Browse publications by year: 2018

  1. Munusamy K, Vadivelu J, Tay ST
    Rev Iberoam Micol, 2018 03 12;35(2):68-72.
    PMID: 29544734 DOI: 10.1016/j.riam.2017.07.001
    BACKGROUND: Biofilm is known to contribute to the antifungal resistance of Candida yeasts. Aureobasidin A (AbA), a cyclic depsipeptide targeting fungal sphingolipid biosynthesis, has been shown to be effective against several Candida species.

    AIMS: The aim of this study was to investigate Candida biofilm growth morphology, its biomass, metabolic activity, and to determine the effects of AbA on the biofilm growth.

    METHODS: The biofilm forming ability of several clinical isolates of different Candida species from our culture collection was determined using established methods (crystal violet and XTT assays). The determination of AbA planktonic and biofilm MICs was performed based on a micro-broth dilution method. The anti-biofilm effect of AbA on Candida albicans was examined using field emission scanning electron microscope (FESEM) analysis.

    RESULTS: A total of 35 (29.7%) of 118 Candida isolates were regarded as biofilm producers in this study. Candida parapsilosis was the largest producer, followed by Candida tropicalis and C. albicans. Two morphological variants of biofilms were identified in our isolates, with 48.6% of the isolates showing mainly yeast and pseudohyphae-like structures, while the remaining ones were predominantly filamentous forms. The biofilm producers were divided into two populations (low and high), based on the ability in producing biomass and their metabolic activity. Candida isolates with filamentous growth, higher biomass and metabolic activity showed lower AbA MIC50 (at least fourfold), compared to those exhibiting yeast morphology, and lower biomass and metabolic activity. The observation of filament detachment and the almost complete removal of biofilm from AbA-treated C. albicans biofilm in FESEM analysis suggests an anti-biofilm effect of AbA.

    CONCLUSIONS: The variability in the growth characteristics of Candida biofilm cultures affects susceptibility to AbA, with higher susceptibility noted in biofilm cultures exhibiting filamentous form and high biomass/metabolic activity.

    MeSH terms: Antifungal Agents/pharmacology*; Candida/drug effects*; Candida/physiology; Candida albicans/drug effects; Candida albicans/physiology; Candida albicans/ultrastructure; Candidiasis, Vulvovaginal/microbiology; Drug Evaluation, Preclinical; Female; Humans; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Species Specificity; Biofilms/drug effects*; Biofilms/growth & development; Biomass; Drug Resistance, Fungal; Depsipeptides/pharmacology*; Candidemia/microbiology
  2. Alsalem MA, Zaidan AA, Zaidan BB, Hashim M, Madhloom HT, Azeez ND, et al.
    Comput Methods Programs Biomed, 2018 May;158:93-112.
    PMID: 29544792 DOI: 10.1016/j.cmpb.2018.02.005
    CONTEXT: Acute leukaemia diagnosis is a field requiring automated solutions, tools and methods and the ability to facilitate early detection and even prediction. Many studies have focused on the automatic detection and classification of acute leukaemia and their subtypes to promote enable highly accurate diagnosis.

    OBJECTIVE: This study aimed to review and analyse literature related to the detection and classification of acute leukaemia. The factors that were considered to improve understanding on the field's various contextual aspects in published studies and characteristics were motivation, open challenges that confronted researchers and recommendations presented to researchers to enhance this vital research area.

    METHODS: We systematically searched all articles about the classification and detection of acute leukaemia, as well as their evaluation and benchmarking, in three main databases: ScienceDirect, Web of Science and IEEE Xplore from 2007 to 2017. These indices were considered to be sufficiently extensive to encompass our field of literature.

    RESULTS: Based on our inclusion and exclusion criteria, 89 articles were selected. Most studies (58/89) focused on the methods or algorithms of acute leukaemia classification, a number of papers (22/89) covered the developed systems for the detection or diagnosis of acute leukaemia and few papers (5/89) presented evaluation and comparative studies. The smallest portion (4/89) of articles comprised reviews and surveys.

    DISCUSSION: Acute leukaemia diagnosis, which is a field requiring automated solutions, tools and methods, entails the ability to facilitate early detection or even prediction. Many studies have been performed on the automatic detection and classification of acute leukaemia and their subtypes to promote accurate diagnosis.

    CONCLUSIONS: Research areas on medical-image classification vary, but they are all equally vital. We expect this systematic review to help emphasise current research opportunities and thus extend and create additional research fields.

    MeSH terms: Acute Disease; Algorithms; Automation; Humans; Leukemia/classification*; Leukemia/diagnosis*; Motivation*; Reproducibility of Results; Early Detection of Cancer; Datasets as Topic
  3. Engku Nur Syafirah EAR, Nurul Najian AB, Foo PC, Mohd Ali MR, Mohamed M, Yean CY
    Acta Trop, 2018 Jun;182:223-231.
    PMID: 29545156 DOI: 10.1016/j.actatropica.2018.03.004
    Cholera, caused by Vibrio cholerae is a foodborne disease that frequently reported in food and water related outbreak. Rapid diagnosis of cholera infection is important to avoid potential spread of disease. Among available diagnostic platforms, loop-mediated isothermal amplification (LAMP) is regarded as a potential diagnostic tool due to its rapidity, high sensitivity and specificity and independent of sophisticated thermalcycler. However, the current LAMP often requires multiple pipetting steps, hence is susceptible to cross contamination. Besides, the strict requirement of cold-chain during transportation and storage make its application in low resource settings to be inconvenient. To overcome these problems, the present study is aimed to develop an ambient-temperature-stable and ready-to-use LAMP assay for the detection of toxigenic Vibrio cholerae in low resource settings. A set of specific LAMP primers were designed and tested against 155 V. cholerae and non-V. cholerae strains. Analytical specifity showed that the developed LAMP assay detected 100% of pathogenic V. cholerae and did not amplified other tested bacterial strains. Upon testing against stool samples spiked with toxigenic V. cholerae outbreak isolates, the LAMP assay detected all of the spiked samples (n = 76/76, 100%), in contrast to the conventional PCR which amplified 77.6% (n = 59/76) of the tested specimens. In term of sensitivity, the LAMP assay was 100-fold more sensitive as compared to the conventional PCR method, with LOD of 10 fg per μL and 10 CFU per mL. Following lyophilisation with addition of lyoprotectants, the dry-reagent LAMP mix has an estimated shelf-life of 90.75 days at room temperature.
    MeSH terms: Cholera/diagnosis*; Cholera/epidemiology; Cytotoxicity Tests, Immunologic/methods*; Disease Outbreaks; Humans; Sensitivity and Specificity; Temperature*; Vibrio cholerae/isolation & purification*; Polymerase Chain Reaction/methods; Nucleic Acid Amplification Techniques/methods*
  4. Low GK, Ogston SA, Yong MH, Gan SC, Chee HY
    Acta Trop, 2018 Jun;182:237-245.
    PMID: 29545158 DOI: 10.1016/j.actatropica.2018.03.014
    BACKGROUND: Since the introduction of 2009 WHO dengue case classification, no literature was found regarding its effect on dengue death. This study was to evaluate the effect of 2009 WHO dengue case classification towards dengue case fatality rate.

    METHODS: Various databases were used to search relevant articles since 1995. Studies included were cohort and cross-sectional studies, all patients with dengue infection and must report the number of death or case fatality rate. The Joanna Briggs Institute appraisal checklist was used to evaluate the risk of bias of the full-texts. The studies were grouped according to the classification adopted: WHO 1997 and WHO 2009. Meta-regression was employed using a logistic transformation (log-odds) of the case fatality rate. The result of the meta-regression was the adjusted case fatality rate and odds ratio on the explanatory variables.

    RESULTS: A total of 77 studies were included in the meta-regression analysis. The case fatality rate for all studies combined was 1.14% with 95% confidence interval (CI) of 0.82-1.58%. The combined (unadjusted) case fatality rate for 69 studies which adopted WHO 1997 dengue case classification was 1.09% with 95% CI of 0.77-1.55%; and for eight studies with WHO 2009 was 1.62% with 95% CI of 0.64-4.02%. The unadjusted and adjusted odds ratio of case fatality using WHO 2009 dengue case classification was 1.49 (95% CI: 0.52, 4.24) and 0.83 (95% CI: 0.26, 2.63) respectively, compared to WHO 1997 dengue case classification. There was an apparent increase in trend of case fatality rate from the year 1992-2016. Neither was statistically significant.

    CONCLUSIONS: The WHO 2009 dengue case classification might have no effect towards the case fatality rate although the adjusted results indicated a lower case fatality rate. Future studies are required for an update in the meta-regression analysis to confirm the findings.

    MeSH terms: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cross-Sectional Studies; Dengue/classification*; Dengue/mortality*; Female; Humans; Male; Middle Aged; Regression Analysis; Global Health/standards; Global Health/statistics & numerical data*; World Health Organization; Odds Ratio; Databases, Factual; International Classification of Diseases; Young Adult
  5. Ahmad MK, Abdollah NA, Shafie NH, Yusof NM, Razak SRA
    Cancer Biol Med, 2018 Feb;15(1):14-28.
    PMID: 29545965 DOI: 10.20892/j.issn.2095-3941.2017.0107
    Mitogen-activated protein kinases (MAPKs) are the main regulators of cellular proliferation, growth, and survival in physiological or pathological conditions. Aberrant MAPK signaling plays a pivotal role in carcinogenesis, which leads to development and progression of human cancer. Dual-specificity phosphatase 6 (DUSP6), a member of the MAPK phosphatase family, interacts with specifically targeted extracellular signal-regulated kinase 1/2 via negative feedback regulation in the MAPK pathway of mammalian cells. This phosphatase functions in a dual manner, pro-oncogenic or tumor-suppressive, depending on the type of cancer. To date, the tumor-suppressive role of DUSP6 has been demonstrated in pancreatic cancer, non-small cell lung cancer, esophageal squamous cell and nasopharyngeal carcinoma, and ovarian cancer. Its pro-oncogenic role has been observed in human glioblastoma, thyroid carcinoma, breast cancer, and acute myeloid carcinoma. Both roles of DUSP6 have been documented in malignant melanoma depending on the histological subtype of the cancer. Loss- or gain-of-function effects of DUSP6 in these cancers highlights the significance of this phosphatase in carcinogenesis. Development of methods that use the DUSP6 gene as a therapeutic target for cancer treatment or as a prognostic factor for diagnosis and evaluation of cancer treatment outcome has great potential. This review focuses on molecular characteristics of the DUSP6 gene and its role in cancers in the purview of development, progression, and cancer treatment outcome.
  6. Sanchez Bornot JM, Wong-Lin K, Ahmad AL, Prasad G
    Brain Topogr, 2018 11;31(6):895-916.
    PMID: 29546509 DOI: 10.1007/s10548-018-0640-0
    The brain's functional connectivity (FC) estimated at sensor level from electromagnetic (EEG/MEG) signals can provide quick and useful information towards understanding cognition and brain disorders. Volume conduction (VC) is a fundamental issue in FC analysis due to the effects of instantaneous correlations. FC methods based on the imaginary part of the coherence (iCOH) of any two signals are readily robust to VC effects, but neglecting the real part of the coherence leads to negligible FC when the processes are truly connected but with zero or π-phase (modulus 2π) interaction. We ameliorate this issue by proposing a novel method that implements an envelope of the imaginary coherence (EIC) to approximate the coherence estimate of supposedly active underlying sources. We compare EIC with state-of-the-art FC measures that included lagged coherence, iCOH, phase lag index (PLI) and weighted PLI (wPLI), using bivariate autoregressive and stochastic neural mass models. Additionally, we create realistic simulations where three and five regions were mapped on a template cortical surface and synthetic MEG signals were obtained after computing the electromagnetic leadfield. With this simulation and comparison study, we also demonstrate the feasibility of sensor FC analysis using receiver operating curve analysis whilst varying the signal's noise level. However, these results should be interpreted with caution given the known limitations of the sensor-based FC approach. Overall, we found that EIC and iCOH demonstrate superior results with most accurate FC maps. As they complement each other in different scenarios, that will be important to study normal and diseased brain activity.
    MeSH terms: Brain/physiology*; Brain Mapping/methods; Electroencephalography/methods*; Humans; Models, Neurological; Neural Pathways/physiology; Magnetoencephalography/methods*
  7. Praveena SM, Teh SW, Rajendran RK, Kannan N, Lin CC, Abdullah R, et al.
    Environ Sci Pollut Res Int, 2018 Apr;25(12):11333-11342.
    PMID: 29546515 DOI: 10.1007/s11356-018-1652-8
    Phthalates have been blended in various compositions as plasticizers worldwide for a variety of purposes. Consequently, humans are exposed to a wide spectrum of phthalates that needs to be researched and understood correctly. The goal of this review is to focus on phthalate's internal exposure pathways and possible role of human digestion on liver toxicity. In addition, special focus was made on stem cell therapy in reverting liver toxicity. The known entry of higher molecular weight phthalates is through ingestion while inhalation and dermal pathways are for lower molecular weight phthalates. In human body, certain phthalates are digested through phase 1 (hydrolysis, oxidation) and phase 2 (conjugation) metabolic processes. The phthalates that are made bioavailable through digestion enter the blood stream and reach the liver for further detoxification, and these are excreted via urine and/or feces. Bis(2-ethylhexyl) phthalate (DEHP) is a compound well studied involving human metabolism. Liver plays a pivotal role in humans for detoxification of pollutants. Thus, continuous exposure to phthalates in humans may lead to inhibition of liver detoxifying enzymes and may result in liver dysfunction. The potential of stem cell therapy addressed herewith will revert liver dysfunction and lead to restoration of liver function properly.
    MeSH terms: Diethylhexyl Phthalate; Environmental Exposure/analysis; Humans; Hydrolysis; Liver/drug effects*; Liver/metabolism; Phthalic Acids/toxicity*; Plasticizers/metabolism
  8. Jusoh N, Zainal H, Abdul Hamid AA, Bunnori NM, Abd Halim KB, Abd Hamid S
    J Mol Model, 2018 Mar 15;24(4):93.
    PMID: 29546582 DOI: 10.1007/s00894-018-3619-6
    Recent outbreaks of highly pathogenic influenza strains have highlighted the need to develop new anti-influenza drugs. Here, we report an in silico study of carvone derivatives to analyze their binding modes with neuraminidase (NA) active sites. Two proposed carvone analogues, CV(A) and CV(B), with 36 designed ligands were predicted to inhibit NA (PDB ID: 3TI6) using molecular docking. The design is based on structural resemblance with the commercial inhibitor, oseltamivir (OTV), ligand polarity, and amino acid residues in the NA active sites. Docking simulations revealed that ligand A18 has the lowest energy binding (∆Gbind) value of -8.30 kcal mol-1, comparable to OTV with ∆Gbind of -8.72 kcal mol-1. A18 formed seven hydrogen bonds (H-bonds) at residues Arg292, Arg371, Asp151, Trp178, Glu227, and Tyr406, while eight H-bonds were formed by OTV with amino acids Arg118, Arg292, Arg371, Glu119, Asp151, and Arg152. Molecular dynamics (MD) simulation was conducted to compare the stability between ligand A18 and OTV with NA. Our simulation study showed that the A18-NA complex is as stable as the OTV-NA complex during the MD simulation of 50 ns through the analysis of RMSD, RMSF, total energy, hydrogen bonding, and MM/PBSA free energy calculations.
    MeSH terms: Binding Sites; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/chemistry*; Hydrogen Bonding; Ligands; Models, Molecular*; Molecular Conformation; Neuraminidase/antagonists & inhibitors; Neuraminidase/chemistry*; Protein Binding; Structure-Activity Relationship; Thermodynamics; Monoterpenes/pharmacology; Monoterpenes/chemistry*; Molecular Dynamics Simulation; Molecular Docking Simulation
  9. Chia KY, Ng KY, Koh RY, Chye SM
    CNS Neurol Disord Drug Targets, 2018;17(9):671-679.
    PMID: 29546836 DOI: 10.2174/1871527317666180315161626
    BACKGROUND & OBJECTIVE: Protein misfolding and aggregation have been considered the common pathological hallmarks for a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). These abnormal proteins aggregates damage mitochondria and induce oxidative stress, resulting in neuronal cell death. Prolonged neuronal damage activates microglia and astrocytes, development of inflammation reaction and further promotes neurodegeneration. Thus, elimination of abnormal protein aggregates without eliciting any adverse effects are the main treatment strategies. To overcome this, recent studies have deployed single- chain fragment variable antibodies (scFvs) to target the pathological protein aggregates, such as amyloid-beta (Aβ) peptides, α-synuclein (α-syn) and Huntingtin (Htt). To date scFv has been effective at inhibiting abnormal protein aggregates formation in both in vitro and in vivo model system of AD, PD and HD.

    CONCLUSION: Currently active research is still ongoing to improve the scFv gene delivery technology, to further enhance brain penetration, intracellular stability, solubility and efficacy of scFv intrabody.

    MeSH terms: Animals; Humans; Neurodegenerative Diseases/drug therapy*; alpha-Synuclein/immunology; Single-Chain Antibodies/therapeutic use*; Amyloidogenic Proteins/immunology; Huntingtin Protein/immunology
  10. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Mar 02;120(9):092301.
    PMID: 29547300 DOI: 10.1103/PhysRevLett.120.092301
    The azimuthal anisotropy Fourier coefficients (v_{n}) in 8.16 TeV p+Pb data are extracted via long-range two-particle correlations as a function of the event multiplicity and compared to corresponding results in pp and PbPb collisions. Using a four-particle cumulant technique, v_{n} correlations are measured for the first time in pp and p+Pb collisions. The v_{2} and v_{4} coefficients are found to be positively correlated in all collision systems. For high-multiplicity p+Pb collisions, an anticorrelation of v_{2} and v_{3} is observed, with a similar correlation strength as in PbPb data at the same multiplicity. The new correlation results strengthen the case for a common origin of the collectivity seen in p+Pb and PbPb collisions in the measured multiplicity range.
    MeSH terms: Data Collection; Lead; Anisotropy
  11. Abdul Aziz SA, Mcstea M, Ahmad Bashah NS, Chong ML, Ponnampalavanar S, Syed Omar SF, et al.
    AIDS, 2018 05 15;32(8):1025-1034.
    PMID: 29547442 DOI: 10.1097/QAD.0000000000001798
    OBJECTIVES: In a clinic-based, treated HIV-infected cohort, we identified individuals with sarcopenia and compared with age, sex and ethnically matched controls; and investigated associated risk factors and health outcomes.

    DESIGN: Sarcopenia (age-related muscle loss) causes significant morbidity to the elderly, leading to frequent hospitalizations, disability and death. Few have characterized sarcopenia in the HIV-infected who experience accelerated aging.

    METHODS: Sarcopenia was defined as low muscle mass with weak grip strength and/or slow gait speed using lower 20th percentiles of controls. Multivariate logistic and linear regression analyses were used to explore risk factors and health-related outcomes associated with sarcopenia among HIV-infected individuals.

    RESULTS: We recruited 315 HIV-infected individuals aged at least 25 years with at least 1-year history of undetectable viral load on treatment (HIV RNA <50 copies/ml). Percentage of sarcopenia in 315 HIV-infected was 8%. Subsequently, 153 of the 315 were paired with age, sex and ethnically matched HIV-uninfected. The percentage of sarcopenia in the HIV-infected (n = 153) compared with uninfected (n = 153) were 10 vs. 6% (P = 0.193) respectively, whereas of those at least 50 years of age among them were 17% vs. 4% (P = 0.049), respectively. Associated risk factors among the HIV-infected include education level, employment status, BMI, baseline CD4 cell count, duration on NRTIs and GGT levels. Identified negative outcomes include mortality risk scores [5.42; 95% CI 1.46-9.37; P = 0.007) and functional disability (3.95; 95% CI 1.57-9.97; P = 0.004).

    CONCLUSION: Sarcopenia is more prevalent in HIV-infected at least 50 years old compared with matched controls. Our findings highlight associations between sarcopenia with loss of independence and greater healthcare burden among treated HIV-infected individuals necessitating early recognition and intervention.

    MeSH terms: Adult; Age Factors; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Risk Factors; HIV Infections/complications*; HIV Infections/drug therapy*; Prevalence; Anti-HIV Agents/therapeutic use*; Asian Continental Ancestry Group; Muscle Strength; Sarcopenia/epidemiology*; Sarcopenia/pathology*; Sarcopenia/physiopathology; Walking Speed
  12. Smith JR, Ghazoul J, Burslem DFRP, Itoh A, Khoo E, Lee SL, et al.
    PLoS One, 2018;13(3):e0193501.
    PMID: 29547644 DOI: 10.1371/journal.pone.0193501
    Documenting the scale and intensity of fine-scale spatial genetic structure (FSGS), and the processes that shape it, is relevant to the sustainable management of genetic resources in timber tree species, particularly where logging or fragmentation might disrupt gene flow. In this study we assessed patterns of FSGS in three species of Dipterocarpaceae (Parashorea tomentella, Shorea leprosula and Shorea parvifolia) across four different tropical rain forests in Malaysia using nuclear microsatellite markers. Topographic heterogeneity varied across the sites. We hypothesised that forests with high topographic heterogeneity would display increased FSGS among the adult populations driven by habitat associations. This hypothesis was not supported for S. leprosula and S. parvifolia which displayed little variation in the intensity and scale of FSGS between sites despite substantial variation in topographic heterogeneity. Conversely, the intensity of FSGS for P. tomentella was greater at a more topographically heterogeneous than a homogeneous site, and a significant difference in the overall pattern of FSGS was detected between sites for this species. These results suggest that local patterns of FSGS may in some species be shaped by habitat heterogeneity in addition to limited gene flow by pollen and seed dispersal. Site factors can therefore contribute to the development of FSGS. Confirming consistency in species' FSGS amongst sites is an important step in managing timber tree genetic diversity as it provides confidence that species specific management recommendations based on species reproductive traits can be applied across a species' range. Forest managers should take into account the interaction between reproductive traits and site characteristics, its consequences for maintaining forest genetic resources and how this might influence natural regeneration across species if management is to be sustainable.
    MeSH terms: Altitude; Inbreeding; Reproduction; Trees/genetics*; Trees/physiology; Tropical Climate*; Genetic Variation; Microsatellite Repeats/genetics; Gene Flow; Rainforest
  13. Ahmed MA, Fauzi M, Han ET
    Malar J, 2018 Mar 14;17(1):115.
    PMID: 29540177 DOI: 10.1186/s12936-018-2256-y
    BACKGROUND: Human infections due to the monkey malaria parasite Plasmodium knowlesi is on the rise in most Southeast Asian countries specifically Malaysia. The C-terminal 19 kDa domain of PvMSP1P is a potential vaccine candidate, however, no study has been conducted in the orthologous gene of P. knowlesi. This study investigates level of polymorphisms, haplotypes and natural selection of full-length pkmsp1p in clinical samples from Malaysia.

    METHODS: A total of 36 full-length pkmsp1p sequences along with the reference H-strain and 40 C-terminal pkmsp1p sequences from clinical isolates of Malaysia were downloaded from published genomes. Genetic diversity, polymorphism, haplotype and natural selection were determined using DnaSP 5.10 and MEGA 5.0 software. Genealogical relationships were determined using haplotype network tree in NETWORK software v5.0. Population genetic differentiation index (F ST ) and population structure of parasite was determined using Arlequin v3.5 and STRUCTURE v2.3.4 software.

    RESULTS: Comparison of 36 full-length pkmsp1p sequences along with the H-strain identified 339 SNPs (175 non-synonymous and 164 synonymous substitutions). The nucleotide diversity across the full-length gene was low compared to its ortholog pvmsp1p. The nucleotide diversity was higher toward the N-terminal domains (pkmsp1p-83 and 30) compared to the C-terminal domains (pkmsp1p-38, 33 and 19). Phylogenetic analysis of full-length genes identified 2 distinct clusters of P. knowlesi from Malaysian Borneo. The 40 pkmsp1p-19 sequences showed low polymorphisms with 16 polymorphisms leading to 18 haplotypes. In total there were 10 synonymous and 6 non-synonymous substitutions and 12 cysteine residues were intact within the two EGF domains. Evidence of strong purifying selection was observed within the full-length sequences as well in all the domains. Shared haplotypes of 40 pkmsp1p-19 were identified within Malaysian Borneo haplotypes.

    CONCLUSIONS: This study is the first to report on the genetic diversity and natural selection of pkmsp1p. A low level of genetic diversity and strong evidence of negative selection was detected and observed in all the domains of pkmsp1p of P. knowlesi indicating functional constrains. Shared haplotypes were identified within pkmsp1p-19 highlighting further evaluation using larger number of clinical samples from Malaysia.

    MeSH terms: Amino Acid Sequence; Base Sequence; Haplotypes; Malaysia; Phylogeny; Selection, Genetic*; Genetic Variation*; Plasmodium knowlesi/genetics*; Merozoite Surface Protein 1/genetics*
  14. Phoon HYP, Hussin H, Hussain BM, Lim SY, Woon JJ, Er YX, et al.
    J Glob Antimicrob Resist, 2018 09;14:132-140.
    PMID: 29540306 DOI: 10.1016/j.jgar.2018.02.022
    OBJECTIVES: Hospital environments are potential reservoirs of bacteria associated with nosocomial infections. In this study, the distribution of cultivable environmental bacteria of clinical importance from a Malaysian tertiary hospital was determined and their resistotypes and genotypes were investigated.

    METHODS: Swab and fluid samples (n=358) from healthcare workers' hands, frequently touched surfaces, medical equipment, patients' immediate surroundings, ward sinks and toilets, and solutions or fluids of 12 selected wards were collected. Biochemical tests, PCR and 16S rRNA sequencing were used for identification following isolation from CHROMagar™ Orientation medium. Clinically important bacteria such as Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter spp., Pseudomonas aeruginosa and Enterobacter spp. were further characterised by disc diffusion method and rep-PCR.

    RESULTS: The 24 Gram-negative and 19 Gram-positive bacteria species identified were widely distributed in the hospital environment. Staphylococci were predominant, followed by Bacillus spp. and P. aeruginosa. Frequently touched surfaces, medical equipment, and ward sinks and toilets were the top three sources of bacterial species. Nine S. aureus, four Acinetobacter spp., one K. pneumoniae and one Enterobacter spp. were multidrug-resistant (MDR). The ESKAPE organisms were genetically diverse and widely dispersed across the hospital wards. A MDR MRSA clone was detected in a surgical ward isolation room.

    CONCLUSION: The large variety of cultivable, clinically important bacteria, especially the genetically related MDR S. aureus, K. pneumoniae, Acinetobacter spp. and Enterobacter spp., from various sampling sites indicated that the surfaces and fomites in the hospital were potential exogenous sources of nosocomial infection in the hospital.

    MeSH terms: Acinetobacter; Bacillus; Cross Infection; Enterobacter; Genotype; Health Personnel; Humans; Klebsiella pneumoniae; Pseudomonas aeruginosa; RNA, Ribosomal, 16S; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Polymerase Chain Reaction; Enterococcus; Fomites; Methicillin-Resistant Staphylococcus aureus; Tertiary Care Centers
  15. Rayagiri SS, Ranaldi D, Raven A, Mohamad Azhar NIF, Lefebvre O, Zammit PS, et al.
    Nat Commun, 2018 03 14;9(1):1075.
    PMID: 29540680 DOI: 10.1038/s41467-018-03425-3
    A central question in stem cell biology is the relationship between stem cells and their niche. Although previous reports have uncovered how signaling molecules released by niche cells support stem cell function, the role of the extra-cellular matrix (ECM) within the niche is unclear. Here, we show that upon activation, skeletal muscle stem cells (satellite cells) induce local remodeling of the ECM and the deposition of laminin-α1 and laminin-α5 into the basal lamina of the satellite cell niche. Genetic ablation of laminin-α1, disruption of integrin-α6 signaling or blocking matrix metalloproteinase activity impairs satellite cell expansion and self-renewal. Collectively, our findings establish that remodeling of the ECM is an integral process of stem cell activity to support propagation and self-renewal, and may explain the effect laminin-α1-containing supports have on embryonic and adult stem cells, as well as the regenerative activity of exogenous laminin-111 therapy.
    MeSH terms: Cell Self Renewal/physiology*; Animals; Basement Membrane/cytology; Basement Membrane/metabolism; Cell Differentiation/physiology; Extracellular Matrix/metabolism; Humans; Mice, Inbred C57BL; Signal Transduction; Muscle, Skeletal/cytology; Muscle, Skeletal/metabolism; Muscle Fibers, Skeletal/cytology; Muscle Fibers, Skeletal/metabolism; Satellite Cells, Skeletal Muscle/cytology*; Satellite Cells, Skeletal Muscle/metabolism; Stem Cell Niche/physiology*
  16. Stebbing J, Shah K, Lit LC, Gagliano T, Ditsiou A, Wang T, et al.
    Oncogene, 2018 06;37(23):3113-3130.
    PMID: 29540829 DOI: 10.1038/s41388-018-0197-0
    Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.
    MeSH terms: Animals; Antineoplastic Agents/pharmacology; Breast Neoplasms/drug therapy*; Breast Neoplasms/pathology; Doxorubicin/pharmacology; Female; Histones/metabolism; Humans; Membrane Proteins/genetics; Membrane Proteins/metabolism*; Mice, Nude; Tumor Cells, Cultured; Gene Expression Regulation, Neoplastic/drug effects*; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism*; Drug Resistance, Neoplasm/drug effects; Drug Resistance, Neoplasm/physiology*; Xenograft Model Antitumor Assays; DNA Breaks, Double-Stranded/drug effects; Ataxia Telangiectasia Mutated Proteins/metabolism
  17. Jamaludin SYN, Azimi I, Davis FM, Peters AA, Gonda TJ, Thompson EW, et al.
    Oncol Lett, 2018 Apr;15(4):4289-4295.
    PMID: 29541196 DOI: 10.3892/ol.2018.7827
    CXC ligand (L)12 is a chemokine implicated in the migration, invasion and metastasis of cancer cells via interaction with its receptors CXC chemokine receptor (CXCR)4 and CXCR7. In the present study, CXCL12-mediated Ca2+signalling was compared with two basal-like breast cancer cell lines, MDA-MB-231 and MDA-MB-468, which demonstrate distinct metastatic potential. CXCL12 treatment induced Ca2+responses in the more metastatic MDA-MB-231 cells but not in the less metastatic MDA-MB-468 cells. Assessment of mRNA levels of CXCL12 receptors and their potential modulators in both cell lines revealed that CXCR4 and CXCR7 levels were increased in MDA-MB-231 cells compared with MDA-MB-468 cells. Cluster of differentiation (CD)24, the negative regulator of CXCL12 responses, demonstrated increased expression in MDA-MB-468 cells compared with MDA-MB-231 cells, and the two cell lines expressed comparable levels of hypoxia-inducible factor (HIF)2α, a CXCR4 regulator. Induction of epithelial-mesenchymal transition (EMT) by epidermal growth factor exhibited opposite effects on CXCR4 mRNA levels compared with hypoxia-induced EMT. Neither EMT inducer exhibited an effect on CXCR7 expression, however hypoxia increased HIF2α expression levels in MDA-MB-468 cells. Analysis of the gene expression profiles of breast tumours revealed that the highest expression levels of CXCR4 and CXCR7 were in the Claudin-Low molecular subtype, which is markedly associated with EMT features.
    MeSH terms: Cell Differentiation; Cell Line; Epidermal Growth Factor; RNA, Messenger; Receptors, CXCR4; Chemokine CXCL12; Claudins; Epithelial-Mesenchymal Transition; Transcriptome
  18. Gan RY, Kong KW, Li HB, Wu K, Ge YY, Chan CL, et al.
    Front Chem, 2018;6:39.
    PMID: 29541634 DOI: 10.3389/fchem.2018.00039
    The red sword bean (Canavalia gladiata) is an underutilized edible bean cultivated in China. It was previously found to have the highest content of antioxidant polyphenols among 42 edible beans, mainly gallic acid, and gallotannins in its red bean coat, an apparently unique characteristic among edible beans. In this study, the main phenolic compounds in red sword bean coats were further separated by Sephadex LH-20 column chromatography, and identified by LC-MS/MS. Furthermore, the FRAP and ABTS antioxidant activities and antibacterial activity (diameter of inhibition zone, DIZ) of main gallotannin-rich fractions were tested. Our results showed that gallotannins of red sword bean coats were mainly comprised of monogalloyl to hexagalloyl hexosides. Interestingly, tetragalloyl, pentagalloyl, and hexagalloyl hexosides were identified as the possible candidates responsible for the red color of the coats. On the other hand, gallotannin-rich fractions exhibited diverse antioxidant and antibacterial activities, and tetragalloyl hexoside overall had the highest free radical scavenging and antibacterial activities. The degree of galloylation did not completely explain the structure-function relationship of gallotannins isolated from red sword bean coats, as there should exist other factors affecting their bioactivities. In conclusion, red sword bean coats are excellent natural sources of gallotannins, and their gallotannin-rich extracts can be utilized as natural antioxidant and antibacterial agents with potential health benefits as well as application in food industry.
    MeSH terms: Anti-Bacterial Agents; Antioxidants; Chromatography, Liquid; Gallic Acid; Fabaceae; Phenols; Plant Extracts; Tannins; Food Industry; Canavalia; Hydrolyzable Tannins; Tandem Mass Spectrometry; Polyphenols
  19. Kumar J, Das S, Teoh SL
    Front Nutr, 2018;5:14.
    PMID: 29541638 DOI: 10.3389/fnut.2018.00014
    Acrylamide (AA) is a water soluble white crystalline solid commonly used in industries. It was listed as an industrial chemical with potential carcinogenic properties. However to date, AA was used to produce polyacrylamide polymer, which was widely used as a coagulant in water treatment; additives during papermaking; grouting material for dams, tunnels, and other underground building constructions. AA in food could be formed during high-temperature cookingviaseveral mechanisms, i.e., formationviaacrylic acid which may be derived from the degradation of lipid, carbohydrates, or free amino acids; formationviathe dehydration/decarboxylation of organic acids (malic acid, lactic acid, and citric acid); and direct formation from amino acids. The big debate is whether this compound is toxic to human beings or not. In the present review, we discuss the formation of AA in food products, its consumption, and possible link to the development of any cancers. We discuss the body enzymatic influence on AA and mechanism of action of AA on hormone, calcium signaling pathways, and cytoskeletal filaments. We also highlight the deleterious effects of AA on nervous system, reproductive system, immune system, and the liver. The present and future mitigation strategies are also discussed. The present review on AA may be beneficial for researchers, food industry, and also medical personnel.
  20. Ab Rahman NS, Abd Majid FA, Abd Wahid ME, Zainudin AN, Zainol SN, Ismail HF, et al.
    Drug Metab Lett, 2018;12(1):62-67.
    PMID: 29542427 DOI: 10.2174/1872312812666180314112457
    BACKGROUND: SynacinnTM contains five standardized herbal extracts of Orthosiphon Stamineus (OS), Syzygium polyanthum (SZ), Curcuma xantorrizza (CX), Cinnamomum zeylanicum (CZ) and Andrographis paniculata (AP) and is standardized against phytochemical markers of rosmarinic acid, gallic acid, curcumin, catechin and andrographolide respectively. This herbal medicine has been used as health supplement for diabetes. SynacinnTM is recommended to be consumed as supplement to the diabetic drugs. However, herb-drug interaction of SynacinnTM polyherbal with present drugs is unknown.

    METHODS: This study was designed to investigate the effect of SynacinnTM and its individual biomarkers on drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam), CYP3A4 (Testosteron)), to assess its herb-drug interaction potential through cytochrome P450 inhibition assay. This study was conducted using liquid chromatography- tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron).

    RESULTS: Result showed that SynacinnTM at maximum concentration (5000 µg/ml) 100% inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron). IC50 values determined were 0.23, 0.60, 0.47, 0.78, 1.23, 0.99, 1.01, and 0.91 mg/ml for CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 (midazolam) and 3A4 (testosterone), respectively. Meanwhile, all individual biomarkers showed no, less or moderate inhibitory effect towards all the tested CYP450 except for curcumin that showed inhibition of CYP2C8 (91%), CYP2C9 (81%) and CYP2C19 (72%) at 10µM.

    CONCLUSION: Curcumin was found to be an active constituent that might contribute to the inhibition of SynacinnTM against CYP2C8, CYP2C9 and CYP2C19. It can be suggested that SynacinnTM can be consumed separately from a drug known to be metabolized by all tested CYP450 enzymes.

    MeSH terms: Cytochrome P-450 Enzyme System/metabolism*; Diabetes Mellitus/drug therapy; Humans; Microsomes, Liver; Midazolam/metabolism; Midazolam/pharmacology; Plant Extracts/pharmacology*; Plant Extracts/therapeutic use; Plants, Medicinal/chemistry*; Testosterone/metabolism; Testosterone/pharmacology; Biomarkers/metabolism; Herb-Drug Interactions*; Enzyme Assays; Cytochrome P-450 Enzyme Inhibitors/pharmacology*; Cytochrome P-450 Enzyme Inhibitors/therapeutic use
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