Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Outcomes of biological therapy in patients with severe asthma with chronic rhinosinusitis in Saudi Arabia: patients with nasal polyps versus those without nasal polyps.

BACKGROUND: This study's purposes were to evaluate the impact of biological therapies on outcomes in patients with severe asthma (SA) and chronic rhinosinusitis (CRS) and to compare these effects among those with NP (CRSwNP) versus those without NP (CRSsNP) in the "real-world" setting in Saudi Arabian patients. METHODS: From March to September 2022, a retrospective observational cohort study was undertaken at the severe asthma clinics of the Armed Forces Hospital-Southern Region (AFHSR) and King Khalid University Hospital, Abha, Saudi Arabia, to delineate the effects of dupilumab therapy. Outcomes were assessed, including clinical outcomes, FEV1, and laboratory findings before and one year after dupilumab. Post-therapy effects were compared between CRSwNP and CRSsNP. RESULTS: Fifty subjects were enrolled, with a mean age of 46.56. There were 27 (54%) females and 23(46%) males. Significant improvements in clinical parameters (frequency of asthma exacerbations and hospitalizations, the use of OCs, anosmia, SNOTT-22, and the ACT), FEV1, and laboratory ones (serum IgE and eosinophilic count) were observed 6 and 12 months after using dupilumab (p < 0.001), respectively. However, after 12 months of dupilumab therapy, there were no significant differences between those with and without NP with regards to clinical (anosmia, ACT, and OCs use), laboratory (eosinophilic count, serum IgE level) parameters, and FEV1%. CONCLUSIONS: Patients with CRS experienced significant improvements in clinical, FEV1, and laboratory outcomes after dupilumab therapy. However, these improvements were not maintained when comparing CRSwNP with CRSsNP. There were no significant differences between those with and without NP regarding ACT and OCs use or laboratory (eosinophilic count, serum IgE level) parameters. Further prospective multicenter studies are warranted.

Computational analysis and in vitro evaluation of TMF 104, for its antioxidant, antimicrobial, and anticancer efficacies.

Benzylidene chromanones are small molecules, structurally similar to active phytochemicals. Herein, we report one novel benzylidene chromanone, TMF 104, for its bio-efficacies. Its computational docking for Vanin-1, antioxidant, free radical scavenging capacities, antimicrobial effects, and anticancer efficacy were analyzed. TMF 104 predicated strong binging to Vanin-1 protein with a docking energy of -8.1 kcal/mol. The compound dose-dependently exhibited free-radical scavenging and antioxidant activities when tested in vitro. The compound also had remarkable activity against Salmonella typhimurium, Enterococcus faecalis, Staphylococcus aureus, and Escherichia coli with minimum inhibitory concentration values of 1.5, 2.0, 12.5, and 13.5 µg/ml, respectively. The compound was also effective against Bacillus cereus and Pseudomonas aeruginosa albeit at higher concentrations. TMF 104 dose-dependently inhibited the proliferation of MCF-7, NCI H460, and Caki-1 cells with respective GI50 values of 24.51, 21.95, and 32.95 µg/ml, whereas the compound was toxic to normal Vero cells at much higher concentration of 264.70 µg/ml. The compound also aided in apoptosis and increased the sub G0 /G1 phase of the cell cycle in all three cancer cells tested. Our study identified a novel, potent benzylidene analogue with potent antioxidant, antimicrobial, and anticancer activities, which drives further attention for further research.

Methotrexate-Induced Alteration of Renal Aquaporins 1 and 2, Oxidative Stress and Tubular Apoptosis Can Be Attenuated by Omega-3 Fatty Acids Supplementation.

Methotrexate (MTX) is a potent anti-cancer drug, commonly associated with nephrotoxicity via the induction of oxidative stress and apoptosis with alteration of renal water channel proteins, namely aquaporins (AQPs). Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) have shown cytoprotective effects through their anti-oxidant and antiapoptotic activities. The present study aims for the first time to explore the role of LC-PUFA against MTX-induced nephrotoxicity. Rats were divided into the following groups: saline control, LC-PUFA control, MTX, MTX + LC-PUFA (150 mg/kg), or MTX + LC-PUFA (300 mg/kg). Then, H&E staining and immunohistochemical staining for the anti-apoptosis marker B-cell lymphoma 2 (BCL-2), the apoptosis marker BCL2-Associated X Protein (BAX), the proinflammatory marker Nuclear factor kappa B (NF-kB), AQPs 1 and 2 were performed in kidney sections with an assessment of renal oxidative stress. The MTX caused a renal histopathological alteration, upregulated renal BAX and NF-kB, downregulated Bcl-2 and AQP1, altered the distribution of AQP2, and caused oxidative stress. The LC-PUFA attenuated the pathological changes and decreased renal BAX and NF-kB, increased BCL-2 and AQP1, restored the normal distribution of AQP2, and decreased the oxidative stress. Therefore, LC-PUFA is a good adjuvant to MTX to prevent its adverse effects on kidneys through its antiapoptotic, antioxidant, and anti-inflammatory effect and its role in the restoration of the expression of AQPs 1 and 2.

Molecular epidemiology of virulent E. coli among rural small scale dairy herds and shops: Efficacy of selected marine algal extracts and disinfectants.

Virulent pathotypes of E. coli seriously affect the livestock regarding the misuse of antibiotics. All 180 samples collected from cow's environment and dairy shops in Qena, Egypt were serologically and molecularly positive for coliforms. Enteropathogenic E. coli (EPEC), Shiga toxin-producing E. coli (STEC), Enteroinvasive E. coli (EIEC) and Enterotoxigenic E. coli (ETEC) pathotypes were isolated from water and milk-related samples. STEC serogroups O26, O55, O111, O113, O145 were also recovered. The non-O157 STEC serotypes were recovered from human diarrheagenic patients contacting cattle or consuming contaminated water/milk products. BlaCTX-M and blaTEM genes were detected in 25.5% and 100%, respectively. Disinfectants and algal extracts, identified by GC-MS, were evaluated in vitro for antibacterial activities. TH4+® disinfectant and methanol extract of Turbinaria decurrens reduced E. coli at 13 log10 at 1.5% and 3 mg/ml concentrations, respectively. Ag-NPs/T. decurrens showed 8-9 log10 reduction at concentration of 1.6 × 105 NPs/ml. Examined water sources, milk and milk products were potential reservoirs for virulent antibiotic-resistant E.coli which may impose animal and public health threats.Abbreviations: APEC: Avian pathogenic E. coli; blaCTX-M: ß-lactamase inhibitors-Cefotaximase gene; blaTEM: ß-lactamase inhibitors-Temoneira gene; CFU: Colony-forming unit; DAEC: Diffusely adherent E. coli; DEC: Diarrheagenic Escherichia coli; DEMSO: Dimethyl sulfoxide; eaeA: Intimin or E. coli attaching gene; EAEC: Enteroaggregative E. coli; EHEC: Enterohemorrhagic E. coli; EIEC: Enteroinvasive E. coli; EOSQC: Egyptian Organization for Standardization and Quality Control; EPEC: Enteropathogenic E. coli; ETEC: Enterotoxigenic E. coli; ExPEC: Extra-intestinal pathogenic E. coli; GC-MS: Gas chromatography-mass spectrometry technique; hly: Hemolysin gene; STEC: Shiga like producing E. coli; stx1: Shiga-toxin 1 gene; ESBLs: Extended-spectrum beta-lactamases.

Measuring the appropriateness of carbamazepine and valproic acid prescribing and utilization using a newly implemented online system in the Tabuk Region of Saudi Arabia.

Epilepsy is a common neurologic disorder, which is efficiently treated with carbamazepine and valproic acid. Moreover, Saudi Ministry of Health implemented a new E-system for Poison Control Centers called Awtar to enhance technology utilization in ensuring patients' satisfaction and to improve treatment outcomes. Therefore, we conducted this study to assess appropriateness of indication of requests and therapeutic levels of carbamazepine and valproic acid in Tabuk area, North West Saudi Arabia. This is a retrospective observational study conducted in Poison Control & Forensic Chemistry Center, Tabuk, Saudi Arabia. Patients' data were obtained for years 2018 and 2019. The blood levels of carbamazepine and valproic acid were measured by Therapeutic Drug Monitoring (TDM) Unit. We selected patients treated with either valproic acid or carbamazepine alone without any history of drug allergy. Data of 264 patients were extracted from Awtar E-system. Serum carbamazepine levels were within therapeutic range in 114 patients (75.50%), above-therapeutic range in 13 patients (8.61%) and sub-therapeutic levels in 24 patients (15.89%). Regarding serum valproic acid, it is within therapeutic range in 62 patients (54.87%), above-therapeutic range in 11 patients (9.73%) and sub-therapeutic levels in 40 patients (35.40%). In conclusion, this study gives information about partial appropriateness of usage of carbamazepine and low level of appropriateness of valproic acid. However, more efforts are needed to improve results of appropriateness of indication of antiepileptic drugs.

Are preterm infants at high altitude at greater risk for the development of bronchopulmonary dysplasia?

OBJECTIVES: To assess the association between altitudes of neonatal intensive care units (NICUs) and the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Data from infants born at <32 weeks' gestation admitted to NICUs at high altitude (2200 m above sea level) between 2002 and 2011 were analyzed and compared with the data from a lower altitude NICU in Saudi Arabia. RESULTS: Of 942 preterm infants admitted to the high altitude NICUs, 266 (28.2%) infants developed BPD. The incidence of BPD was significantly higher in infants admitted to the NICU at high altitude than in those at lower altitude (28.2 vs. 17.7%, respectively, p = 0.003). In multivariable analysis, high altitude was significantly associated with a higher risk of BPD (odds ratio: 0.54, 95% confidence interval: 0.36-0.81). CONCLUSION: Findings suggest that high altitude may increase the risk of BPD development among preterm infants.

Combination use of human menstrual blood stem cell- derived exosomes and hyperbaric oxygen therapy, synergistically promote recovery after spinal cord injury in rats.

Traumatic spinal cord injury (TSCI) is one of the catastrophic events in the nervous system that leads to the loss of sensory and motor function of the spinal cord at the site of injury. Considering that several factors such as apoptosis, inflammation, and oxidative stress play a role in the spread of damage caused by trauma, therefore, the treatment should also be based on multifactorial approaches. Currently, we investigated the effects of human menstrual blood stem cells (MenSCs)-derived exosomes in combination with hyperbaric oxygen therapy (HBOT) in the recovery of TSCI in rats. Ninety male mature Sprague-Dawley (SD) rats were planned into five equal groups, including; control group, TSCI group, Exo group (underwent TSCI and received MenSCs -derived exosomes), HBOT group (underwent TSCI and received HBOT), and Exo+HBOT group (underwent TSCI and received MenSCs -derived exosomes plus HBOT). After the behavioral evaluation, tissue samples were obtained for stereological, immunohistochemical, biochemical, and molecular assessments. Our results showed that the numerical density of neurons, the concentrations of antioxidative biomarkers (CAT, GSH, and SOD), and neurological function scores were significantly greater in the treatments group than in the TSCI group, and these changes were more obvious in the Exo+HBOT ones (P<0.05). This is while the numerical densities of apoptotic cells and glial cells, the levels of an oxidative factor (MDA) and proinflammatory cytokines (IL-1ß and TNF-α) were considerably decreased in the treatment groups, specially the Exo+HBOT group, compared to the TSCI group (P<0.05). We conclude that the co-administration of exosomes derived from MenSCs and HBOT has more neuroprotective effects in animals with TSCI.

Experimental study on the effects of human amniotic membrane in combination with menstrual blood-derived stem cells on wound healing in a diabetic rat model.

One of the serious challenges in diabetic patients is the occurrence of complications caused by the disease. One of the most important side effects is wounding in limbs. Due to the multifactorial nature of these wounds, treatments require a multifaceted approach. Therefore, the aim of the present study was whether the human amniotic membrane (HAM) in combination with menstrual blood-derived stem cells (MenSCs) could promote wound healing in diabetic rats. Thirty days after induction of diabetes, the animals were randomly allocated into four equal groups (n=15): the control group, HAM group, MenSC group, and HAM+MenSC group. Sampling was done on days 7, 14, and 21 for histological, molecular, and tensiometrical evaluations. The results showed that the wound healing rate, collagen deposition, volumes of new epidermis and dermis, as well as tensiometrical characteristics were significantly increased in the treatment groups compared to the control group, and these changes were more obvious in the HAM+MenSC ones (P<0.05). Moreover, the expression levels of TGF-ß, bFGF, and VEGF genes were considerably increased in treatment groups compared to the control group and were greater in the HAM+MenSC group (P<0.05). This is while expression levels of TNF-α and IL-1ß decreased more significantly in the HAM+MenSC group than the other groups (P<0.05). We concluded that the combined use of HAM and MenSCs has a more significant effect on diabetic wound healing.

Assessment of depression in children and adolescents with Type 1 diabetes mellitus: Impact and intervention strategies.

Depression is a common comorbidity in children and adolescents with type 1 diabetes mellitus (T1DM), yet its prevalence, impact, and intervention strategies remain underexplored. This study aims to assess the prevalence of depression among children and adolescents with T1DM, investigate its impact on health outcomes, and explore potential intervention strategies. A convenient sampling method was employed to recruit 229 participants aged 6 to 18 years from a single center. Data collection involved validated assessments, demographic surveys, and diabetes-related factor examinations during routine clinic visits. The patient health questionnaire-9 was utilized to evaluate the severity of depressive symptoms. Associations between depression and sociodemographic variables, diabetes management factors, and health behaviors were analyzed using chi-squared tests and logistic regression analysis. The prevalence of depression among participants was 43.23%. Older age, lower parental education levels, lower household income, smoking, and comorbidities were identified as significant risk factors for depression. Associations were found between depression and diabetes management factors, including glycemic control and frequency of glucose monitoring. Depression is highly prevalent among children and adolescents with T1DM and is associated with sociodemographic factors, health behaviors, and diabetes management. Integrated approaches to care that address both physical and mental health aspects are crucial for improving outcomes in this population.

Prevalence of depression in postmyocardial infarction patients in a tertiary care center in Riyadh.

BACKGROUND: The coexistence of coronary artery disease (CAD) and depression is a growing concern, as both conditions lead to disability. Although depression is more prevalent in CAD patients than in the general population and has been associated with adverse cardiac outcomes, the underlying mechanisms linking depression and CAD are not yet fully understood. This study aims to assess the prevalence of depression in postmyocardial infarction (MI) patients as baseline data in Saudi Arabia. MATERIALS AND METHODS: A cross-sectional study was conducted at King Saud Medical City, Riyadh. The study population included male and female patients who had survived MI from January 2022 to June 2022. A sample size of 323 patients was initially planned, but only 249 patients could be included on account of exclusions. The patients underwent screening for depression using Patient Health Questionnaire-2 (PHQ-2), and those who were positive on screening were further assessed using the PHQ-9 according to DSM-5 criteria. Sociodemographic data, comorbidities, and previous cardiac interventions were collected from medical records. RESULTS: The mean age of the study participants was 57.15 years, and majority (76.6%) were males. The prevalence of previously diagnosed depression was 9.2%, and 5.2% of patients reported using antidepressant medication. According to the PHQ-9 scores, 33.33% had depression, 9% had moderate depression, and 2.4% had severe depression. There were significant associations between the severity of depression and previous CAD (P < 0.05), previous coronary artery bypass graft surgery (P < 0.05), and heart failure (P < 0.05). CONCLUSION: This study reveals a high prevalence of depression in post-MI patients at King Saud Medical City. The findings highlight the need for comprehensive management of depression in this population to improve outcomes. Further research into the underlying mechanisms linking depression and CAD to develop effective interventions is required.

Mechanistic insights into carvedilol's potential protection against doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is an anthracycline chemotherapy drug widely employed in the treatment of various cancers, known for its potent antineoplastic properties but often associated with dose-dependent cardiotoxicity, limiting its clinical use. This review explores the complex molecular details that determine the heart-protective effectiveness of carvedilol in relation to cardiotoxicity caused by DOX. The harmful effects of DOX on heart cells could include oxidative stress, DNA damage, iron imbalance, disruption of autophagy, calcium imbalance, apoptosis, dysregulation of topoisomerase 2-beta, arrhythmogenicity, and inflammatory responses. This review carefully reveals how carvedilol serves as a strong protective mechanism, strategically reducing each aspect of cardiac damage caused by DOX. Carvedilol's antioxidant capabilities involve neutralizing free radicals and adjusting crucial antioxidant enzymes. It skillfully manages iron balance, controls autophagy, and restores the calcium balance essential for cellular stability. Moreover, the anti-apoptotic effects of carvedilol are outlined through the adjustment of Bcl-2 family proteins and activation of the Akt signaling pathway. The medication also controls topoisomerase 2-beta and reduces the renin-angiotensin-aldosterone system, together offering a thorough defense against cardiotoxicity induced by DOX. These findings not only provide detailed understanding into the molecular mechanisms that coordinate heart protection by carvedilol but also offer considerable potential for the creation of targeted treatment strategies intended to relieve cardiotoxicity caused by chemotherapy.

ACTL6A: unraveling its prognostic impact and paving the way for targeted therapeutics in carcinogenesis.

Introduction: Increased Actin-like 6A (ACTL6A) expression is associated with various cancers, but its comprehensive investigation across different malignancies is lacking. We aimed to analyze ACTL6A as a potential oncogene and therapeutic target using bioinformatics tools. Methods: We comprehensively analyzed ACTL6A expression profiles across human malignancies, focusing on correlations with tumor grade, stage, metastasis, and patient survival. Genetic alterations were examined, and the epigenetic landscape of ACTL6A was assessed using rigorous methods. The impact of ACTL6A on immune cell infiltration in the tumor microenvironment was evaluated, along with molecular docking studies and machine learning models. Results: Our analysis revealed elevated ACTL6A expression in various tumors, correlating with poor prognostic indicators such as tumor grade, stage, metastasis, and patient survival. Genetic mutations and epigenetic modifications were identified, along with associations with immune cell infiltration and key cellular pathways. Machine learning models demonstrated ACTL6A's potential for cancer detection. Discussion: ACTL6A emerges as a promising diagnostic and therapeutic target in cancer, with implications for prognosis and therapy. Our study provides comprehensive insights into its carcinogenic actions, highlighting its potential as both a prognostic indicator and a target for anti-cancer therapy. This integrative approach enhances our understanding of ACTL6A's role in cancer pathogenesis and treatment.

Vinpocetine and Lactobacillus improve fatty liver in rats: role of adiponectin and gut microbiome.

Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates for hepatic inflammation like that occurring in non-alcoholic fatty liver disease (NAFLD). In the current study, we examined the therapeutic impact of the phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results show that Vinpo (10 and 20 mg/kg/day) dose-dependently curbed HFD-induced elevation of liver injury parameters in serum (ALT, AST) and tissue histopathology. These effects were concordant with Vinpo's potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-ß1) and oxidative stress (MDA, NOx) alongside restoring the antioxidant-related parameters (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like high mobility group box (HMGB)1 alongside lowering the overactivation of the pattern recognition receptors including, toll-like receptor (TLR)4 and receptor for advanced glycation end-products (RAGE). Consequently, there was less activation of the transcription factor nuclear factor-kappa B that lowered production of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes rats. Compared to Vinpo treatment alone, Lactobacillus probiotics as adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting NAFLD in humans.

Oncogenic Potential of Replication Factor C Subunit 4: Correlations with Tumor Progression and Assessment of Potential Inhibitors.

Replication Factor C Subunit 4 (RFC4), an oncogene implicated in many human cancers, has yet to be extensively studied in many cancer types to determine its expression patterns and tumor tissue function. Various bioinformatics tools were used to analyze RFC4 as a potential oncogene and therapeutic target across many cancers. We first examined RFC4 expression levels in several human tumor types to determine relationships with tumor grade, stage, metastasis, and patient survival. We also examined RFC4's genetic changes, epigenetic methylation, and effect on tumor microenvironment (TME) immune cell infiltration. We also analyzed RFC4's connections with immunological checkpoints to identify potential molecular pathways involved in carcinogenesis. Our findings show that RFC4 is upregulated in several tumor types and associated with poor prognoses in many human cancers. This study shows that RFC4 significantly affects the tumor immunological microenvironment, specifically immune cell populations. Finally, we screened for RFC4-inhibiting pharmacological compounds with anti-cancer potential. This study fully elucidates RFC4's carcinogenic activities, emphasizing its potential as a prognostic biomarker and a target for anti-cancer therapy.

Retraction: Vesicourachal Diverticulum: A Rare Cause of Recurrent Urinary Tract Infections.

[This retracts the article DOI: 10.7759/cureus.20118.].

A detailed insight of the tumor targeting using nanocarrier drug delivery system.

Human struggle against the deadly disease conditions is continued since ages. The contribution of science and technology in fighting against these diseases cannot be ignored exclusively due to the invention of novel procedure and products, extending their size ranges from micro to nano. Recently nanotechnology has been gaining more consideration for its ability to diagnose and treat different cancers. Different nanoparticles have been used to evade the issues related with conservative anticancer delivery systems, including their nonspecificity, adverse effects and burst release. These nanocarriers including, solid lipid nanoparticles (SLNs), liposomes, nano lipid carriers (NLCs), nano micelles, nanocomposites, polymeric and magnetic nanocarriers, have brought revolutions in antitumor drug delivery. Nanocarriers improved the therapeutic efficacy of anticancer drugs with better accumulation at the specific site with sustained release, improved bioavailability and apoptosis of the cancer cells while bypassing the normal cells. In this review, the cancer targeting techniques and surface modification on nanoparticles are discussed briefly with possible challenges and opportunities. It can be concluded that understanding the role of nanomedicine in tumor treatment is significant, and therefore, the modern progressions in this arena is essential to be considered for a prosperous today and an affluent future of tumor patients.

Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy.

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure. The residues' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

Potential role for vitamin D vs. intermittent fasting in controlling aquaporin-1 and aquaporin-3 expression in HFD-induced urinary bladder alterations in rats.

Background: High-fat diet-induced obesity is linked to suppression of aquaporins (AQPs) expression in different tissues. Both vitamin D and intermittent fasting were identified to enhance AQPs expression. In the urinary bladder, AQP-1 and AQP-3 mRNA transcripts were identified. Vitamin D has an impact on a variety of genes that encode proteins that control cell proliferation, differentiation, and death. Aim: To assess potential benefits of vitamin D and intermittent fasting (IF) and to explore alterations to the urinary bladder triggered by high-fat diet (HFD) in a rat model of obesity. Methods: Each of the 4 groups contained six adult male albino rats; control: a standard rodent chew for 12 weeks, HFD: HFD and fructose were administered orally via gastric gavage for 12 weeks, and vitamin D: HFD and fructose were administered orally for 8 weeks, then 4 weeks of intraperitoneal injection of vitamin D (5 microns/Kg/2 days) and IF group: Received intraperitoneal injections of vitamin D (5 microns/Kg/2 days) for 4 weeks after consumption of HFD and fructose orally for 8 weeks. The serum lipid profile was conducted at end of the experiment. In the bladder homogenates, the levels of oxidative stress indicators were assessed. Quantitative real-time PCR was performed on recently collected bladder samples. AQP-1 and AQP-3 immunohistochemistry was done. Results: When compared to the HFD group, the vitamin D and IF groups both demonstrated a substantial improvement in histopathological, immunohistochemical, biochemical, and molecular markers. Conclusion: In all examined parameters, IF exceeded vitamin D as a preventive factor for the urinary bladder deterioration.

Impact of viral co-infection on clinical outcomes and mortality of COVID-19 patients: a study from Saudi Arabia.

Background: In COVID-19 patients undetected co-infections may have severe clinical implications associated with prolonged hospitalization, ICU admission, and mortality. Therefore, we aimed to investigate the impact of viral coinfections on the outcomes of hospitalized patients with COVID-19 in a large tertiary Saudi Arabian Hospital. Methods: A total of 178 adult patients with confirmed SARS-CoV-2 who were hospitalized at the Armed Forces Hospital Southern Region (AFHSR), Saudi Arabia, from March 1st to June 30th 2022, were enrolled. Real-time PCR for the detection of viral co­infections was carried out. Cases (SARS-CoV-2 with viral coinfections) and control (SARS-CoV-2 mono-infection) groups were compared. Results: 12/178 (7%) of enrolled COVID-19 patients had viral coinfections. 82/178 (46%) of patients were males. 58% of patients had comorbidities. During the study period, 4/12 (33%) and 21/166 (13%) cases and control patients died, p=0.047, respectively. Duration of hospitalization was the only significant independent factor associated with SARS-CoV-2 coinfections, OR 1.140, 95% CI 1.020-1.274, p=0.021. Conclusions: The findings of this study from a large tertiary Saudi Arabian Center revealed a prevalence of 7% for SARS-CoV-2 viral coinfections. SARS-CoV-2 coinfected patients had a significantly prolonged duration of hospitalization and higher mortality than those with SARS-CoV-2 alone. Future studies are needed.