AlphaFold2 Predictions of Conformational Ensembles and Atomistic Simulations of the SARS-CoV-2 Spike XBB Lineages Reveal Epistatic Couplings between Convergent Mutational Hotspots that Control ACE2 Affinity.

In this study, we combined AlphaFold-based atomistic structural modeling, microsecond molecular simulations, mutational profiling, and network analysis to characterize binding mechanisms of the SARS-CoV-2 spike protein with the host receptor ACE2 for a series of Omicron XBB variants including XBB.1.5, XBB.1.5+L455F, XBB.1.5+F456L, and XBB.1.5+L455F+F456L. AlphaFold-based structural and dynamic modeling of SARS-CoV-2 Spike XBB lineages can accurately predict the experimental structures and characterize conformational ensembles of the spike protein complexes with the ACE2. Microsecond molecular dynamics simulations identified important differences in the conformational landscapes and equilibrium ensembles of the XBB variants, suggesting that combining AlphaFold predictions of multiple conformations with molecular dynamics simulations can provide a complementary approach for the characterization of functional protein states and binding mechanisms. Using the ensemble-based mutational profiling of protein residues and physics-based rigorous calculations of binding affinities, we identified binding energy hotspots and characterized the molecular basis underlying epistatic couplings between convergent mutational hotspots. Consistent with the experiments, the results revealed the mediating role of the Q493 hotspot in the synchronization of epistatic couplings between L455F and F456L mutations, providing a quantitative insight into the energetic determinants underlying binding differences between XBB lineages. We also proposed a network-based perturbation approach for mutational profiling of allosteric communications and uncovered the important relationships between allosteric centers mediating long-range communication and binding hotspots of epistatic couplings. The results of this study support a mechanism in which the binding mechanisms of the XBB variants may be determined by epistatic effects between convergent evolutionary hotspots that control ACE2 binding.

Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial.

BACKGROUND: The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2-2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8-1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data. CONCLUSION: Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04475666 . Registered on July 17, 2020.

Pattern of Virtual Consultations in the Kingdom of Saudi Arabia: An Epidemiological Nationwide Study.

BACKGROUND: In the Kingdom of Saudi Arabia (KSA), little is known about the adoption of virtual consultations (VCs), with most studies being survey-based leading to varying results. This study aims to utilise secondary collected data on the use of both kinds of VCs currently available, and to epidemiologically describe the adoption of these consultations. METHODS: This retrospective study analysed data provided by the Ministry of Health between January 1st 2021 and June 30th 2022. For both the home-based and the hospital-based consultations, variables included the age and sex of patients, date of consultation, duration in minutes, closure status for the appointment and the governorate in which the patient is residing. A heat map was drawn to present patterns of utilisation across the country. RESULTS: The total number of VCs for both types were 1,008,228. For both types, females were higher adopters (54.73%). Of the total number of consultations, 751,156 were hospital-based. Of these consultations, family medicine consultations were the most common (20.42%), followed by internal medicine. Maternity follow-up clinics were higher in home-based clinics. The proportion of patient no-shows was high overall (48.30%). Utilisation was high in urban governorates, and low in rural ones. CONCLUSION: Findings have several implications on health policy. It provides further evidence of the importance of family medicine, where it was the most common speciality even in hospital-based settings. The high variability in the adoption of consultations across rural and urban areas as well as the extremely high number of patient-no-shows warrants further investigation.

Folliculotropic mycosis fungoides associated with follicular mucinosis: A case report and mini review.

Key Clinical Message: F-MF is a rare non-classic variant of MF. In the case of hair loss, this should be a diagnostic consideration. The essence of the diagnosis of F-MF is a careful medical history, physical examination, and a combination of immunohistological and molecular analyses (Cureus. 2022; 14:e21231, Ann Saudi Med. 2012; 32:283, Oman Med J. 2012; 27:134, Int J Dermatol. 2016; 55:1396, Saudi Med J. 2018; 39:994 and Case Rep Oncol. 2018; 11:436). Abstract: Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma with multiple subtypes. Follicular MF (F-MF) is a non-classic variant of MF. Histological features entail folliculotropism and damage of the epithelium lining of the hair follicles with or without mucin deposition. A 52-year-old male patient complained of recurrent skin lesions on the scalp over 8 months. The lesions appeared suddenly, enlarged over time, and became itchy. A skin punch biopsy was performed. Histological features included mucin deposits in the epithelium of the hair follicles and dense, predominantly perifollicular atypical lymphocytes infiltrating the follicular epithelium. The lymphoid cells were composed of CD3-positive T cells (CD4/CD8-positive T cells) with a shift in favor of the former. The case was diagnosed as F-MF on an immunohistological basis. The diagnosis of F-MF is often difficult for dermatologists and dermatopathologists alike. Not only clinicopathological correlations but also immunohistochemical and molecular analysis are required.

Predicting Functional Conformational Ensembles and Binding Mechanisms of Convergent Evolution for SARS-CoV-2 Spike Omicron Variants Using AlphaFold2 Sequence Scanning Adaptations and Molecular Dynamics Simulations.

In this study, we combined AlphaFold-based approaches for atomistic modeling of multiple protein states and microsecond molecular simulations to accurately characterize conformational ensembles and binding mechanisms of convergent evolution for the SARS-CoV-2 Spike Omicron variants BA.1, BA.2, BA.2.75, BA.3, BA.4/BA.5 and BQ.1.1. We employed and validated several different adaptations of the AlphaFold methodology for modeling of conformational ensembles including the introduced randomized full sequence scanning for manipulation of sequence variations to systematically explore conformational dynamics of Omicron Spike protein complexes with the ACE2 receptor. Microsecond atomistic molecular dynamic simulations provide a detailed characterization of the conformational landscapes and thermodynamic stability of the Omicron variant complexes. By integrating the predictions of conformational ensembles from different AlphaFold adaptations and applying statistical confidence metrics we can expand characterization of the conformational ensembles and identify functional protein conformations that determine the equilibrium dynamics for the Omicron Spike complexes with the ACE2. Conformational ensembles of the Omicron RBD-ACE2 complexes obtained using AlphaFold-based approaches for modeling protein states and molecular dynamics simulations are employed for accurate comparative prediction of the binding energetics revealing an excellent agreement with the experimental data. In particular, the results demonstrated that AlphaFold-generated extended conformational ensembles can produce accurate binding energies for the Omicron RBD-ACE2 complexes. The results of this study suggested complementarities and potential synergies between AlphaFold predictions of protein conformational ensembles and molecular dynamics simulations showing that integrating information from both methods can potentially yield a more adequate characterization of the conformational landscapes for the Omicron RBD-ACE2 complexes. This study provides insights in the interplay between conformational dynamics and binding, showing that evolution of Omicron variants through acquisition of convergent mutational sites may leverage conformational adaptability and dynamic couplings between key binding energy hotspots to optimize ACE2 binding affinity and enable immune evasion.

Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape.

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with the host cell receptor ACE2 and a panel of diverse class one antibodies. The central objective of this investigation was to examine the molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing of ACE2 binding and antibody evasion for Omicron variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.5 + L455F/F456L. By combining evolutionary analysis, molecular dynamics simulations, and ensemble-based mutational scanning of spike protein residues in complexes with ACE2, we identified structural stability and binding affinity hotspots that are consistent with the results of biochemical studies. In agreement with the results of deep mutational scanning experiments, our quantitative analysis correctly reproduced strong and variant-specific epistatic effects in the XBB.1.5 and BA.2 variants. It was shown that Y453W and F456L mutations can enhance ACE2 binding when coupled with Q493 in XBB.1.5, while these mutations become destabilized when coupled with the R493 position in the BA.2 variant. The results provided a molecular rationale of the epistatic mechanism in Omicron variants, showing a central role of the Q493/R493 hotspot in modulating epistatic couplings between convergent mutational sites L455F and F456L in XBB lineages. The results of mutational scanning and binding analysis of the Omicron XBB spike variants with ACE2 receptors and a panel of class one antibodies provide a quantitative rationale for the experimental evidence that epistatic interactions of the physically proximal binding hotspots Y501, R498, Q493, L455F, and F456L can determine strong ACE2 binding, while convergent mutational sites F456L and F486P are instrumental in mediating broad antibody resistance. The study supports a mechanism in which the impact on ACE2 binding affinity is mediated through a small group of universal binding hotspots, while the effect of immune evasion could be more variant-dependent and modulated by convergent mutational sites in the conformationally adaptable spike regions.

Unmet Needs and Strategies to Promote Patient Engagement in the Arab World: Experts' Opinion.

BACKGROUND: The significance of patient engagement (PE) is widely acknowledged as a crucial element in fostering positive health outcomes, elevating care quality, and streamlining healthcare systems. Despite its recognized advantages, the level of patient engagement in Arab nations remains suboptimal. METHODS: A high-level assembly was convened in Dubai with 11 distinguished patient advocates from diverse Arab countries. Their collective aim was to dissect the obstacles hindering patient engagement in the Arab world and propose pragmatic strategies to surmount them. First, a series of five open-ended, comprehensive questions were posed and thoroughly deliberated upon. Second, the barriers to patient engagement within the experts' respective communities were debated. A qualitative thematic analysis was conducted and two reports were generated by two independent researchers from the original meeting recordings. RESULTS: This paper highlights the importance of patient engagement in advancing healthcare and categorizes barriers to patient engagement as patient-related, provider-related, or system/government-related. The experts identified the primary gaps in patient engagement and proposed strategies to promote it, with a primary focus on motivating both patients and providers toward shared decision-making. CONCLUSIONS: This paper amalgamates the insights and recommendations distilled from the expert gathering, juxtaposing them within the broader context of existing literature on patient engagement. Offering a comprehensive viewpoint, this article delves into the challenges and opportunities intrinsic to bolstering patient engagement in the Arab world. Moreover, it spotlights invaluable tools often overlooked within Arab countries. The practical insights provided here can serve as a roadmap for administrators and decision-makers, providing guidance to enhance patient engagement on both a national and institutional scale.

A support vector machine based drought index for regional drought analysis.

The increased global warming has increased the likelihood of recurrent drought hazards. Potential links between the frequency of extreme weather events and global warming have been suggested by earlier research. The spatial variability of meteorological factors over short distances can cause distortions in conclusions or limit the scope of drought analysis in a particular region when extreme values predominate. Therefore, it is challenging to make trustworthy judgments regarding the spatiotemporal characteristics of regional drought. This study aims to improve the quality and accuracy of regional drought characterization and the process of continuous monitoring. The new drought indicator presented in this study is called the Support Vector Machine based drought index (SVM-DI). It is created by adding different weights to an SVM-based X-bar chart that is displayed with regional precipitation aggregate data. The SVM-DI application site is located in Pakistan's northern area. Using the Pearson correlation coefficient for pairwise comparison, the study compares the SVM-DI and the Regional Standard Precipitation Index (RSPI). Interestingly, compared to RSPI, SVM-DI shows more pronounced regional characteristics in its correlations with other meteorological stations, with a significantly lower Coefficient of Variation. These results confirm that SVM-DI is a useful tool for regional drought analysis. The SVM-DI methodology offers a unique way to reduce the impact of extreme values and outliers when aggregating regional precipitation data.

Comparative phenotypic and genotypic analysis of community-acquired and hospital-acquired intra-abdominal infections among liver transplanted patients.

AIM: During liver transplantation, both hospital-acquired (HA) and community-acquired (CA) intra-abdominal infections (IAIs) are involved causing life-threatening diseases. Therefore, comparative studies of aerobic and facultative anaerobic HA-IAIs and CA-IAIs after liver transplantation surgery are necessary. METHODS AND RESULTS: The species of detected isolates (310) from intra-abdominal fluid were identified and classified into hospital-acquired intra-abdominal infections (HA-IAIs) and community-acquired intra-abdominal infections (CA-IAIs). Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii were the most commonly detected species. The resistant phenotypes were commonly detected among the HA-IAIs; however, the virulent phenotypes were the predominant strains of CA-IAIs. Regrettably, the resistance profiles were shocking, indicating the inefficacy of monotherapy in treating these isolates. Therefore, we confirmed the use of empirical combination therapies of amikacin and meropenem for treating all IAIs (FICI ≤ 0.5). Unfortunately, the high diversity and low clonality of all identified HA and CA-IAIs were announced with D-value in the range of 0.992-1. CONCLUSION: This diversity proves that there are infinite numbers of infection sources inside and outside healthcare centers.

The incorporation of sumac seed powder (Rhus coriaria L.) into the diet of quail breeders as a novel feed additive.

A total of 150 adult quails, aged 8 wk, were divided into 5 groups to study the effect of sumac seed powder on reproductive and productive parameters, egg quality, digestive enzymes, and quail breeders' blood profiles. Dietary supplements containing sumac powder were formulated as follows: group 1 (G1) (control, only basal diet); group 2 (G2) (basal diet + 1 g sumac powder/kg diet); group 3 (G3) (basal diet + 2 g sumac powder/kg diet); group 4 (G4) (basal diet + 3 g sumac powder/kg diet); and group 5 (G5) (basal diet + 4 g sumac powder/kg diet). The feed conversion ratio was significantly higher at all levels of sumac powder (P < 0.05) compared to the control group (G1). Overall, during the study (8-16 wk), quail-fed 3 g sumac powder/kg diet (G4) showed no significant increase (P > 0.05) in the feed intake compared to the control group. Sumac powder supplementation significantly (P < 0.05) increased egg number, egg weight, egg mass, fertility, and hatchability. While supplementing with sumac powder did not impact other egg quality parameters, it did significantly (P < 0.05) increase yolk percentage, Haugh unit, and unit surface shell weight. Furthermore, when compared to the control group (G1), birds given 2, 3, or 4 g of sumac powder/kg diet showed a significant improvement (P < 0.05) in hematological parameters such as red blood cells, white blood cells, and hemoglobin, as well as a decrease in glucose levels. Feeding quail with a 3 g sumac powder/kg diet (G4) resulted in significantly (P < 0.05) higher globulin levels and improved albumin/globulin ratio compared to other treatments and control (G1). Sumac powder intake significantly (P < 0.05) reduced plasma lipid profile, liver enzymes (aspartate aminotransferase, and alanine aminotransferase), and kidney functions (creatinine, and urea). Furthermore, the supplementation of sumac powder resulted in a substantial increase (P < 0.05) in the levels of amylase, lipase, and protease. Sumac powder administration also significantly (P < 0.05) improves immunity by boosting IgM, IgG, IgA, and lysozyme levels in quail breeders' plasma. Supplementing with sumac powder, on the other hand, increased levels of reduced glutathione, total antioxidant capacity, catalase, and superoxide dismutase. The results of the current study indicated that the addition of 1, 2, 3, and 4 g of sumac powder to the diet of Japanese quail breeders led to improvements in egg quality, digestive enzymes, reproductive and productive performances, and most blood hematological and biochemical parameters.

Interpretable Atomistic Prediction and Functional Analysis of Conformational Ensembles and Allosteric States in Protein Kinases Using AlphaFold2 Adaptation with Randomized Sequence Scanning and Local Frustration Profiling.

The groundbreaking achievements of AlphaFold2 (AF2) approaches in protein structure modeling marked a transformative era in structural biology. Despite the success of AF2 tools in predicting single protein structures, these methods showed intrinsic limitations in predicting multiple functional conformations of allosteric proteins and fold-switching systems. The recent NMR-based structural determination of the unbound ABL kinase in the active state and two inactive low-populated functional conformations that are unique for ABL kinase presents an ideal challenge for AF2 approaches. In the current study we employ several implementations of AF2 methods to predict protein conformational ensembles and allosteric states of the ABL kinase including (a) multiple sequence alignments (MSA) subsampling approach; (b) SPEACH_AF approach in which alanine scanning is performed on generated MSAs; and (c) introduced in this study randomized full sequence mutational scanning for manipulation of sequence variations combined with the MSA subsampling. We show that the proposed AF2 adaptation combined with local frustration mapping of conformational states enable accurate prediction of the ABL active and intermediate structures and conformational ensembles, also offering a robust approach for interpretable characterization of the AF2 predictions and limitations in detecting hidden allosteric states. We found that the large high frustration residue clusters are uniquely characteristic of the low-populated, fully inactive ABL form and can define energetically frustrated cracking sites of conformational transitions, presenting difficult targets for AF2 methods. This study uncovered previously unappreciated, fundamental connections between distinct patterns of local frustration in functional kinase states and AF2 successes/limitations in detecting low-populated frustrated conformations, providing a better understanding of benefits and limitations of current AF2-based adaptations in modeling of conformational ensembles.

Dermoscopy aids in lesion selection for microbiological and histopathological assessment of mycetoma.

Mycetoma, a chronic granulomatous infection of the skin and the subcutaneous tissue, is characterized by discharge of exudate containing grains. This report illustrates the importance of dermoscopy in selecting lesions for both microbiological and histopathological assessment, which are considered the gold standard of diagnosis in mycetoma.

Analysis of dermoscopy images of multi-class for early detection of skin lesions by hybrid systems based on integrating features of CNN models.

Skin cancer is one of the most fatal skin lesions, capable of leading to fatality if not detected in its early stages. The characteristics of skin lesions are similar in many of the early stages of skin lesions. The AI in categorizing diverse types of skin lesions significantly contributes to and helps dermatologists to preserve patients' lives. This study introduces a novel approach that capitalizes on the strengths of hybrid systems of Convolutional Neural Network (CNN) models to extract intricate features from dermoscopy images with Random Forest (Rf) and Feed Forward Neural Networks (FFNN) networks, leading to the development of hybrid systems that have superior capabilities early detection of all types of skin lesions. By integrating multiple CNN features, the proposed methods aim to improve the robustness and discriminatory capabilities of the AI system. The dermoscopy images were optimized for the ISIC2019 dataset. Then, the area of the lesions was segmented and isolated from the rest of the image by a Gradient Vector Flow (GVF) algorithm. The first strategy for dermoscopy image analysis for early diagnosis of skin lesions is by the CNN-RF and CNN-FFNN hybrid models. CNN models (DenseNet121, MobileNet, and VGG19) receive a region of interest (skin lesions) and produce highly representative feature maps for each lesion. The second strategy to analyze the area of skin lesions and diagnose their type by means of CNN-RF and CNN-FFNN hybrid models based on the features of the combined CNN models. Hybrid models based on combined CNN features have achieved promising results for diagnosing dermoscopy images of the ISIC 2019 dataset and distinguishing skin cancers from other skin lesions. The Dense-Net121-MobileNet-RF hybrid model achieved an AUC of 95.7%, an accuracy of 97.7%, a precision of 93.65%, a sensitivity of 91.93%, and a specificity of 99.49%.

Ceiba pentandra ethyl acetate extract improves doxorubicin antitumor outcomes against chemically induced liver cancer in rat model: a study supported by UHPLC-Q-TOF-MS/MS identification of the bioactive phytomolecules.

Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide. Late-stage detection, ineffective treatments, and tumor recurrence contribute to the low survival rate of the HCC. Conventional chemotherapeutic drugs, like doxorubicin (DOX), are associated with severe side effects, limited effectiveness, and tumor resistance. To improve therapeutic outcomes and minimize these drawbacks, combination therapy with natural drugs is being researched. Herein, we assessed the antitumor efficacy of Ceiba pentandra ethyl acetate extract alone and in combination with DOX against diethylnitrosamine (DENA)-induced HCC in rats. Our in vivo study significantly revealed improvement in the liver-function biochemical markers (ALT, AST, GGT, and ALP), the tumor marker (AFP-L3), and the histopathological features of the treated groups. A UHPLC-Q-TOF-MS/MS analysis of the Ceiba pentandra ethyl acetate extract enabled the identification of fifty phytomolecules. Among these are the dietary flavonoids known to have anticancer, anti-inflammatory, and antioxidant qualities: protocatechuic acid, procyanidin B2, epicatechin, rutin, quercitrin, quercetin, kaempferol, naringenin, and apigenin. Our findings highlight C. pentandra as an affordable source of phytochemicals with possible chemosensitizing effects, which could be an intriguing candidate for the development of liver cancer therapy, particularly in combination with chemotherapeutic drugs.

Awareness of Risk Factors for Coronary Artery Disease in the Population of Al-Majma'ah Region, Saudi Arabia.

BACKGROUND: Coronary artery disease (CAD) is a significant global health concern and a leading cause of morbidity and mortality. As a complex cardiovascular condition, CAD arises from the accumulation of atherosclerotic plaques within the coronary arteries, leading to restricted blood flow to the heart muscle. While CAD has been extensively studied, its prevalence remains a challenge, particularly in diverse populations with distinct cultural and lifestyle practices. OBJECTIVES:  To assess the awareness of risk factors for CAD in the population of Al-Majma'ah Region, Saudi Arabia. METHODS:  The purpose of this cross-sectional descriptive study was to determine participants' awareness of CAD risk factors among the population of Al-Majma'ah Region, Saudi Arabia. It was conducted by the use of a self-administered questionnaire that had been validated in prior research publications. Sociodemographic information as well as the prevalence of cardiovascular disease risk factors were covered in the survey. The data analysis was done using IBM SPSS Statistics for Windows, Version 26 (Released 2019; IBM Corp., Armonk, New York, United States). RESULTS: A total of 919 individuals were enrolled in the current study after meeting the inclusion criteria. The results showed that most of the respondents 626 (68.1%) had a good level of awareness, 261 (28.4%) had a fair level of awareness, while only 32 (3.5%) of the respondents had a poor level of CAD risk factors awareness. CONCLUSION: The majority of participants had a good level of knowledge regarding CAD risk factors. The correlation between monthly income and awareness of coronary artery risk factors was statistically significant.

AlphaFold2-Enabled Atomistic Modeling of Structure, Conformational Ensembles, and Binding Energetics of the SARS-CoV-2 Omicron BA.2.86 Spike Protein with ACE2 Host Receptor and Antibodies: Compensatory Functional Effects of Binding Hotspots in Modulating Mechanisms of Receptor Binding and Immune Escape.

The latest wave of SARS-CoV-2 Omicron variants displayed a growth advantage and increased viral fitness through convergent evolution of functional hotspots that work synchronously to balance fitness requirements for productive receptor binding and efficient immune evasion. In this study, we combined AlphaFold2-based structural modeling approaches with atomistic simulations and mutational profiling of binding energetics and stability for prediction and comprehensive analysis of the structure, dynamics, and binding of the SARS-CoV-2 Omicron BA.2.86 spike variant with ACE2 host receptor and distinct classes of antibodies. We adapted several AlphaFold2 approaches to predict both the structure and conformational ensembles of the Omicron BA.2.86 spike protein in the complex with the host receptor. The results showed that the AlphaFold2-predicted structural ensemble of the BA.2.86 spike protein complex with ACE2 can accurately capture the main conformational states of the Omicron variant. Complementary to AlphaFold2 structural predictions, microsecond molecular dynamics simulations reveal the details of the conformational landscape and produced equilibrium ensembles of the BA.2.86 structures that are used to perform mutational scanning of spike residues and characterize structural stability and binding energy hotspots. The ensemble-based mutational profiling of the receptor binding domain residues in the BA.2 and BA.2.86 spike complexes with ACE2 revealed a group of conserved hydrophobic hotspots and critical variant-specific contributions of the BA.2.86 convergent mutational hotspots R403K, F486P, and R493Q. To examine the immune evasion properties of BA.2.86 in atomistic detail, we performed structure-based mutational profiling of the spike protein binding interfaces with distinct classes of antibodies that displayed significantly reduced neutralization against the BA.2.86 variant. The results revealed the molecular basis of compensatory functional effects of the binding hotspots, showing that BA.2.86 lineage may have evolved to outcompete other Omicron subvariants by improving immune evasion while preserving binding affinity with ACE2 via through a compensatory effect of R493Q and F486P convergent mutational hotspots. This study demonstrated that an integrative approach combining AlphaFold2 predictions with complementary atomistic molecular dynamics simulations and robust ensemble-based mutational profiling of spike residues can enable accurate and comprehensive characterization of structure, dynamics, and binding mechanisms of newly emerging Omicron variants.

Prevalence of nocturnal enuresis among children of Aseer region in Saudi Arabia.

Introduction: Nocturnal enuresis (NE) in children is a very common problem managed in pediatric urology. In this study, we present the prevalence of NE in children in Aseer region in Saudi Arabia. Methodology: This study was conducted as a descriptive cross-sectional survey to estimate the prevalence of NE among 555 Saudi children aged 5-15 years in Aseer region in Saudi Arabia. Data collection was done through a questionnaire, which included questions on sociodemographic data, personal knowledge, enuresis-related characteristics, risk factors, and management modalities. Results: This study identified a prevalence of enuresis of 24% of the study population, most of whom were boys. The majority of the parents had a high educational level. Clinical characteristics of the study population showed: 9% have a family history of NE, 2.2% have a history of neurological disorder, 10.0% have a history of urinary tract infections, 66.8% have associated daytime urgency, 67% have urine-holding behavior, and 19.5% have associated daytime enuresis of the study population. Conclusion: Our study found that 24% of children in the Aseer region in Saudi Arabia have NE. Our study finding helps us to understand the prevalence of NE in Aseer region in Saudi Arabia, and this can be applied to other regions in the kingdom. Furthermore, this finding helps us to understand the need to raise awareness in the community about NE and the need to educate the nonpediatric urologist health-care provider about the best management practice for NE.

Consumption of aphrodisiac drugs without prescription among men in Saudi Arabia: cross-sectional study.

Background: The prevalence and patterns of aphrodisiac drug consumption without prescription among men in Saudi Arabia remain underexplored, with limited empirical evidence available. Given the potential health implications and societal considerations, a comprehensive investigation is warranted. Aim: Assess the Prevalence, pattern of use and the associated factors of Aphrodisiac drugs consumption without prescription among men at Najran City, Saudi Arabia. Methods: Employing a cross-sectional descriptive study, 500 participants were included through convenience sampling. The utilized questionnaires covered a range of data, including socio-demographic information, patterns of aphrodisiac use, knowledge about aphrodisiacs, lifestyle details, a sexual health inventory for men, and a perceived stress level scale. Results: The study reveals a significant prevalence of unsanctioned aphrodisiac drug use (31%) among men in Najran City, Saudi Arabia, with a majority (79.3%) consuming these substances four times monthly. Associated disparities in knowledge, lifestyle, stress, and sexual function underscore the urgent need for policy interventions and tailored health education initiatives for this demographic. Conclusion: Approximately one-third of the sampled population engaged in the unsanctioned use of aphrodisiac drugs, with the majority utilizing them four times monthly. Tablets emerged as the most prevalent form of consumption. Commonly cited motives and justifications included peer influence and the perceived safety of aphrodisiacs. Influential factors encompassed levels of knowledge, lifestyle, stress levels, erectile function, age, education, and the number of wives. Recommendations: Urgent policy interventions are warranted to regulate the acquisition and distribution of aphrodisiacs. Tailored health education initiatives should be implemented for married and prospective married men.

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection.

The Marburg virus (MBV), a deadly pathogen, poses a serious threat to world health due to the lack of effective treatments, calling for an immediate search for targeted and efficient treatments. In this study, we focused on compounds originating from marine fungi in order to identify possible inhibitory compounds against the Marburg virus (MBV) VP35-RNA binding domain (VP35-RBD) using a computational approach. We started with a virtual screening procedure using the Lipinski filter as a guide. Based on their docking scores, 42 potential candidates were found. Four of these compounds-CMNPD17596, CMNPD22144, CMNPD25994, and CMNPD17598-as well as myricetin, the control compound, were chosen for re-docking analysis. Re-docking revealed that these particular compounds had a higher affinity for MBV VP35-RBD in comparison to the control. Analyzing the chemical interactions revealed unique binding properties for every compound, identified by a range of Pi-cation interactions and hydrogen bond types. We were able to learn more about the dynamic behaviors and stability of the protein-ligand complexes through a 200-nanosecond molecular dynamics simulation, as demonstrated by the compounds' consistent RMSD and RMSF values. The multidimensional nature of the data was clarified by the application of principal component analysis, which suggested stable conformations in the complexes with little modification. Further insight into the energy profiles and stability states of these complexes was also obtained by an examination of the free energy landscape. Our findings underscore the effectiveness of computational strategies in identifying and analyzing potential inhibitors for MBV VP35-RBD, offering promising paths for further experimental investigations and possible therapeutic development against the MBV.

Inhibition of SARS-CoV-2 NSP-15 by Uridine-5'-Monophosphate Analogues Using QSAR Modelling, Molecular Dynamics Simulations, and Free Energy Landscape.

SARS-CoV-2 is accountable for severe social and economic disruption around the world causing COVID-19. Non-structural protein-15 (NSP15) possesses a domain that is vital to the viral life cycle and is known as uridylate-specific endoribonuclease (EndoU). This domain binds to the uridine 5'-monophosphate (U5P) so that the protein may carry out its native activity. It is considered a vital drug target to inhibit the growth of the virus. Thus, in this current study, ML-based QSAR and virtual screening of U5P analogues targeting Nsp15 were performed to identify potential molecules against SARS-CoV-2. Screening of 816 unique U5P analogues using ML-based QSAR identified 397 compounds ranked on their predicted bioactivity (pIC50). Further, molecular docking and hydrogen bond interaction analysis resulted in the selection of the top three compounds (53309102, 57398422, and 76314921). Molecular dynamics simulation of the most promising compounds showed that two molecules 53309102 and 57398422 acted as potential binders of Nsp15. The compound was able to inhibit nsp15 activity as it was successfully bound to the active site of the nsp15 protein. This was achieved by the formation of relevant contacts with enzymatically critical amino acid residues (His235, His250, and Lys290). Principal component analysis and free energy landscape studies showed stable complex formation while MM/GBSA calculation showed lower binding energies for 53309102 (ΔGTOTAL = -29.4 kcal/mol) and 57398422 (ΔGTOTAL = -39.4 kcal/mol) compared to the control U5P (ΔGTOTAL = -18.8 kcal/mol). This study aimed to identify analogues of U5P inhibiting the NSP15 function that potentially could be used for treating COVID-19.