Novel Comprehensive Bioinformatics Approaches to Determine the Molecular Genetic Susceptibility Profile of Moderate and Severe Asthma.

Asthma is a chronic inflammatory condition linked to hyperresponsiveness in the airways. There is currently no cure available for asthma, and therapy choices are limited. Asthma is the result of the interplay between genes and the environment. The exact molecular genetic mechanism of asthma remains elusive. The aim of this study is to provide a comprehensive, detailed molecular etiology profile for the molecular factors that regulate the severity of asthma and pathogenicity using integrative bioinformatics tools. The GSE43696 omnibus gene expression dataset, which contains 50 moderate cases, 38 severe cases, and 20 healthy controls, was used to investigate differentially expressed genes (DEGs), susceptible chromosomal loci, gene networks, pathways, gene ontologies, and protein-protein interactions (PPIs) using an intensive bioinformatics pipeline. The PPI network analysis yielded DEGs that contribute to interactions that differ from moderate-to-severe asthma. The combined interaction scores resulted in higher interactions for the genes and for moderate asthma and and for severe asthma. Enrichment analysis (EA) demonstrated differential enrichment between moderate and severe asthma phenotypes; the ion transport regulation pathway was significantly enhanced in severe asthma phenotypes compared to that in moderate asthma phenotypes and involved , and The most enriched common pathway in both moderate and severe asthma is the development of the glucocorticoid receptor (GR) signaling pathway followed by glucocorticoid-mediated inhibition of proinflammatory and proconstrictory signaling in the airway of smooth muscle cell pathways. Gene sets were shared between severe and moderate asthma at 16 chromosome locations, including 17p13.1, 16p11.2, 17q21.31, 1p36, and 19q13.2, while 60 and 48 chromosomal locations were unique for both moderate and severe asthma, respectively. Phylogenetic analysis for DEGs showed that several genes have been intersected in phases of asthma in the same cluster of genes. This could indicate that several asthma-associated genes have a common ancestor and could be linked to the same biological function or gene family, implying the importance of these genes in the pathogenesis of asthma. New genetic risk factors for the development of moderate-to-severe asthma were identified in this study, and these could provide a better understanding of the molecular pathology of asthma and might provide a platform for the treatment of asthma

Mobilizing dissent: community organizing for informal housing

Rapid and uneven urban growth across the globe has been accompanied by increasing informality. In Egypt, as the state attempts to address urban housing informality, its urban development plans have been accused of being economically driven, unrepresentative of the demands of residents of informal areas, and threatening to their livelihoods and wellbeing, thus prompting many acts of resistance and dissent by those who dwell in informal areas. This thesis aims to explore reasons behind mobilization of residents of informal areas and their subsequent resistance to state urban plans by addressing a) the role played by the state in framing and identifying the present housing crisis, b) the role played by non-state actors in providing support to the state, and c) the avenues of participation available to residents of informal settlements through which they can partake in the decision-making process. It is hypothesized that resistance occurs within informal settlements in response to the inability of the state to play the role it set out for itself, reflecting a misdiagnosis of the nature of informality and an incomprehensive understanding of the housing crisis. Moreover, while non-state actors have been unable to compensate for the state\u27s shortcomings, and as there are no formal channels of participation available for the residents of informal settlements, communities have found no other way but to resist through informal means. Additionally, this thesis explores the main drivers of social mobilization by examining two case studies, Bab El-Nasr and Ramlet Boulaq. In the latter, residents had been able to successfully mobilize resources and mount strong resistance against state housing policy; while in the former, efforts at resisting state policies were short-lived, scattered, and failed to bring about real change. In these case studies, perception of threat and deprivation, access to moral, cultural, human, material, and socio-organizational resources, along with the presence of networks of trust were found to be determining factors in explaining the transformation of granular acts of protest into structured and patterned collective action

The identification of highly upregulated genes in claudin-low breast cancer through an integrative bioinformatics approach

Breast cancer (BC) is one of the leading causes of cancer-related death among women worldwide, and claudin-low breast cancer (CLBC) is a subtype of BC that remains poorly described. This study aimed to identify upregulated genes and significant pathways involved in CLBC. The SUM159 cell line is derived from human CLBC tissue; the GSE50697 dataset contains three replicates of SUM159 cells treated with pBabe puro miR-203 and three replicates of control SUM159 cells (pBabe puro). The data were normalized and upregulated, and downregulated genes were identified based on the logFC values. Gene Ontology (GO) and pathway analysis identified the most significant pathways and genes involved in CLBC pathogenesis. A total of 156 significant genes were identified (69 upregulated genes and 64 downregulated genes). From the pathway analysis, the senescence-associated secretory phenotype, which involves the CXCL8, IL1A, and IL6 genes, was found to be mapped through more than one pathway (WikiPathways and Reactome). From the refined GO analysis, the IL-13 signaling pathway was identified; this pathway includes the IL6, CXCL8, VEGF-C, NRG1, and EREG genes, which were mapped as hub genes in several pathogenesis pathways. From the survival analysis, high levels of IL6, CXCL8, and EREG were related to high survival rates, and low levels of VEGFC and NRG1 were related to high survival rates. The IL6 and CXCL8 genes were the most significant and the most highly represented in the GO and refined GO analyses. This study might provide a potential biomarker for the treatment of CLBC

Novel CD44-downstream signaling pathways mediating breast tumor invasion

CD44, also known as homing cell adhesion molecule is a multi-structural cell molecule involved in cell-cell and cell-extracellular matrix communications. CD44 regulates a number of central signaling pathways, including PI3K/AKT, Rho GTPases and the Ras-MAPK pathways, but also acts as a growth/arrest sensor, and inhibitor of angiogenesis and invasion, in response to signals from the microenvironment. The function of CD44 has been very controversial since it acts as both, a suppressor and a promoter of tumor growth and progression. To address this discrepancy, we have previously established CD44-inducible system both in vitro and in vivo. Next, using microarray analysis, we have identified and validated Survivin, Cortactin and TGF-β2 as novel CD44-downstream target genes, and characterized their signaling pathways underpinning CD44-promoted breast cancer (BC) cell invasion. This report aims to update the literature by adding and discussing the impact of these novel three signaling pathways to better understand the CD44-signaling pathways involved in BC tumor cell invasion

CD146, a novel target of CD44-signaling, suppresses breast tumor cell invasion.

We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways. In the present study, we identified CD146 as a potential novel target, negatively regulated by CD44. While the exact function of CD146 in breast cancer (BC) is not completely understood, substantial evidence from our work and others support the hypothesis that CD146 is a suppressor of breast tumor progression. Therefore, using molecular and pharmacological approaches both in vitro and in breast tissues of human samples, the present study validated CD146 as a novel target of CD44-signaling suppressed during BC progression. Our results revealed that CD44 activation could cause a substantial decrease of CD146 expression with an equally notable converse effect upon CD44-siRNA inhibition. More interestingly, activation of CD44 decreased cellular CD146 and increased soluble CD146 through CD44-dependent activation of MMP. Here, we provide a possible mechanism by which CD146 suppresses BC progression as a target of CD44-downstream signaling, regulating neovascularization and cancer cell motility

An extensive computational approach to analyze and characterize the functional mutations in the galactose-1-phosphate uridyl transferase (GALT) protein responsible for classical galactosemia

Type I galactosemia is a very rare autosomal recessive genetic metabolic disorder that occurs because of the mutations present in the galactose-1-phosphate uridyl transferase (GALT) gene, resulting in a deficiency of the GALT enzyme. The action of the GALT enzyme is to convert galactose-1-phosphate and uridine diphosphate glucose into glucose-1-phosphate (G1P) and uridine diphosphate-galactose, a crucial second step of the Leloir pathway. A missense mutation in the GALT enzyme leads to variable galactosemia's clinical presentations, ranging from mild to severe. Our study aimed to employ a comprehensive computational pipeline to analyze the most prevalent missense mutations (p.S135L, p.K285 N, p.Q188R, and p.N314D) responsible for galactosemia; these genes could serve as potential targets for chaperone therapy. We analyzed the four mutations through different computational analyses, including amino acid conservation, in silico pathogenicity and stability predictions, and macromolecular simulations (MMS) at 50 ns The stability and pathogenicity predictors showed that the p.Q188R and p.S135L mutants are the most pathogenic and destabilizing. In agreement with these results, MMS analysis demonstrated that the p.Q188R and p.S135L mutants possess higher deviation patterns, reduced compactness, and intramolecular H-bonds of the protein. This could be due to the physicochemical modifications that occurred in the mutants p.S135L and p.Q188R compared to the native. Evolutionary conservation analysis revealed that the most prevalent mutations positions were conserved among different species except N314. The proposed research study is intended to provide a basis for the therapeutic development of drugs and future treatment of classical galactosemia and possibly other genetic diseases using chaperone therapy

CD44 mediates stem cell mobilization to damaged lung its novel transcriptional targets, Cortactin and Survivin

Beyond their role in bone and lung homeostasis, mesenchymal stem cells (MSCs) are becoming popular in cell therapy. Various insults may disrupt the repair mechanisms involving MSCs. One such insult is smoking, which is a major risk factor for osteoporosis and respiratory diseases. Upon cigarette smoke-induced damage, a series of reparatory mechanisms ensue; one such mechanism involves Glycosaminoglycans (GAG). One of these GAGs, namely hyaluronic acid (HA), serves as a potential therapeutic target in lung injury. However, much of its mechanisms of action through its major receptor CD44 remains unexplored. Our previous studies have identified and functionally validated that both cortactin (CTTN: marker of motility) and Survivin (BIRC5: required for cell survival) act as novel HA/CD44-downstream transcriptional targets underpinning cell motility. Here, human MSCs were treated with "" smoke to investigate the effects of cigarette smoke condensate (CSC) on these HA-CD44 novel signaling pathways. Our results show that CSC decreased the expression of both CD44 and its downstream targets CTTN and BIRC5 in MSCs, and that HA reversed these effects. Interestingly, CSC inhibited migration and invasion of MSCs upon CD44-targeted RNAi treatment. This shows the importance of CD44-HA/CTTN and CD44-HA/BIRC5 signaling pathways in MSC motility, and further suggests that these signaling pathways may provide a novel mechanism implicated in migration of MSCs during repair of lung tissue injury. These findings suggest that one should use caution before utilizing MSC from donors with history of smoking, and further pave the way towards the development of targeted therapeutic approaches against CD44-associated diseases

Potential routes of spread of Zika virus to the Middle East, North Africa and Asia: Action must be taken

[No abstract available]Scopu

Bioinformatics investigation on blood-based gene expressions of Alzheimer's disease revealed ORAI2 gene biomarker susceptibility: An explainable artificial intelligence-based approach

The progressive, chronic nature of Alzheimer's disease (AD), a form of dementia, defaces the adulthood of elderly individuals. The pathogenesis of the condition is primarily unascertained, turning the treatment efficacy more arduous. Therefore, understanding the genetic etiology of AD is essential to identifying targeted therapeutics. This study aimed to use machine-learning techniques of expressed genes in patients with AD to identify potential biomarkers that can be used for future therapy. The dataset is accessed from the Gene Expression Omnibus (GEO) database (Accession Number: GSE36980). The subgroups (AD blood samples from frontal, hippocampal, and temporal regions) are individually investigated against non-AD models. Prioritized gene cluster analyses are conducted with the STRING database. The candidate gene biomarkers were trained with various supervised machine-learning (ML) classification algorithms. The interpretation of the model prediction is perpetrated with explainable artificial intelligence (AI) techniques. This experiment revealed 34, 60, and 28 genes as target biomarkers of AD mapped from the frontal, hippocampal, and temporal regions. It is identified ORAI2 as a shared biomarker in all three areas strongly associated with AD's progression. The pathway analysis showed that STIM1 and TRPC3 are strongly associated with ORAI2. We found three hub genes, TPI1, STIM1, and TRPC3, in the network of the ORAI2 gene that might be involved in the molecular pathogenesis of AD. Naive Bayes classified the samples of different groups by fivefold cross-validation with 100% accuracy. AI and ML are promising tools in identifying disease-associated genes that will advance the field of targeted therapeutics against genetic diseases.Open Access funding provided by the Qatar National Library

Anaphylaxis triggers in a large tertiary care hospital in Qatar: a retrospective study

Anaphylaxis is a serious allergic disease that may lead to death if not immediately recognized and treated. Triggers of anaphylaxis including food, drugs, and insect stings can vary widely. The incidence of anaphylaxis seems to be affected by age, sex, atopy, and geographic location. This study aims to examine the common triggers of anaphylaxis in Qatar. A total of 1068 electronic medical records were audited using power chart system: 446 from the medical coding system of anaphylaxis and 622 from the epinephrine auto-injectors (EAIs) dispensed during January 2012-December 2017. Of 1068 patients, 574 (53.5%) had anaphylaxis; male to female ratio was 1.2, and 300 patients (77.9%) were less than 10 years old. The common triggers were food ( = 316, 55.0%), insect stings ( = 161, 28.0%), and drugs ( = 103, 17.9%). Common anaphylaxis food triggers were nuts ( = 173, 30.1%), eggs ( = 89, 15.5%), and seafood ( = 72, 12.5%), and common anaphylaxis medication triggers were antibiotics ( = 49, 8.5%) and nonsteroidal anti-inflammatory drugs ( = 30, 5.2%). Interestingly, 135 anaphylactic patients (23.5%) were due to black ant stings. The anaphylaxis triggers varied significantly between children and adults. Among children (less than 10 years), three quarters of the events were triggered by food (223, 74.3%) while among adults (20-55 years), insect stings ( = 59, 43.0%) and drugs ( = 44, 32.0%) were dominant. This is the first national study stratifying anaphylaxis triggers among different age groups in Qatar. This study will serve as a guide for clinical practice in allergy clinics in Qatar and will help to assess future trends of anaphylaxis in Qatar