Drug repurposing: identification of SARS-CoV-2 potential inhibitors by virtual screening and pharmacokinetics strategies.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. METHODOLOGY: We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. RESULTS: Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. CONCLUSIONS: Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.

Antibiotic Resistance in Salmonella typhi Strains Isolated From Patients in Pakistan: A Hospital Database Study.

BACKGROUND: The surge in antibiotic-resistant Salmonella enterica serotype Typhi strains has led to heightened morbidity, mortality, and treatment expenses. This study aims to assess the resistance patterns of Salmonella Typhi to diverse antibiotics among patients seeking care at a tertiary hospital in Pakistan. METHODS: A database from a tertiary care hospital in Pakistan was reviewed, and data on blood cultures that isolated Salmonella enterica serotype Typhi were collected. Data were collected and analyzed using Microsoft Excel (Microsoft Corporation, USA) and IBM SPSS software (IBM Corp., Armonk, NY). RESULTS: Demographic information of the selected data was retrieved from the hospital database, and the results showed that 63.7% were male, 36.1% were female, and 0.2% were categorized as neutered. Regarding antibiotic resistance, ampicillin exhibited the highest resistance rate (91.50%), while meropenem demonstrated the lowest (3.00%). Antibiotic sensitivity patterns also varied across different age groups, although statistical analysis indicated no significant differences. Significant associations were found between antibiotic resistance and comorbidities, as well as previous antibiotic use. CONCLUSION:  Salmonella enterica serotype Typhi showed a high resistance to ampicillin and fluoroquinolones, such as ciprofloxacin. The emergence of resistance and decreased sensitivity to current first-line antibiotics necessitates a shift towards alternative options, such as third-generation cephalosporins, azithromycin, and newer antibiotics like meropenem.

Factors influencing pregnancy rate and loss after laparoscopic artificial insemination with frozen-thawed semen in Lohi sheep under sub-tropical conditions.

This study evaluates factors influencing pregnancy rates per artificial insemination (P/AI) and pregnancy loss in Lohi ewes undergoing laparoscopic AI with frozen-thawed semen under sub-tropical conditions. Data from three experiments comprising ewes (n = 358) of mixed parity (nulliparous; NP and parous; P), various body condition score (BCS) and assigned to long-term (LTP, 11 days) and short-term (STP, 5 days) oestrus synchronization regimen across high breeding season (HBS) and low breeding season (LBS) were analysed. Laparoscopic insemination was conducted 54 h post-sponge removal. Pregnancy diagnosis and loss were evaluated on days 35 and 90 post-insemination via ultrasonography. Results showed parity significantly influenced P/AI, with nulliparous ewes achieving higher pregnancy ratios than parous ewes (p = .001). BCS significantly influenced P/AI (p < .05), with a quadratic relationship observed between BCS and season (BCS*BCS*Season; p = .07). Progestin treatment did not significantly influence the ratio of pregnant ewes (p = .07). Pregnancy losses were significantly higher during LBS than HBS (p < .05), irrespective of progestin treatment. In conclusion, parity and BCS significantly influenced P/AI, with BCS demonstrating a quadratic association with season. Ewes bred during LBS experienced higher pregnancy losses than HBS, irrespective of progestin treatment.

Impact of frailty on endoscopic retrograde cholangiopancreatography outcomes in nonagenarians: A United States national experience.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an essential therapeutic tool for biliary and pancreatic diseases. Frail and elderly patients, especially those aged ≥ 90 years are generally considered a higher-risk population for ERCP-related complications. AIM: To investigate outcomes of ERCP in the Non-agenarian population (≥ 90 years) concerning Frailty. METHODS: This is a cohort study using the 2018-2020 National Readmission Database. Patients aged ≥ 90 were identified who underwent ERCP, using the international classification of diseases-10 code with clinical modification. Johns Hopkins's adjusted clinical groups frailty indicator was used to classify patients as frail and non-frail. The primary outcome was mortality, and the secondary outcomes were morbidity and the 30 d readmission rate related to ERCP. We used univariate and multivariate regression models for analysis. RESULTS: A total of 9448 patients were admitted for any indications of ERCP. Frail and non-frail patients were 3445 (36.46%) and 6003 (63.53%) respectively. Indications for ERCP were Choledocholithiasis (74.84%), Biliary pancreatitis (9.19%), Pancreatico-biliary cancer (7.6%), Biliary stricture (4.84%), and Cholangitis (1.51%). Mortality rates were higher in frail group [adjusted odds ratio (aOR) = 1.68, P = 0.02]. The Intra-procedural complications were insignificant between the two groups which included bleeding (aOR = 0.72, P = 0.67), accidental punctures/lacerations (aOR = 0.77, P = 0.5), and mechanical ventilation rates (aOR = 1.19, P = 0.6). Post-ERCP complication rate was similar for bleeding (aOR = 0.72, P = 0.41) and post-ERCP pancreatitis (aOR = 1.4, P = 0.44). Frail patients had a longer length of stay (6.7 d vs 5.5 d) and higher mean total charges of hospitalization ($78807 vs $71392) compared to controls (P < 0.001). The 30 d all-cause readmission rates between frail and non-frail patients were similar (P = 0.96). CONCLUSION: There was a significantly higher mortality risk and healthcare burden amongst nonagenarian frail patients undergoing ERCP compared to non-frail. Larger studies are warranted to investigate and mitigate modifiable risk factors.

Exploring dermoscopic structures for melanoma lesions' classification.

Background: Melanoma is one of the deadliest skin cancers that originate from melanocytes due to sun exposure, causing mutations. Early detection boosts the cure rate to 90%, but misclassification drops survival to 15-20%. Clinical variations challenge dermatologists in distinguishing benign nevi and melanomas. Current diagnostic methods, including visual analysis and dermoscopy, have limitations, emphasizing the need for Artificial Intelligence understanding in dermatology. Objectives: In this paper, we aim to explore dermoscopic structures for the classification of melanoma lesions. The training of AI models faces a challenge known as brittleness, where small changes in input images impact the classification. A study explored AI vulnerability in discerning melanoma from benign lesions using features of size, color, and shape. Tests with artificial and natural variations revealed a notable decline in accuracy, emphasizing the necessity for additional information, such as dermoscopic structures. Methodology: The study utilizes datasets with clinically marked dermoscopic images examined by expert clinicians. Transformers and CNN-based models are employed to classify these images based on dermoscopic structures. Classification results are validated using feature visualization. To assess model susceptibility to image variations, classifiers are evaluated on test sets with original, duplicated, and digitally modified images. Additionally, testing is done on ISIC 2016 images. The study focuses on three dermoscopic structures crucial for melanoma detection: Blue-white veil, dots/globules, and streaks. Results: In evaluating model performance, adding convolutions to Vision Transformers proves highly effective for achieving up to 98% accuracy. CNN architectures like VGG-16 and DenseNet-121 reach 50-60% accuracy, performing best with features other than dermoscopic structures. Vision Transformers without convolutions exhibit reduced accuracy on diverse test sets, revealing their brittleness. OpenAI Clip, a pre-trained model, consistently performs well across various test sets. To address brittleness, a mitigation method involving extensive data augmentation during training and 23 transformed duplicates during test time, sustains accuracy. Conclusions: This paper proposes a melanoma classification scheme utilizing three dermoscopic structures across Ph2 and Derm7pt datasets. The study addresses AI susceptibility to image variations. Despite a small dataset, future work suggests collecting more annotated datasets and automatic computation of dermoscopic structural features.

Investigation of the dynamical structures of double-chain deoxyribonucleic acid model in biological sciences.

The present research investigates the double-chain deoxyribonucleic acid model, which is important for the transfer and retention of genetic material in biological domains. This model is composed of two lengthy uniformly elastic filaments, that stand in for a pair of polynucleotide chains of the deoxyribonucleic acid molecule joined by hydrogen bonds among the bottom combination, demonstrating the hydrogen bonds formed within the chain's base pairs. The modified extended Fan sub equation method effectively used to explain the exact travelling wave solutions for the double-chain deoxyribonucleic acid model. Compared to the earlier, now in use methods, the previously described modified extended Fan sub equation method provide more innovative, comprehensive solutions and are relatively straightforward to implement. This method transforms a non-linear partial differential equation into an ODE by using a travelling wave transformation. Additionally, the study yields both single and mixed non-degenerate Jacobi elliptic function type solutions. The complexiton, kink wave, dark or anti-bell, V, anti-Z and singular wave shapes soliton solutions are a few of the creative solutions that have been constructed utilizing modified extended Fan sub equation method that can offer details on the transversal and longitudinal moves inside the DNA helix by freely chosen parameters. Solitons propagate at a consistent rate and retain their original shape. They are widely used in nonlinear models and can be found everywhere in nature. To help in understanding the physical significance of the double-chain deoxyribonucleic acid model, several solutions are shown with graphics in the form of contour, 2D and 3D graphs using computer software Mathematica 13.2. All of the requisite constraint factors that are required for the completed solutions to exist appear to be met. Therefore, our method of strengthening symbolic computations offers a powerful and effective mathematical tool for resolving various moderate nonlinear wave problems. The findings demonstrate the system's potentially very rich precise wave forms with biological significance. The fundamentals of double-chain deoxyribonucleic acid model diffusion and processing are demonstrated by this work, which marks a substantial development in our knowledge of double-chain deoxyribonucleic acid model movements.

Impact of multiple isolation procedures on the differentiation potential of adipose derived canine mesenchymal stem cells.

OBJECTIVE: In regenerative biology, the most commonly used cells are adipose tissue-derived mesenchymal stem cells (AD-MSCs). This is due to the abundance and easy accessibility of AD-MSCs. METHODS: In this study, canine AD-MSCs were harvested from different anatomical locations, i.e., subcutaneous (SC), omental (OM), and perirenal (PR). Various isolation techniques namely explants (TRT-I), collagenase-digestion (TRT-II), collagenase-digested explants (TRT-III), and trypsin-digested explants (TRT-IV) were used to segregate the MSCs to evaluate cell doubling time, viability, and adipogenic/osteogenic lineage differentiation potential. RESULTS: The study showed that the SC stem cells had superior growth kinetics compared to other tissues, while the cells isolated through TRT-II performed better than the other cell isolation procedures. The metabolic status of cells isolated from dog adipose tissue indicated that all cells had adequate metabolic rates. However, SC-MSCs derived from TRT-III and TRT-IV outperformed those derived from TRT-I and TRT-II. The differentiation analysis revealed that cells differentiate into adipogenic and osteogenic lineage regardless of treatment, as demonstrated by positive oil red O (ORO) and Alizarin Red S (ALZ) stain. It is worth mentioning that cells derived from TRT-III had larger and more intracellular droplets compared to the other treatments. The TRT-I, -II, and -III showed greater osteogenic differentiation in cells isolated from PR and OM regions compared to SC-derived cells. However, the TRT-IV resulted in better osteogenic differentiation in cells from SC, followed by the OM and PR-derived cells. CONCLUSION: It is concluded that all methods of MSCs isolation from adipose tissues are successful; however, the TRT-II had the highest rate of cell re-assortment from the SC, while, TRT-II and -IV are most suitable for isolating cells from PR and OM adipose tissue.

Dynamics of soil biota and nutrients at varied depths in a Tamarix ramosissima-dominated natural desert ecosystem: Implications for nutrient cycling and desertification management.

The underground community of soil organisms, known as soil biota, plays a critical role in terrestrial ecosystems. Different ecosystems exhibit varied responses of soil organisms to soil physical and chemical properties (SPCPs). However, our understanding of how soil biota react to different soil depths in naturally established population of salinity tolerant Tamarix ramosissima in desert ecosystems, remains limited. To address this, we employed High-Throughput Illumina HiSeq Sequencing to examine the population dynamics of soil bacteria, fungi, archaea, protists, and metazoa at six different soil depths (0-100 cm) in the naturally occurring T. ramosissima dominant zone within the Taklimakan desert of China. Our observations reveal that the alpha diversity of bacteria, fungi, metazoa, and protists displayed a linear decrease with the increase of soil depth, whereas archaea exhibited an inverse pattern. The beta diversity of soil biota, particularly metazoa, bacteria, and protists, demonstrated noteworthy associations with soil depths through Non-Metric Dimensional Scaling analysis. Among the most abundant classes of soil organisms, we observed Actinobacteria, Sordariomycetes, Halobacteria, Spirotrichea, and Nematoda for bacteria, fungi, archaea, protists, and metazoa, respectively. Additionally, we identified associations between the vertical distribution of dominant biotic communities and SPCPs. Bacterial changes were mainly influenced by total potassium, available phosphorus (AP), and soil water content (SWC), while fungi were impacted by nitrate (NO3-) and available potassium (AK). Archaea showed correlations with total carbon (TC) and AK thus suggesting their role in methanogenesis and methane oxidation, protists with AP and SWC, and metazoa with AP and pH. These correlations underscore potential connections to nutrient cycling and the production and consumption of greenhouse gases (GhGs). This insight establishes a solid foundation for devising strategies to mitigate nutrient cycling and GHG emissions in desert soils, thereby playing a pivotal role in the advancement of comprehensive approaches to sustainable desert ecosystem management.

Type V gastric ulcer: An unusual etiology of gastrosplenic fistula associated with upper gastrointestinal bleeding.

Type V gastric ulcer is an unusual etiology of gastrosplenic fistula (GSF). Prompt diagnosis and early embolization of splenic vessels prior to esophagogastroduodenoscopy and surgical resection is crucial.

Economic and social determinants of health care utilization during the first wave of COVID-19 pandemic among adults in Ghana: a population-based cross-sectional study.

BACKGROUND: The COVID-19 pandemic had socioeconomic effects in Africa. This study assessed the social and economic determinants of healthcare utilization during the first wave of COVID-19 among adults in Ghana. METHODS: Information about individuals residing in Ghana was derived from a survey conducted across multiple countries, aiming to evaluate the impact of the COVID-19 pandemic on the mental health and overall well-being of adults aged 18 and above. The dependent variable for the study was healthcare utilization (categorized as low or high). The independent variables were economic (such as financial loss, job loss, diminished wages, investment/retirement setbacks, and non-refunded travel cancellations) and social (including food scarcity, loss of financial support sources, housing instability, challenges affording food, clothing, shelter, electricity, utilities, and increased caregiving responsibilities for partners) determinants of health. A multinomial logistic regression was conducted to identify factors associated with healthcare utilization after adjusting for confounders (age, gender, access to medical insurance, COVID-19 status, educational background, employment, and marital status of the participants). RESULTS: The analysis included 364 responses. Individuals who encountered a loss of financial support (AOR: 9.58; 95% CI: 3.44-26.73; p < 0.001), a decrease or loss of wages (AOR: 7.44, 95% CI: 3.05-18.16, p < 0.001), experienced investment or retirement setbacks (AOR: 10.69, 95% CI: 2.60-43.88, p = 0.001), and expressed concerns about potential food shortages (AOR: 6.85, 95% CI: 2.49-18.84, p < 0.001) exhibited significantly higher odds of low healthcare utilization during the initial phase of the pandemic. Contrastingly, participants facing challenges in paying for basic needs demonstrated lower odds of low healthcare utilization compared to those who found it easy to cover basic expenses (AOR: 0.19, 95% CI: 0.06-0.67, p = 0.001). CONCLUSION: Economic and social factors were associated with low healthcare utilization in Ghana during the first wave of the pandemic. Investment or retirement loss and financial support loss during the pandemic had the largest effect on healthcare utilization. Further research is needed to understand the connection between concerns about food shortages, welfare losses during pandemics and healthcare utilization during pandemics in Ghana.

Berberine ameliorates the progression of primary sclerosing cholangitis by activating farnesoid X receptor.

Primary sclerosing cholangitis (PSC) is a rare cholestatic disease characterized by biliary infiltration, hepatic fibrosis and bile duct destruction. To date, treatment options for PSC are very limited. Therefore, the current study is aimed to investigate the therapeutic potential of berberine (BBR) against PSC. The disease was induced by feeding the mice with 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC) for four weeks. The serum biochemistry and liver histology were analyzed. Furthermore, the expression of farnesoid X receptor (FXR) was also evaluated by real-time PCR. The results indicated that berberine prevents the progression of PSC by modulating the expression of FXR which ultimately regulates other genes (including Cyp7A1 and BSEP) thus maintaining bile acids homeostasis. Furthermore, the docking analysis showed that berberine interacts with the binding pocket of FXR to activate the protein thus acting as an FXR agonist. In conclusion, data indicate that berberine protects the liver from PSC-related injury. This effect might be due to the modulation of FXR activity.

Se-p Orbitals Induced "Strong d-d Orbitals Interaction" Enable High Reversibility of Se-Rich ZnSe/MnSe@C Electrode as Excellent Host for Sodium-Ion Storage.

The heterostructure of transition-metal chalcogenides is a promising approach to boost alkali ion storage due to fast charge kinetics and reduction of activation energy. However, cycling performance is a paramount challenge that is suffering from poor reversibility. Herein, it is reported that Se-rich particles can chemically interact with local hexagonal ZnSe/MnSe@C heterostructure environment, leading to effective ions insertion/extraction, enabling high reversibility. Enlightened by theoretical understanding, Se-rich particles endow high intrinsic conductivities in term of low energy barriers (1.32 eV) compared with those without Se-rich particles (1.50 eV) toward the sodiation process. Moreover, p orbitals of Se-rich particles may actively participate and further increase the electronegativity that pushes the Mn d orbitals (dxy and dx2 -y2 ) and donate their electrons to dxz and dyz orbitals, manifesting strong d-d orbitals interaction between ZnSe and MnSe. Such fundamental interaction will adopt a well-stable conducive electronic bridge, eventually, charges are easily transferred from ZnSe to MnSe in the heterostructure during sodiation/desodiation. Therefore, the optimized Se-rich ZnSe/MnSe@C electrode delivered high capacity of 576 mAh g-1 at 0.1 A g-1 after 100 cycles and 384 mAh g-1 at 1 A g-1 after 2500 cycles, respectively. In situ and ex situ measurements further indicate the integrity and reversibility of the electrode materials upon charging/discharging.

Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.

Cancer is a medical condition that is caused by the abnormal growth and division of cells, leading to the formation of tumors. The E2F1 and RB pathways are critical in regulating cell cycle, and their dysregulation can contribute to the development of cancer. In this study, we analyzed experimentally reported SNPs in E2F1 and assessed their effects on the binding affinity with RB. Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure. Molecular docking of wild-type and mutant E2F1 with RB revealed a docking score of -242 kcal/mol for wild-type, while the mutant complexes had scores ranging from -217 to -220 kcal/mol. Molecular simulation analysis revealed variations in the dynamics features of both mutant and wild-type complexes due to the acquired mutations. Furthermore, the total binding free energy for the wild-type E2F1-RB complex was -64.89 kcal/mol, while those of the L206W, R232C, I254T, and A267T E2F1-RB mutants were -45.90 kcal/mol, -53.52 kcal/mol, -55.67 kcal/mol, and -61.22 kcal/mol, respectively. Our study is the first to extensively analyze E2F1 gene mutations and identifies candidate mutations for further validation and potential targeting for cancer therapeutics.

Comparison of Platelets-to-Lymphocyte and Neutrophil-to-Lymphocyte Ratios in Rheumatoid Arthritis and Ankylosing Spondylitis.

OBJECTIVE: To calculate and compare the platelets-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), to be used as a complementary diagnostic tool in patients of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). STUDY DESIGN: Cross-sectional, comparative study. Place and Duration of the Study: Pak Emirates Military Hospital (PEMH), Rawalpindi, from February to November 2022. METHODOLOGY: A total of two hundred and ten patients, aged between 25 to 70 years, were included in the study. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) along with platelets, leukocyte, and neutrophil count were estimated. PLR and NLR were calculated and compared between the groups. RESULTS: The PLR was significantly high in the RA group (p-value <0.001) followed by AS and control groups. NLR also followed the same trend and was significantly raised in both the disease groups as compared to controls. Pearson correlation depicted significant positive correlation between PLR and ESR (r = 0.43, p <0.001), NLR and ESR (r = 0.34, p <0.001), PLR and CRP (r = 0.15, p = 0.034) and NLR and CRP (r = 0.18, p = 0.018). Logistic regression analysis displayed the diagnostic value of PLR and NLR. CONCLUSION: Both PLR and NLR are effective as complementary diagnostic indices in RA and AS patients. These may be used in addition to the inflammatory markers ESR and CRP as cost-effective and promptly available indices. KEY WORDS: Ankylosing spondylitis, Platelets-lymphocyte ratio, Neutrophils-lymphocyte ratio, Rheumatoid arthritis.

Nitrogen-vacancy-rich molybdenum nitride nanosheets as highly efficient electrocatalysts for nitrogen reduction reaction.

The development of low-cost earth-abundant electrocatalysts to produce ammonia (NH3) with high efficiency for the nitrogen (N2) reduction reaction (NRR) remains challenging. Herein, we propose the development of highly efficient ultrathin nitrogen-vacancy-rich molybdenum nitride nanosheets (MoN-NV) for NRR using basic electrolytes under ambient conditions. In 0.1 M KOH, this catalyst attained a high faradaic efficiency (FE) of ∼14% with an NH3 yield of 22.5 µg h-1 mg-1cat at -0.3 V vs. a reversible hydrogen electrode under ambient conditions. The characterization results and electrochemical studies disclosed that nitrogen vacancies in the MoN-NV nanosheets played a critical role in the enhanced electrocatalytic activity for NRR. Furthermore, the recycling tests confirmed the stability of the catalyst during NRR electrolysis.