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Bushra Mdkhana,1 Narjes Saheb Sharif-Askari,1 Rakhee K Ramakrishnan,1 Swati Goel,1 Qutayba Hamid,1– 3 Rabih Halwani1,2 1Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 3Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, Quebec, CanadaCorrespondence: Rabih HalwaniCollege of Medicine, University of Sharjah, Sharjah, United Arab EmiratesEmail rhalwani@sharjah.ac.aeAbstract: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1β and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.Keywords: COVID-19, SARS-CoV-2, innate immune system, nucleic acid sensing, immune evasion, NLRP3, cGAS-STING, coronavirus

Basema Saddik,1,2 Amal Hussein,1 Fatemeh Saheb Sharif-Askari,2 Waad Kheder,3 Mohamad-Hani Temsah,4 Rim Adnan Koutaich,5 Enad Sami Haddad,5 Nora Marwan Al-Roub,5 Fatema Adel Marhoon,5 Qutayba Hamid,2,5 Rabih Halwani2,5 1Department of Family and Community Medicine, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 3College of Dental Medicine, University of Sharjah, Sharjah, United Arab Emirates; 4Prince Abdullah Ben Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Saudi Arabia; 5Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesCorrespondence: Rabih Halwani Email rhalwani@sharjah.ac.aeIntroduction: The COVID-19 pandemic is likely to increase anxiety levels within the community and in particular medical students who are already considered psychologically vulnerable groups. Since the COVID-19 outbreak, no study has yet estimated the effect of this pandemic on university students in the UAE or its impact on the psychological well-being of medical students.Methods and Materials: We surveyed 1485 medical (comprising medical and dental) and non-medical university students across 4 emirates within the UAE. We used an online platform to assess knowledge, sources of information, changes in hygienic behavior, perceptions of fear and worry and anxiety levels using the generalized anxiety disorder 7 (GAD-7) scale. The GAD-7 score was measured at three time points: during hospital visits for medical/dental students, before the introduction of online learning and after online learning for all students.Results: The majority of students demonstrated high levels of knowledge and utilized reliable sources of information. Non-medical students exercised higher compliance with social restrictions, while medical students practiced better hand hygiene. Almost half of students reported anxiety levels ranging from mild to severe with females reporting higher anxiety scores during hospital visits (OR=2.02, 95% CI, 1.41 to 2.91) and medical students reporting lower anxiety levels in comparison to dental students (OR=0.61, 95% CI, 0.45 to 0.84). Medical students reported higher levels of anxiety during their clinical rotations which decreased with the introduction of online learning, yet, non-medical students’ anxiety levels increased with online learning.Conclusion: This study provides important information on the initial response and anxiety levels in university students across the UAE during the COVID-19 pandemic. The findings from our study can be used to support the development of effective screening strategies and interventions to build psychological resilience among university students during the COVID-19 pandemic or any other public health emergencies in the future.Keywords: COVID-19, anxiety, medical students, GAD-7, United Arab Emirates

Maria Plesa,1 Mellissa Gaudet,1 Andrea Mogas,1 Ronald Olivenstein,1,2 Saba Al Heialy,1,3 Qutayba Hamid1,2,4 1Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada; 2Faculty of Medicine, McGill University, Montréal, QC, Canada; 3Mohammed Bin Rashid University of Medicine and Health Sciences, College of Medicine, Dubai, United Arab Emirates; 4College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesCorrespondence: Qutayba HamidTranslational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, 1001 Boulevard Decarie, Montréal, QC H4A 3J1, CanadaTel +1-514-934-1934 ext 76121Email qutayba.hamid@mcgill.caBackground: Airway fibroblasts are major contributors to the histopathological feature of airway remodeling in asthma by their implication in the cell invasiveness and profibrogenic secretory phenotype observed in subepithelial fibrosis. 1,25 Dihydroxy vitamin D3 (1,25(OH)2D3) is an important therapeutic agent that blocks many features of airway remodeling induced by profibrogenic mediators, such as transforming growth factor beta 1 (TGF-β 1) or T helper type 1 inflammatory cytokines.Objective: We hypothesized that 1,25(OH)2D3 opposes the TGF-β 1 or tumor necrosis factor alpha (TNF-α)-Interleukin 1 beta (IL-1β) stimulation on airway fibroblast profibrogenic secretory phenotype observed in severe asthmatic patients. Our aim was to investigate the anti-fibrogenic effect of 1,25(OH)2D3 in TGF-β 1 or TNF-α-IL-1β-stimulated human bronchial fibroblast cells (HBFCs) from severe asthmatic compared with non-asthmatic subjects.Patients and Methods: All experiments were performed on primary HBFCs from asthmatic (DHBFCs, n=4) and non-asthmatic subjects (NHBFCs, n=4). mRNA expression and protein quantification of key fibrogenic markers were analyzed by RT-qPCR and ELISA, comparing HBFCs from asthmatic and non-asthmatic subjects. Vitamin D receptor (VDR) mRNA expression and its functionality in HBFCs were assessed by RT-qPCR. HBFCs proliferation was assessed by flow cytometry using BrdU-FITC/7AAD bivariate staining, while HBFCs apoptosis by Annexin V-FITC/7AAD.Results: VDR is constitutively expressed in HBFCs and the addition of 1,25(OH)2D3 significantly increased mRNA expression of CYP24A1 (a direct VDRs’ target gene) in both HBFCs groups. DHBFCs cultured in the presence of TGF-β 1 or TNF-α-IL-1β showed increased mRNA expression and protein secretion of fibrogenic markers when compared to NHBFCs. Additionally, we observed decreased mRNA expression of FN 1, LUM, BGN, MMP2, COL5A1, TIMP1 and CC-chemokines (CCL2, CCL5, CCL11) in response to 1,25(OH)2D3 addition to the TGF-β 1 or TNF-α-IL-1β-stimulated HBFCs. Cell culture media obtained from TGF-β 1 or TNF-α-IL-1β-stimulated DHBFCs showed decreased protein secretion (fibronectin 1, lumican, MCP1, RANTES and eotaxin-1) in response to 1,25(OH)2D3 when compared to NHBFCs. 1,25(OH)2D3 inhibited proliferation in TGF-β 1-stimulated HBFCs through G0/G1 cell cycle arrest and these effects were not correlated with the induction of apoptosis.Conclusion: DHBFCs under TGF-β 1 or TNF-α-IL-1β stimulation showed higher fibrogenic capacity when compared to NHBFCs. 1,25(OH)2D3 significantly blocked these effects and highlight 1,25(OH)2D3 as a possible therapeutic target for severe asthma.Keywords: 1,25(OH)2D3, 1,25 dihydroxy vitamin D3 or calcitriol, asthma airway remodeling, fibrogenic markers, human airway fibroblasts, cell proliferation, apoptosis

Fatemeh Saheb Sharif-Askari,1 Narjes Saheb Sharif-Askari,1 Adnane Guella,2 Ali Alabdullah,1,* Hour Bashar Al Sheleh,1,* Afnan Maher Hoory AlRawi,1,* Enad Sami Haddad,1,* Qutayba Hamid,1,3 Rabih Halwani,1,3,4 Rifat Hamoudi1,3 1Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Department of Nephrology, University Hospital Sharjah, Sharjah, United Arab Emirates; 3Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 4Prince Abdullah Ben Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia*These authors contributed equally to this workCorrespondence: Rifat Hamoudi; Rabih HalwaniCollege of Medicine, University of Sharjah, Sharjah, United Arab EmiratesEmail rhamoudi@sharjah.ac.ae; rhalwani@sharjah.ac.aeBackground: Extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) are the most common uropathogens causing UTI (urinary tract infection) in type 2 diabetes mellitus (T2DM). Circulatory inflammatory markers such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) are usually dysregulated during UTI. However, the differential regulation of these inflammatory signatures during E. coli and K. pneumoniae UTI in T2DM has not been determined.Methods: A case–control study on 466 patients was performed to investigate the inflammatory signatures indicative of ESBL-E. coli and K. pneumoniae UTIs in T2DM. Serum CRP levels and blood NLR for these patients were determined and associated with E. coli and K. pneumoniae ESBL uropathogen using multivariate logistic regression analysis. Urinary interleukin 8 (IL-8) levels were also assessed and associated with these two UTI uropathogens in T2DM. The association of the two ESBL-uropathogens with the survival outcomes of T2DM patients was also analyzed using Cox-proportional hazard model.Results: T2DM patients with ESBL-E. coli UTI had lower serum CRP levels (median, CRP mg/dL 33.7 vs 39.8, respectively; P=0.023) and higher blood NLR (median, NLR 3.2 vs 2.6, respectively; P=0.010) compared to those with K. pneumoniae UTIs (P< 0.001). Moreover, in T2DM, the urinary IL-8 levels was higher in ESBL-E. coli compared to those with K. pneumoniae UTIs (P< 0.0001). After adjusting for confounders, including age, gender, serum albumin, hemoglobulin, leukocytes, and platelet counts, T2DM patients with blood NLR ≥ 3.5 were at higher risk for ESBL-E. coli UTIs than ESBL-K. pneumoniae UTIs (odds ratio [OR], 3.61, 95% confidence interval, Cl, 1.49– 8.73; P=0.004). Moreover, T2DM patients with ESBL-E. coli UTIs had higher all-cause mortality (hazard ratio [HR], 4.09; 95%, 1.14– 14.59) than those with K. pneumoniae UTIs.Conclusion: Serum CRP levels, blood NLR, and IL-8 urinary levels differentiate ESBL-E. coli from K. pneumoniae UTIs in T2DM.Keywords: extended-spectrum ß-lactamase, Klebsiella pneumoniae, Escherichia coli, urinary tract infection, C-reactive protein, survival

Mahmood Yaseen Hachim,1 Noha Mousaad Elemam,1 Rakhee K Ramakrishnan,1 Ibrahim Yaseen Hachim,1 Laila Salameh,1 Bassam Mahboub,1 Saba Al Heialy,2,3 Rabih Halwani,1 Rifat Hamoudi,1 Qutayba Hamid1,2 1Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada; 3College of Medicine, Mohammed Bin Rashid University, Dubai, United Arab EmiratesCorrespondence: Rifat HamoudiCollege of Medicine, University of Sharjah, PO Box 27272, Sharjah, United Arab EmiratesEmail rhamoudi@sharjah.ac.aeIntroduction: The proper use of serum periostin (POSTN) as a biomarker for asthma is hindered by inconsistent performance in different clinical settings.Objective: To explore patient’s factors that may affect POSTN expression locally and systematically and its utility as a biomarker for asthma development.Materials and Methods: Here we used bioinformatics analysis of publicly available transcriptomics data to confirm that POSTN is an asthma specific gene involved in core signaling pathways enriched in the bronchial epithelium during asthma. We then explored a large number of datasets to identify possible confounders that may affect the POSTN gene expression and consequently, its interpretation as a reliable biomarker for asthma. Plasma and saliva levels of POSTN were determined in locally recruited asthmatic patients (mild, moderate and severe) compared to healthy controls to confirm the bioinformatics findings.Results: Our bioinformatics results confirmed that POSTN was consistently upregulated in the bronchial epithelium in asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) bronchial epithelium. In asthma, its mRNA expression was affected by gender, sample anatomical site and type, steroid therapy, and smoking. In our cohort, plasma POSTN was upregulated in severe and non-severe asthmatic patients. Saliva POSTN was significantly higher in non-severe asthmatic patients compared to healthy and severe asthmatic patients (specifically those who are not on Xolair (omalizumab)). Patients’ BMI, inhaled steroid use and Xolair treatment affected POSTN plasma levels.Conclusion: Up to our knowledge, this is the first study examining the level of POSTN in the saliva of asthmatic patients. Both plasma and saliva POSTN levels can aid in early diagnosis of asthma. Saliva POSTN level was more sensitive than plasma POSTN in differentiating between severe and non-severe asthmatics. Patients’ characteristics like BMI, the use of inhaled steroids, or Xolair treatment should be carefully reviewed before any meaningful interpretation of POSTN level in clinical practice.Keywords: periostin, biomarkers, transcriptomics

Eosinophils, along with mast cells are key cells involved in the innate immune response against parasitic infection whereas the adaptive immune response is largely dependent on lymphocytes. In chronic parasitic disease and in chronic allergic disease, IL-5 is predominantly a T cell derived cytokine which is particularly important for the terminal differentiation, activation and survival of committed eosinophil precursors. The human IL-5 gene is located on chromosome 5 in a gene cluster that contains the evolutionary related IL-4 family of cytokine genes. The human IL-5 receptor complex is a heterodimer consisting of a unique a subunit (predominantly expressed on eosinophils) and a beta subunit which is shared between the receptors for IL-3 & GM-CSF (more widely expressed). The a subunit is required for ligand-specific binding whereas association with the beta subunit results in increased binding affinity. The alternative splicing of the alphaIL-5R gene which contains 14 exons can yield several alphaIL-5R isoforms including a membrane-anchored isoform (alphaIL-5Rm) and a soluble isoform (alphaIL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1 and STAT 5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD 4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of alphaIL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased alphaIL-5R mRNA expression. We have also shown that the subset of activated eosinophils that expressed mRNA for membrane bound alpha IL5r inversely correlated with FEV1, whereas the subset of activated eosinophils that expressed mRNA for soluble alphaIL5r directly correlated with FEV1. Hence, not only does this data suggest that the presence of eosinophils expressing alphaIL-5R mRNA contribute towards the pathogenesis of bronchial asthma, but also that the eosinophil phenotype with respect to alphaIL-5R isoform expression is of central importance. Finally, there are several animal, and more recently in vitro lung explant, models of allergen induced eosinophilia, late airway responses(LARS), and bronchial hyperresponsiveness(BHR) - all of which support a link between IL-5 and airway eosinophila and bronchial hyperresponsiveness. The most direct demonstration of T cell involvement in LARS is the finding that these physiological responses can be transferred by CD4+ but not CD8+ T cells in rats. The importance of IL-5 in animal models of allergen induced bronchial hyperresponsiveness has been further demonstrated by a number of studies which have indicated that IL-5 administration is able to induce late phase responses and BHR and that anti-IL-5 antibody can block allergen induced late phase responses and BHR. In summary, activated T lymphocytes, IL5 production and eosinophil activation are particularly important in the asthmatic response. Human studies in asthma and studies in allergic animal models have clearly emphasised the unique role of IL-5 in linking T lymphocytes and adaptive immunity, the eosinophil effector cell, and the asthma phenotype. The central role of activated lymphocytes and eosinophils in asthma would argue for the likely therapeutic success of strategies to block T cell and eosinophil activation (eg steroids). Importantly, more targeted therapies may avoid the complications associated with steroids. Such therapies could target key T cell activation proteins and cytokines by various means including blocking antibodies (eg anti-CD4, anti-CD40, anti-IL-5 etc), antisense oligonucleotides to their specific mRNAs, and/or selective inhibition of the promoter sites for these genes. Another option would be to target key eosinophil activation mechanisms including the aIL5r. As always, the risk to benefit ratio of such strategies await the results of well conducted clinical trials.

We have shown previously that the 5-lipoxygenase product 5-oxo-6,8, 11,14-eicosatetraenoic acid (5-oxo-ETE) is a highly potent eosinophil chemoattractant in vitro. To determine whether this substance can induce pulmonary eosinophil infiltration in vivo, it was administered to Brown Norway rats by tracheal insufflation. Eosinophils were then counted in lung sections that had been immunostained with an antibody to eosinophil major basic protein. 5-Oxo-ETE induced a dramatic increase in the numbers of eosinophils (ED50, 2.5 microg) around the walls of the airways, which reached maximal levels (five times control levels) between 15 and 24 h after administration, and then declined. LTB4 also induced pulmonary eosinophil infiltration with a similar ED50 but appeared to be somewhat less effective. In contrast, LTD4 and LTE4 were inactive. 5-Oxo-ETE-induced eosinophilia was unaffected by the LTB4 and PAF antagonists LY255283 and WEB 2170, respectively. However, it was inhibited by approximately 75% by monoclonal antibodies to CD49d (VLA-4) or CD11a (LFA-1) but was not significantly affected by an antibody to CD11b (Mac-1). In conclusion, 5-oxo-ETE induces pulmonary eosinophilia in Brown Norway rats, raising the possibility that it may be a physiological mediator of inflammation in asthma.

The objective of this article is to investigate the mechanism of unsteady heat and mass transfer (HMT) in a magnetohydrodynamics Carreau nanofluid flow (MHD-CNFF). To accomplish this, we utilized a novel artificial intelligence-based (AI) method, deep learning predictive technique combined with Levenberg-Marquardt scheme (DLPT-LMS). The similarity transformation is applied to convert the partial differential equations (PDEs) into a set of non-linear ordinary differential equations (ODEs). We numerically solved these resulting ODEs using the Adam numerical approach in sophisticated “Mathematica” software. The influence of Brownian motion parameter, thermophoresis parameters, Prandtl number, Lewis number, and mass transfer parameters on the temperature, velocity, and concentration profile is analyzed using a synthetic dataset. This evaluation is conducted across different variation of MHD-CNFF by leveraging DLPT-LMS. The absolute error (AE) across various iteration of MHD-CNFF demonstrated a progressive drop, indicating the accuracy of DLPT-LMS. The outcomes of this investigation revealed that the AE ranged from 10−3 to 10−8 which shows a minimum error between actual and predicted value. Additionally, the MSE confirmed the accuracy of proposed DLPT-LMS in predicting the behavior of velocity, temperature, and concentration profiles, with lower values showing better predictions. The model accuracy was reinforced by performance results, including regression analysis and error histograms. Error values gradually decreased during training, validation, and testing phases, exhibiting a robust convergence and indicating the highly reliability of AI-based algorithm for investigating intricate fluid dynamics in MHD-CNFF systems.

This article explores the enhancement of thermal exchange in a dissipative Triple-nanoparticle (Al2O3+CuO+Cu) hybrid fluid over a stretchable wavy cylindrical surface with slip effect, incorporating Python bvp algorithm with artificial intelligence AI analysis of numerical results. The stochastic AI analysis gives the enhanced and optimized results with predictive modeling, incorporating randomness of influencing parameters and nonlinear turbulent behavior of model. The model has significant importance and application in noise reducing and drag reduction devices or structures. Moreover, the presented geometrical structure is useful in enhancing thermal conduction characteristic. The intricate interplay of constituent nanoparticles and their effect on complex heat transfer in drag optimization devices is the main focus of this study. Mathematical Model of PDEs of this flow problem is converted into system of ODEs by similarity transformations with introducing dimensionless parameters. Numerical solutions of the emerged system are obtained by Python bvp solver algorithm and graphical solutions by Python are presented. To expedite the solution process and enhance the accuracy of prediction, advanced AI algorithm, such as neural network and machine learning technique is adopted. Numerical dataset obtained from Python is embedded for further AI analysis by using Levenberg Marquardt Feed-forward Algorithm (LMFA) with 10 computing neurons and 4 output layers representing results for 4 parametric variations.A rise in the fluid flow speed is observed with higher of value yield stress or Newtonian-behavior i.e. of Casson parameter a1 and stretching parameter λ for the sheet, but shows a decline with enhancing turbulence s2. Temperature profile show a descending behavior with inclination of Eckert ratio Ec, and Prandtl ratio of momentum-thermal diffusivity.

A study was conducted to examine the action of glucocorticoid on glucocorticoid receptor (GR) mRNA expression and protein elaboration in rat lung cells. An area of rat GR cDNA open reading frame was excised between the Xba I and Pst I restriction sites of the pRdN93 construct while rats were injected daily with the solvent dimethyl sulfoxide. Results indicated that glucocorticoids and androgens support opposite effects on fetal lung GR.