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Background: Stroke refers to an abrupt neurological deficit, caused by an acute focal injury of the central nervous system via infarction or hemorrhage due to impaired vascularity, and remains among the leading causes of disability and death worldwide. Stroke is often preceded by an episode of neuronal deficit termed transient ischemic attack (TIA), which presents an effective opportunity for mitigating the risk of an eminent acute ischemic stroke (AIS). Circulating non-coding RNAs (ncRNAs) have emerged as important biomarkers for stroke, but PIWI-interacting RNAs (piRNAs), a class of small regulatory ncRNAs, have not been previously explored as diagnostic or prognostic biomarkers for stroke. Methods: We conducted comprehensive circulating piRNA profiling of AIS and TIA patients using RNA-seq on serum samples collected within 24 h of clinical diagnosis. The study cohort was divided into discovery and cross-validation datasets to identify replicated piRNAs using stringent analysis cut-offs. The expression levels of the panel of differentially regulated piRNAs between AIS and TIA patients were also compared with healthy controls. Results: We identified a panel of 10 differentially regulated piRNAs between AIS and TIA patients; hsa-piR-28272, -piR-32972, -piR-28247, -piR-24553, -piR-24552, -piR-28275, -piR-28707 and -piR-32882 were upregulated, while hsa-piR-23058 and -piR-23136 were downregulated in AIS patients. Moreover, these 10 piRNAs were also differentially expressed in AIS patients compared to healthy controls. In addition, we investigated the potential gene targets of the dysregulated piRNAs and their plausible involvement in pathophysiological processes affected in stroke. Conclusions: The imbalances in the circulating piRnome of AIS and TIA patients presented herein provide important insights into the roles of piRNAs following ischemic brain injury and potentially provide opportunities to mitigate stroke-induced mortality and morbidity.

BackgroundThe relationship between salivary α-amylase activity (sAAa) and susceptibility to cardiovascular disorders lacks a definitive consensus in available studies. To fill this knowledge gap, the present study endeavors to investigate this association among overweight/obese otherwise healthy Qatari adults. The study specifically categorizes participants based on their sAAa into high and low subgroups, aiming to provide a more comprehensive understanding of the potential link between sAAa levels and cardiovascular and inflammation markers in this population.MethodsPlasma samples of 264 Qatari overweight/obese (Ow/Ob) participants were used to quantify the sAAa and to profile the proteins germane to cardiovascular, cardiometabolic, metabolism, and organ damage in low sAAa (LsAAa) and high sAAa (HsAAa) subjects using the Olink technology. Comprehensive statistical tools as well as chemometric and enrichments analyses were used to identify differentially expressed proteins (DEPs) and their associated signaling pathways and cellular functions.ResultsA total of ten DEPs were detected, among them five were upregulated (QPCT, LCN2, PON2, DPP7, CRKL) while five were down regulated in the LsAAa subgroup compared to the HsAAa subgroup (ARG1, CTSH, SERPINB6, OSMR, ALDH3A). Functional enrichment analysis highlighted several relevant signaling pathways and cellular functions enriched in the DEPs, including myocardial dysfunction, disorder of blood pressure, myocardial infraction, apoptosis of cardiomyocytes, hypertension, chronic inflammatory disorder, immunes-mediated inflammatory disease, inflammatory response, activation of leukocytes and activation of phagocytes.ConclusionOur study unveils substantial alterations within numerous canonical pathways and cellular or molecular functions that bear relevance to cardiometabolic disorders among Ow/Ob Qatari adults exhibiting LsAAa and HsAAa in the plasma. A more comprehensive exploration of these proteins and their associated pathways and functions offers the prospect of elucidating the mechanistic underpinnings inherent in the documented relationship between sAAa and metabolic disorders.

IntroductionObesity, prevalent in approximately 80% of Qatar’s adult population, increases the risk of complications like type 2 diabetes and cardiovascular diseases. Predictive biomarkers are crucial for preventive strategies. Salivary α-amylase activity (sAAa) inversely correlates with obesity and insulin resistance in adults and children. However, the connection between sAAa and cardiometabolic risk factors or chronic low-grade inflammation markers remains unclear. This study explores the association between serum sAAa and adiposity markers related to cardiovascular diseases, as well as markers indicative of chronic low-grade inflammation.MethodsSerum samples and clinical data of 1500 adult, non-diabetic, Overweight/Obese participants were obtained from Qatar Biobank (QBB). We quantified sAAa and C reactive protein (CRP) levels with an autoanalyzer. Cytokines, adipokines, and adiponectin of a subset of 228 samples were quantified using a bead-based multiplex assay. The associations between the sAAa and the adiposity indices and low-grade inflammatory protein CRP and multiple cytokines were assessed using Pearson’s correlation and adjusted linear regression.ResultsThe mean age of the participants was 36 ± 10 years for both sexes of which 76.6% are women. Our analysis revealed a significant linear association between sAAa and adiposity-associated biomarkers, including body mass index β -0.032 [95% CI -0.049 to -0.05], waist circumference β -0.05 [95% CI -0.09 to -0.02], hip circumference β -0.052 [95% CI -0.087 to -0.017], and HDL β 0.002 [95% CI 0.001 to 0.004], albeit only in women. Additionally, sAAa demonstrated a significant positive association with adiponectin β 0.007 [95% CI 0.001 to 0.01]while concurrently displaying significant negative associations with CRP β -0.02 [95% CI -0.044 to -0.0001], TNF-α β -0.105 [95% CI -0.207 to -0.004], IL-6 β [95% CI -0.39 -0.75 to -0.04], and ghrelin β -5.95 [95% CI -11.71 to -0.20], specifically within the female population.ConclusionOur findings delineate significant associations between sAAa and markers indicative of cardiovascular disease risk and inflammation among overweight/obese adult Qatari females. Subsequent investigations are warranted to elucidate the nuances of these gender-specific associations comprehensively.

Introduction Pre-diabetes stands as a prominent, independent risk factor for the onset of type 2 diabetes (T2D), with 5%–10% of individuals with pre-diabetes progressing to T2D annually. The effectiveness of rigorous lifestyle interventions in averting the transition from pre-diabetes to T2D has been substantiated across multiple investigations and populations. Consequently, the clinical imperative of early pre-diabetes detection becomes unequivocal. This study assessed the validity of the recently developed pre-diabetes risk score in Qatar (PRISQ) in a real-world clinical setting.Research design and methods We recruited 1021 walk-in participants from 3 different health centres of Qatar’s Primary Health Care Corporation. Only adult people without known pre-diabetes or diabetes were included in the study. Along with blood collected for the haemoglobin A1c (HbA1c) test to confirm pre-diabetes, we recorded the age, gender, weight, waist circumference, systolic and diastolic blood pressure, nationality, smoking state and family history of diabetes. Negative predictive value, positive predictive value, sensitivity and specificity of PRISQ were computed.Results Of the 1021 participants, 797 agreed to provide blood. HbA1c test revealed that 21.9% of the 797 subjects had pre-diabetes (HbA1c between 5.7% and 6.5%) while 3.3% had undiagnosed diabetes (HbA1c≥ 6.5%). Using a PRISQ cut-off of 16, PRISQ sensitivity exceeded 90% in all subgroups of individuals aged 40 years and above, regardless of ethnicity. We did not see any significant improvement in PRISQ sensitivity when we considered the family history of diabetes.Conclusions We confirmed a good PRISQ diagnostic rate for pre-diabetes from a representative sample of the Qatar population recruited in a real-world clinical setting. PRISQ can potentially play a significant role in curbing the T2D epidemic sweeping Qatar and beyond.

BackgroundDementia is a debilitating neurological disease affecting millions of people worldwide. The exact mechanisms underlying the initiation and progression of the disease remain to be fully defined. There is an increasing body of evidence for the role of immune dysregulation in the pathogenesis of dementia, where blood-borne autoimmune antibodies have been studied as potential markers associated with pathological mechanisms of dementia.MethodsThis study included plasma from 50 cognitively normal individuals, 55 subjects with MCI (mild cognitive impairment), and 22 subjects with dementia. Autoantibody profiling for more than 1,600 antigens was performed using a high throughput microarray platform to identify differentially expressed autoantibodies in MCI and dementia.ResultsThe differential expression analysis identified 33 significantly altered autoantibodies in the plasma of patients with dementia compared to cognitively normal subjects, and 38 significantly altered autoantibodies in the plasma of patients with dementia compared to subjects with MCI. And 20 proteins had significantly altered autoantibody responses in MCI compared to cognitively normal individuals. Five autoantibodies were commonly dysregulated in both dementia and MCI, including anti-CAMK2A, CKS1B, ETS2, MAP4, and NUDT2. Plasma levels of anti-ODF3, E6, S100P, and ARHGDIG correlated negatively with the cognitive performance scores (MoCA) (r2 –0.56 to −0.42, value of p

Insulin resistance (IR) is type 2 diabetes’ hallmark. MiRNAs regulate many target genes that makes them attractive candidates for regulating insulin production, secretion and action. Therefore, we anticipate a change in the circulatory profile of miRNAs in IR subjects compared to normal glucose tolerance subjects. In the present study, we sought to identify the circulating miRNAs associated with IR as biomarkers in Qatari population. The circulating miRNA profile was assessed in a pilot study of healthy volunteers (n = 22) whose insulin sensitivity was quantitated by euglycemic hyperinsulemic clamp. Moreover, in the validation phase (n = 40) subjects were added including lean and obese T2D. MiR-186 showed a consistent significant increase in insulin resistance subjects compared to NGT in the discovery and validation phase analysis. In addition, intergroup comparison of circulating miRNA pinpointed 2 miRNAs: MiR-122 increased substantially in obese T2D subjects, with diagnostic value to predict obesity in T2D subjects, and let-7b increased significantly in lean T2D subjects. Our results suggest that circulating miRNAs serve as biomarkers for IR, T2D and obesity in Qatari population. Further functional studies are warranted to better identify the targets of these miRNAs and understand the underlying molecular and cellular mechanisms.

IntroductionAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by defects in two core domains, social/communication skills and restricted/repetitive behaviors or interests. There is no approved biomarker for ASD diagnosis, and the current diagnostic method is based on clinical manifestation, which tends to vary vastly between the affected individuals due to the heterogeneous nature of ASD. There is emerging evidence that supports the implication of the immune system in ASD, specifically autoimmunity; however, the role of autoantibodies in ASD children is not yet fully understood.Materials and methodsIn this study, we screened serum samples from 93 cases with ASD and 28 healthy controls utilizing high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. Our goal was to identify autoantibodies with differential expressions in ASD and to gain insights into the biological significance of these autoantibodies in the context of ASD pathogenesis.ResultOur autoantibody expression analysis identified 29 differential autoantibodies in ASD, 4 of which were upregulated and 25 downregulated. Subsequently, gene ontology (GO) and network analysis showed that the proteins of these autoantibodies are expressed in the brain and involved in axonal guidance, chromatin binding, and multiple metabolic pathways. Correlation analysis revealed that these autoantibodies negatively correlate with the age of ASD subjects.ConclusionThis study explored autoantibody reactivity against self-antigens in ASD individuals' serum using a high-throughput assay. The identified autoantibodies were reactive against proteins involved in axonal guidance, synaptic function, amino acid metabolism, fatty acid metabolism, and chromatin binding.

Background: Coronavirus disease (COVID-19) manifests many clinical symptoms, including an exacerbated immune response and cytokine storm. Autoantibodies in COVID-19 may have severe prodromal effects that are poorly understood. The interaction between these autoantibodies and self-antigens can result in systemic inflammation and organ dysfunction. However, the role of autoantibodies in COVID-19 complications has yet to be fully understood.Methods: The current investigation screened two independent cohorts of 97 COVID-19 patients [discovery (Disc) cohort from Qatar (case = 49 vs. control = 48) and replication (Rep) cohort from New York (case = 48 vs. control = 28)] utilizing high-throughput KoRectly Expressed (KREX) Immunome protein-array technology. Total IgG autoantibody responses were evaluated against 1,318 correctly folded and full-length human proteins. Samples were randomly applied on the precoated microarray slides for 2 h. Cy3-labeled secondary antibodies were used to detect IgG autoantibody response. Slides were scanned at a fixed gain setting using the Agilent fluorescence microarray scanner, generating a 16-bit TIFF file. Group comparisons were performed using a linear model and Fisher’s exact test. Differentially expressed proteins were used for KEGG and WIKIpathway annotation to determine pathways in which the proteins of interest were significantly over-represented.Results and conclusion: Autoantibody responses to 57 proteins were significantly altered in the COVID-19 Disc cohort compared to healthy controls (p ≤ 0.05). The Rep cohort had altered autoantibody responses against 26 proteins compared to non-COVID-19 ICU patients who served as controls. Both cohorts showed substantial similarities (r2 = 0.73) and exhibited higher autoantibody responses to numerous transcription factors, immunomodulatory proteins, and human disease markers. Analysis of the combined cohorts revealed elevated autoantibody responses against SPANXN4, STK25, ATF4, PRKD2, and CHMP3 proteins in COVID-19 patients. The sequences for SPANXN4 and STK25 were cross-validated using sequence alignment tools. ELISA and Western blot further verified the autoantigen–autoantibody response of SPANXN4. SPANXN4 is essential for spermiogenesis and male fertility, which may predict a potential role for this protein in COVID-19-associated male reproductive tract complications, and warrants further research.

Abstract Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p

IntroductionThe triglyceride-glucose (TyG)-driven indices, incorporating obesity indices, have been proposed as reliable markers of insulin resistance and related comorbidities such as diabetes. This study evaluated the effectiveness of these indices in detecting prediabetes in normal-weight individuals from a Middle Eastern population.MethodsUsing the data of 5,996 adult Qatari participants from the Qatar Biobank cohort, we employed adjusted logistic regression to assess the ability of various obesity and triglyceride-related indices to detect prediabetes in normal-weight (18.5 ≤ BMI

Abstract Elevated serum ferritin (SFer) levels are implicated in many energy metabolism abnormalities. The association between SFer levels and metabolic disorders has not been studied in Middle Eastern populations. We aimed at exploring the association between SFer levels and serum lipids, diabetes determinants, and metabolic syndrome in a sample of Qatari adults. This study used biochemical parameters obtained from 1928 participants from the Qatar Biobank cohort. We utilized adjusted multivariable logistic regression analysis to estimate the odds ratios (ORs) for dyslipidemia, type 2 diabetes, the homeostasis model assessment of insulin resistance (HOMA-IR), and metabolic syndrome (MetS) according to sex-specific SFer quartiles (Q1 to Q4). Results revealed that the ORs for dyslipidemia increased progressively and significantly across the SFer quartiles, up to two folds in Q4 for women (OR 2.47 (1.68–3.62)) and men (OR 2.24 (1.41–3.55)) versus Q1 (OR:1). Exclusively in women, the ORs for IR (HOMA-IR > 3.58) increased significantly in Q4 (OR 1.79 (1.19–2.70)) versus OR 1 in Q1 as did the ORs for diabetes (OR: 2.03 (1.15–3.57) in Q4 versus OR 1 in Q1). We observed the same result when we pooled the participants with prediabetes and diabetes in one group. The OR for MetS also increased significantly across the Sfer Quartiles from OR: 1 in Q1 to 1.92 (1.06–3.02) in Q4 for women and to 2.07 (1.08–3.98) in Q4 in men. Our results suggest the elevated Sfer levels as a potential risk biomarker for dyslipidemia and MetS in adult Qatari men and women, and diabetes and IR in women only.

Stroke is the second leading cause of global mortality and continued efforts aim to identify predictive, diagnostic, or prognostic biomarkers to reduce the disease burden. Circulating microRNAs (miRNAs) have emerged as potential biomarkers in stroke. We performed comprehensive circulating miRNA profiling of ischemic stroke patients with or without type 2 diabetes mellitus (T2DM), an important risk factor associated with worse clinical outcomes in stroke. Serum samples were collected within 24 h of acute stroke diagnosis and circulating miRNAs profiled using RNA-Seq were compared between stroke patients with T2DM (SWDM; n = 92) and those without T2DM (SWoDM; n = 98). Our analysis workflow involved random allocation of study cohorts into discovery (n = 96) and validation (n = 94) datasets. Five miRNAs were found to be differentially regulated in SWDM compared to SWoDM patients. Hsa-miR-361-3p and -664a-5p were downregulated, whereas miR-423-3p, -140-5p, and -17-3p were upregulated. We also explored the gene targets of these miRNAs and investigated the downstream pathways associated with them to decipher the potential pathways impacted in stroke with diabetes as comorbidity. Overall, our novel findings provide important insights into the differentially regulated miRNAs, their associated pathways and potential utilization for clinical benefits in ischemic stroke patients with diabetes.

Abstract Background and aims The hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro. Methods Steatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs. Results We confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-β, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways. Conclusion Our results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies.

Abstract The association of salivary α-amylase activity (SAA) activity or low copy number of its coding gene AMY1 with diabetes remains controversial. We aimed to reinvestigate the association of these factors with diabetes in Qatar, where diabetes prevalence is about 16%. We obtained cross-sectional data of 929 Qataris (age > 18 years) from the Qatar Biobank. We estimated AMY1 copy number variants (CNV) from whole-genome data, and quantified the SAA activity in plasma (pSAA). We used adjusted logistic regression to examine the association between pSAA activity or AMY1 CNV and diabetes odds. We found a significant association between high pSAA activity, but not AMY1 CNV, and reduced odds of diabetes in Qatari women. The OR per pSAA activity unit was 0.95 [95% CI 0.92, 0.98] (p = 0.002) (pSAA activity range: 4.7 U/L to 65 U/L) in women. The association is driven largely by the highest levels of pSAA activity. The probability of having diabetes was significantly lower in the fifth pSAA activity quintile relative to the first (0.21 ± 0.03 (Q1) versus 0.82 ± 0.02 (Q5)), resulting in significantly reduced diabetes prevalence in Q5 in women. Our study indicates a beneficial effect of high pSAA activity, but not AMY1 CN, on diabetes odds in Qatari women, and suggests pSAA activity levels as a potential marker to predict future diabetes in Qatari women.

Abstract Aims/Introduction The progression from prediabetes to type 2 diabetes is preventable by lifestyle intervention and/or pharmacotherapy in a large fraction of individuals with prediabetes. Our objective was to develop a risk score to screen for prediabetes in the Middle East, where diabetes prevalence is one of the highest in the world. Materials and Methods In this cross‐sectional, case–control study, we used data of 4,895 controls and 2,373 prediabetic adults obtained from the Qatar Biobank cohort. Significant risk factors were identified by logistic regression and other machine learning methods. The receiver operating characteristic was used to calculate the area under curve, cut‐off point, sensitivity, specificity, positive and negative predictive values. The prediabetes risk score was developed from data of Qatari citizens, as well as long‐term (≥15 years) residents. Results The significant risk factors for the Prediabetes Risk Score in Qatar were age, sex, body mass index, waist circumference and blood pressure. The risk score ranges from 0 to 45. The area under the curve of the score was 80% (95% confidence interval 78–83%), and the cut‐off point of 16 yielded sensitivity and specificity of 86.2% (95% confidence interval 82.7–89.2%) and 57.9% (95% confidence interval 65.5–71.4%), respectively. Prediabetes Risk Score in Qatar performed equally in Qatari nationals and long‐term residents. Conclusions Prediabetes Risk Score in Qatar is the first prediabetes screening score developed in a Middle Eastern population. It only uses risk factors measured non‐invasively, is simple, cost‐effective, and can be easily understood by the general public and health providers. Prediabetes Risk Score in Qatar is an important tool for early detection of prediabetes, and can help tremendously in curbing the diabetes epidemic in the region.

Background: The relationship between salivary a-amylase activity (sAAa) and susceptibility to cardiovascular disorders lacks a definitive consensus in available studies. To fill this knowledge gap, the present study endeavors to investigate this association among overweight/obese otherwise healthy Qatari adults. The study specifically categorizes participants based on their sAAa into high and low subgroups, aiming to provide a more comprehensive understanding of the potential link between sAAa levels and cardiovascular and inflammation markers in this population. Methods: Plasma samples of 264 Qatari overweight/obese (Ow/Ob) participants were used to quantify the sAAa and to profile the proteins germane to cardiovascular, cardiometabolic, metabolism, and organ damage in low sAAa (LsAAa) and high sAAa (HsAAa) subjects using the Olink technology. Comprehensive statistical tools as well as chemometric and enrichments analyses were used to identify differentially expressed proteins (DEPs) and their associated signaling pathways and cellular functions. Results: A total of ten DEPs were detected, among them five were upregulated (QPCT, LCN2, PON2, DPP7, CRKL) while five were down regulated in the LsAAa subgroup compared to the HsAAa subgroup (ARG1, CTSH, SERPINB6, OSMR, ALDH3A). Functional enrichment analysis highlighted several relevant signaling pathways and cellular functions enriched in the DEPs, including myocardial dysfunction, disorder of blood pressure, myocardial infraction, apoptosis of cardiomyocytes, hypertension, chronic inflammatory disorder, immunesmediated inflammatory disease, inflammatory response, activation of leukocytes and activation of phagocytes. Conclusion: Our study unveils substantial alterations within numerous canonical pathways and cellular or molecular functions that bear relevance to cardiometabolic disorders among Ow/Ob Qatari adults exhibiting LsAAa and HsAAa in the plasma. A more comprehensive exploration of these proteins and their associated pathways and functions offers the prospect of elucidating the mechanistic underpinnings inherent in the documented relationship between sAAa and metabolic disorders. [ABSTRACT FROM AUTHOR]

The relationship between salivary α-amylase activity (ssAAa) and the risk of metabolic disorders remains equivocal. We aimed to assess this relationship in adults from Qatar, where obesity and type 2 diabetes are highly prevalent. We cross-sectionally quantified ssAAa in saliva and estimated AMY1 CN from whole-genome sequencing data from 1499 participants. Linear regression was used to assess the relationship between ssAAa and adiposity and glycemic markers. Logistic regression was used to examine the association between ssAAa and occurrence of obesity or diabetes. The mean and median ssAAa were significantly lower in obese individuals. There were significant inverse associations between ssAAa and BMI, and fat mass. We detected a marked effect of ssAAa on reduced odds of obesity after adjusting for age and sex, glucose, LDL, HLD, total cholesterol, and systolic and diastolic blood pressure (OR per ssAAa unit 0.998 [95% CI 0.996–0.999], p = 0.005), with ssAAa ranging between 6.8 and 422U/mL. The obesity odds were significantly lower in the upper half of the ssAAa distributional (OR 0.58 [95% CI 0.42–0.76], p

IntroductionCystic fibrosis (CF) is a hereditary autosomal recessive disorder caused by a range of mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. This gene encodes the CFTR protein, which acts as a chloride channel activated by cyclic AMP (cAMP). This meta-analysis aimed to compare the responsiveness of induced pluripotent stem cells (iPSCs) to cAMP analogues to that of commonly used animal models.MethodsDatabases searched included PubMed, Scopus, and Medline from inception to January 2020. A total of 8 and 3 studies, respectively, for animal models and iPSCs, were analyzed. Studies were extracted for investigating cAMP-stimulated anion transport by measuring the short circuit current (Isc) of chloride channels in different animal models and iPSC systems We utilized an inverse variance heterogeneity model for synthesis.ResultsOur analysis showed considerable heterogeneity in the mean Isc value in both animal models and iPSCs studies (compared to their WT counterparts), and both suffer from variable responsiveness based on the nature of the underlying model. There was no clear advantage of one over the other.ConclusionsStudies on both animal and iPSCs models generated considerable heterogeneity. Given the potential of iPSC-derived models to study different diseases, we recommend paying more attention to developing reproducible models of iPSC as it has potential if adequately developed.

Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier transform infrared (FTIR) spectroscopy, we sought to investigate the biochemical changes in a steatosis cell model treated or not with the GLP-1R agonist Exendin-4 (Ex-4). HepG2 cells were made steatotic with 400 µM of oleic acid and then treated with 200 nM Ex-4 in order to reduce lipid accumulation. We quantified steatosis using the Oil Red O staining method. We investigated the biochemical alterations induced by steatosis and Ex-4 treatment using Fourier transform infrared (FTIR) spectroscopy and chemometric analyses. Analysis of the Oil Red O staining showed that Ex-4 significantly reduces steatosis. This reduction was confirmed by FTIR analysis, as the phospholipid band (C=O) at 1740 cm−1 in Ex-4 treated cells is significantly decreased compared to steatotic cells. The principal component analysis score plots for both the lipid and protein regions showed that the untreated and Ex-4-treated samples, while still separated, are clustered close to each other, far from the steatotic cells. The biochemical and structural changes induced by OA-induced lipotoxicity are at least partially reversed upon Ex-4 treatment. FTIR and chemometric analyses revealed that Ex-4 significantly reduces OA-induced lipid accumulation, and Ex-4 also restored the lipid and protein biochemical alterations caused by lipotoxicity-induced oxidative stress. In combination with chemometric analyses, FTIR spectroscopy may offer new approaches for investigating the mechanisms underpinning NAFLD.

Beyond the suffering of the affected subjects, type 2 diabetes (T2D) and obesity epidemics gripping the Gulf Cooperation Council (GCC) states are expected to seriously jeopardize these nations’ economies and development due to productivity losses. Available data show that healthcare budgets in GCC nations are under tremendous pressure because of diabetes- and obesity-linked comorbidities. Furthermore, T2D, once an over-forties disease, risks becoming a whole-adult-life condition because of obesity-associated early-onset T2D and prediabetes. The incidence of T2D is set to worsen unless efficient actions are taken to fight obesity and prevent the conversion of prediabetes to T2D. There is a consensus that the concomitant increase in obesity rates drives T2D rates upward. Fighting obesity at all levels should, therefore, take center stage for the GCC nations. The battle against obesity and T2D is a long-term and complex one. Therefore, only through concerted efforts between several public and private actors, including health, economic, and urbanization agencies, food producers and retailers, schools, families, youth organizations, sports clubs, and voluntary organizations, can this battle be won. The present review tries to assess the current status of diabetes and obesity epidemics in the GCC context and take stock of some of the policies and initiatives that have been, or need to be, implemented to address their growing burden.

No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a cell model of steatosis to overcome pleiotropy. We treated steatotic HepG2 cells with the GLP-1RA Exendin-4 (Ex-4). We compared the transcriptome profiles of untreated steatotic, and Ex-4-treated steatotic cells, and used Ingenuity Pathway Analysis (IPA) to identify the signaling pathways and associated genes involved in the protective effect of Ex-4. Ex-4 treatment significantly reduces steatosis. RNA-seq analysis revealed 209 differentially expressed genes (DEGs) between steatotic and untreated cells, with farnesoid X receptor/retinoid X receptor (FXR/RXR) (p = 8.9 × 10−7) activation being the top regulated canonical pathway identified by IPA. Furthermore, 1644 DEGs were identified between steatotic cells and Ex-4-treated cells, with liver X receptor/retinoid X receptor (LXR/RXR) (p = 2.02 × 10−7) and FXR/RXR (p = 3.28 × 10−7) activation being the two top canonical pathways. The top molecular and cellular functions between untreated and steatotic cells were lipid metabolism, molecular transport, and small molecular biochemistry, while organismal injury and abnormalities, endocrine system disorders, and gastrointestinal disease were the top three molecular and cellular functions between Ex-4-treated and steatotic cells. Genes overlapping steatotic cells and Ex-4-treated cells were associated with several lipid metabolism processes. Unique transcriptomic differences exist between steatotic cells and Ex-4-treated steatotic cells, providing an important resource for understanding the mechanisms that underpin the protective effect of GLP-1RAs on NAFLD and for the identification of novel therapeutic targets for NAFLD.

Abstract Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation.

Abstract Background A microRNA (miRNA) collection on the imprinted 14q32 MEG3 region has been associated with outcome in osteosarcoma. We assessed the clinical utility of this miRNA set and their association with methylation status. Methods We integrated coding and non-coding RNA data from three independent annotated clinical osteosarcoma cohorts (n = 65, n = 27, and n = 25) and miRNA and methylation data from one in vitro (19 cell lines) and one clinical (NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) osteosarcoma dataset, n = 80) dataset. We used time-dependent receiver operating characteristic (tdROC) analysis to evaluate the clinical value of candidate miRNA profiles and machine learning approaches to compare the coding and non-coding transcriptional programs of high- and low-risk osteosarcoma tumors and high- versus low-aggressiveness cell lines. In the cell line and TARGET datasets, we also studied the methylation patterns of the MEG3 imprinting control region on 14q32 and their association with miRNA expression and tumor aggressiveness. Results In the tdROC analysis, miRNA sets on 14q32 showed strong discriminatory power for recurrence and survival in the three clinical datasets. High- or low-risk tumor classification was robust to using different microRNA sets or classification methods. Machine learning approaches showed that genome-wide miRNA profiles and miRNA regulatory networks were quite different between the two outcome groups and mRNA profiles categorized the samples in a manner concordant with the miRNAs, suggesting potential molecular subtypes. Further, miRNA expression patterns were reproducible in comparing high-aggressiveness versus low-aggressiveness cell lines. Methylation patterns in the MEG3 differentially methylated region (DMR) also distinguished high-aggressiveness from low-aggressiveness cell lines and were associated with expression of several 14q32 miRNAs in both the cell lines and the large TARGET clinical dataset. Within the limits of available CpG array coverage, we observed a potential methylation-sensitive regulation of the non-coding RNA cluster by CTCF, a known enhancer-blocking factor. Conclusions Loss of imprinting/methylation changes in the 14q32 non-coding region defines reproducible previously unrecognized osteosarcoma subtypes with distinct transcriptional programs and biologic and clinical behavior. Future studies will define the precise relationship between 14q32 imprinting, non-coding RNA expression, genomic enhancer binding, and tumor aggressiveness, with possible therapeutic implications for both early- and advanced-stage patients.

Epidemiological Modeling supports the evaluation of various disease management activities. The value of epidemiological models lies in their ability to study various scenarios and to provide governments with a priori knowledge of the consequence of disease incursions and the impact of preventive strategies. A prevalent method of modeling the spread of pandemics is to categorize individuals in the population as belonging to one of several distinct compartments, which represents their health status with regard to the pandemic. In this work, a modified SIR epidemic model is proposed and analyzed with respect to the identification of its parameters and initial values based on stated or recorded case data from public health sources to estimate the unreported cases and the effectiveness of public health policies such as social distancing in slowing the spread of the epidemic. The analysis aims to highlight the importance of unreported cases for correcting the underestimated basic reproduction number. In many epidemic outbreaks, the number of reported infections is likely much lower than the actual number of infections which can be calculated from the model’s parameters derived from reported case data. The analysis is applied to the COVID-19 pandemic for several countries in the Gulf region and Europe.

Background: Dementia is a debilitating neurological disease affecting millions of people worldwide. The exact mechanisms underlying the initiation and progression of the disease remain to be fully defined. There is an increasing body of evidence for the role of immune dysregulation in the pathogenesis of dementia, where blood-borne autoimmune antibodies have been studied as potential markers associated with pathological mechanisms of dementia. Methods: This study included plasma from 50 cognitively normal individuals, 55 subjects with MCI (mild cognitive impairment), and 22 subjects with dementia. Autoantibody profiling for more than 1,600 antigens was performed using a high throughput microarray platform to identify differentially expressed autoantibodies in MCI and dementia. Results: The differential expression analysis identified 33 significantly altered autoantibodies in the plasma of patients with dementia compared to cognitively normal subjects, and 38 significantly altered autoantibodies in the plasma of patients with dementia compared to subjects with MCI. And 20 proteins had significantly altered autoantibody responses in MCI compared to cognitively normal individuals. Five autoantibodies were commonly dysregulated in both dementia and MCI, including anti-CAMK2A, CKS1B, ETS2, MAP4, and NUDT2. Plasma levels of anti-ODF3, E6, S100P, and ARHGDIG correlated negatively with the cognitive performance scores (MoCA) (r 2 –0.56 to −0.42, value of p <  0.001). Additionally, several proteins targeted by autoantibodies dysregulated in dementia were significantly enriched in the neurotrophin signaling pathway, axon guidance, cholinergic synapse, long-term potentiation, apoptosis, glycolysis and gluconeogenesis. Conclusion: We have shown multiple dysregulated autoantibodies in the plasma of subjects with MCI and dementia. The corresponding proteins for these autoantibodies are involved in neurodegenerative pathways, suggesting a potential impact of autoimmunity on the etiology of dementia and the possible benefit for future therapeutic approaches. Further investigations are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Chronic hypertension remains a major cause of global mortality and morbidity. It is a complex disease that is the clinical manifestation of multiple genetic, environmental, nutritional, hormonal, and aging-related disorders. Evidence supports a role for vascular aging in the development of hypertension involving an impairment in endothelial function together with an alteration in vascular smooth muscle cells (VSMCs) calcium homeostasis leading to increased myogenic tone. Changes in free intracellular calcium levels ([Ca2+]i) are mediated either by the influx of Ca2+ from the extracellular space or release of Ca2+ from intracellular stores, mainly the sarcoplasmic reticulum (SR). The influx of extracellular Ca2+ occurs primarily through voltage-gated Ca2+ channels (VGCCs), store-operated Ca2+ channels (SOC), and Ca2+ release-activated channels (CRAC), whereas SR-Ca2+ release occurs through inositol trisphosphate receptor (IP3R) and ryanodine receptors (RyRs). IP3R-mediated SR-Ca2+ release, in the form of Ca2+ waves, not only contributes to VSMC contraction and regulates VGCC function but is also intimately involved in structural remodeling of resistance arteries in hypertension. This involves a phenotypic switch of VSMCs as well as an alteration of cytoplasmic Ca2+ signaling machinery, a phenomena tightly related to the aging process. Several lines of evidence implicate changes in expression/function levels of IP3R isoforms in the development of hypertension, VSMC phenotypic switch, and vascular aging. The present review discusses the current knowledge of these mechanisms in an integrative approach and further suggests potential new targets for hypertension management and treatment.