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The study aimed to measure the effect of the Balanced Scorecard (BSC), with its four dimensions (financial, clients, internal operations, learning and growth) on reducing banking services costs in commercial banks in Palestine. The study used the descriptive, analytical, and also the regression analysis methods. The study depends on the questionnaire which was addressed, to (general manager, financial director, observer, head of accounting department). The study sample contained (47) employees working in commercial banks in Palestine. The study results showed a significant effect of using the Balanced Scorecard (BSC) and its four dimensions (financial, clients, internal operations, learning and growth) on reducing banking services costs in commercial banks in Palestine, The study recommended the necessity for commercial banks departments in Palestine to pay more attention to clarifying the importance of the Balanced Scorecard (BSC) method, which is one of the modern methods of accounting and its role in reducing banking services costs. And developing service cost plans using the Balanced Scorecard (BSC) and paying attention to all dimensions of the Balanced Scorecard for its role in reducing the costs of the services provided.

After surgery, oral cavity healing occurs in a hostile environment and requires proper oral care and hygiene to accelerate recovery. The aim of the current study is to investigate and compare the bioreactivity characteristics of chlorhexidine based (CHX) mouth rinse and a novel bone bioactive liquid (BBL) mouth rinse on oral healing within seven days application post-surgery. A randomized, double blind clinical trial conducted in 81 patients. The mouth rinses were applied twice a day for a period of 7 days. The visual analog scale (VAS) protocol was applied to measure pain index. Early wound healing score (EHI) was determined in evaluate the oral cavity healing progress. No adverse effects were observed using the mouth washes, but CHX resulted in teeth staining. CHX and BBL were sufficient to reduce pain over a period of 7 days. However, the BBL group demonstrated a statistically significant reduction in VAS stating day 4. Relative to CHX group, the EHI scores were significantly higher in the BBL group, independent from the tooth location. No gender differences were observed in both VAS and EHI scores. Relative to the commercially available CHX, BBL mouth rinse reduced pain and accelerated oral cavity healing. Suggesting an improvements of oral cavity microenvironment at the wound site that mediates soft tissue regeneration.

Supplementary Methods from Evaluation of Human Thymidine Kinase 1 Substrates as New Candidates for Boron Neutron Capture Therapy

IntroductionBoth obesity and a poor diet are considered major risk factors for triggering insulin resistance syndrome (IRS) and the development of type 2 diabetes mellitus (T2DM). Owing to the impact of low-carbohydrate diets, such as the keto diet and the Atkins diet, on weight loss in individuals with obesity, these diets have become an effective strategy for a healthy lifestyle. However, the impact of the ketogenic diet on IRS in healthy individuals of a normal weight has been less well researched. This study presents a cross-sectional observational study that aimed to investigate the effect of low carbohydrate intake in healthy individuals of a normal weight with regard to glucose homeostasis, inflammatory, and metabolic parameters.MethodsThe study included 120 participants who were healthy, had a normal weight (BMI 25 kg/m2), and had no history of a major medical condition. Self-reported dietary intake and objective physical activity measured by accelerometry were tracked for 7 days. The participants were divided into three groups according to their dietary intake of carbohydrates: the low-carbohydrate (LC) group (those consuming ResultsLow carbohydrate intake (DiscussionOverall, the findings of the study showed that, for the first time, low-carbohydrate intake in healthy individuals of a normal weight might lead to dysfunctional glucose homeostasis, increased metabolic acidosis, and the possibility of triggering inflammation by C-peptide elevation in plasma.

This study investigated potentially toxic elements (PTEs) pollution in groundwater across the Maros karst area. The groundwater quality was evaluated using three indexing methods, the heavy metal pollution index (HPI), the heavy metal evaluation index (HMEI) and the contamination index ( The levels of PTEs were calculated to determine the noncancer and cancer risks to the residents through ingestion and dermal adsorption. To obtain high-level accuracy in cancer risk estimation, a Monte Carlo simulation model and sensitivity analysis were performed. The mean values of PTEs in rainy and summer season were followed the order of Cr > Pb > Zn > Cu and Cr > Zn > Pb > Cu, respectively. The high level of Pb and Cr were exceeded the permissible limit of the World Health Organization (WHO) and Indonesian Standards. However, TDS, pH, EC and temperature were still in accordance with WHO guidelines. The geostatistical interpolation of HPI, HMEI and revealed that the groundwater quality around Maros karst is low, particularly in Tukamasea and Leang-Leang village. Hazard index values were lower than one, implying no possibility of noncancer risk. The Monte Carlo simulation results with 95% confidence demonstrated children and adults are at risk for developing cancer due to PTE exposure.

Obesity is characterized by chronic low-grade inflammation. Caveolin-1 (CAV1), a structural and functional protein found in adipose tissues (AT), is augmented in obese individuals. We aimed to define the inflammatory mediators that influence CAV1 gene regulation and associated mechanism in obesity. Using subcutaneous AT from 27 (7 lean/20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). CAV1 gene expression was associated with that of proinflammatory cytokines/chemokines, and their cognate receptor (r ≥ 0.447, p ≤ 0.030) but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-kB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and TNF-α signaling pathway is interesting and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.

Background: Animal and cell model studies have implicated CAV1 in the pathophysiology of metabolic disorders. Our previous studies demonstrated a potential association of CAV1 rs1997623 C/A variant with pediatric metabolic syndrome (MetS) in Arab children. In the present study, we evaluate whether the CAV1 variant associates with MetS Arab adults as well. The association signal is further examined for ancestry-specific variation by considering cohorts of other ethnicities.Method: The CAV1 rs1997623 was genotyped in three cohorts of Arab (n = 479), South Asian (n = 660), and South East Asian (n = 362) ethnic adults from Kuwait. MetS status of the individuals was diagnosed using the IDF criteria (presence of central obesity and at least two abnormalities out of: elevated TG, low HDL, hypertension, or T2D). The quantitative measure of MetS was calculated as siMS = 2 × WC/Height + FBG/5.6 + TG/1.7 + SBP/130–HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous MetS traits were assessed using linear and logistic regression models adjusted for age and sex. In addition, empirical p-values (Pemp) were generated using max(T) permutation procedure based on 10,000 permutations.Results: The CAV1 variant was significantly associated with MetS status (OR = 1.811 [1.25–2.61]; p-value = 0.0015; Pemp = 0.0013) and with siMS (Effect size = 0.206; p-value = 0.0035; Pemp = 0.0028) in the cohort of Arab individuals. The association was weak and insignificant in the South Asian and South East Asian cohorts (OR = 1.19 and 1.11; p-values = 0.25 and 0.67, respectively).Conclusion: The reported association of CAV1 rs1997623 C/A with MetS in Arab pediatric population is now demonstrated in an adult Arab cohort as well. The weak association signal seen in the Asian cohorts lead us to propose a certain extent of ethnic-specificity in CAV1 rs1997623 association with MetS.

Background: Diabetes is associated with several complications, including neuropathic pain, which is difficult to manage with currently available drugs. Descending noradrenergic neurons possess antinociceptive activity; however, their involvement in diabetic neuropathic pain remains to be explored. Methods: To infer the regulatory role of this system, we examined as a function of diabetes, the expression and localization of alpha-2A adrenoceptors (α2-AR) in the dorsal root ganglia and key regions of the central nervous system, including pons and lumbar segment of the spinal cord using qRT-PCR, Western blotting, and immunofluorescence-based techniques. Results: The data revealed that presynaptic synaptosomal-associated protein-25 labeled α2-AR in the central and peripheral nervous system of streptozotocin diabetic rats was upregulated both at the mRNA and protein levels. Interestingly, the levels of postsynaptic density protein-95 labeled postsynaptic neuronal α2-AR remained unaltered as a function of diabetes. These biochemical abnormalities in the noradrenergic system of diabetic animals were associated with increased pain sensitivity as typified by the presence of thermal hyperalgesia and cold/mechanical allodynia. The pain-related behaviors were assessed using Hargreaves apparatus, cold-plate and dynamic plantar aesthesiometer. Chronically administered guanfacine, a selective α2-AR agonist, to diabetic animals downregulated the upregulation of neuronal presynaptic α2-AR and ameliorated the hyperalgesia and the cold/mechanical allodynia in these animals. Conclusion: Together, these findings demonstrate that guanfacine may function as a potent analgesic and highlight α2-AR, a key component of the descending neuronal autoinhibitory pathway, as a potential therapeutic target in the treatment of diabetic neuropathic pain.

Chronic low-grade inflammation induced by obesity is a central risk factor for the development of metabolic syndrome. High low-density lipoprotein cholesterol (LDL-c) induces inflammation, which is a common denominator in metabolic syndrome. IL-23 plays a significant role in the pathogenesis of meta-inflammatory diseases; however, its relationship with LDL-c remains elusive. In this cross-sectional study, we determined whether the adipose tissue IL-23 expression was associated with other inflammatory mediators in people with increased plasma LDL-c concentrations. Subcutaneous adipose tissue biopsies were collected from 60 people, sub-divided into two groups based on their plasma LDL-c concentrations (

Caveolin-1 (CAV1) is implicated in the pathophysiology of diabetes and obesity. Previously, we demonstrated an association between the CAV1 rs1997623 C > A variant and metabolic syndrome (MetS). Here, we decipher the functional role of rs1997623 in CAV1 gene regulation. A cohort of 38 patients participated in this study. The quantitative MetS scores (siMS) of the participants were computed. CAV1 transcript and protein expression were tested in subcutaneous adipose tissue using RT-PCR and immunohistochemistry. Chromatin immunoprecipitation assays were performed using primary preadipocytes isolated from individuals with different CAV1 rs1997623 genotypes (AA, AC, and CC). The regulatory region flanking the variant was cloned into a luciferase reporter plasmid and expressed in human preadipocytes. Additional knockdown and overexpression assays were carried out. We show a significant correlation between siMS and CAV1 transcript levels and protein levels in human adipose tissue collected from an Arab cohort. We found that the CAV1 rs1997623 A allele generates a transcriptionally active locus and a new transcription factor binding site for early B-cell factor 1 (EBF1), which enhanced CAV1 expression. Our in vivo and in vitro combined study implicates, for the first time, EBF1 in regulating CAV1 expression in individuals harboring the rs1997623 C > A variant.

Fatema Al-Rashed,1 Sardar Sindhu,2 Ashraf Al Madhoun,2,3 Abdulwahab Alghaith,4 Rafaat Azim,1 Fahd Al-Mulla,3 Rasheed Ahmad1 1Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait; 2Animal and Imaging Core Facility, Dasman Diabetes Institute, Dasman, Kuwait; 3Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, Kuwait; 4Royal College of Surgeons in Ireland, Dublin, IrelandCorrespondence: Fatema Al-Rashed; Rasheed AhmadMicrobiology & Immunology Department, Dasman Diabetes Institute, Al-Soor Street, Kuwait, P.O. Box 1180, Dasman, 15462, KuwaitTel +965 2224 2999 Ext. 4335; 4311Fax +965 2249 2406Email fatema.alrashed@dasmaninstitute.org; rasheed.ahmad@dasmaninstitute.orgBackground: Efficient sleep duration and its quality are increasingly recognized as important contributors for maintaining normal body weight. However, lifestyle and social structure within the Arab-gulf region differ compared to those in the western world. This study was specifically conducted in Kuwait’s population to investigate the link between sleep quality (SQ) and obesity in the absence of sleep apnea (SA) onset.Methods: SQ was measured by the Pittsburgh Sleep Quality Index (PQSI) in 984 participants, then verified in 60 individuals including 20 lean (Body mass index/BMI: 18.5– 24.9 kg/m2), 20 overweight (BMI: 25– 29.9 kg/m2) and 20 obese (BMI: ≥ 30 kg/m2) through actigraph worn over the right-hip for 7 consecutive days to characterize their sleep–wake cycle, rest-activity, and physical activity. Blood samples were collected for metabolic markers.Results: 59.6% of participants reported a PSQI score higher than 5, with 57.6% of the participants reporting less than 6 hours of sleep per day. The data show that both SQ and sleep duration are considered inadequate in comparison to the international SQ standards. We found a significant association between SQ and obesity independent of age and sex. Actigraph data further supported the independent association of sleep duration on BMI within the population (p < 0.001). Additionally, total sleep time (TST) was found to significantly correlate with several other metabolic factors including diastolic blood pressure, elevated resting heart rate (RHR), triglycerides, total cholesterol, homeostatic model assessment for insulin resistance (HOMA-IR), C-peptide, and C-Reactive Protein (CRP) secretion. Further multiple-regression analysis showed a significant independent association between blood pressure (p < 0.03), HOMA-IR (p < 0.04), and C-peptide (p < 0.3) and sleep duration.Conclusion: These findings suggest that sleep deprivation and disturbance could be indirect factors involved in the development of not only obesity in Kuwait but also other metabolic syndromes such as type 2 diabetes.Keywords: sleep, Kuwait, obesity, PSQI

The imipramine ONC201 has antiproliferative effects in several cancer cell types and activates integrated stress response pathway associated with the induction of Damage Inducible Transcript 3 (DDIT3, also known as C/EBP homologous protein or CHOP). We investigated the signaling pathways through which ONC201/CHOP crosstalk is regulated in ONC201-treated nonmetastatic and metastatic cancer cell lines (Dukes' type B colorectal adenocarcinoma nonmetastatic SW480 and metastatic LS-174T cells, respectively). Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry, gene expression was assessed by Affymetrix microarray, signaling pathway perturbations were assessed in silico, and key regulatory proteins were validated by Western blotting. Unlike LS-174T cells, SW480 cells were resistant to ONC201 treatment; Gene Ontology analysis of differentially expressed genes showed that cellular responsiveness to ONC201 treatment also differed substantially. In both ONC201-treated cell lines, CHOP expression was upregulated; however, its upstream regulatory mechanisms were perturbed. Although, PERK, ATF6 and IRE1 ER-stress pathways upregulated CHOP in both cell types, the Bak/Bax pathway regulated CHOP only LS-174T cells. Additionally, CHOP RNA splicing profiles varied between cell lines; these were further modified by ONC201 treatment. In conclusion, we delineated the signaling mechanisms by which CHOP expression is regulated in ONC201-treated non-metastatic and metastatic colorectal cell lines. The observed differences could be related to cellular plasticity and metabolic reprogramming, nevertheless, detailed mechanistic studies are required for further validations.

Studies have implicated CAV1 in the pathophysiology of diabetes and obesity. Previously, we demonstrated a potential association between the CAV1 rs1997623 C/A variant and metabolic syndrome (MetS) in Kuwaiti children. In the present study, we substantiate the association of CAV1 with MetS in adult Arab individuals. Method: The CAV1 rs1997623 was genotyped in three cohorts of Arabs (n=479) , South Asians (n=660) and South East Asians (n=362) . MetS status of the individuals was diagnosed using the IDF criteria (i.e., presence of central obesity and of at least two abnormalities of high TG, low HDL, hypertension, or type 2 diabetes) . The quantitative measure of MetS was calculated as siMS=2*WC/Height + FBG/5.6 + TG/1.7 + SBP/130 - HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous traits were assessed using linear and logistic regression, respectively, with and adjustment for age and sex. CAV1 transcripts were quantified in adipose tissues from a cohort of 50 Arab individuals differing in siMS score. Results: The CAV1 variant was significantly associated with MetS status (OR=1.8[1.25-2.61]; P-value=0.0015; Pemp=0.0013) and with siMS (Effect size = 0.206; P-value=0.0035; Pemp=0.0028) in the cohort of Arab individuals. The variant was weakly and insignificantly associated in the cohorts of South Asian and South East Asian individuals (OR= 1.and 1.11; P-values= 0.25 and 0.67, respectively) . siMS scores correlated positively with mRNA levels of CAV1 in adipose tissue. Conclusion: The association of CAV1 rs1997623 C/A with MetS in Arab pediatric is now demonstrated in adults as well. Higher expression levels were seen in individuals poses increasing MetS rates further validates the implication of CAV1 rs1997623 C/A variant in MetS phenotype. Only a weak association signal was seen in the South Asian and South East Asian populations leading us to propose that the CAV1 rs1997623 association with MetS is probably specific to Arab ethnicity. Disclosure A.Al madhoun: None. P.Hebbar: None. R.Nizam: None. D.Haddad: None. M.H.Dashti: None. M.Abu-farha: None. R.Ahmad: None. A.T.Thangavel: None. F.Almulla: None. Funding Kuwait Foundation for the Advancement of Sciences (KFAS) and Dasman Diabetes Institute, Project RA CB-2021-007

We Have previously established that caveolin-1 (CAV1) rs1997623 C/A variant is associated with metabolic syndrome in obese children (PMID: 30622557) and adults (ADA 82) . Here, we evaluated the functional role of the identified variant in association with obesity. Sequence analysis revealed that the variant is located at CAV1 regulatory region and creates a site for EBF Transcription Factor 1 (EBF1) . DNA fragment (240pb) flanking the variant was cloned upstream luciferase reporter gene. Wildtype, CAV1-C-Luc, and the generated mutant, CAV1-A-Luc, were individually transfected into pre-adipocytes. CAV1-A-luc significantly upregulated Luciferase activity indicating a prospective functional role of CAV1-A allele in CAV1 regulation. The reporter gene activity was differential regulated in lean versus obese pre-adipocytes. Co-transfections with EBF1 construct resulted in a significant upregulation in CAV1-A Luc activity, particularly in pre-adipocytes from obese individuals. The role of EBF1 was further evaluated in vivo using ChIP assays. PCR analysis using specific primers flanking the CAV1 variant and anti-bodies against EBF1 showed a significant elevated enrichment of chromatins from obese individuals, which was also associated with an enrichment for H3K27ac at the same locus, indicating active transcription. Moreover, CAV1 expression was differentially regulated in response to EBF1 siRNA/overexpression in pre-adipocytes harboring CAV1 A/A or A/C alleles relative to that with C/C allele. Furthermore, a significant reduction of DNA methylation at the variant locus was observed particularly in preadipocytes with A/A alleles. Finally, RNA isolated from adipose tissue of lean and obese individuals showed a significant correlation between CAV1 and cytokines transcripts in healthy obese individuals, at least in part, is due to CAV1 rs1997623 variant as verified by sequence analysis. Taken together, our study delineates the role of CAV1 rs1997623 variant in the context of obesity and MetS. Disclosure A.Al madhoun: None. D.Haddad: None. S.P.Kochumon: None. R.Nizam: None. S.Jacob: None. S.T.Sindhu: None. R.Ahmad: None. F.Almulla: None. Funding Kuwait Foundation for the Advancement of Sciences (KFAS) and Dasman Diabetes Institute, Project RA CB-2021-007

Diabetes is associated with several complications, including neuropathic pain, which is challenging to manage with currently available drugs. Descending noradrenergic neurons possess anti-nociceptive activity; however their involvement in diabetic neuropathic pain remains to be explored. To infer the regulatory role of this system, we examined in the pons, a part of the brainstem, lumbar nerves of the spinal cord and dorsal root ganglia of streptozotocin (STZ) -treated rats, a model for type 1 diabetes (T1D) , the localization (immunofluorescence) and the mRNA (qRT-PCR) and protein (Western blotting) expression of alpha-2A adrenoceptor (ADRA2A) . The data revealed that presynaptic SNAP-25 labeled ADRA2A in the central and peripheral nervous system of STZ diabetic rats were up-regulated both at the mRNA and protein levels. Interestingly, the levels of PSD-95 labeled postsynaptic neuronal ADRA2A remain unaltered as a function of diabetes. These biochemical abnormalities in the noradrenergic system of diabetic animals were associated with increased pain sensitivity as typified by the presence of hyperalgesia and cold/mechanical allodynia. The latter pain-related behaviors were assessed using Hargreaves apparatus, cold-plate and dynamic plantar aesthesiometer. Chronically administered guanfacine, a selective ADRA2A agonist, to diabetic animals downregulated the upregulation of neuronal presynaptic ADRA2A and ameliorated the hyperalgesia and the cold/mechanical allodynia in these animals. Together, these findings demonstrate that guanfacine may function as a potent analgesic and highlight ADRA2A, a key component of the descending neuronal autoinhibitory pathway as a potential therapeutic target in the treatment of diabetic neuropathic pain. Disclosure N. Munawar: None. A. Al madhoun: None. J. Nader: None. W. Al-ali: None. W. Masocha: None. F. Al-mulla: None. M. S. Bitar: None. Funding Grant YM05/19 from Kuwait University Research Sector.

The onset of obesity is vastly associated with low levels of high-density lipoprotein cholesterol (HDL-C) , which predisposes to cardiovascular diseases. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially in lipid metabolic homeostasis. Yet, the precise nature of the HDL/IL-6 dynamics has not been fully elucidated. Therefore, we evaluated the expression of IL-6 in circulatory monocytes of the individuals with various body mass index and we also determined their lipid profile. Our data show that monocytic IL-6 expression was found to be negatively associated with HDL-C levels in obese individuals and positively associated with C-reactive protein and other monocytic pro-inflammatory markers. Mechanistically, chemical inhibition or genetic silencing of IL-6 receptor gp130/IL-6ST gene induced severe upregulation of intracellular lipid accumulation in THP-1 transformed macrophages that was found to be further augmented under fatty acid rich culture conditions. Moreover, analysis of the genes involved in lipid and cholesterol metabolism showed up-regulation of the LDLR along with a remarkable inhibition of ATP Binding Cassette (ABC) Subfamily transporters ABCG1 and ABCB1. We also found that the macrophages lacking gp130/IL-6 receptors had very low beta-oxidation genes expression (CPT1A and CPT2) , however, with no effect on triglyceride synthesis genes expression (DGAT, ACACA, FASN and Srebp1c) . In conclusion, our data support a role for IL-6 receptor signaling pathways in lipid alteration and cholesterol efflux which may have potential as a therapeutic target for metabolic syndrome. Disclosure F.Alrashed: None. F.Alzaqqah: None. A.Al madhoun: None. R.Alqabandi: None. S.T.Sindhu: None. F.Almulla: None. R.Ahmad: None. Funding (KFAS) (Grant #: RA AM 2016-007)

Following surgery, healing within the oral cavity occurs in a hostile environment, and proper oral care and hygiene are required to accelerate recovery. The aim of the current study is to investigate and compare the bioreactivity characteristics of mouthwashes based on either chlorhexidine (CHX) or a novel bone bioactive liquid (BBL) in terms of oral healing within seven days application post-surgery. A randomized, double blind clinical trial was conducted in 81 patients, wherein the mouthwashes were applied twice a day for a period of 7 days. The visual analog scale (VAS) protocol was applied to determine pain index scores. Early wound healing index (EHI) score was determined for evaluating oral cavity healing progress. No adverse effects were observed using the mouthwashes, but CHX application resulted in stained teeth. Applications of both CHX and BBL were sufficient to reduce pain over a period of 7 days. However, the BBL group demonstrated a statistically significant reduction in VAS scores starting on day 4. The EHI scores were significantly higher in the BBL group compared with the CHX group, independent of tooth location. No differences in either VAS or EHI scores due to gender were observed. Compared with the commercially available CHX mouthwash, application of the BBL mouthwash reduced pain and accelerated oral cavity healing to a greater extent, suggesting it effectively improves the oral cavity microenvironment at the wound site in mediating soft tissue regeneration. This study was funded by the OTRI project, reference number 2020907094, signed in May 2020 with the Public University of Navarra, Navarra, Spain.

Carbohydrates form the major source of energy in Asian diets. A lower carbohydrate diet became the recommended golden standard for healthy lifestyle. However, the effects of low-carbohydrates diet on health in apparently healthy individuals have been poorly studied, especially in relation to insulin resistance syndrome (IRS). A total of 120 healthy weight participants with no previous history of a major medical condition and an average BMI of ≤ 25kg/m2 were recruited. Self-reported dietary intake and objective physical activity by accelerometry were tracked for seven days. Participants were divided into three categories according to their dietary intake of carbohydrates. Blood samples were collected for metabolic markers analysis. HOMA of insulin resistance (HOMA-IR), β-cell function (HOMA-B) and C-peptide were used to evaluate glucose homeostasis. The consumption of low carbohydrates (less than 45% of total energy) significantly correlated with higher HOMA-IR, Lower HOMA-β % compared to moderate carbohydrate intake (between 45% to 65%). However, only the HOMA-β % was significantly influenced by carbohydrates intake. Moreover, low carbohydrates intake was significantly associated with elevated C-peptide secretion. The substitution of carbohydrates with other macronutrients, such as fat and proteins in the Atkins/ketogenic diet, resulted in a pronounced induction of IRS-related inflammatory markers; FGF2, IP-10, IL-6, IL-17A, MDC and reduction of IL-13. Overall, the presented data highlight, for the first time, that low carbohydrate intake results in significant glucose homeostasis imbalance that may be driven by a heightened state of inflammatory response.

Nadeem Akhter,1 Shihab Kochumon,1 Amal Hasan,1 Ajit Wilson,1 Rasheeba Nizam,2 Ashraf Al Madhoun,2,3 Fatema Al-Rashed,1 Hossein Arefanian,1 Fawaz Alzaid,2,4 Sardar Sindhu,1,3 Fahd Al-Mulla,1 Rasheed Ahmad1 1Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait; 2Genetics & Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait; 3Animal and Imaging Core Facility, Dasman Diabetes Institute, Kuwait City, Kuwait; 4Institut Necker Enfants Malades (INEM), French Institute of Health and Medical Research (INSERM), Immunity & Metabolism of Diabetes (IMMEDIAB), Université de Paris Cité, Paris, FranceCorrespondence: Rasheed Ahmad, Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait, Tel +965 2224 2999 Ext. 4311, Email rasheed.ahmad@dasmaninstitute.orgBackground: Overexpression of CCL2 (MCP-1) has been implicated in pathogenesis of metabolic conditions, such as obesity and T2D. However, the mechanisms leading to increased CCL2 expression in obesity are not fully understood. Since both IFN-γ and LPS levels are found to be elevated in obesity and shown to be involved in the regulation of metabolic inflammation and insulin resistance, we investigated whether these two agents could synergistically trigger the expression of CCL2 in obesity.Methods: Monocytes (Human monocytic THP-1 cells) were stimulated with IFN-γ and LPS. CCL2 gene expression was determined by real-time RT-PCR. CCL2 protein was determined by ELISA. Signaling pathways were identified by using epigenetic inhibitors and STAT1 siRNA. Acetylation of H3K27 was analyzed by Western blotting. The acetylation level of histone H3K27 in the transcriptional initiation region of CCL2 gene was determined by ChIP-qPCR.Results: Our results show that the co-incubation of THP-1 monocytes with IFN-γ and LPS significantly enhanced the expression of CCL2, compared to treatment with IFN-γ or LPS alone. Similar results were obtained using primary monocytes and macrophages. Interestingly, IFN-γ priming was found to be more effective than LPS priming in inducing synergistic expression of CCL2. Moreover, STAT1 deficiency significantly suppressed this synergy for CCL2 expression. Mechanistically, we showed that IFN-γ priming induced acetylation of lysine 27 on histone 3 (H3K27ac) in THP-1 cells. Chromatin immunoprecipitation (ChIP) assay followed by qRT-PCR revealed increased H3K27ac at the CCL2 promoter proximal region, resulting in stabilized gene expression. Furthermore, inhibition of histone acetylation with anacardic acid suppressed this synergistic response, whereas trichostatin A (TSA) could substitute IFN-γ in this synergy.Conclusion: Our findings suggest that IFN-γ, in combination with LPS, has the potential to augment inflammation via the H3K27ac-mediated induction of CCL2 in monocytic cells in the setting of obesity.Keywords: CCL2, monocytes/macrophages, LPS, IFN-γ, H3K27 ac, inflammation

BackgroundHealthcare workers (HCWs) have been impacted psychologically due to their professional responsibilities over the prolonged era of the coronavirus disease 2019 (COVID-19) pandemic. The study aimed to identify the predictors of psychological distress, fear, and coping during the COVID-19 pandemic among HCWs.MethodsA cross-sectional online survey was conducted among self-identified HCWs across 14 countries (12 from Asia and two from Africa). The Kessler Psychological Distress Scale, the Fear of COVID-19 Scale, and the Brief Resilient Coping Scale were used to assess the psychological distress, fear, and coping of HCWs, respectively.ResultsA total of 2447 HCWs participated; 36% were doctors, and 42% were nurses, with a mean age of 36 (±12) years, and 70% were females. Moderate to very-high psychological distress was prevalent in 67% of the HCWs; the lowest rate was reported in the United Arab Emirates (1%) and the highest in Indonesia (16%). The prevalence of high levels of fear was 20%; the lowest rate was reported in Libya (9%) and the highest in Egypt (32%). The prevalence of medium-to-high resilient coping was 63%; the lowest rate was reported in Libya (28%) and the highest in Syria (76%).ConclusionCOVID-19 has augmented the psychological distress among HCWs. Factors identified in this study should be considered in managing the wellbeing of HCWs, who had been serving as the frontline drivers in managing the crisis successfully across all participating countries. Furthermore, interventions to address their psychological distress should be considered.

Obesity is characterized by chronic low-grade inflammation. Obese people have higher levels of caveolin-1 (CAV1), a structural and functional protein present in adipose tissues (ATs). We aimed to define the inflammatory mediators that influence CAV1 gene regulation and the associated mechanisms in obesity. Using subcutaneous AT from 27 (7 lean and 20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor-alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). CAV1 gene expression was associated with proinflammatory cytokines and chemokines and their cognate receptors (r ≥ 0.447, p ≤ 0.030), but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in the adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-κB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and the TNF-α signaling pathway is intriguing and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.

Air quality deterioration is a major environmental problem in Indonesia. This study evaluated the levels and health risks of potentially toxic elements (PTEs) in Maros Regency, Indonesia. Total suspended particulate matter was collected from industrial areas for PTE (Al, Pb, Cr, Cu, Ni, As and Zn) analysis using inductively coupled plasma optical emission spectrometry (ICP-OES). Samples were collected from six critical areas in the Bantimurung region as that is where marble, cement and limestone industries are located. A calculation of the non-carcinogenic and cancer risks was performed to determine the potential health exposures in adults and children. A Monte Carlo simulation with 10,000 iterations and a sensitivity analysis was carried out to identify the risk probability and the most sensitive variable contributing to cancer risk from PTE exposure in humans. The results showed that the concentration of PTEs decreased in the order of Zn > Al > Cr > Pb > Cu > Ni > As in the wet season, and Zn > Al > Pb > As > Cr > Cu > Ni in the dry season. The hazard index (HI) value for children was 2.12, indicating a high non-carcinogenic risk for children. The total cancer risk (TCR) values in adults and children were 3.11 × 10−5 and 1.32 × 10−4, respectively, implying that both are at risk for developing cancer. The variables with the most contribution to cancer risk from As, Cr and Pb exposure in adults and children were As concentration (33.9% and 41.0%); exposure duration (ED) (34.3%) and SA (40.7%); and SA (98.7 % and 45.4%), respectively. These findings could be used as the scientific basis for public health intervention and to raise awareness of the harmful health effects of particulate bound PTEs

"Introduction: Ovarian cancer (OC) is often diagnosed at advanced stages. This study aimed to assess the Palestinian women’s knowledge about OC symptoms and determine the factors associated with having good knowledge. Methods: A cross-sectional study was conducted from July 2019 to March 2020 in the two main areas of Palestine: the West Bank and Jerusalem as well as the Gaza Strip. A translated-into-Arabic version of the validated OC awareness measure (OCAM) was utilized for data collection. Stratified convenience sampling was used to recruit adult women attending hospitals, primary healthcare centers, and public spaces at 11 governorates. The knowledge level was categorized into three categories based on the number of symptoms recognized: poor (0 to 4), fair (5 to 8), and good (9 to 11). Results: Of 6095 approached, 5618 participants completed the Arabic OCAM (response rate = 92.1%).A total of 5411 questionnaires were included in the analysis: 2278 from the Gaza Strip and 3133 from the West Bank and Jerusalem. Participants living in the West Bank and Jerusalem were older, of higher monthly income, and with more chronic diseases than those living in the Gaza Strip. The most frequently identified symptoms were ‘extreme generalized fatigue’ (n = 3821, 70.6%), ‘unexplained weight loss’ (n = 3607, 66.7%), and ‘increased abdominal size on most days’ (n = 3252, 60.1%). On the other hand, the least recognized symptoms were ‘feeling full persistently’ (n = 1553, 28.7%) and ‘difficulty eating on most days’ (n = 1971, 36.4%). Only 943 participants (17.4%) displayed good knowledge of OC symptoms. Participants from the Gaza Strip had a higher likelihood than participants from the West Bank and Jerusalem to have a good level of knowledge (21.0% vs. 14.8%). Being married, knowing someone with cancer, and visiting hospitals were all associated with a higher likelihood of having good knowledge level. However, living in the West Bank and Jerusalem was associated with a lower likelihood of having good knowledge. Conclusion: The overall knowledge of OC symptoms in this study was low. Educational interventions are needed to improve Palestinian women’s knowledge about OC symptoms." "مقدمة: غالبًا ما يتم تشخيص سرطان المبيض في مراحل متقدمة. هدفت هذه الدراسة إلى تقييم معرفة المرأة الفلسطينية بأعراض سرطان المبيض وتحديد العوامل المرتبطة بالحصول بالمعرفة . المنهجية: أجريت دراسة مقطعية في الفترة من تموز (يوليو) 2019 إلى آذار (مارس) 2020 في المنطقتين الرئيسيتين في فلسطين: الضفة الغربية والقدس وقطاع غزة. تم استخدام نسخة مترجمة إلى العربية من مقياس الوعي ذو المصداقة (OCAM) لجمع البيانات. تم جمع البيانات من عينات من النساء البالغات المتواجدات في المستشفيات ومراكز الرعاية الصحية الأولية والأماكن العامة في 11 محافظة. تم تصنيف مستوى المعرفة إلى ثلاث فئات بناءً على عدد الأعراض المعترف بها: ضعيف (0 إلى 4) ، متوسط (5 إلى 8) ، وجيد (9 إلى 11). النتائج: أكمل 5618 مشاركًا اختبار OCAM باللغة العربية (معدل الاستجابة = 92.1٪) ، وشمل التحليل 5411 استبيانًا: 2278 من قطاع غزة و 3133 من الضفة الغربية والقدس. كان المشاركون الذين يعيشون في الضفة الغربية والقدس أكبر سناً ، وذوي دخل شهري أعلى ، ومصابين بأمراض مزمنة أكثر من أولئك الذين يعيشون في قطاع غزة. كانت الأعراض الأكثر تحديدًا هي ""التعب الشديد العام"" (العدد = 3821 ، 70.6٪) ، ""فقدان الوزن غير المبرر"" (العدد = 3607 ، 66.7٪) ، ""زيادة حجم البطن في معظم الأيام"" (العدد = 3252 ، 60.1٪ ). من ناحية أخرى ،كانت أقل الأعراض التي تم التعرف عليها ""الشعور بالشبع باستمرار"" (العدد = 1553 ، 28.7٪) و ""صعوبة الأكل في معظم الأيام"" (العدد = 1971 ، 36.4٪). أظهر 943 مشاركًا فقط (17.4٪) معرفة جيدة بأعراض سرطان المبيض. كان لدى المشاركين من قطاع غزة احتمالية أعلى من المشاركين من الضفة الغربية والقدس في الحصول على مستوى جيد من المعرفة (21.0٪ مقابل 14.8٪). ارتبط الزواج ومعرفة شخص مصاب بالسرطان وزيارة المستشفيات بارتفاع احتمالية امتلاك مستوى معرفة جيد. ومع ذلك ، ارتبط العيش في الضفة الغربية والقدس بانخفاض احتمالية امتلاك المعرفة الجيدة. الخلاصة: كانت المعرفة العامة لأعراض سرطان المبيض في هذه الدراسة منخفضة. هناك حاجة إلى التدخلات التعليمية لتحسين معرفة المرأة الفلسطينية بأعراض سرطان المبيض."

IL-6 was found to be overexpressed in the adipose tissue of obese individuals, which may cause insulin resistance. However, the regulation of IL-6 in adipocytes in obesity setting remains to be explored. Since IL-1β and TNFα are increased in obese adipose tissue and promote inflammation, we investigated whether cooperation between IL-1β and TNFα influences the production of IL-6. Our data show that IL-1β and TNFα cooperatively enhance IL-6 expression in 3T3L-1 adipocytes. Similar results were seen in human adipocytes isolated from subcutaneous and visceral fat. Although adipocytes isolated from lean and obese adipose tissues showed similar responses for production of IL-6 when incubated with IL-1β/TNFα, secretion of IL-6 was higher in adipocytes from obese tissue. TNFα treatment enhanced CREB binding at CRE locus, which was further enhanced with IL-1β, and was associated with elevated histone acetylation at CRE locus. On the other hand, IL-1β treatments mediated C/EBPβ binding to NF-IL-6 consensus, but not sufficiently to mediate significant histone acetylation. Interestingly, treatment with both stimulatory factors amplifies CREB binding and H3K14 acetylation. Furthermore, histone acetylation inhibition by anacardic acid or curcumin reduces IL-6 production. Notably, inhibition of histone deacetylase (HDAC) activity by trichostatin A (TSA) resulted in the further elevation of IL-6 expression in response to combined treatment of adipocytes with IL-1β and TNFα. In conclusion, our results show that there is an additive interaction between IL-1β and TNFα that depends on CREB binding and H3K14 acetylation, and leads to the elevation of IL-6 expression in adipocytes, providing interesting pathophysiological connection among IL-1β, TNFα, and IL-6 in settings such as obesity.

This paper is a summary of the collaborative work between ADNOC (Abu Dhabi National Oil Company) and nybl, a deep tech development company, and the results of applying nybl's proprietary "Science-Based Artificial Intelligence" to ADNOC Electrical Submersible Pump (ESP) wells in real-time applications. The paper demonstrates the potential benefits of the real-life application of Artificial Intelligence (AI) / Machine Learning (ML) in conjunction with traditional Petroleum Engineering concepts and algorithms to predict imminent and future failures, extend and monitor run life, and maximize the production of ESPs. This paper will highlight ADNOC's innovative approach to pilot new technology through successful deployment on 27 wells, spread onshore and offshore, in real-time, with prescriptive actions.

Globalization and health 17(1), 117 (2021). doi:10.1186/s12992-021-00768-3, Published by BioMed Central, London

The fields of regenerative medicine and stem cell-based tissue engineering have the potential of treating numerous tissue and organ defects. The use of adult stem cells is of particular interest when it comes to dynamic applications in translational medicine. Recently, dental pulp stem cells (DPSCs) have been traced in third molars of adult humans. DPSCs have been isolated and characterized by several groups. DPSCs have promising characteristics including self-renewal capacity, rapid proliferation, colony formation, multi-lineage differentiation, and pluripotent gene expression profile. Nevertheless, genotypic, and phenotypic heterogeneities have been reported for DPSCs subpopulations which may influence their therapeutic potentials. The underlying causes of DPSCs’ heterogeneity remain poorly understood; however, their heterogeneity emerges as a consequence of an interplay between intrinsic and extrinsic cellular factors. The main objective of the manuscript is to review the current literature related to the human DPSCs derived from the third molar, with a focus on their physiological properties, isolation procedures, culture conditions, self-renewal, proliferation, lineage differentiation capacities and their prospective advances use in pre-clinical and clinical applications.

IL-8/MCP-1 act as neutrophil/monocyte chemoattractants, respectively. Oxidative stress emerges as a key player in the pathophysiology of obesity. However, it remains unclear whether the TNF-α/oxidative stress interplay can trigger IL-8/MCP-1 expression and, if so, by which mechanism(s). IL-8/MCP-1 adipose expression was detected in lean, overweight, and obese individuals, 15 each, using immunohistochemistry. To detect the role of reactive oxygen species (ROS)/TNF-α synergy as a chemokine driver, THP-1 cells were stimulated with TNF-α, with/without H2O2 or hypoxia. Target gene expression was measured by qRT-PCR, proteins by flow cytometry/confocal microscopy, ROS by DCFH-DA assay, and signaling pathways by immunoblotting. IL-8/MCP-1 adipose expression was significantly higher in obese/overweight. Furthermore, IL-8/MCP-1 mRNA/protein was amplified in monocytic cells following stimulation with TNF-α in the presence of H2O2 or hypoxia (p ˂ 0.0001). Synergistic chemokine upregulation was related to the ROS levels, while pre-treatments with NAC suppressed this chemokine elevation (p ≤ 0.01). The ROS/TNF-α crosstalk involved upregulation of CHOP, ERN1, HIF1A, and NF-κB/ERK-1,2 mediated signaling. In conclusion, IL-8/MCP-1 adipose expression is elevated in obesity. Mechanistically, ROS/TNF-α crosstalk may drive expression of these chemokines in monocytic cells by inducing ER stress, HIF1A stabilization, and signaling via NF-κB/ERK-1,2. NAC had inhibitory effect on oxidative stress-driven IL-8/MCP-1 expression, which may have therapeutic significance regarding meta-inflammation.

The automated classification of ambient air pollutants is an important task in air pollution hazard assessment and life quality research. In the current study, machine learning (ML) algorithms are ...

BACKGROUND/AIMS Innate immune toll-like receptors (TLRs) are emerging as nutrient sensors. Oxidative stress in the adipose tissue in obesity acts as a critical early trigger of altered pathophysiology. TLR2/TLR4 adipose upregulation has been associated with insulin resistance in humans; however, it remains unclear whether oxidative stress can modulate expression of TLR2/4 and related immune-metabolic regulators (IRF3/5) in immune cells. We, therefore, assessed their expression along with proinflammatory cytokines in the human PBMC following induction of oxidative stress. METHODS PBMC were isolated from blood of healthy donors using Ficoll-Paque method and cells were treated with H2O2 to induce oxidative stress. ROS was measured by DCFH-DA assay. Target gene and protein expression was determined using real-time RT-PCR and flow cytometry/confocal microscopy, respectively. TLR2/4 expression by H2O2 in presence of ROS-inhibitors or leptin/LPS/fatty acids was also assessed. Expression of phosphorylated/total ERK1/2, c-Jun, p38, and NF-κB was determined by western blotting. The data (mean±SEM) were compared using unpaired student's t-test or ANOVA; all P-values

The ATPase AAA-domain protein 3 (ATAD3) is a ubiquitously expressed mitochondrial protein involved in mitochondrial dynamics, DNA-nucleoid structural organization, cholesterol transport and steroidogenesis. Mutations within the ancestral ATAD3A gene are strongly associated with neurological abnormalities due to alterations in the mitochondrial function and homeostasis. Here, we report the case of a subject diagnosed with developmental delay associated with ataxia and progressive atrophy of both cerebellar hemispheres and cerebellar vermis, despite exhibiting a normal biochemical profile. By whole exome sequencing, we identified two biallelic single nucleotide variants within the coding region of ATAD3A in the affected subject. Both variants were previously reported as monoallelic variants with uncertain clinical significance. Importantly, the variant ATAD3A c.251T>C leads to an amino acid change of a highly conserved residue across species and in silico analysis revealed structural alteration in the ATAD3A protein. Ketogenic diet was administered to the subject as a novel therapeutic approach. Notably, the treatment correlated with a reduction in cerebellum atrophy progression and the gradual enhancement of the subject’s physical skills, vitality and personal interactions. Thus, we report the first subject with a homozygous status for the ATAD3A c.251T>C (p.Thr84Met) variant. We propose that this mutation led to an alteration of the mitochondrial function, causing the neurological symptoms observed in the subject. The symptoms were partially alleviated following ketogenic diet, improving the subject’s quality of life.

The ATPase AAA-domain protein 3 (ATAD3) is a ubiquitously expressed mitochondrial protein involved in mitochondrial dynamics, DNA-nucleoid structural organization, cholesterol transport and steroidogenesis. Mutations within the ancestral ATAD3A gene are strongly associated with neurological abnormalities due to alterations in the mitochondrial function and homeostasis. Here, we report the case of a subject diagnosed with developmental delay associated with ataxia and progressive atrophy of both cerebellar hemispheres and cerebellar vermis, despite exhibiting a normal biochemical profile. By whole exome sequencing, we identified two biallelic single nucleotide variants within the coding region of ATAD3A in the affected subject. Both variants were previously reported as monoallelic variants with uncertain clinical significance. Importantly, the variant ATAD3A c.251T>C leads to an amino acid change of a highly conserved residue across species and in silico analysis revealed structural alteration in the ATAD3A protein. Ketogenic diet was administered to the subject as a novel therapeutic approach. Notably, the treatment correlated with a reduction in cerebellum atrophy progression and the gradual enhancement of the subject's physical skills, vitality and personal interactions. Thus, we report the first subject with a homozygous status for the ATAD3A c.251T>C (p.Thr84Met) variant. We propose that this mutation led to an alteration of the mitochondrial function, causing the neurological symptoms observed in the subject. The symptoms were partially alleviated following ketogenic diet, improving the subject's quality of life.

Ashraf Al Madhoun,1,2 Fahad Alnaser,3 Motasem Melhem,1 Rasheeba Nizam,1 Tala Al-Dabbous,4 Fahd Al-Mulla11Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait; 2Animal and Imaging Core Facility Department, Dasman Diabetes Institute, Dasman, Kuwait City, 15462, Kuwait; 3Radiology Department, Ibn Sina Hospital, Ministry of Health, Kuwait City, Kuwait; 4Bayt Abdullah Children’s Hospice, NBK Children’s Cancer Hospital, Al- Adan ICU, Kuwait City, KuwaitAbstract: The ATPase AAA-domain protein 3 (ATAD3) is a ubiquitously expressed mitochondrial protein involved in mitochondrial dynamics, DNA-nucleoid structural organization, cholesterol transport and steroidogenesis. Mutations within the ancestral ATAD3A gene are strongly associated with neurological abnormalities due to alterations in the mitochondrial function and homeostasis. Here, we report the case of a subject diagnosed with developmental delay associated with ataxia and progressive atrophy of both cerebellar hemispheres and cerebellar vermis, despite exhibiting a normal biochemical profile. By whole exome sequencing, we identified two biallelic single nucleotide variants within the coding region of ATAD3A in the affected subject. Both variants were previously reported as monoallelic variants with uncertain clinical significance. Importantly, the variant ATAD3A c.251T>C leads to an amino acid change of a highly conserved residue across species and in silico analysis revealed structural alteration in the ATAD3A protein. Ketogenic diet was administered to the subject as a novel therapeutic approach. Notably, the treatment correlated with a reduction in cerebellum atrophy progression and the gradual enhancement of the subject’s physical skills, vitality and personal interactions. Thus, we report the first subject with a homozygous status for the ATAD3A c.251T>C (p.Thr84Met) variant. We propose that this mutation led to an alteration of the mitochondrial function, causing the neurological symptoms observed in the subject. The symptoms were partially alleviated following ketogenic diet, improving the subject’s quality of life.Keywords: cerebellar atrophy, ATAD3A, SNV, ATAD3A c.251T>C (p.Thr84Met) rs546711654, ketogenic diet, whole exome sequencing

Background: The association of mitochondrial DNA (mtDNA) variations with obesity has been investigated in diverse populations across the world. However, such obesity-associated mtDNA examinations are rarely conducted in Arab populations. Materials and methods: We re-sequenced mtDNA displacement loop (D-loop) region of 395 Arab individuals of Kuwait. We categorized the individuals based on their BMI scores as obese (n=232; BMI ≥30 kg/m2), overweight (n=110; BMI ≥25 kg/m2 and G, and m.523delAC were positively correlated with obesity, while m.310T>C, and m.16318A>T were negatively associated. All these variants, except m.16318A>T, remain statistically significant after adjusting for age and gender. We found that the variant m.73A>G increases the likelihood of being obese by 6-fold, whereas haplogroup H decreases the probability of being obese in Arab individuals of Kuwait. Haplotype analysis revealed that a haplotype, A263G-C309CT-T310C, defining the H2a clade of H haplogroup, reduces the probability of being obese. Conclusion: Our study reports, for the first time, the obesity-related mtDNA variants in Arabs of Kuwait. Based on the mtDNA D-loop region variations, we detected particular variants and haplogroup that are related with increased and decreased probability of being obese in the Kuwait Arab population.

Muthukrishnan Eaaswarkhanth,1,* Motasem Melhem,1,* Prem Sharma,1 Rasheeba Nizam,1 Ashraf Al Madhoun,1 Gyaneshwer Chaubey,2 Osama Alsmadi,3 Ebaa AlOzairi,1 Fahd Al-Mulla11Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, 15462, Kuwait; 2Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India; 3Department of Cell Therapy & Applied Genomics, King Hussein Cancer Center, Amman, Jordan*These authors contributed equally to this workBackground: The association of mitochondrial DNA (mtDNA) variations with obesity has been investigated in diverse populations across the world. However, such obesity-associated mtDNA examinations are rarely conducted in Arab populations.Materials and methods: We re-sequencedmtDNA displacement loop (D-loop) region of 395 Arab individuals of Kuwait. We categorized the individuals based on their BMI scores as obese (n=232; BMI ≥30 kg/m2), overweight (n=110; BMI ≥25 kg/m2and G, and m.523delAC were positively correlated with obesity, while m.310T>C, and m.16318A>T were negatively associated. All these variants, except m.16318A>T, remain statistically significant after adjusting for age and gender. We found that the variant m.73A>Gincreases the likelihood of being obese by 6-fold, whereas haplogroup H decreases the probability of being obese in Arab individuals of Kuwait. Haplotype analysis revealed that a haplotype, A263G-C309CT-T310C, defining the H2a clade of H haplogroup, reduces the probability of being obese.Conclusion: Our study reports, for the first time, the obesity-related mtDNA variants in Arabs of Kuwait. Based on the mtDNA D-loop region variations, we detected particular variants and haplogroup that are related with increased and decreased probability of being obese in the Kuwait Arab population. Keywords: obesity, mitochondrial DNA, D-loop, haplogroup, haplotype, SNVs

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited monogenic renal disease characterised by the accumulation of clusters of fluid-filled cysts in the kidneys and is caused by mutations in PKD1 or PKD2 genes. ADPKD genetic diagnosis is complicated by PKD1 pseudogenes located proximal to the original gene with a high degree of homology. The next generation sequencing (NGS) technology including whole exome sequencing (WES) and whole genome sequencing (WGS), is becoming more affordable and its use in the detection of ADPKD mutations for diagnostic and research purposes more widespread. However, how well does NGS technology compare with the Gold standard (Sanger sequencing) in the detection of ADPKD mutations? Is a question that remains to be answered. We have evaluated the efficacy of WES, WGS and targeted enrichment methodologies in detecting ADPKD mutations in the PKD1 and PKD2 genes in patients who were clinically evaluated by ultrasonography and renal function tests. Our results showed that WES detected PKD1 mutations in ADPKD patients with 50% sensitivity, as the reading depth and sequencing quality were low in the duplicated regions of PKD1 (exons 1–32) compared with those of WGS and target enrichment arrays. Our investigation highlights major limitations of WES in ADPKD genetic diagnosis. Enhancing reading depth, quality and sensitivity of WES in the PKD1 duplicated regions (exons 1–32) is crucial for its potential diagnostic or research applications.

In obesity, macrophage activation and infiltration in adipose tissue (AT) underlie chronic low-grade inflammation-induced insulin resistance. Although dectin-1 is primarily a pathogen recognition receptor and innate immune response modulator, its role in metabolic syndromes remains to be clarified. This study aimed to investigate the dectin-1 gene expression in subcutaneous AT in the context of obesity and associated inflammatory markers. Subcutaneous AT biopsies were collected from 59 nondiabetic (lean/overweight/obese) individuals. AT gene expression levels of dectin-1 and inflammatory markers were determined via real-time reverse transcriptase-quantitative polymerase chain reaction. Dectin-1 protein expression was assessed using immunohistochemistry. Plasma lipid profiles were measured by ELISA. AT dectin-1 transcripts and proteins were significantly elevated in obese as compared to lean individuals. AT dectin-1 transcripts correlated positively with body mass index and fat percentage (r ≥ 0.340, p ≤ 0.017). AT dectin-1 RNA levels correlated positively with clinical parameters, including plasma C-reactive protein and CCL5/RANTES, but negatively with that of adiponectin. The expression of dectin-1 transcripts was associated with that of various proinflammatory cytokines, chemokines, and their cognate receptors (r ≥ 0.300, p ≤ 0.05), but not with anti-inflammatory markers. Dectin-1 and members of the TLR signaling cascade were found to be significantly associated, suggesting an interplay between the two pathways. Dectin-1 expression was correlated with monocyte/macrophage markers, including CD16, CD68, CD86, and CD163, suggesting its monocytes/macrophage association in an adipose inflammatory microenvironment. Dectin-1 expression was independently predicted by CCR5, CCL20, TLR2, and MyD88. In conclusion, dectin-1 may be regarded as an AT biomarker of metabolic inflammation in obesity.

Η κινάση της δεοξυτιδίνης καταλύει τη φωσφορυλίωση της 2-δεοξυκυτιδίνης στην μονοφωσφορική της μορφή. Έχει βρεθεί να φωσφορυλιώνει μεγάλη ποικιλία υποστρωμάτων όπως δεοξυπουρίνες και δεοξυπυριμιδίνες. Η κυνάση αυτή είναι επίσης υπεύθυνη για την αρχική ενεργοποίηση ενός μεγάλου αριθμού κλινικά σημαντικών αναλόγων των νουκλεοσιδίων που χρησιμοποιούνται ως αντικαρκινικά και αντιϊικά φάρμακα. Η έλλειψη έκφρασης ή ενεργότητας της κινάσης dCK σε κύτταρα οδηγεί σε ανθεκτικότητα των κυττάρων αυτών στα παραπάνω φάρμακα, γεγονός που υποδηλώνει ότι το ένζυμο αυτό παίζει ρόλο "κλειδί" στον μεταβολισμό τους που τουσ προσδίδει και την φαρμακολογική τους δραστικότητα. Για τους λόγους αυτούς η αποσαφήνιση των πιθανών ρυθμιστικών μηχανισμών που παίζουν ρόλο στην ενεργοποίηση της dCK είναι ιδιαίτερα σημαντική. Στην εργασία αυτή μελετάμε τους μηχανισμούς που ρυθμίζουν την έκφραση της dCK σε μεταγραφικό και μετα-μεταγραφικό επίπεδο. 1. Το πρότυπο ρύθμισης της έκφρασης της dCK του ποντικού βρέθηκε ότι είναι αρκετά πολύπλοκο. Μεταλλαγές-ελλείψεις της 5' περιοχής του υποκινητή και in votro footprinting πειράματα έδειξαν ότι οι περιοχές του υποκινητή πλησιέστερες στο σημείο εκκίνησης της μεταγραφής συμβάλλουν στην ιστοειδική έκφραση του γονιδίου. Αναπάντεχα, πειράματα παροδικής διαμόλυνσης έδειξαν ότι η 5' μη μεταφραζόμενη περιοχή του dCK mRNA είχε την μέγιστη ενεργότητα γεγονός που υποδηλώνει ότι πιθανά παίζει σημαντικό ρόλο στη ρύθμιση του γονιδίου. Παρ' όλα αυτά, χρειάζονται επιπλέον πειράματα για να αποδειχθεί αν τα αποτελέσματα αυτά συμβαδίζουν με την in vivo κατάσταση. 2. Παρ'όλο που βιοχημικές μελέτες έδειξαν ότι η dCK κινάση δεν έχει ισομορφές όπως η κινάση της θυμιδίνης η εργασία αυτή δείχνει την ύπαρξη ενός δεύτερου γονιδίου με μεγάλη ομολογία με το mdck. Τα χαμηλά επίπεδα έκφρασης και η πιθανή ιστοειδική έκφρασή του αποτέλεσαν εμπόδια στην κλωνοποίηση του cDNA του γονιδίου αυτού. Ανάλυση της αλληλουχίας του έδειξε ότι αυτό το γονίδιο δεν έχει ιντρόνια και μπορεί να δημιουργήθηκε από ένα 'πρόγονο' που περιείχε ιντρόνια. Η ένθεση ενός τέτοιου τμήματος DNA που προέρχεται από το MRNA του προγόνου του, στο οποίο έχει προηγηθεί μάτισμα, στο γένωμα του ποντικού, γίνεται συνήθως με τη μεσολάβηση επαναλαμβανόμενων νουκλεοτιδίων, συνήθως στο 5' άκρο του γονιδίου. 3. Η μελέτη μας πάνω σε μία κυτταρική σειρά ανθεκτική στο φάρμακο dFdCyd έδειξε ότι το φαινόμενο της ανθεκτικότητας κάποιων κυττάρων σε φάρμακα που συνήθως συνοδεύεται από έλλειψη της ενεργότητας της dCK κινάσης οφείλεται σε κάποια ανακατάταξη της περιοχής του γενώματος που εντοπίζεται το dck αλλά σε πιθανούς μετα-μεταγραφικούς και μετα-μεταφραστικούς μηχανισμούς. 4. Επίσης αναλύσαμε τον ενδοκυτταρικό εντοπισμό της dCK κάνοντας πειράματα ανοσοεντοπισμού σε πυρηνικά και κυτταροπλασματικά εκχυλίσματα βιοχημικά διαμερισματοποιημένων κυττάρων, καθώς και in situ ανοσοιστοχημεία χρησιμοποιώντας υψηλής ειδικότητας dCK αντίσωμα. H dCK πρωτεΐνη εντοπίζεται κυρίως στο κυτταρόπλασμα αλλά ότνα την υπερεκφράσουμε σε κύτταρα εντοπίζεται κυρίως στον πυρήνα. Τα αποτελέσματα αυτά προτείνουν την ύπαρξη ενός μηχανισμού συγκράτησης της dCK στο κυτταρόπλασμα στον οποίο πιθανά ενέχεται μία άλλη πρωτεΐνη που δημιουργεί σύμπλοκο με την dCK. 5. Μία επιπλέον εργασία συμπεριλήφθηκε σε αυτή τη διατριβή που εμπεριέχει την προσπάθεια αναβάθμισης της ειδικότητας της κινάσης δεοξυνουκλεοσιδίων της δροσόφιλας melanogaster (Dm-dNK) σε διάφορα υποστρώματα. Χρησιμοποιώντας την τεχνική PCR και με τυχαία μεταλλαξογένεση δείξαμε ότι αντικαταστάσεις αμινοξέων στην Dm-dNK πρωτεΐνη μπορούν να αλλάξουν την ενζυματική της ενεργότητα απέναντι σε συγκεκριμένα υποστρώματα. Οι μεταλλαγμένες μορφές της κινάσης με τον επιθυμητό φαινότυπο θα μπορούσαν να χρησιμοποιηθούν μακροπρόθεσμα σε εφαρμογές της γονιδιακής θεραπείας ως γονίδια 'αυτοκαταστροφής' ενός καρκινικού κυττάρου (suicide gene).

Fatema Al-Rashed,1 Sardar Sindhu,2 Ashraf Al Madhoun,2,3 Abdulwahab Alghaith,4 Rafaat Azim,1 Fahd Al-Mulla,3 Rasheed Ahmad1 1Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait; 2Animal and Imaging Core Facility, Dasman Diabetes Institute, Dasman, Kuwait; 3Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, Kuwait; 4Royal College of Surgeons in Ireland, Dublin, IrelandCorrespondence: Fatema Al-Rashed; Rasheed AhmadMicrobiology & Immunology Department, Dasman Diabetes Institute, Al-Soor Street, Kuwait, P.O. Box 1180, Dasman, 15462, KuwaitTel +965 2224 2999 Ext. 4335; 4311Fax +965 2249 2406Email fatema.alrashed@dasmaninstitute.org; rasheed.ahmad@dasmaninstitute.orgBackground: Efficient sleep duration and its quality are increasingly recognized as important contributors for maintaining normal body weight. However, lifestyle and social structure within the Arab-gulf region differ compared to those in the western world. This study was specifically conducted in Kuwait’s population to investigate the link between sleep quality (SQ) and obesity in the absence of sleep apnea (SA) onset.Methods: SQ was measured by the Pittsburgh Sleep Quality Index (PQSI) in 984 participants, then verified in 60 individuals including 20 lean (Body mass index/BMI: 18.5– 24.9 kg/m2), 20 overweight (BMI: 25– 29.9 kg/m2) and 20 obese (BMI: ≥ 30 kg/m2) through actigraph worn over the right-hip for 7 consecutive days to characterize their sleep–wake cycle, rest-activity, and physical activity. Blood samples were collected for metabolic markers.Results: 59.6% of participants reported a PSQI score higher than 5, with 57.6% of the participants reporting less than 6 hours of sleep per day. The data show that both SQ and sleep duration are considered inadequate in comparison to the international SQ standards. We found a significant association between SQ and obesity independent of age and sex. Actigraph data further supported the independent association of sleep duration on BMI within the population (p < 0.001). Additionally, total sleep time (TST) was found to significantly correlate with several other metabolic factors including diastolic blood pressure, elevated resting heart rate (RHR), triglycerides, total cholesterol, homeostatic model assessment for insulin resistance (HOMA-IR), C-peptide, and C-Reactive Protein (CRP) secretion. Further multiple-regression analysis showed a significant independent association between blood pressure (p < 0.03), HOMA-IR (p < 0.04), and C-peptide (p < 0.3) and sleep duration.Conclusion: These findings suggest that sleep deprivation and disturbance could be indirect factors involved in the development of not only obesity in Kuwait but also other metabolic syndromes such as type 2 diabetes.Keywords: sleep, Kuwait, obesity, PSQI

Elevated levels of circulating inflammatory macrophages are associated with several metabolic syndrome (MetS) such as obesity and type II diabetes (T2D). The ingestion of high-fat meals was proven by several groups to act as a stimulus for systemic inflammatory responses via activation of peroxisome proliferator-activated receptors (PPARs). However, little is known about the lipid metabolism involved in macrophage-mediated inflammation under the influence of acute high fat feeding (AHFF). ACSL1 is a member of the long chain acyl-CoA synthetase (ACSL) family that plays key roles in fatty acid metabolism in various tissues. Our previous studies showed that attenuation of ACSL1 was sufficient to dampen inflammatory responses in macrophages challenged with TNF-α or LPS. In this study, we investigated the molecular mechanisms underlying AHFF-induced ACSL1 gene transcription in macrophages. In our work, we showed that four hours feeding of palmitic acid induced significant up-regulation of ACSL1 at both gene and protein levels. Both the inhibition and the deficiency of ACSL1, showed a significant impact on downregulating AHFF-induced inflammatory responses. Furthermore, the inhibition ACSL1 reduced mRNA levels of fatty acid uptake-related genes cluster of differentiation 36 (CD36) and fatty acid transport protein 4 (FATP4). However, inhibition of ACSL1 had no impact on lipogenesis related genes; SREBS, FAS and ACACA or fatty acid-oxidation genes; CPT-1a, CPT-1b and CPT2. Our data also showed that ACSL1 inhibition reduced PPARδ gene expression, while PPARα and PPARγ were not affected. Of note, macrophage intracellular lipid accumulation was attenuated during ACSL inhibition. Our findings suggest that targeting ACSL1 has a therapeutic potential to prevent AHFF-induced macrophage inflammation. Disclosure F. Alrashed: None. A. Al madhoun: None. S. T. Sindhu: None. A. Al-sayyar: None. F. Almulla: None. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences (CB-2020-004)

The role of leukocyte inflammatory markers and toll like receptors (TLRs)2/4 in pathologies associated with elevated resting heart rate (RHR) levels in healthy obese (HO) individuals is not well elucidated. Herein, we investigated the relationship of RHR with expression of leukocyte-inflammatory markers and TLRs in HO individuals. 58-obese and 57-lean participants with no history of a major medical condition, were recruited in this study. In HO individuals, the elevated-RHR correlated positively with diastolic blood pressure, cholesterol, pro-inflammatory monocytes CD11b + CD11c + CD206-phenotype (r=0.52,P=0.0003) as well as with activated T cells CD8 + HLA-DR + phenotype (r=0.27,P=0.039). No association was found between RHR and the percentage of CD16 + CD11b + neutrophils. Interestingly, elevated RHR positively correlated with cells expressing TLR4 and TLR2 (CD14 + TLR4 + , r=0.51,P≤ 0.0001; and CD14 + TLR2 + ,r =0.42,P=0.001). TLR4 + expressing cells also associated positively with the plasma concentrations of proinflammatory or vascular permeability/matrix modulatory markers including TNF-α (r=0.36,P=0.005), VEGF (r= 0.47,P=0.0002), and MMP-9 (r=0.53,P≤0.0001). Multiple regression revealed that RHR is independently associated with CD14 + TLR4 + monocytes and VEGF. We conclude that in HO individuals, increased CD14 + TLR4 + monocytes and circulatory VEGF levels associated independently with RHR, implying that RHR monitoring could be used as a non-invasive clinical indicator to identify healthy obese individuals at risk for inflammation and cardiovascular disease.

The role of leukocyte inflammatory markers and toll like receptors (TLRs)2/4 in pathologies associated with elevated resting heart rate (RHR) levels in healthy obese (HO) individuals is not well elucidated. Herein, we investigated the relationship of RHR with expression of leukocyte-inflammatory markers and TLRs in HO individuals. 58-obese and 57-lean participants with no history of a major medical condition, were recruited in this study. In HO individuals, the elevated-RHR correlated positively with diastolic blood pressure, cholesterol, pro-inflammatory monocytes CD11b+CD11c+CD206− phenotype (r = 0.52, P = 0.0003) as well as with activated T cells CD8+HLA-DR+ phenotype (r = 0.27, P = 0.039). No association was found between RHR and the percentage of CD16+CD11b+ neutrophils. Interestingly, elevated RHR positively correlated with cells expressing TLR4 and TLR2 (CD14+TLR4+, r = 0.51, P ≤ 0.0001; and CD14+TLR2+, r = 0.42, P = 0.001). TLR4+ expressing cells also associated positively with the plasma concentrations of proinflammatory or vascular permeability/matrix modulatory markers including TNF-α (r = 0.36, P = 0.005), VEGF (r = 0.47, P = 0.0002), and MMP-9 (r = 0.53, P ≤ 0.0001). Multiple regression revealed that RHR is independently associated with CD14+TLR4+ monocytes and VEGF. We conclude that in HO individuals, increased CD14+TLR4+ monocytes and circulatory VEGF levels associated independently with RHR, implying that RHR monitoring could be used as a non-invasive clinical indicator to identify healthy obese individuals at an increased risk of developing inflammation and cardiovascular disease.

Purpose - This paper aims to evaluate whether the earnings management diagnostic using changes in asset turnover and profit margin as proposed by Jansen et al., (2012) is informative in identifying earnings managementMethodology - Two tests were employed: firstly, the association between the diagnostic and discretionary accruals using Kothari et al., (2005) model, was tested by using Pearson correlation and contingency tables. Secondly, by using future profitability reversals as an indicator of earnings management, the investigation of whether the diagnostic has incremental information in identifying earnings management as compared to Kothari et al., (2005) model was performed using multivariate regression analysis. Data was collected for the period from 2006 to 2017 and comprises a total of (3,108) firm-year observations from the Palestinian stock exchange. Findings- The results indicate that the diagnostic proposed by Jansen et al., (2012) is a useful indicator for earnings management, as well as this diagnostic, provides higher information content in identifying earnings management than the discretionary accruals model i.e. Kothari et al., (2005) model.Conclusion- This study contributes to the limited earnings management literature in emerging economies generally, and in the Palestinian context particularly. The results of the study benefit financial statement users to have diagnostics for earnings management that are informative.