Publications by authors named "Abdul Waheed Khan"

33 Publications

Combating COVID-19 pandemic with technology: Perceptions of Mental Health Professionals towards Telepsychiatry.

Asian J Psychiatr 2021 07 10;61:102677. Epub 2021 May 10.

Hamad Medical Corporation, Department of Psychiatry, Doha, Qatar; Qatar University, College of Medicine, Doha, Qatar.

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http://dx.doi.org/10.1016/j.ajp.2021.102677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108472PMC
July 2021

Cell-specific epigenetic changes in atherosclerosis.

Clin Sci (Lond) 2021 May;135(9):1165-1187

Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.

Atherosclerosis is a disease of large and medium arteries that can lead to life-threatening cerebrovascular and cardiovascular consequences such as heart failure and stroke and is a major contributor to cardiovascular-related mortality worldwide. Atherosclerosis development is a complex process that involves specific structural, functional and transcriptional changes in different vascular cell populations at different stages of the disease. The application of single-cell RNA sequencing (scRNA-seq) analysis has discovered not only disease-related cell-specific transcriptomic profiles but also novel subpopulations of cells once thought as homogenous cell populations. Vascular cells undergo specific transcriptional changes during the entire course of the disease. Epigenetics is the instruction-set-architecture in living cells that defines and maintains the cellular identity by regulating the cellular transcriptome. Although different cells contain the same genetic material, they have different epigenomic signatures. The epigenome is plastic, dynamic and highly responsive to environmental stimuli. Modifications to the epigenome are driven by an array of epigenetic enzymes generally referred to as writers, erasers and readers that define cellular fate and destiny. The reversibility of these modifications raises hope for finding novel therapeutic targets for modifiable pathological conditions including atherosclerosis where the involvement of epigenetics is increasingly appreciated. This article provides a critical review of the up-to-date research in the field of epigenetics mainly focusing on in vivo settings in the context of the cellular role of individual vascular cell types in the development of atherosclerosis.
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http://dx.doi.org/10.1042/CS20201066DOI Listing
May 2021

Multiconstraint-Aware Routing Mechanism for Wireless Body Sensor Networks.

J Healthc Eng 2021 31;2021:5560809. Epub 2021 Mar 31.

Computer School, Hubei University of Arts and Science, Xiangyang 441000, China.

The merger of wireless sensor technologies, pervasive computing, and biomedical engineering has resulted in the emergence of wireless body sensor network (WBSN). WBSNs assist human beings in various monitoring applications such as health-care, entertainment, rehabilitation systems, and sports. Life-critical health-care applications of WBSNs consider both reliability and delay as major Quality of Service (QoS) parameters. In addition to the common limitations and challenges of wireless sensor networks (WSNs), WBSNs pose distinct constraints due to the behavior and chemistry of the human body. The biomedical sensor nodes (BMSNs) adopt multihop communication while reporting the heterogeneous natured physiological parameters to the nearby base station also called local coordinator. Routing in WBSNs becomes a challenging job due to the necessary QoS considerations, overheated in-body BMSNs, and high and dynamic path loss. To the best of our knowledge, none of the existing routing protocols integrate the aforementioned issues in their designs. In this research work, a multiconstraint-aware routing mechanism (modular-based) is proposed which considers the QoS parameters, dynamic and high path loss, and the overheated nodes issue. Two types of network frameworks, with and without relay/forwarder nodes, are being used. The data packets containing physiological parameters of the human body are categorized into delay-constrained, reliability-constrained, critical (both delay- and reliability-constrained), and nonconstrained data packets. NS-2 is being used to carry out the simulations of the proposed mechanism. The simulation results reveal that the proposed mechanism has improved the QoS-aware routing for WBSNs by adopting the proposed multiconstraint-aware strategy.
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http://dx.doi.org/10.1155/2021/5560809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032516PMC
March 2021

Nuclear functions of microRNAs relevant to the cardiovascular system.

Transl Res 2021 Apr 10;230:151-163. Epub 2020 Nov 10.

Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia. Electronic address:

A fraction of the transcriptome is translated into proteins. The rest is classified as non-protein coding RNA (Ribonucleic Acid) but has gained increased attention as functional and regulatory group of transcripts. The gene regulatory role of non-coding RNAs (ncRNAs) has now been widely accepted in diverse biological processes in both physiology and disease. MicroRNAs fall into this latter group and are widely known for their diverse post-transcriptional regulatory role. MicroRNA sequences are embedded in the long ncRNAs, known as primary microRNAs, are processed into precursor microRNAs and are typically transported out of the nucleus for maturation and loading into a protein complex forming RNA-induced silencing complex (RISC) that either drives the degradation of messenger RNA (mRNA) or blocks its translation. A new phenomenon is emerging where microRNAs have active roles within the nucleus. The presence of RISC components including microRNAs in the nucleus supports this notion. They may integrate with chromatin modifiers, microprocessing machinery and mRNA stabilizing transcripts to play a multifunctional role in the nucleus. Although a limited number of studies appreciate this novel activity of microRNAs relevant to the cardiovascular system, they provide proof-of-concept that requires consideration while targeting miRNAs with therapeutic potential.
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http://dx.doi.org/10.1016/j.trsl.2020.11.004DOI Listing
April 2021

1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach.

Brain Sci 2020 Oct 13;10(10). Epub 2020 Oct 13.

Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

The production and up-regulation of inflammatory mediators are contributing factors for the development and maintenance of neuropathic pain. In the present study, the post-treatment of synthetic 1,3,4 oxadiazole derivative (B3) for its neuroprotective potential in chronic constriction injury-induced neuropathic pain was applied. In-silico studies were carried out through Auto Dock, PyRx, and DSV to obtain the possible binding and interactions of the ligands (B3) with COX-2, IL-6, and iNOS. The sciatic nerve of the anesthetized rat was constricted with sutures 3/0. Treatment with 1,3,4-oxadiazole derivative was started a day after surgery and continued until the 14th day. All behavioral studies were executed on day 0, 3rd, 7th, 10th, and 14th. The sciatic nerve and spinal cord were collected for further molecular analysis. The interactions in the form of hydrogen bonding stabilizes the ligand target complex. B3 showed three hydrogen bonds with IL-6. B3, in addition to correcting paw posture/deformation induced by CCI, attenuates hyperalgesia ( 0.001) and allodynia ( 0.001). B3 significantly raised the level of GST and GSH in both the sciatic nerve and spinal cord and reduced the LPO and iNOS ( 0.001). B3 attenuates the pathological changes induced by nerve injury, which was confirmed by H&E staining and IHC examination. B3 down-regulates the over-expression of the inflammatory mediator IL-6 and hence provides neuroprotective effects in CCI-induced pain. The results demonstrate that B3 possess anti-nociceptive and anti-hyperalgesic effects and thus minimizes pain perception and inflammation. The possible underlying mechanism for the neuroprotective effect of B3 probably may be mediated through IL-6.
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http://dx.doi.org/10.3390/brainsci10100731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601954PMC
October 2020

Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD.

Circ Res 2020 10 20;127(10):1261-1273. Epub 2020 Aug 20.

Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.).

Rationale: Hyperglycemia -induced reactive oxygen species are key mediators of cardiac dysfunction. JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated.

Objective: The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species-driven myocardial dysfunction.

Methods And Results: JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 2) and NOX4 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-κB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α MHC (α- myosin heavy chain) promoter (α MHC ) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects.

Conclusions: Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317132DOI Listing
October 2020

DNA methylation patterns from peripheral blood separate coronary artery disease patients with and without heart failure.

ESC Heart Fail 2020 10 2;7(5):2468-2478. Epub 2020 Jul 2.

Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.

Aims: Natriuretic peptides are useful for diagnosis and prognostication of heart failure of any cause. Now, research aims to discover novel biomarkers that will more specifically define the heart failure phenotype. DNA methylation plays a critical role in the development of cardiovascular disease with the potential to predict fundamental pathogenic processes. There is a lack of data relating DNA methylation in heart failure that specifically focuses on patients with severe multi-vessel coronary artery disease. To begin to address this, we conducted a pilot study uniquely exploring the utility of powerful whole-genome methyl-binding domain-capture sequencing in a cohort of cardiac surgery patients, matched for the severity of their coronary artery disease, aiming to identify candidate peripheral blood DNA methylation markers of ischaemic cardiomyopathy and heart failure.

Methods And Results: We recruited a cohort of 20 male patients presenting for coronary artery bypass graft surgery with phenotypic extremes of heart failure but who otherwise share a similar coronary ischaemic burden, age, sex, and ethnicity. Methylation profiling in patient blood samples was performed using methyl-binding domain-capture sequencing. Differentially methylated regions were validated using targeted bisulfite sequencing. Gene set enrichment analysis was performed to identify differences in methylation at or near gene promoters in certain known Reactome pathways. We detected 567 188 methylation peaks of which our general linear model identified 68 significantly differentially methylated regions in heart failure with a false discovery rate <0.05. Of these regions, 48 occurred within gene bodies and 25 were located near enhancer elements, some within coding genes and some in non-coding genes. Gene set enrichment analyses identified 103 significantly enriched gene sets (false discovery rate <0.05) in heart failure. Validation analysis of regions with the strongest differential methylation data was performed for two genes: HDAC9 and the uncharacterized miRNA gene MIR3675. Genes of particular interest as novel candidate markers of the heart failure phenotype with reduced methylation were HDAC9, JARID2, and GREM1 and with increased methylation PDSS2.

Conclusions: We demonstrate the utility of methyl-binding domain-capture sequencing to evaluate peripheral blood DNA methylation markers in a cohort of cardiac surgical patients with severe multi-vessel coronary artery disease and phenotypic extremes of heart failure. The differential methylation status of specific coding genes identified are candidates for larger longitudinal studies. We have further demonstrated the value and feasibility of examining DNA methylation during the perioperative period to highlight biological pathways and processes contributing to complex phenotypes.
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http://dx.doi.org/10.1002/ehf2.12810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524212PMC
October 2020

Chromosome Missegregation in Single Human Oocytes Is Related to the Age and Gene Expression Profile.

Int J Mol Sci 2020 Mar 12;21(6). Epub 2020 Mar 12.

Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), 56124 Pisa, Italy.

The growing trend for women to postpone childbearing has resulted in a dramatic increase in the incidence of aneuploid pregnancies. Despite the importance to human reproductive health, the events precipitating female age-related meiotic errors are poorly understood. To gain new insight into the molecular basis of age-related chromosome missegregation in human oocytes, we combined the transcriptome profiles of twenty single oocytes (derived from females divided into two groups according to age <35 and ≥35 years) with their chromosome status obtained by array comparative genomic hybridization (aCGH). Furthermore, we compared the transcription profile of the single oocyte with the surrounding cumulus cells (CCs). RNA-seq data showed differences in gene expression between young and old oocytes. Dysregulated genes play a role in important biological processes such as gene transcription regulation, cytoskeleton organization, pathways related to RNA maturation and translation. The comparison of the transcription profile of the oocyte and the corresponding CCs highlighted the differential expression of genes belonging to the G protein-coupled receptor superfamily. Finally, we detected the loss of a X chromosome in two oocytes derived from women belonging to the ≥35 years age group. These aneuploidies may be caused by the detriment of REEP4, an endoplasmic reticulum protein, in women aged ≥35 years. Here we gained new insight into the complex regulatory circuit between the oocyte and the surrounding CCs and uncovered a new putative molecular basis of age-related chromosome missegregation in human oocytes.
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http://dx.doi.org/10.3390/ijms21061934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139522PMC
March 2020

Targeting Treatment Refractory by EZH2 Inhibition in Postural Tachycardia Syndrome.

Circ Res 2020 04 3;126(8):1058-1060. Epub 2020 Mar 3.

From the Epigenetics in Human Health and Disease Laboratory (H.K., A.W.K., J.O., A.E.-O.), Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.315654DOI Listing
April 2020

Challenges towards quality assurance of Basic Medical Education in Pakistan.

Pak J Med Sci 2020 Jan-Feb;36(2):4-9

Prof. Raheela Yasmeen, BDS, DCPS-HPE, JMHPE, MHPE. Department of Medical Education, Riphah International University, Islamabad, Pakistan.

Objective: There are growing concerns towards the quality of medical education in Pakistan. To help strengthen accreditation processes, this study identifies the challenges towards quality assurance of Basic Medical Education in Pakistan.

Methods: A qualitative case study was carried out from March to August 2018. Participants included inspectors from various disciplines in both public and private medical colleges, and medical educationists from Pakistan. Semi-structured interviews were conducted with 12 inspectors, while focus group discussion included 10 medical educationists. All the interviews were audio recorded and transcribed verbatim. Thematic analysis was conducted to capture the intricacies of meaning within the data.

Results: Data identified 14 sub-themes grouped under three major themes. Challenges towards quality assurance included mounting political influence, commercialism in medical education, weak regulatory capacity of accrediting body, violation of rules, lack of valid accreditation standards and skilled inspectors.

Conclusion: Quality assurance of Basic Medical Education in Pakistan involves various systemic, resource and personnel related challenges. The accrediting body needs to bring major reforms in its accreditation system and strengthen its regulatory and technical educational capacity to ensure the quality of medical education in nearly 168 medical and dental colleges of the country.
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http://dx.doi.org/10.12669/pjms.36.2.1319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994875PMC
February 2020

Microarray expression studies on bone marrow of patients with Shwachman-Diamond syndrome in relation to deletion of the long arm of chromosome 20, other chromosome anomalies or normal karyotype.

Mol Cytogenet 2020 2;13. Epub 2020 Jan 2.

1Genetica Umana e Medica, Dipartimento di Medicina e Chirurgia, Università dell'Insubria, Via J. H. Dunant, 5, 21100 Varese, Italy.

Background: Clonal chromosome changes are often found in the bone marrow (BM) of patients with Shwachman-Diamond syndrome (SDS). The most frequent ones include an isochromosome of the long arm of chromosome 7, i (7)(q10), and an interstitial deletion of the long arm of chromosome 20, del (20)(q). These two imbalances are mechanisms of somatic genetic rescue. The literature offers few expression studies on SDS.

Results: We report the expression analysis of bone marrow (BM) cells of patients with SDS in relation to normal karyotype or to the presence of clonal chromosome anomalies: del (20)(q) (five cases), i (7)(q10) (one case), and other anomalies (two cases). The study was performed using the microarray technique considering the whole transcriptome (WT) and three gene subsets selected as relevant in BM functions. The expression patterns of nine healthy controls and SDS patients with or without chromosome anomalies in the bone marrow showed clear differences.

Conclusions: There is a significant difference between gene expression in the BM of SDS patients and healthy subjects, both at the WT level and in the selected gene sets. The deletion del (20)(q), with the gene consistently lost, even in patients with the smallest losses of material, changes the transcription pattern: a low proportion of abnormal cells led to a pattern similar to SDS patients without acquired anomalies, whereas a high proportion yields a pattern similar to healthy subjects. Hence, the benign prognostic value of del (20)(q). The case of i (7)(q10) showed a transcription pattern similar to healthy subjects, paralleling the positive prognostic role of this anomaly as well.
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http://dx.doi.org/10.1186/s13039-019-0466-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941278PMC
January 2020

High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized controlled trial (EXAMIN AGE).

Eur Heart J 2020 04;41(15):1514-1519

Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Birsstrasse 320 B, 4052 Basel, Switzerland.

Aims: Impairments of retinal vessel diameter are associated with major adverse cardiovascular (CV) events. Promoter DNA methylation is a repressor of the mitochondrial adaptor p66Shc gene transcription, a key driver of ageing-induced reactive oxygen species. The study aimed to investigate whether high-intensity interval training (HIIT) affects retinal microvascular phenotype as well as p66Shc expression and oxidative stress in ageing subjects with increased CV risk from the EXAMIN AGE cohort.

Methods And Results: Eighty-four sedentary subjects (mean age 59.4 ± 7.0 years) with ≥2 CV risk factors were randomized into either a 12-week HIIT or standard physical activity recommendations. Retinal arteriolar and venular diameters were measured by use of a retinal vessel analyser. As a marker of oxidative stress plasma 3-nitrotyrosine (3-NT) level was determined by ELISA. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by RT-qPCR and methylated-DNA capture (MethylMiner Enrichment Kit) coupled with qPCR, respectively. High-intensity interval training reduced body mass index, fat mass, low-density lipoprotein and increased muscle mass, as well as maximal oxygen uptake (VO2max). Moreover, HIIT restored microvascular phenotype by inducing retinal arteriolar widening (pre: 175 ± 14 µm vs. post: 181 ± 13 µm, P = 0.001) and venular narrowing (pre: 222 ± 14 µm vs. post: 220 ± 14 µm, P = 0.007). After HIIT, restoration of p66Shc promoter methylation (P = 0.034) reduced p66Shc gene expression (P = 0.037) and, in turn, blunted 3-NT plasma levels (P = 0.002).

Conclusion: High-intensity interval training rescues microvascular dysfunction in ageing subjects at increased CV risk. Exercise-induced reprogramming of DNA methylation of p66Shc gene may represent a putative mechanistic link whereby exercise protects against age-related oxidative stress.

Clinical Trial Registration: ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ct2/show/NCT02796976).
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http://dx.doi.org/10.1093/eurheartj/ehz196DOI Listing
April 2020

Sex-Based Mhrt Methylation Chromatinizes MeCP2 in the Heart.

iScience 2019 Jul 27;17:288-301. Epub 2019 Jun 27.

Epigenetics in Human Health and Disease, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC 3004, Australia; Baker Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR; University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark. Electronic address:

In the heart, primary microRNA-208b (pri-miR-208b) and Myheart (Mhrt) are long non-coding RNAs (lncRNAs) encoded by the cardiac myosin heavy chain genes. Although preclinical studies have shown that lncRNAs regulate gene expression and are protective for pathological hypertrophy, the mechanism underlying sex-based differences remains poorly understood. In this study, we examined DNA- and RNA-methylation-dependent regulation of pri-miR-208b and Mhrt. Expression of pri-miR-208b is elevated in the left ventricle of the female heart. Despite indistinguishable DNA methylation between sexes, the interaction of MeCP2 on chromatin is subject to RNase digestion, highlighting that affinity of the methyl-CG reader is broader than previously thought. A specialized procedure to isolate RNA from soluble cardiac chromatin emphasizes sex-based affinity of an MeCP2 co-repressor complex with Rest and Hdac2. Sex-specific Mhrt methylation chromatinizes MeCP2 at the pri-miR-208b promoter and extends the functional relevance of default transcriptional suppression in the heart.
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http://dx.doi.org/10.1016/j.isci.2019.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639684PMC
July 2019

An Updated List of Neuromedicinal Plants of Pakistan, Their Uses, and Phytochemistry.

Evid Based Complement Alternat Med 2019 3;2019:6191505. Epub 2019 Mar 3.

Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.

Background: Almost every region of Pakistan is stacked with a large number of medicinal plants. Due to high cost and unavailability of allopathic medicines for the neurological diseases, especially in rural areas, traditional healers prescribe phytotherapy for various neurological diseases like epilepsy, depression, anxiety, insomnia, Alzheimer, and migraine. Such treatments are considered to be most effective by the native people.

Methods: The data was collected from articles published on medicinal plants of various districts of Pakistan, using article search engines like Medline, Pubmed, Web of Science, Science Direct, and Google Scholar. Also, information regarding various neurological uses and mode of applications of medicinal plants was obtained from traditional healers, folk medicine users, and local elderly people having knowledge of medicinal plants.

Results: A total of 54 families were found to be used in various neurological diseases, of which the highest use was of Solanaceae (22.22%), Asteraceae (12.96%), Lamiaceae, Papaveraceae, and Poaceae, 9% each, and Caprifoliaceae, Cucurbitaceae, Rhamnaceae, and Rosaceae, 5.5% each. According to districts, 15% of plants that were effective in neurological affections were found in Bahawalpur, 11% in Swat, 8% in Muzaffarabad, 7% in Malakand, and 6% in Bahawalnagar, Dir, Gilgat, and Sarghoda each, with 5% in Dera ghazi khan and Jhelum each. According to the plant's habit, out of total of 103 plants, 61.15% were found to be herbs, 22.33% trees, 11.65% shrubs, and 4.85% climbers. According to the part used of plant, whole plant, leaves, fruits, roots, seeds, and flowers were found to be used 32.03%, 24.27%, 20.38%, 16.50%, 13.59%, and 11.65%, respectively. According to disease's types, 45.63% were found to be effective in insomnia, 31.06% in epilepsy 12.62% in depression, 6.80% in anxiety, 7.77% in hysteria, and 5.88% in migraine.

Conclusion: Taking into consideration this useful knowledge on medicinal properties of the plants for curing neurologic diseases, it is believed that research in areas of ethnomedicine and ethnopharmacology can bring auspicious results that have potential of adding value to the very rich natural resources of Pakistan. This study will help all the researchers from diverse backgrounds working on plants based medicine for neurological diseases.
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http://dx.doi.org/10.1155/2019/6191505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420976PMC
March 2019

MeCP2 interacts with chromosomal microRNAs in brain.

Epigenetics 2017 ;12(12):1028-1037

a Central Clinical School, Faculty of Medicine , Monash University , Victoria , Australia.

Although methyl CpG binding domain protein-2 (MeCP2) is commonly understood to function as a silencing factor at methylated DNA sequences, recent studies also show that MeCP2 can bind unmethylated sequences and coordinate gene activation. MeCP2 displays broad binding patterns throughout the genome, with high expression levels similar to histone H1 in neurons. Despite its significant presence in the brain, only subtle gene expression changes occur in the absence of MeCP2. This may reflect a more complex regulatory mechanism of MeCP2 to complement chromatin binding. Using an RNA immunoprecipitation of native chromatin technique, we identify MeCP2 interacting microRNAs in mouse primary cortical neurons. In addition, comparison with mRNA sequencing data from Mecp2-null mice suggests that differentially expressed genes may indeed be targeted by MeCP2-interacting microRNAs. These findings highlight the MeCP2 interaction with microRNAs that may modulate its binding with chromatin and regulate gene expression.
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http://dx.doi.org/10.1080/15592294.2017.1391429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810764PMC
December 2018

Pattern of hepatitis C virus genotypes and subtypes circulating in war-stricken Khyber Pakhtunkhwa, Pakistan: Review of published literature.

Asian Pac J Trop Med 2017 Nov 7;10(11):1037-1042. Epub 2017 Nov 7.

Institute of Biotechnology and Genetic Engineering, The University of Agriculture, Peshawar, Pakistan.

Infection due to hepatitis C virus (HCV) is a major cause of fibrosis and hepatocellular carcinoma in Pakistan. In the current review, pattern of HCV genotypes and subtypes in Khyber Pakhtunkhwa province was ascertained in light of the available literature. After thorough analysis, genotype 3 (58.27%) was determined to be the leading HCV genotype, followed by genotypes 2 (12.39%), 1 (9.54%) and 4 (0.86%). The proportions of genotypes 5 and 6 were recorded as 0.09% and 0.22% respectively. Subtype wise, 3a accounted for 48.67%, followed by subtype 2a (10.91%), 3b (9.43%), 1a (5.84%), 1b (3.66%), 2b (1.45%) and genotype 4 with its undefined subtypes contributed a portion of 0.86%. The cumulative share of subtypes 1c, 2c, 3c, 5a and 6a was less than 1%. In 11.51% cases, the subtype was untypeable while in 7.17% cases mixed subtypes were recorded. Gender wise, proportions of most HCV subtypes were marginally higher among males as compared to females. On the basis of studied groups, 3a was pervasive among all groups except in intravenous drug users where 2a was the major HCV subtype. Similarly, based on various geographical locations (provincial divisions), subtype 3a revealed a ubiquitous distribution. Conclusively, HCV 3a persists to be the principal subtype across the province of Khyber Pakhtunkhwa. The considerable number of untypeable subtypes in most studies urges for an improved genotyping system on the basis of local sequence data and practice of sequencing for determination of underlying subtype in untypeable cases. Further, studies on identification of subtypes transmission pattern are imperative for assessment of transmission origin and reinforcement of efficient control strategies. In addition, the current review emphasizes the need of attention toward HCV risk groups and ignored southern side of Khyber Pakhtunkhwa province for better holistic understanding of HCV genotype distribution pattern in the province.
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http://dx.doi.org/10.1016/j.apjtm.2017.10.002DOI Listing
November 2017

Resurgence of yellow fever in Brazil: Overview and possible control options.

Acta Microbiol Immunol Hung 2017 Sep 11;64(3):353-356. Epub 2017 Sep 11.

5 Department of Zoology, Islamia College Peshawar , Peshawar, Pakistan.

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http://dx.doi.org/10.1556/030.64.2017.034DOI Listing
September 2017

Major shift in national health policy towards poliomyelitis in Pakistan reaps rewards.

Infect Dis Health 2017 Sep 10;22(3):153-155. Epub 2017 Jul 10.

School of Health, Medical & Applied Sciences, Central Queensland University, Brisbane, QLD, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.idh.2017.06.001DOI Listing
September 2017

silencing by in postural tachycardia syndrome.

JCI Insight 2017 03 23;2(6):e90183. Epub 2017 Mar 23.

Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.

While strongly implicated in postural tachycardia syndrome (POTS), considerable controversy exists regarding norepinephrine transporter () loss of function. POTS is characterized by the clinical symptoms of orthostatic intolerance, lightheadedness, tachycardia, and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence that the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with massive parallel sequencing (RICh-seq) we show that miRNA suppresses by methyl-CpG-binding protein 2 (MeCP2). Vorinostat restores epigenetic control and expression in leukocytes derived from POTS participants.
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http://dx.doi.org/10.1172/jci.insight.90183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358482PMC
March 2017

Anticonvulsant, Anxiolytic, and Sedative Activities of .

Front Pharmacol 2016 21;7:499. Epub 2016 Dec 21.

Neurobiology Laboratory, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology Islamabad, Pakistan.

We describe different neuropharmacological effects of crude extract (Vo.Cr). Pentylenetetrazole (PTZ)-induced seizures, elevated plus maze, light-dark box (LDB), open field and thiopental-induced sleeping test models were employed to evaluate Vo.Cr actions in mice. Vo.Cr dose-dependently (100-500 mg/Kg) delayed onset time of myoclonic jerks and tonic-clonic seizures, while decreased duration of tonic-clonic seizures ( < 0.05, < 0.001 vs. saline group). Vo.Cr at 100 and 300-500 mg/Kg doses reduced animals' mortality in PTZ-induced seizures test to 75 and 0%, respectively. Vo.Cr (50-300 mg/Kg) significantly increased time spent and number of entries into open arms, while decreased time spent and number of entries into closed arms ( < 0.05, < 0.01, < 0.001 vs. saline group), measured in elevated plus maze. Vo.Cr (50-300 mg/Kg) increased time spent in light compartment, while decreased time spent in dark compartment ( < 0.01, < 0.001 vs. saline group) in LDB, like caused by diazepam. In open field test, Vo.Cr decreased number of ambulations and rearings frequencies, while increased the number of central squares crossings. In thiopental-induced sleeping test, Vo.Cr (50-300 mg/Kg) decreased onset time of sleep, while increased the duration of sleep ( < 0.05, < 0.01, < 0.001 vs. saline group). These results indicate that possess anticonvulsant, anxiolytic and sedative activities, which provides scientific background for its medicinal application in various neurological ailments, such as epilepsy, anxiety, and insomnia.
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http://dx.doi.org/10.3389/fphar.2016.00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5174135PMC
December 2016

Untypeable hepatitis C virus subtypes in Pakistan: A neglected section.

Acta Microbiol Immunol Hung 2016 Dec;63(4):427-431

1 Institute of Biotechnology and Genetic Engineering, The University of Agriculture , Peshawar, Pakistan.

Diagnostically untypeable subtypes contribute a considerable percent of hepatitis C virus (HCV) subtypes in Pakistan. In the present study, chronically infected HCV patients with known viremia were subjected to HCV genotyping. Among the total retrieved samples, 92.7% (64/69) were found typeable while 7.24% (5/69) were diagnostically untypeable. In conclusion, the presence of large number of untypeable HCV subtypes emphasizes the need of an updated type-specific genotyping assay and consideration of primers for proportionally rare subtypes to minimize the number of untypeable HCV subtypes.
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http://dx.doi.org/10.1556/030.63.2016.025DOI Listing
December 2016

Pakistan as a major obstacle in global end to poliomyelitis program: background and 2016 update.

Braz J Infect Dis 2016 Sep-Oct;20(5):518-20. Epub 2016 Aug 12.

University of Swat, Center for Biotechnology and Microbiology, Odigram, Pakistan.

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http://dx.doi.org/10.1016/j.bjid.2016.07.009DOI Listing
April 2017

Epigenomic changes associated with impaired norepinephrine transporter function in postural tachycardia syndrome.

Neurosci Biobehav Rev 2017 Mar 23;74(Pt B):342-355. Epub 2016 Jun 23.

Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia; Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia. Electronic address:

The postural tachycardia syndrome (POTS) is characterised clinically by symptoms of light-headedness, palpitations, fatigue and exercise intolerance occurring with standing and relieved by lying down. Symptoms occur in association with an inappropriate rise in heart rate in the absence of a fall in blood pressure with the assumption of standing. The pathophysiology of POTS is complicated and poorly understood. Plasma norepinephrine (NE) is often elevated in patients with POTS, resulting in consideration of dysfunction of the norepinephrine transporter (NET) encoded by SLC6A2 gene. Whilst some studies have implicated a defect in the SLC6A2 gene, the cause of reduced SLC6A2 expression and function remains unclear. The search to explain the molecular mechanism of NET dysfunction has focused on genetic variation in the SLC6A2 gene and remains inconclusive. More recent studies show epigenetic mechanisms implicated in the regulation of SLC6A2 expression. In this article, we discuss the epigenetic mechanisms involved in SLC6A2 repression and highlight the potential therapeutic application of targeting these mechanisms in POTS.
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http://dx.doi.org/10.1016/j.neubiorev.2016.06.015DOI Listing
March 2017

Improving understanding of chromatin regulatory proteins and potential implications for drug discovery.

Expert Rev Proteomics 2016 17;13(4):435-45. Epub 2016 Mar 17.

a Epigenetics in Human Health and Disease Laboratory , Baker IDI Heart and Diabetes Institute , Melbourne , Victoria , Australia.

Many epigenetic-based therapeutics, including drugs such as histone deacetylase inhibitors, are now used in the clinic or are undergoing advanced clinical trials. The study of chromatin-modifying proteins has benefited from the rapid advances in high-throughput sequencing methods, the organized efforts of major consortiums and by individual groups to profile human epigenomes in diverse tissues and cell types. However, while such initiatives have carefully characterized healthy human tissue, disease epigenomes and drug-epigenome interactions remain very poorly understood. Reviewed here is how high-throughput sequencing improves our understanding of chromatin regulator proteins and the potential implications for the study of human disease and drug development and discovery.
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http://dx.doi.org/10.1586/14789450.2016.1159960DOI Listing
December 2016

Fifteen years of sector-wide approach (SWAp) in Bangladesh health sector: an assessment of progress.

Health Policy Plan 2016 Jun 18;31(5):612-23. Epub 2015 Nov 18.

Program Management & Monitoring Unit, Ministry of Health & Family Welfare, Dhaka-1000, Bangladesh.

The Ministry of Health and Family Welfare (MOHFW) of the Government of Bangladesh embarked on a sector-wide approach (SWAp) modality for the health, nutrition and population (HNP) sector in 1998. This programmatic shift initiated a different set of planning disciplines and practices along with institutional changes in the MOHFW. Over the years, the SWAp modality has evolved in Bangladesh as the MOHFW has learnt from its implementation and refined the program design. This article explores the progress made, both in terms of achievement of health outcomes and systems strengthening results, since the implementation of the SWAp for Bangladesh's health sector. Secondary analyses of survey data from 1993 to 2011 as well as a literature review of published and grey literature on health SWAp in Bangladesh was conducted for this assessment. Results of the assessment indicate that the MOHFW made substantial progress in health outcomes and health systems strengthening. SWAps facilitated the alignment of funding and technical support around national priorities, and improved the government's role in program design as well as in implementation and development partner coordination. Notable systemic improvements have taken place in the country systems with regards to monitoring and evaluation, procurement and service provision, which have improved functionality of health facilities to provide essential care. Implementation of the SWAp has, therefore, contributed to an accelerated improvement in key health outcomes in Bangladesh over the last 15 years. The health SWAp in Bangladesh offers an example of a successful adaptation of such an approach in a complex administrative structure. Based on the lessons learned from SWAp implementation in Bangladesh, the MOHFW needs to play a stronger stewardship and regulatory role to reap the full benefits of a SWAp in its subsequent programming.
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http://dx.doi.org/10.1093/heapol/czv108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857486PMC
June 2016

Data-Centric Routing for Intra Wireless Body Sensor Networks.

J Med Syst 2015 Sep 5;39(9):91. Epub 2015 Aug 5.

Faculty of Computing, Universiti Teknologi Malaysia (UTM), 81310, Skudai, Johor, Malaysia,

A significant proportion of the worldwide population is of the elderly people living with chronic diseases that result in high health-care cost. To provide continuous health monitoring with minimal health-care cost, Wireless Body Sensor Networks (WBSNs) has been recently emerged as a promising technology. Depending on nature of sensory data, WBSNs might require a high level of Quality of Service (QoS) both in terms of delay and reliability during data reporting phase. In this paper, we propose a data-centric routing for intra WBSNs that adapts the routing strategy in accordance with the nature of data, temperature rise issue of the implanted bio-medical sensors due to electromagnetic wave absorption, and high and dynamic path loss caused by postural movement of human body and in-body wireless communication. We consider the network models both with and without relay nodes in our simulations. Due to the multi-facet routing strategy, the proposed data-centric routing achieves better performance in terms of delay, reliability, temperature rise, and energy consumption when compared with other state-of-the-art.
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http://dx.doi.org/10.1007/s10916-015-0268-5DOI Listing
September 2015

Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.

J Med Genet 2014 Aug 4;51(8):502-11. Epub 2014 Jul 4.

Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.

Background: Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS; MIM 130650) and the Silver-Russell (SRS; MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor.

Methods: We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively.

Results: We identified a 4.5 kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170 kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motif.

Conclusions: This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.
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http://dx.doi.org/10.1136/jmedgenet-2014-102368DOI Listing
August 2014

Deep sequencing reveals novel Set7 networks.

Cell Mol Life Sci 2014 Nov 30;71(22):4471-86. Epub 2014 May 30.

Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC, 3004, Australia.

Background: Methyl-dependent regulation of transcription has expanded from a traditional focus on histones to encompass transcription factor modulation. While the Set7 lysine methyltransferase is associated with pro-inflammatory gene expression in vascular endothelial cells, genome-wide regulatory roles remain to be investigated. From initial characterization of Set7 as specific for methyl-lysine 4 of H3 histones (H3K4m1), biochemical activity toward non-histone substrates has revealed additional mechanisms of gene regulation.

Results: mRNA-Seq revealed transcriptional deregulation of over 8,000 genes in an endothelial model of Set7 knockdown. Gene ontology identified up-regulated pathways involved in developmental processes and extracellular matrix remodeling, whereas pathways regulating the inflammatory response as well as nitric oxide signaling were down-regulated. Chromatin maps derived from ChIP-Seq profiling of H3K4m1 identified several hundred loci with loss of H3K4m1 at gene regulatory elements associated with an unexpectedly subtle effect on gene expression. Transcription factor network analysis implicated six previously described Set7 substrates in mRNA-Seq changes, and we predict that Set7 post-translationally regulates other transcription factors associated with vascular endothelial gene expression through the presence of Set7 amino acid methylation motifs.

Conclusion: We describe a role for Set7 in regulating developmental pathways and response to stimuli (inflammation/immune response) in human endothelial cells of vascular origin. Set7-dependent gene expression changes that occurred independent of H3K4m1 may involve transcription factor lysine methylation events. The method of mapping measured transcriptional changes to transcription factors to identify putative substrates with strong associations to functional changes is applicable to substrate prediction for other broad-substrate histone modifiers.
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http://dx.doi.org/10.1007/s00018-014-1651-yDOI Listing
November 2014

Vascular histone deacetylation by pharmacological HDAC inhibition.

Genome Res 2014 Aug 14;24(8):1271-84. Epub 2014 Apr 14.

Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; Faculty of Medicine, Monash University, Victoria 3800, Australia

HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ∼30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition.
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http://dx.doi.org/10.1101/gr.168781.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120081PMC
August 2014