimental validation of the target protein is required for pharmaceutical intervention.

Structural and energetic analysis of NS5 protein inhibition by small molecules in Japanese encephalitis virus using machine learning and steered molecular dynamics approach.

One of the viral diseases that affect millions of people around the world, particularly in developing countries, is Japanese encephalitis (JE). In this study, the conserved protein of this virus, that is, non-structural protein 5 (NS5), was used as a target protein for this study, and a compound library of 749 antiviral molecules was screened against NS5. The current study employed machine learning-based virtual screening combined with molecular docking. Here, three hits (24360, 123519051 and 213039) had lower binding energies (< -8 kcal/mol) than the control, S-Adenosyl-L-homocysteine (SAH). All the compounds showed significant H-bond interactions with functional residues, which were also observed by the control. Molecular dynamics simulation, MM/GBSA for binding free energy analysis, principal component analysis and free energy landscape were also performed to study the stability of the complex formation. All three compounds had similar root mean square deviation trends, which were comparable to the control, SAH. Post-MD, the 123519051-receptor complex had the highest number of H-bonds (4 to 5) after the control, out of which three exhibited the highest percentage occupancy (50%, 24% and 79%). Both docking and MD, 123519051 showed an H-bond with the residue Gly111, which was also found for the control-protein complex. 123519051 showed the lowest binding free energy with ΔGbind of -89 kJ/mol. Steered molecular dynamics depicted that 123519051 had the maximum magnitude of dissociation (1436.43 kJ/mol/nm), which was more than the control, validating its stable complex formation. This study concluded that 123519051 is a binder and could inhibit the protein NS5 of JE.Communicated by Ramaswamy H. Sarma.

Awareness of Bariatric Sleeve Gastrectomy Complications Among the General Population of Saudi Arabian Regions.

Sleeve gastrectomy (SG) is a type of procedure called bariatric surgery that provides large weight loss and has a positive impact on diseases associated with obesity. However, it has brought several complications that have an impact on those undergoing surgery, which are classified into intraoperative and postoperative issues. The study's goal is to assess the Saudi Arabian population's awareness of SG consequences. This study assessed the general population's knowledge in Saudi Arabia in 2023 using a cross-sectional approach. The total number of participants was 1,013, the majority of whom were individuals between the ages of 18 and 25 (471, 46%), and females (692, 68%). A total of 692 (68%) participants showed awareness of BMI; in addition, 987 (97%) were aware of gastric sleeve surgery, and 538 (53%) understood its indications correctly. Regarding SG complications, approximately 821 (81%) of participants showed awareness. There were significant associations between knowledge of gastric sleeve surgery and residence in the northern region of Saudi Arabia. In conclusion, our study indicated that the general population is aware of the complications of gastric sleeve surgery, but it found a deficiency in their knowledge about BMI.

Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1.

Integrin-linked kinase (ILK), a ß1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23µM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation.

Management of 'floating arm': a case report of adolescent ipsilateral proximal humerus fracture with open distal complex intraarticular fracture.

Simultaneous ipsilateral fractures of the proximal and distal humerus, known as 'floating arm', are rarely seen in adolescents and are considered challenging to manage. Most of the published cases have involved proximal humerus and distal supracondylar fractures. This paper presents a special case of floating arm injury in a 14-year-old boy following a motor vehicle accident that was managed in a well-established trauma center. The injury consisted of displaced proximal humerus and open distal T-condylar intraarticular fractures. The patient was discharged in good condition and regained functionality with no reported complications.