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Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by chronic hyperglycaemia. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play important roles in post-transcriptional gene regulation. They are negative regulators of their target messenger RNAs (mRNAs), in which they bind either to inhibit mRNA translation, or to induce mRNA decay. Similar to proteins, miRNAs exist in different isoforms (isomiRs). miRNAs and isomiRs are selectively loaded into small extracellular vesicles, such as the exosomes, to protect them from RNase degradation. In T2DM, exosomal miRNAs produced by different cell types are transported among the primary sites of insulin action. These interorgan crosstalk regulate various T2DM-associated pathways such as adipocyte inflammation, insulin signalling, and β cells dysfunction among many others. In this review, we first focus on the mechanism of exosome biogenesis, followed by miRNA biogenesis and isomiR formation. Next, we discuss the roles of exosomal miRNAs and isomiRs in the development of T2DM and provide evidence from clinical studies to support their potential roles as T2DM biomarkers. Lastly, we highlight the use of exosomal miRNAs and isomiRs in personalized medicine, as well as addressing the current challenges and future opportunities in this field. This review summarizes how research on exosomal miRNAs and isomiRs has developed from the very basic to clinical applications, with the goal of advancing towards the era of personalized medicine., Competing Interests: All authors declared that there are no conflict of interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)

Cancer, an incurable global disease, demands urgent anti-cancer drug development. Marine alkaloids like Manzamine and its derivatives show promise as RSK inhibitors against cancer cell invasion. Replacing the hydrogen at the 8-position of Manzamine A with a hydroxyl group has been shown to significantly enhance its biological activity. In this article, we designed various functional group compounds (A1-A21) substituted 8-Manzamine A by docking, MM-GBSA, molecular dynamics (MD) simulation, and well-tempered metadynamics (WT-MetaD) simulations to evaluate their potential as RSK1 inhibitors. Ligands A1-A21 were docked in the RSK1 N-terminal kinase domain (PDB ID: 2Z7Q) using the Glide module. The calculation of binding energy was performed using Prime MM-GB/SA, while MD simulations were conducted with the Desmond module of Schrodinger suite 2023. Compound A5 exhibits the highest G-score (-7.01) compared to 8-Hydroxymanzamine A (-6.08). Additionally, compounds A6, A10, A12, A17, A11, A4, and A13 demonstrate increased activity against RSK1 when compared to both 8-Hydroxymanzamine A and Manzamine A. Residues LEU68, VAL76, LEU141, PHE143, LEU144, PHE150, ASP148, GLU191, and LEU194 of RSK1 protein play a key role in binding with ligands. An MD simulation of Compound A5 was carried out to explore the dynamic interactions within the protein-ligand complex. Furthermore, WT-MetaD simulations validated the docking study results and identified the most energetically favored conformations for the A5/RSK1 complex. Ligands A5, A6, A10, A12, A17, A11, A4, and A13, featuring diverse functional groups and good Glide scores, may have the potential for significant RSK1 activity and merit further development.Communicated by Ramaswamy H. Sarma.

In the attempt to create a delivery system for an alkali-cation stimulated drug release, a computational study was conducted, aiming for the evaluation of synthetic access towards glycolipid crown ethers analogs and their potential for coordination-induced changes of packing constraints for molecular assemblies. The results disfavor amide-linkages for the creation of macrocycles around the inter-glycosidic bond of a disaccharide. Conformational changes upon cation coordination of the macrocycle decrease the intersection area for easily accessible macrocycles based on lactose. This leads to shrinking intersection areas upon alkali complexation. Maltose-based analogs, on the other hand, exhibited the targeted increase of the glycolipid intersection area and, hence, may be considered as a promising resource., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thorsten Heidelberg has received industrial research funding from Petronas R&D Sdn. Bhd., Malaysia., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Killer cell immunoglobulin-like receptors (KIR) genotype and haplotype frequencies have been reported to vary distinctly between populations, which in turn contributes to variation in the alloreactivity of natural killer (NK) cells. Utilizing the diverse KIR genes to identify suitable transplant donors would prove challenging in multi-ethnic countries, even more in resource-limited countries where KIR genotyping has not been established. In this study, we determined the KIR genotypes from 124 unrelated Malaysians consisting of the Malays, Chinese, Indians, and aboriginal people through polymerase chain reaction sequence-specific primer (PCR-SSP) genotyping and employing an expectation-maximization (EM) algorithm to assign haplotypes based on pre-established reference haplotypes. A total of 27 distinct KIR haplotypes were discerned with higher frequencies of haplotype A (55.2%) than haplotype B (44.8%). The most frequent haplotypes were cA01:tA01 (55.2%), cB01:tB01 (18.1%), and cB02:tA01 (13.3%), while the least frequent haplotypes were cB03:tB01 (1.2%), cB04:tB03 (0.4%), and cB03:tA01 (0.4%). Several haplotypes were identified to be unique to a specific ethnic group. The genotype with the highest frequency was genotype AB (71.8%), followed by AA (19.4%), and BB (8.9%). The Indians exhibited the lowest genotype AA but the highest genotype BB, whereas genotype BB was absent in the aboriginal people. Despite the limitations, the genotype and haplotypes in the Malaysian population were successfully highlighted. The identification of ethnic-specific KIR genotypes and haplotypes provides the first step to utilizing KIR in identifying suitable transplant donors to further improve the transplant outcome in the Malaysian population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Self-care behaviour is fundamental in preventing hypertension in the general population. According to the Health Belief Model, health beliefs and perceptions influence the success in adopting disease prevention strategies. While factors influencing hypertension self-care behaviour have been examined previously in patient populations, they have not been assessed in the general community., Methods: This was a cross-sectional study conducted between 12 June 2020 to 26 July 2021. An online survey was administered via email and social media to Malaysians in the Selangor and Kuala Lumpur communities. Respondents were over 18 years old, without a formal diagnosis of hypertension. The survey evaluated hypertension knowledge, Health Belief Model constructs, self-care behaviour frequency, and motivators and barriers to self-care behaviour. Multiple linear regression was performed to determine the main predictors of self-care behaviour, and descriptive statistics were used to characterise motivators and barriers of each self-care behaviour., Results: Only health motivations (β = 0.217, p < 0.001) and perceived barriers (β = 0.571, p < 0.001) significantly influenced self-care behaviour. Maintaining a healthy diet, regular physical activity and blood pressure checks need to be improved in the community, particularly in reducing salt and calorie intake. Lack of time, limited choices and laziness are the biggest challenges that need to be tackled in adopting a healthy diet and an active lifestyle in the community. Many are ignorant towards their health status, therefore, do not prioritize blood pressure screenings, suggesting a need to enhance community blood pressure checks for early diagnosis of hypertension., Conclusion and Implications: Motivations and barriers were the main determinants of self-care behaviour in the Selangor and Kuala Lumpur community. Targeting these aspects of self-care behaviour should be considered when developing interventions and education programmes tailored to local cultural, environmental and personal factors, to more effectively reduce the hypertension prevalence and burden., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Tan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Gestational diabetes mellitus (GDM) is a severe global issue that requires immediate attention. MicroRNA expression abnormalities are possibly disease-specific and may contribute to GDM pathological processes. To date, there is limited data on miRNA profiling in GDM, especially that involves a longitudinal study. Here, we performed miRNA expression profiling in the entire duration of pregnancy (during pregnancy until parturition and postpartum) using a miRNA- polymerase chain reaction array (miRNA-PCRArray) and in-silico analysis to identify unique miRNAs expression and their anticipated target genes in Malay maternal serum. MiRNA expression levels and their unique potential as biomarkers were explored in this work. In GDM patients, the expression levels of hsa-miR-193a, hsa-miR-21, hsa-miR-23a, and hsa-miR-361 were significantly increased, but miR-130a was significantly downregulated. The area under the curve (AUC) and receiver operating characteristic (ROC) curve study demonstrated that hsa-miR-193a (AUC = 0.89060 ± 04,470, P = 0.0001), hsa-miR-21 (AUC = 0.89500 ± 04,411, P = 0.0001), and miR-130a (AUC = 0.6939 ± 0.05845, P = 0.0025) had potential biomarker features in GDM. In-silico analysis also revealed that KLF (Kruppel-Like family of transcription factor), ZNF25 (Zinc finger protein 25), AFF4 (ALF transcription elongation factor 4), C1orf143 (long intergenic non-protein coding RNA 2869), SRSF2 (serine and arginine rich splicing factor 2), and ZNF655 (Zinc finger protein 655) were prominent genes targeted by the common nodes of miR23a, miR130, miR193a, miR21, and miR361.Our findings suggest that circulating microRNAs in the first trimester has the potential for GDM screening in the Malay population., (© 2022. The Author(s).)

Background: Elevated circulating vaspin levels is linked with type 2 diabetes mellitus (T2DM) and obesity. The genetic basis of the association between vaspin rs2236242 and T2DM and obesity is still being investigated. We executed a meta-analysis to evaluate the magnitude of effect caused by vaspin rs2236242 on T2DM and obesity., Methods: We searched Pubmed, Embase, MEDLINE, Scopus, Web of Science, and Google Scholar for relevant articles published up to 19 February 2022. Data were extracted and summary estimates of the association between vaspin rs2236242 and T2DM and obesity were assessed. Odds ratios (ORs) and confidence intervals (CIs) were used to measure the effect., Results: This meta-analysis included 2206 cases and 2715 controls in the T2DM cohort, meanwhile 271 cases and 444 controls in the obesity cohort. The pooled estimates revealed no link between vaspin rs2236242 and T2DM, but allele-A was significantly higher in the controls of the obesity cohort, showing that this single nucleotide polymorphism (SNP) has a reduced obesity risk effect. Sensitivity analysis revealed no studies that would modify the estimates or the heterogeneity. Begg and Mazumdar's and Egger's tests indicated no substantial publication bias., Conclusion: Our meta-analysis provides evidence of significant association between vaspin rs2236242 and reduced risk of obesity but not T2DM., Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01119-8., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Author(s), under exclusive licence to Tehran University of Medical Sciences 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: Routine categorization of DLBCL patients into GCB and non-GCB groups by Hans' criteria could not accurately predict chemotherapy resistance and disease progression in patients treated with standard R-CHOP therapy. There is a need to identify better biomarker predictors to enhance assisted selection of chemotherapy regimens for DLBCL patients., Aim of the Study: To identify dysregulated miRNAs and mRNAs that are predictive of resistance to R-CHOP chemotherapy or disease progression in patients with DLBCL., Methods: miRNA and mRNA profiling were performed on archival FFPE samples of the DLBCL patients. miRabel and miRNet bioinformatic tools were applied to determine experimental validated miRNA-mRNA target interaction. The significance of the genomic predictive values was assessed using adjusted odds ratios (AOR) and 95% confidence intervals (CI)., Results: 19/36 were R-CHOP therapy-resistant whilst 17/36 were R-CHOP therapy-sensitive. Ten dysregulated miRNAs and 12 dysregulated mRNAs were identified in therapy-resistant DLBCL patients. These dysregulated miRNAs and mRNA cause therapy resistance and disease progression in DLBCL patients, most likely via upregulation of the anti-apoptotic protein bcl2, activation of the JAK/STAT signalling pathway and dysregulation of p53 pathway. Downregulation of hsa-miR-548d-3p and overexpression of HOXA9 mRNA were significantly associated with therapy resistance and disease progression in DLBCL patients [hsa-miR-548d-3p AOR: 0.258, 95%CI: 0.097-0.684, p = 0.006]., Conclusion: DLBCL patients with downregulation of hsa-miR-548d-3p and overexpression of HOXA9 mRNA are more likely to experience R-CHOP therapy resistance and disease progression., (© 2022 John Wiley & Sons Ltd.)

Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the PDHA1 gene. The PDHA1 gene encodes one of the subunits of the PDH enzyme found in a carbohydrate metabolism pathway involved in energy production. Pathogenic variants of PDHA1 gene usually impact the α-subunit of PDH causing energy reduction. It potentially leads to increased mortality in sufferers. Potential treatments for this disease include dichloroacetate and phenylbutyrate, previously used for other diseases such as cancer and maple syrup urine disease. However, not much is known about their efficacy in treating PDH deficiency. Effective treatment for PDH deficiency is crucial as carbohydrate is needed in a healthy diet and rice is the staple food for a large portion of the Asian population. This review analysed the efficacy of dichloroacetate and phenylbutyrate as potential treatments for PDH deficiency caused by PDHA1 pathogenic variants. Based on the findings of this review, dichloroacetate will have an effect on most PDHA1 pathogenic variant and can act as a temporary treatment to reduce the lactic acidosis, a common symptom of PDH deficiency. Phenylbutyrate can only be used on patients with certain pathogenic variants (p.P221L, p.R234G, p.G249R, p.R349C, p.R349H) on the PDH protein. It is hoped that the review would provide an insight into these treatments and improve the quality of lives for patients with PDH deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Karissa, Simpson, Dawson, Low, Tay, Nordin, Zain, Lee and Pung.)

Vascular aging is highly associated with cardiovascular morbidity and mortality. Although the senescence of vascular smooth muscle cells (VSMCs) has been well established as a major contributor to vascular aging, intracellular and exosomal microRNA (miRNA) signaling pathways in senescent VSMCs have not been fully elucidated. This study aimed to identify the differential expression of intracellular and exosomal miRNA in human VSMCs (hVSMCs) during replicative senescence. To achieve this aim, intracellular and exosomal miRNAs were isolated from hVSMCs and subsequently subjected to whole genome small RNA next-generation sequencing, bioinformatics analyses, and qPCR validation. Three significant findings were obtained. First, senescent hVSMC-derived exosomes tended to cluster together during replicative senescence and the molecular weight of the exosomal protein tumor susceptibility gene 101 (TSG-101) increased relative to the intracellular TSG-101, suggesting potential posttranslational modifications of exosomal TSG-101. Second, there was a significant decrease in both intracellular and exosomal hsa-miR-155-5p expression [ n = 3, false discovery rate (FDR) < 0.05], potentially being a cell type-specific biomarker of hVSMCs during replicative senescence. Importantly, hsa-miR-155-5p was found to associate with cell-cycle arrest and elevated oxidative stress. Lastly, miRNAs from the intracellular pool, that is, hsa-miR-664a-3p , hsa-miR-664a-5p , hsa-miR-664b-3p , hsa-miR-4485-3p, hsa-miR-10527-5p , and hsa-miR-12136 , and that from the exosomal pool, that is, hsa-miR-7704 , were upregulated in hVSMCs during replicative senescence ( n = 3, FDR < 0.05). Interestingly, these novel upregulated miRNAs were not functionally well annotated in hVSMCs to date. In conclusion, hVSMC-specific miRNA expression profiles during replicative senescence potentially provide valuable insights into the signaling pathways leading to vascular aging. NEW & NOTEWORTHY This is the first study on intracellular and exosomal miRNA profiling on human vascular smooth muscle cells during replicative senescence. Specific dysregulated sets of miRNAs were identified from human vascular smooth muscle cells. Hsa-miR-155-5p was significantly downregulated in both intracellular and exosomal hVSMCs, suggesting its crucial role in cellular senescence. Hsa-miR-155-5p might be the mediator in linking cellular senescence to vascular aging and atherosclerosis.

Cardiovascular disease (CVD) is among the leading causes of death worldwide. MicroRNAs (miRNAs), regulatory molecules that repress protein expression, have attracted considerable attention in CVD research. The vasculature plays a big role in CVD development and progression and dysregulation of vascular cells underlies the root of many vascular diseases. This review provides a brief introduction of the biogenesis of miRNAs and exosomes, followed by overview of the regulatory mechanisms of miRNAs in vascular smooth muscle cells (VSMCs) intracellular signaling during phenotypic switching, senescence, calcification, and neointimal hyperplasia. Evidence of extracellular signaling of VSMCs and other cells via exosomal and circulating miRNAs is also presented. Lastly, current drawbacks and limitations of miRNA studies in CVD research and potential ways to overcome these disadvantages are discussed in detail. In-depth understanding of VSMC regulation via miRNAs will add substantial knowledge and advance research in diagnosis, disease progression, and (or) miRNA-derived therapeutic approaches in CVD research.

Studies on metacognitive skills have started in the past 30 years and cover various fields, including education. In general, metacognitive skills refer to awareness and monitoring cognitive processes and their ability to sharpen the mind enhancement process. However, much attention has been given to metacognition alone and less focusing on its manifestation in behaviors. Thus, this study aims to conceptualize how metacognitive concepts can be adapted in the context of behaviors. In achieving this, an in-depth analysis of relevant behavioral theories and metacognitive models was conducted. The proposed conceptual framework, named the meta-behavior framework, underscores the importance of the thinking process before an individual engages in action. Undoubtfully, this skill is vital in influencing an individual to plan, monitor and evaluate his/her actions in daily life. In short, the proposed framework is essential in expanding the current knowledge terrain on psychology, which specifically provides a new perspective in understanding how the thinking process determines behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Amran, Zain, Jamaludin and Surat.)

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins-designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2-DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala → Asp and Ser → Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions.

Background/aims: 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients., Methods: Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded., Results: HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00-0.64; P=0.033 and HR, 0.01; 95% CI, 0.00-0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese., Conclusion: HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

The main focus of this study is exploring the spatial distribution of polyaromatics hydrocarbon links between oil spills in the environment via Support Vector Machines based on Kernel-Radial Basis Function (RBF) approach for high precision classification of oil spill type from its sample fingerprinting in Peninsular Malaysia. The results show the highest concentrations of Σ Alkylated PAHs and Σ EPA PAHs in ΣTAH concentration in diesel from the oil samples PP3&#95;liquid and GP6&#95;Jetty achieving 100% classification output, corresponding to coherent decision boundary and projective subspace estimation. The high dimensional nature of this approach has led to the existence of a perfect separability of the oil type classification from four clustered oil type components; i.e diesel, bunker C, Mixture Oil (MO), lube oil and Waste Oil (WO) with the slack variables of ξ ≠ 0. Of the four clusters, only the SVs of two are correctly predicted, namely diesel and MO. The kernel-RBF approach provides efficient and reliable oil sample classification, enabling the oil classification to be optimally performed within a relatively short period of execution and a faster dataset classification where the slack variables ξ are non-zero.

Background: The association between dysregulated microRNAs (miRNAs) and acute myeloid leukemia (AML) is well known. However, our understanding of the regulatory role of miRNAs in the cytogenetically normal AML (CN-AML) subtype pathway is still poor. The current study integrated miRNA and mRNA profiles to explore novel miRNA-mRNA interactions that affect the regulatory patterns of de novo CN-AML. Methods: We utilized a multiplexed nanoString nCounter platform to profile both miRNAs and mRNAs using similar sets of patient samples ( n  = 24). Correlations were assessed, and an miRNA-mRNA network was constructed. The underlying biological functions of the mRNAs were predicted by gene enrichment. Finally, the interacting pairs were assessed using TargetScan and microT-CDS. We identified 637 significant negative correlations (false discovery rate <0.05). Results: Network analysis revealed a cluster of 12 miRNAs representing the majority of mRNA targets. Within the cluster, five miRNAs (miR-495-3p, miR-185-5p, let-7i-5p, miR-409-3p, and miR-127-3p) were posited to play a pivotal role in the regulation of CN-AML, as they are associated with the negative regulation of myeloid leukocyte differentiation, negative regulation of myeloid cell differentiation, and positive regulation of hematopoiesis. Conclusion: Three novel interactions in CN-AML were predicted as let-7i-5p: HOXA9 , miR-495-3p: PIK3R1 , and miR-495-3p: CDK6 may be responsible for regulating myeloid cell differentiation in CN-AML.

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.

Objective: Epilepsy is a common chronic neurological condition characterized by recurrent seizures. Approximately 30 - 40% of epileptic patients do not respond to antiepileptic drugs. Previous studies suggest that CYP3A5 polymorphisms affect carbamazepine metabolism., Materials and Methods: To examine this hypothesis, in the present study, the associations between CYP3A5 variants (rs776746 and rs1419745) and response to carbamazepine and valproic acid monotherapy in Malaysian epileptic patients were evaluated., Results: A total of 288 Malaysian epileptic patients were recruited and further reviewed, of whom 63 patients were on carbamazepine monotherapy, and 85 patients were on valproic acid monotherapy. There was no patient with drug hypersensitivity syndrome within the population. Subjects were genotyped by using Sequenom MassARRAY platform. This study found a significant association of CYP3A5 rs776746 with the carbamazepine treatment response in total patients (p = 0.026) and Malay ethnic subgroup (p = 0.006). In addition, a marginal significant association of CYP3A5 rs1419745 with carbamazepine treatment response was reported in the Malays. Similarly, CYP3A5 rs776746 was associated with valproic acid response in total patients (p = 0.037) and Malays (marginal p = 0.05)., Conclusion: Our findings suggest that CYP3A5 polymorphisms affect carbamazepine and valproic acid response in Malaysian epileptic patients.

Background and Aim: Advanced fibrosis is the most important predictor of liver-related mortality in non-alcoholic fatty liver disease (NAFLD). The aim of this study was to compare the diagnostic performance of noninvasive scoring systems in identifying advanced fibrosis in a Malaysian NAFLD cohort and propose a simplified strategy for the management of NAFLD in a primary care setting., Methods: We enrolled and reviewed 122 biopsy-proven NAFLD patients. Advanced fibrosis was defined as fibrosis stages 3-4. Noninvasive assessments included aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, AST-to-platelet ratio index (APRI), AST/ALT ratio, diabetes (BARD) score, fibrosis-4 (FIB-4) score, and NAFLD fibrosis score., Results: FIB-4 score had the highest area under the receiver operating characteristic curve (AUROC) and negative predictive value (NPV) of 0.86 and 94.3%, respectively, for the diagnosis of advanced fibrosis. FIB-4 score < 1.3 ruled out advanced fibrosis in 72% of the patients, with 6% being understaged. Further stratification of the indeterminate group patients by other non-alcoholic steatohepatitis (NASH) clinical predictors, such as abnormal gamma-glutamyl transpeptidase (GGT) level and presence diabetes mellitus (DM), could further reduce the number of patients who are unlikely to have advanced fibrosis by 52% and 35%, respectively., Conclusion: We found that FIB-4 score outperforms other scoring systems based on AUROC and NPV. The use of a simple scoring system such as FIB-4 as first-line triage to risk-stratify NAFLD patients in the primary care setting, with further stratification of those in the indeterminate group using clinical predictors of NASH, can help in the development of a simplified strategy for a public health approach in the management of NAFLD., (© 2020 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Aim: Human leukocyte antigen (HLA) regions were highlighted as important genetic markers for various liver diseases by hepatology-related genome-wide association studies. Replication studies in non-alcoholic fatty liver disease (NAFLD) are limited and none has investigated the association of HLA alleles with non-alcoholic steatohepatitis (NASH) and other histological characteristics. In the current study, we examined the association of HLA-DQA1 and HLA-DQB1 alleles with NAFLD spectrum and its histological characteristics., Methods: Consecutive biopsy-proven NAFLD patients (n = 191) and healthy controls (n = 188) were enrolled and genotyped for HLA-DQA1 and HLA-DQB1 alleles using the sequence-specific oligonucleotide-polymerase chain reaction method., Results: No association was found between the HLA alleles and NAFLD or NASH in a case-control setting. Nevertheless, among NAFLD patients, the frequency of HLA-DQB1*06 allele was significantly the lowest in NASH with significant fibrosis (10.4%) and approximately similar for NASH without significant fibrosis (22.9%) and NAFL (22.5%) (P = 0.004). It is noteworthy that the association remains significant after correction for multiple comparisons (P c  = 0.04). Multivariate analysis revealed that HLA-DQB1*06 allele is also associated with fibrosis score (P = 0.001); the result remains significant after correction for multiple comparisons., Conclusion: These findings suggest that HLA-DQB1*06 is associated with lower fibrosis score in NAFLD patients., (© 2020 The Japan Society of Hepatology.)

Human health is threatened by significant emissions of heavy metals into the urban environment due to various activities. Various studies describing health risk analyses on soil and dust have been conducted previously. However, there are limited studies that have been carried out regarding the potential health risk assessment of heavy metals in urban road dust of < 63-μm diameter, via incidental ingestion, dermal contact, and inhalation exposure routes by children and adults in developing countries. Therefore, this study evaluated the health risks of heavy metal exposure via ingestion, dermal contact, and inhalation of urban dust particles in Petaling Jaya, Malaysia. Heavy metals such as lead (Pb), chromium (Cr), zinc (Zn), copper (Cu), and manganese (Mn) were measured using dust samples obtained from industrial, high-traffic, commercial, and residential areas by using inductively coupled plasma mass spectrometry (ICP-MS). The principal component and hierarchical cluster analysis showed the dominance of these metal concentrations at sites associated with anthropogenic activities. This was suggestive of industrial, traffic emissions, atmospheric depositions, and wind as the significant contributors towards urban dust contamination in the study sites. Further exploratory analysis underlined Cr, Pb, Cu, and Zn as the most representative metals in the dust samples. In accommodating the uncertainties associated with health risk calculations and simulating the reasonable maximum exposure of these metals, the related health risks were estimated at the 75th and 95th percentiles. Furthermore, assessing the exposure to carcinogenic and non-carcinogenic metals in the dust revealed that ingestion was the primary route of consumption. Children who ingested dust particles in Petaling Jaya could be more vulnerable to carcinogenic and non-carcinogenic risks, but the exposure for both children and adults showed no potential health effects. Therefore, this study serves as an important premise for a review and reformation of the existing environmental quality standards for human health safety.

Spectra data from two instruments (UV-Vis/NIR and FT-NIR) consisting of three and one detectors, respectively, were employed in order to discriminate the geographical origin of milk as a way to detect adulteration. Initially, principal component analysis (PCA) was used to see if clusters of milk from different origins are formed. Separation between samples of different origins were not observed with PCA, hence, feed-forward multi-layer perceptron artificial neural network (MLP-ANN) models were designed. ANN models were developed by changing the number of input variables and the best models were chosen based on high values of generalized R-square and entropy R-square, as well as small values of root mean square error (RMSE), mean absolute deviation (Mean Abs. Dev), and -loglikelihood while considering 100% classification rate. Based on the results, whether the spectra data was collected from a single or three detector instrument the same clustering was observed based on geographical origin., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

After twenty-four years of government efforts, the latest national recycling rate in Malaysia rose from 5% in 1993 to approximately 24.6% in 2017. However, the practice of solid waste recycling in developing countries is still challenging compared to developing countries. Especially in Malaysia, a multi-ethnic country where people with different ethics have different living lifestyles. Still, Malaysia faces rapidly increasing solid waste and management costs, lacks appropriate data on solid waste management and recycling, lacks awareness of the 3R's (reduce, reuse and recycle) culture and lacks policies to promote 3R's culture. In addition, prior to the enforcement of ACT 672, information and networks between stakeholders have been limited for more than 20 years. Some scholars believe that the success of recycling practices is mainly influenced by community recycling behaviours. Therefore, in order to improve and evaluate the effectiveness of current national solid waste recycling management systems, research and assessment of community recycling behaviours are essential. This paper aims to evaluate the factors that attract communities to implement recycling in their daily lives and to obtain data through quantitative survey methods. Face-to-face questionnaires are conducted through purposive sampling and collected data is further analysed by PASW statistical tools. The comparison between recyclers and non-recyclers are presented in terms of frequency, means scores and radar chart. The results indicate that policy makers involved in the planning, organisation, and implementation of community recycling programs have to focus on strategies that engage community members and adopt recycling practices to improve environmental impact by changing their attitudes. Based on the results of means scores, the type of age, occupation and place of life must be taken into consideration in order to organize future recycling campaigns or awareness programs. In conclusion, the information will help policymakers make better solid waste recycling management to meet the needs of the public., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Seven fungal species were isolated from soil samples collected from the University of Sultan Qaboos, Muscat, Sultanate of Oman. The fungal isolates were identified as Aspergillus athecius , A. terreus var. africans , A. flavus , A. terreus , A. foetidus , Fusarium chlamydosporum and F. nygamai . Phytochemical and chromatographic investigation showed variety of secondary metabolites in all of the fugal extracts (extra and intra cellular). The antimicrobial activity of internal and external extracts of the isolated fungal species were screened against Candida albicans , C. glabrata , C. parapsilosis , C. tropicalis , Pseudomonas aeruginosa , Lactobacillus acidophilus , Streptococcus gordonii , S. mutans . The antimicrobial activity of external secondary metabolites was generally better than the internal metabolites. The highest antimicrobial activity (32 mm, 30 mm and 29 mm) was obtained from external secondary metabolites of Aspergillus flavus against Candida tropicals , Candida parapsilosis and Candida albicans , respectively.

In this study, we investigate the binding interactions of two synthetic antiviral peptides (DET2 and DET4) on type II dengue virus (DENV2) envelope protein domain III. These two antiviral peptides are designed based on the domain III of the DENV2 envelope protein, which has shown significant inhibition activity in previous studies and can be potentially modified further to be active against all dengue strains. Molecular docking was performed using AutoDock Vina and the best-ranked peptide-domain III complex was further explored using molecular dynamics simulations. Molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) was used to calculate the relative binding free energies and to locate the key residues of peptide-protein interactions. The predicted binding affinity correlated well with the previous experimental studies. DET4 outperformed DET2 and is oriented within the binding site through favorable vdW and electrostatic interactions. Pairwise residue decomposition analysis has revealed several key residues that contribute to the binding of these peptides. Residues in DET2 interact relatively lesser with the domain III compared to DET4. Dynamic cross-correlation analysis showed that both the DET2 and DET4 trigger different dynamic patterns on the domain III. Correlated motions were seen between the residue pairs of DET4 and the binding site while binding of DET2 results in anti-correlated motion on the binding site. This work showcases the use of computational study in elucidating and explaining the experiment observation on an atomic level.

We have performed computational molecular modelling to study the polarization switching and hysteresis loop behaviours of DNA and RNA nucleobases using the PM3 semi-empirical quantum mechanical approaches. All the nucleobases: adenine (A), thymine (T), guanine (G), cytosine (C), and uracil (U) were modelled. Our study indicates that all the nucleobases exhibit a zero-field polarization due to the presence of polar atoms or molecules such as amidogen and carbonyl. The shape of polarization P versus an applied electric field E hysteresis loop is square, implying typical ferroelectrics behaviour. The total energy U as a function of an applied electric field E exhibits a butterfly-like loop. The presence of zero-field polarization and ferroelectrics hysteresis loop behaviours in nucleobases may support the hypothesis of the existence of bioferroelectricity in DNA and RNA. We also found an interesting relationship between the minimum electric field required for switching [Formula: see text] and the ratio of the topological polar surface area (TPSA) to the total surface area (TSA) of a nucleobase. In particular, the [Formula: see text] of a nucleobase is inversely proportional to the TPSA/TSA ratio. This work may provide useful information for understanding the possible existence of ferroelectricity in biomaterials.

Background: Although the influence of a common variant in the glucokinase regulatory gene (GCKR rs780094) in type 2 diabetes mellitus has been well documented, less data however, is available of its role in gestational diabetes mellitus (GDM). We carried out a case control study to assess the association between GCKR rs780094 and GDM in the Asian, and also a meta-analysis to further assess the strength of the association., Methods: Demographic, clinical and genotype data were determined for 1122 women (267 cases and 855 controls) recruited from the University of Malaya Medical Centre in the Klang Valley, Kuala Lumpur. Relevant articles were identified from Pubmed, Embase, MEDLINE, and Web of Science. Extraction of data was carried out and summary estimates of the association between rs780094 and GDM were examined., Results: The frequency of risk allele C was significantly higher in the cases than controls (OR 1.34, 95% CI 1.09-1.66, P = 0.006). The C allele was also associated with increased level of random 2-hour fasting plasma glucose and pregravid body mass index. Meta-analysis further confirmed the association of the GCKR rs780094 with GDM (OR 1.32, 95% CI 1.14-1.52, P = 0.0001)., Conclusion: This study strongly suggests that GCKR rs780094-C is associated with increased risk of GDM., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Evaluation of health risks due to heavy metals exposure via drinking water from ex-mining ponds in Klang Valley and Melaka has been conducted. Measurements of As, Cd, Pb, Mn, Fe, Na, Mg, Ca, and dissolved oxygen, pH, electrical conductivity, total dissolved solid, ammoniacal nitrogen, total suspended solid, biological oxygen demand were collected from 12 ex-mining ponds and 9 non-ex-mining lakes. Exploratory analysis identified As, Cd, and Pb as the most representative water quality parameters in the studied areas. The metal exposures were simulated using Monte Carlo methods and the associated health risks were estimated at 95th and 99th percentile. The results revealed that As was the major risk factor which might have originated from the previous mining activity. For Klang Valley, adults that ingested water from those ponds are at both non-carcinogenic and carcinogenic risks, while children are vulnerable to non-carcinogenic risk; for Melaka, only children are vulnerable to As complications. However, dermal exposure showed no potential health consequences on both adult and children groups., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Behaviors of cationic and nonionic mixed micelles in the form of hexadecyltrimethylammonium bromide (HDABr) and hexadecyltrimethylammonium bromide-Polyethylene glycol hexadecyl ether (C 16 E 20 ), in the presence of inert salts (NaBr and 3,5-dichlorosodium benzoate), by the use of reaction probe between Pp and ionized PhSH (Pp = piperidine and PhSH = phenyl salicylate), has been reported in this work. The values of R X Br (R X Br denotes ion exchange constants obtained in the presence of micelles of different structural features) or K X Br (K X Br denotes ion exchange constants obtained in the presence of micelles of the same structural features) for 3,5-Cl 2 C 6 H 3 CO 2 - were almost the same at three different [HDABr] T (0.006, 0.010 and 0.015 M). The average value of R X Br or K X Br determined, in the presence of pure HDABr micelles, using semi empirical kinetic (SEK) method appeared to be almost 2½-fold larger (R X Br or K X Br = 198) than that in the presence of mixed HDABr-C 16 E 20 micelles (R X Br or K X Br = 78). Rheological measurements indicated the existence of wormlike/twisted micelles and vesicle at 0.015 M pure HDABr, various [3,5-Cl 2 C 6 H 3 CO 2 Na], and 25 and 35℃ whereas there were evidence of only spherical micelles in the presence of mixed HDABr-C 16 E 20 ([HDABr] T = 0.015 M and [C 16 E 20 ] T = 0.006 M) at both temperatures.

Carbamazepine (CBZ) is a commonly prescribed antiepileptic drug, and is mainly metabolized to 10,11-CBZ epoxide in humans. Its biotransformation is catalyzed by cytochrome P450 (CYP) enzymes, with the predominant isoforms being CYP3A4 and CYP3A5. In the present study, the effects of the CYP3A5*3 (rs776746) polymorphism on CBZ 10,11-epoxidation in human liver microsomes genotyped as CYP3A5*3 were examined using a kinetic analysis. The kinetics for CBZ 10,11-epoxidation fit the Hill model with n of approximately 1.9-2.1 in all liver microsomes of the wild-type (CYP3A5*1/*1) and heterozygous (CYP3A5*1/*3) and homozygous (CYP3A5*3/*3) variants. The S50, Vmax, and CLmax values of wild-type liver microsomes were 263-327 μM, 793-1590 pmol/min/mg protein, and 1.51-2.95 μL/min/mg protein, respectively. The Vmax and CLmax values of liver microsomes of the heterozygous variant were approximately 15-40% those of wild-type liver microsomes. On the other hand, the Vmax and CLmax values of liver microsomes of the homozygous variant were more similar to those of the wild-type than the heterozygous variant. These results suggest that the CYP3A5*3 polymorphism has a negligible effect on CBZ 10,11-epoxidation in an in vitro system using human liver microsomes.

Background: Although aberrant expression of cytokines and small molecules (analytes) is well documented in acute myeloid leukaemia (AML), their co-expression patterns are not yet identified. In addition, plasma baselines for some analytes that are biomarkers for other cancers have not been previously reported in AML., Methods: We used multiplex array technology to simultaneously detect and quantify 32 plasma analyte (22 reported analytes and 10 novel analytes) levels in 38 patients., Results: In our study, 16 analytes are found to be significantly deregulated (13 higher, 3 lower, Mann-Whitney U-test, P-value <0.005), where 5 of them have never been reported before in AML. We predicted a seven-analyte-containing multiplex panel for diagnosis of AML and, among them, MIF could be a possible therapeutic target. In addition, we observed that circulating analytes show five co-expression signatures., Conclusions: Circulating analyte expression in AML significantly differs from normal, and follow distinct expression patterns.

This study involves the use of quality engineering in oil spill classification based on oil spill fingerprinting from GC-FID and GC-MS employing the six-sigma approach. The oil spills are recovered from various water areas of Peninsular Malaysia and Sabah (East Malaysia). The study approach used six sigma methodologies that effectively serve as the problem solving in oil classification extracted from the complex mixtures of oil spilled dataset. The analysis of six sigma link with the quality engineering improved the organizational performance to achieve its objectivity of the environmental forensics. The study reveals that oil spills are discriminated into four groups' viz. diesel, hydrocarbon fuel oil (HFO), mixture oil lubricant and fuel oil (MOLFO) and waste oil (WO) according to the similarity of the intrinsic chemical properties. Through the validation, it confirmed that four discriminant component, diesel, hydrocarbon fuel oil (HFO), mixture oil lubricant and fuel oil (MOLFO) and waste oil (WO) dominate the oil types with a total variance of 99.51% with ANOVA giving F stat >F critical at 95% confidence level and a Chi Square goodness test of 74.87. Results obtained from this study reveals that by employing six-sigma approach in a data-driven problem such as in the case of oil spill classification, good decision making can be expedited., (Copyright © 2017. Published by Elsevier Ltd.)

The spatial distributions of Na, Mg, K, Ca, Cr, Fe, Ni, Cu, Zn, As, Se and Pb in Hemibagrus sp. from Selangor River and a reference site were determined with inductively coupled plasma-mass spectrometer, in comparison to the levels in their surrounding water body and sediments. The results demonstrated significant differences in elemental accumulation pattern in different fish tissues originated from both sites. The variations observed were mainly subjected to their metabolic activities, and also the influence of the surrounding medium. In general, the liver tends to accumulate higher concentration of metals followed by the gills, and muscle tissues. The data also indicate associations between the concentrations of metal contaminants measured in the fish and the levels observed at the sites. The concentrations of hazardous metals As, Se and Pb in all the studied tissues reflect the influence of anthropogenic inputs. This suggests the potential utility of widely available Hemibagrus sp. as a valuable bioindicator of metal pollution in environmental monitoring and assessment.

The efficiency of counterion affinity towards ionic micelles is often described in terms of the degree of counterion binding (β X ) to ionic micelles or the conventional ion-exchange constant ([Formula: see text]) or relative binding constant ([Formula: see text]) of X - and Br - counterions. This review describes the use of ionized phenyl salicylate ions, PSa - , as a new probe to determine [Formula: see text] values using a semiempirical spectrophotometric method. The value of [Formula: see text] is found to be comparable to reported values obtained using different probes by the semiempirical kinetic method as well as different physical methods. Application of semiempirical methods for calculation of [Formula: see text] or [Formula: see text] values involves an inherent assumption that these values are independent of the physicochemical characteristics of the probe molecule.

The potential for the isotopic ratio analysis of cattle tail hair in determining the geographical origin of raw cow milk in Peninsular Malaysia had been investigated in this research using exploratory visualization. A significant positive correlation (p<0.0001) (n=54) was noticed between δ(13)C and δ(15)N in milk with that of hair which indicated that these matrices could be used in tracing the geographical origin of animal produce and tissues, and there is a possibility that hair could be used as a substitute in building the database for the geographical traceability of milk. It was also observed that both hair and milk isotopic ratio correlations exhibited separation between the northern and southern regions. The accuracy of using isotopic ratio in determining geographical discrimination had been clearly demonstrated when several commercial milk samples from the same regions under the study were correctly assigned to the appropriate geographical clusters., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The objective of this work is to prepare a cost-effective, low reagent consumption and high performance polytetrafluoroethylene (PTFE) vessel that is capable to work in domestic microwave for digesting food and environmental samples. The designed vessel has a relatively thicker wall compared to that of commercial vessels. In this design, eight vessels are placed in an acrylonitrile butadiene styrene (ABS) holder to keep them safe and stable. This vessel needs only 2.0 mL of HNO 3 and 1.0 mL H 2 O 2 to digest 100 mg of biological sample. The performance of this design is then evaluated with an ICP-MS instrument in the analysis of the several NIST standard reference material of milk 1849a, rice flour 1568b, spinach leave 1570a and Peach Leaves 1547 in a domestic microwave oven with inverter technology. Outstanding agreement to (SRM) values are observed by using the suggested power to time microwave program, which simulates the reflux action occurring in this closed vessel. Taking into account the high cost of commercial microwave vessels and the volume of chemicals needed for various experiments (8-10 mL), this simple vessel is cost effective and suitable for digesting food and environmental samples.

Extended use of GC-FID and GC-MS in oil spill fingerprinting and matching is significantly important for oil classification from the oil spill sources collected from various areas of Peninsular Malaysia and Sabah (East Malaysia). Oil spill fingerprinting from GC-FID and GC-MS coupled with chemometric techniques (discriminant analysis and principal component analysis) is used as a diagnostic tool to classify the types of oil polluting the water. Clustering and discrimination of oil spill compounds in the water from the actual site of oil spill events are divided into four groups viz. diesel, Heavy Fuel Oil (HFO), Mixture Oil containing Light Fuel Oil (MOLFO) and Waste Oil (WO) according to the similarity of their intrinsic chemical properties. Principal component analysis (PCA) demonstrates that diesel, HFO, MOLFO and WO are types of oil or oil products from complex oil mixtures with a total variance of 85.34% and are identified with various anthropogenic activities related to either intentional releasing of oil or accidental discharge of oil into the environment. Our results show that the use of chemometric techniques is significant in providing independent validation for classifying the types of spilled oil in the investigation of oil spill pollution in Malaysia. This, in consequence would result in cost and time saving in identification of the oil spill sources., (Copyright © 2016. Published by Elsevier Ltd.)

Although major progress has been achieved in research and development of antipsychotic medications for bipolar disorder (BPD), knowledge of the molecular mechanisms underlying this disorder and the action of atypical antipsychotics remains incomplete. The levels of microRNAs (miRNAs)-small non-coding RNA molecules that regulate gene expression, including genes involved in neuronal function and plasticity-are frequently altered in psychiatric disorders. This study aimed to examine changes in miRNA expression in bipolar mania patients after treatment with asenapine and risperidone. Using a miRNA microarray, we analyzed miRNA expression in the blood of 10 bipolar mania patients following 12 weeks of treatment with asenapine or risperidone. Selected miRNAs were validated by using real-time PCR. A total of 16 miRNAs were differentially expressed after treatment in the asenapine group, 14 of which were significantly upregulated and the other two significantly downregulated. However, all three differentially expressed miRNAs in the risperidone group were downregulated. MiRNA target gene prediction and gene ontology analysis revealed significant enrichment for pathways associated with immune system response and regulation of programmed cell death and transcription. Our results suggest that candidate miRNAs may be involved in the mechanism of action of both antipsychotics in bipolar mania. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

This study presents the determination of the spatial variation and source identification of heavy metal pollution in surface water along the Straits of Malacca using several chemometric techniques. Clustering and discrimination of heavy metal compounds in surface water into two groups (northern and southern regions) are observed according to level of concentrations via the application of chemometric techniques. Principal component analysis (PCA) demonstrates that Cu and Cr dominate the source apportionment in northern region with a total variance of 57.62% and is identified with mining and shipping activities. These are the major contamination contributors in the Straits. Land-based pollution originating from vehicular emission with a total variance of 59.43% is attributed to the high level of Pb concentration in the southern region. The results revealed that one state representing each cluster (northern and southern regions) is significant as the main location for investigating heavy metal concentration in the Straits of Malacca which would save monitoring cost and time., Capsule: The monitoring of spatial variation and source of heavy metals pollution at the northern and southern regions of the Straits of Malacca, Malaysia, using chemometric analysis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Phosphatidylethanolamine N-methyltransferase (PEMT) governs the secretion of hepatic triglycerides in the form of very low-density lipoprotein and has been implicated in nonalcoholic fatty liver disease (NAFLD). Studies on the role of the PEMT rs7946 polymorphism as a genetic modifier of NAFLD have reported inconsistent results. This meta-analysis was carried out to evaluate and summarize the association of PEMT rs7946 with susceptibility to NAFLD., Methods: A comprehensive literature search in Scopus, PubMed, Embase, Science Direct and Google Scholar was performed up to 31 August 2015, followed by data extraction and examination of summary estimates., Results: Six independent studies with a total of 792 NAFLD cases and 2722 controls fulfilled the inclusion criteria. Pooled results indicated that the rs7946 A-allele was associated significantly with an increased risk of NAFLD [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.14-2.11, P=0.005]. A significant association was also found in alternative genetic models of inheritance: dominant, recessive and homozygote (OR 1.62, 95% CI 1.10-2.39, P=0.01; OR 1.42, 95% CI 1.12-1.81, P=0.003; and OR 1.64, 95% CI 1.18-2.29, P=0.004, respectively). Subgroup analysis by ethnicity indicated a significant association only in the East-Asians in the additive (OR=2.08, 95% CI 1.12-3.86, P=0.02), recessive (OR=2.94, 95% CI 1.60-5.37, P=0.0005) and homozygote (OR=1.86, 95% CI 1.15-3.01, P=0.01) models., Conclusion: This study provides evidence of a significant association between the PEMT rs7946 A-allele and a risk of NAFLD, with the effect being more prominent in East-Asians, but not in non-Asians.

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

Background: Orexigenic actions mediated by neuropeptide-Y (NPY) promote body weight regulation. Genetic variations in the NPY gene could therefore influence susceptibility to obesity, but results have been conflicting. We have carried out, for the first time, a case-control study to examine the effect of NPY rs16147 and rs5574 variants with the risk of obesity in Asians and also a meta-analysis to summarize the effect of these variants including that of the widely studied rs16139., Materials and Methods: Genotypes and biochemistry data were determined for 942 children (262 cases and 680 controls) recruited from 23 randomly selected schools in Malaysia. Relevant articles were identified from Pubmed, Embase, Web of Science and Google Scholar. Data were extracted and summary estimates of the association between the NPY variants and obesity were examined., Results: The frequency of the rs16147 T allele was significantly higher in the cases than controls (odds ratio 1.27, 95% confidence interval 1.04-1.55, P = 0.022), whereas the rs5574 T allele was significantly higher in the controls (odds ratio 0.76, 95% confidence interval 0.61-0.96, P = 0.020). In addition, NPY rs16147 was significantly correlated with obesity parameters including BMI, waist circumference, triglyceride and body fat percentage (P < 0.05). Meta-analysis including nine case-control studies further confirmed the findings of the association of the two variants with the risk of obesity and also found that rs16139 was associated with increased risk., Conclusion: This study suggests that NPY rs16147 T and rs16139 C minor alleles are associated with increased risk, whereas the minor allele T of the rs5574 is associated with a reduced risk of obesity.

A recent genome-wide copy number (CNV) scan identified a 13q12.11 duplication in the exportin-4 (XPO4) gene to be associated with non-alcoholic steatohepatitis (NASH). We sought to confirm the finding in a larger cohort and to assess the serum XPO4 pattern in a broad spectrum of non-alcoholic fatty liver disease (NAFLD) cases. We analysed 249 NAFLD patients and 232 matched controls using TaqMan assay and serum XPO4 was measured. Copy number distribution was as follows: copy number neutral (NAFLD: 53.8%, controls: 68.6%), copy number losses (NAFLD: 13.3%, controls: 12.9%), copy number gains (NAFLD: 32.9%, controls: 18.5%). CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42-3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47-3.68, P = 0.0003). Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05). Serum XPO4 levels progressively declined (P = 0.043) from controls (24.6 ng/mL) to simple steatosis (20.8 ng/mL) to NASH (13.8 ng/mL). In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development.