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Fulltext New to Galleria mellonella: modeling an ExPEC infection

Nathan S

Virulence, 2014 Apr 1;5(3):371-4.
PMID: 24569500 DOI: 10.4161/viru.28338
Badminton instructional in Malaysian schools: a comparative analysis of TGfU and SDT pedagogical models

Nathan S

Springerplus, 2016;5(1):1215.
PMID: 27516953 DOI: 10.1186/s40064-016-2872-3

Model based physical education curriculum of Teaching Games for Understanding (TGfU) is still at early stage of implementation in Malaysian schools whereby the technical or skill-led model continues to dominate the physical education curriculum. Implementing TGfU seems to be problematic and untested in this environment. Therefore, this study examined, the effects that a revised model of TGfU compared to Skill Drill Technical (SDT) a technical model had on learning movement skills in Badminton, including returning to base, decision making and skill execution whilst performing in a doubles game play and also explored teachers' perceptions of navigating between the two models. Participants aged 15.5 ± 1.0 years, N = 32, school Badminton players were randomly selected and assigned equally into groups of TGfU and SDT. Reflective data was gathered from two experienced physical education teachers who were involved in this study. Findings indicated for movement to the base in doubles game play indicated significant improvement, after intervention via TGfU. As for decision-making and skill execution in doubles game play, analysis revealed no significant difference after intervention. Findings from teachers reflection, indicated the importance of mini game play in both TGfU and SDT models, as the students enjoyed, and built up positive attitudes for both winning or losing in game situations. However, when negotiating the TGfU model, the teacher found it difficult at times to execute the pedagogical model, as students needed guidance to discuss aspects related to tactics. However, to keep this pedagogical model viable further research findings ought to be circulated among teachers in Malaysia and similar Southeast Asian counties.
Fulltext The Effect of Teaching Games of Understanding as a Coaching Instruction had on Adjust, Cover and Heart Rate among Malaysian and Indian Junior Hockey Players

Nathan S

Sports (Basel), 2017 Jun 20;5(2).
PMID: 29910404 DOI: 10.3390/sports5020044

The field hockey coaching process across both Malaysia and India favours a traditional, coach-centred approach of mastering technical skills in terms of game play parameters, fitness, intensity, and load training, whereas a tactical- and player-centred pedagogical approach still takes a backseat. On the other hand, the Teaching Games for Understanding (TGfU) model offers tactical-cognitive instruction and is gaining international recognition for its ability to produce intelligent players via a problem-solving approach in game play. Therefore, the purpose of this quasi-experimental study was to investigate the effect of TGfU compared to skill mastery instruction, termed as Skill Drill Technical (SDT), among Malaysian and Indian elite junior hockey players in term of the game play attributes of adjust and cover in 5 vs. 5 small-sided game play and game play intensity via heart rate (HR) at different points of game play. A total of n = 60 players with an average age of 15 ± 1.03 was selected via simple random sampling from both countries involved in this study and assigned equally to groups, with 15 per group for TGfU and for SDT across Malaysia and India. Gathered data were analysed using the ANOVA and ANCOVA techniques. Findings indicated that there were no significant differences for adjust in 5 vs. 5 game play between TGfU and SDT across Malaysia and India after the intervention. For cover, there was significant improvement for Malaysian players using the TGfU model compared to SDT. In contrast, there was no significant difference between these two models among the Indian players after the intervention. There was significant difference between these two models in terms of warm-up HR across the two countries, and HR was higher via TGfU. For HR immediately after the 5 vs. 5 game play intervention and HR after three minutes' recovery, Indian players with TGfU recorded a higher and significant difference compared to SDT. However, findings indicated no significant difference between these two instruction types among Malaysians, although TGfU proved to have higher HR intensity. Therefore, these findings reiterated that TGfU is a useful approach for game play to enhance intensity and cardiac output. In conclusion, for TGfU to be more relevant to the coaching environment, future research should link game play and physiological parameters. TGfU should able to overcome the barriers of tradition and cultural background that may hinder its momentum.
Prospective full-term-derived pluripotent amniotic fluid stem (AFS) cells

Ferdaos N, Nathan S, Nordin N

Med J Malaysia, 2008 Jul;63 Suppl A:75-6.
PMID: 19024991

Amniotic fluid (AF) serves as an excellent alternative source of pluripotent stem cells, as they are not bound with ethical issues and the stem cells are more primitive than adult stem (AS) cells. Hence, they have higher potential. Here we aim to isolate and characterize pluripotent stem cells from mid-term and full-term pregnant rat amniotic fluid. The results demonstrate the evidence of heterogeneous population of cells in the amniotic fluid and some of the cells morphology shows similarity with ES cells.
Epitope mapping of Burkholderia pseudomallei serine metalloprotease: identification of serine protease epitope mimics

Chan SW, Nathan S

FEMS Immunol. Med. Microbiol., 2005 Jan 1;43(1):37-44.
PMID: 15607634

Filamentous phage random peptide libraries were used to identify the epitopes of Burkholderia pseudomallei protease by panning against IgG polyclonal sera that exhibited protease neutralizing properties. The isolated fusion peptides presented a consensus peptide sequence, TKSMALSG, which closely resembles part of the active site sequence, 435GTSMATPHVAG445, of B. pseudomallei serine metalloprotease. By comparing the consensus sequence, TKSMALSG, with the predicted three-dimensional molecular model of B. pseudomallei serine metalloprotease, it appears that the potential antibody binding epitope was buried within the molecule. This active site was conformational whereby one continuous sub-region (SMA) was located between two discontinuous sub-regions, supplied by the flanking residues in the same polypeptide. All phages selected from the biopanning with IgG polyclonal sera showed good binding towards the polyclonal antibodies when compared to the negative control. In addition, these peptide-bearing phages showed competitive inhibition of B. pseudomallei serine metalloprotease binding to the polyclonal IgG.
Fulltext Curcumin rescues Caenorhabditis elegans from a Burkholderia pseudomallei infection

Eng SA, Nathan S

Front Microbiol, 2015;6:290.
PMID: 25914690 DOI: 10.3389/fmicb.2015.00290

The tropical pathogen Burkholderia pseudomallei requires long-term parenteral antimicrobial treatment to eradicate the pathogen from an infected patient. However, the development of antibiotic resistance is emerging as a threat to this form of treatment. To meet the need for alternative therapeutics, we proposed a screen of natural products for compounds that do not kill the pathogen, but in turn, abrogate bacterial virulence. We suggest that the use of molecules or compounds that are non-bactericidal (bacteriostatic) will reduce or abolish the development of resistance by the pathogen. In this study, we adopted the established Caenorhabditis elegans-B. pseudomallei infection model to screen a collection of natural products for any that are able to extend the survival of B. pseudomallei infected worms. Of the 42 natural products screened, only curcumin significantly improved worm survival following infection whilst not affecting bacterial growth. This suggested that curcumin promoted B. pseudomallei-infected worm survival independent of pathogen killing. To validate that the protective effect of curcumin was directed toward the pathogen, bacteria were treated with curcumin prior to infection. Worms fed with curcumin-treated bacteria survived with a significantly extended mean-time-to-death (p < 0.0001) compared to the untreated control. In in vitro assays, curcumin reduced the activity of known virulence factors (lipase and protease) and biofilm formation. To determine if other bacterial genes were also regulated in the presence of curcumin, a genome-wide transcriptome analysis was performed on curcumin-treated pathogen. A number of genes involved in iron acquisition and transport as well as genes encoding hypothetical proteins were induced in the presence of curcumin. Thus, we propose that curcumin may attenuate B. pseudomallei by modulating the expression of a number of bacterial proteins including lipase and protease as well as biofilm formation whilst concomitantly regulating iron transport and other proteins of unknown function.
Fulltext Protein thaw loss in meat systems: Biochemical influence towards meat authentication of fresh versus thawed

Nathan, S., Chowdhury, M.E.H., Anuar, Z.M.Z., Iekhsan, O., Sharifah, S.H., Ahmed, N.

International Food Research Journal, 2016;23(5):1857-1864.
MyJurnal

Meat quality is always subject to consumer scrutiny when purchasing from retail markets on
mislabeling as fresh meat. Repeated cycles of ‘freeze-thaw’ degrade the quality of meat. Existing
studies have primarily embarked on physical, chemical and biochemical changes induced by
variable storage conditions. The authentication of fresh versus thawed meat quality can be
further explored with the data involving a series of biochemical pathways that were largely
well-studied in living muscle tissues. However, these pathways are less predictable in postslaughter
condition where muscle turns to meat. In addition, there is far less known about how
various management or environmental stimuli impact these pathways, either by substrate load
or altered cellular environment during storage. Though the rate of post-slaughter metabolism
is quite important in driving meat quality development, it is also fairly well established.
Alternatively, the biochemical mechanisms responsible for the cessation of postmortem
metabolism, or protracted carbohydrate metabolism are particularly puzzling. Likewise,
there is little information about the relationship between volatility profiles of biomolecules
with regards to functional groups, enzymatic activity, protein solubility and protein surface
properties in meat during storage. The studies of these changes could be used to distinguish
between fresh and thawed meat.
Transcriptome analysis of Burkholderia pseudomallei T6SS identifies Hcp1 as a potential serodiagnostic marker

Chieng S, Mohamed R, Nathan S

Microb Pathog, 2015 Feb;79:47-56.
PMID: 25616255 DOI: 10.1016/j.micpath.2015.01.006

Burkholderia pseudomallei, the causative agent of melioidosis, is able to survive extreme environments and utilizes various virulence factors for survival and pathogenicity. To compete and survive within these different ecological niches, B. pseudomallei has evolved specialized pathways, including the Type VI secretion systems (T6SSs), that have a role in pathogenesis as well as interbacterial interactions. We examined the expression profile of B. pseudomallei T6SS six gene clusters during infection of U937 macrophage cells. T6SS-5 was robustly transcribed while the other five clusters were not significantly regulated proposing the utility of T6SS-5 as a potential biomarker of exposure to B. pseudomallei. Transcription of T6SS regulators VirAG and BprB was also not significant during infection when compared to bacteria grown in culture. Guided by these findings, three highly expressed T6SS genes, tssJ-4, hcp1 and tssE-5, were expressed as recombinant proteins and screened against melioidosis patient sera by western analysis and ELISA. Only Hcp1 was reactive by both types of analysis. The recombinant Hcp1 protein was further evaluated against a cohort of melioidosis patients (n = 32) and non-melioidosis individuals (n = 20) sera and the data clearly indicates a higher sensitivity (93.7%) and specificity (100%) for Hcp1 compared to bacterial lysate. The detection of anti-Hcp1 antibodies in patients' sera indicating the presence of B. pseudomallei highlights the potential of Hcp1 to be further developed as a serodiagnostic marker for melioidosis.
Fulltext Burkholderia pseudomallei transcriptional adaptation in macrophages

Chieng S, Carreto L, Nathan S

BMC Genomics, 2012;13:328.
PMID: 22823543 DOI: 10.1186/1471-2164-13-328

Burkholderia pseudomallei is a facultative intracellular pathogen of phagocytic and non-phagocytic cells. How the bacterium interacts with host macrophage cells is still not well understood and is critical to appreciate the strategies used by this bacterium to survive and how intracellular survival leads to disease manifestation.
Inhibition of macromolecular synthesis in cultured macrophages by Pseudomonas pseudomallei exotoxin

Mohamed R, Nathan S, Embi N, Razak N, Ismail G

Microbiol. Immunol., 1989;33(10):811-20.
PMID: 2615673

Pseudomonas pseudomallei exotoxin was found to be a potent inhibitor of protein and DNA synthesis in cultured macrophages. Inhibition of DNA synthesis occurred at toxin concentrations as low as 1-2 micrograms/ml and inhibition of 3H-thymidine uptake was almost complete at concentrations of 8 micrograms/ml or more. A close correlation between cell damage and inhibition by DNA synthesis was observed. For protein synthesis, inhibition was obtained at much lower doses (0.06-2.0 micrograms/ml) of the toxin. At similar toxin concentrations, DNA synthesis was marginally affected. Further, it was shown that protein synthesis inhibition occurred almost immediately after incubation, reaching its maximal inhibitory effect of 70% after 6 hr. DNA synthesis, however, was minimally affected by a similar toxin concentration even after 10 hr of incubation. The inhibition of macromolecular synthesis in macrophages by P. pseudomallei exotoxin may be relevant to its modulatory effect on the host defense mechanism.
Fulltext Comparison of serum F2 isoprostane levels in diabetic patients and diabetic patients infected with Burkholderia pseudomallei

Puthucheary SD, Nathan SA

Singapore Med J, 2008 Feb;49(2):117-20.
PMID: 18301838

Oxidative stress can occur in sepsis and infection, when overproduction of free radicals is not countered by the host antioxidant system, leading to impairment of host cellular functions. Various disease states are accompanied by the accumulation of 15-F2t-IsoP in biological fluids. These isoprostanes are considered as markers of oxidative stress, and inflammation and inflammatory mediators.
Fulltext Comparison by electron microscopy of intracellular events and survival of Burkholderia pseudomallei in monocytes from normal subjects and patients with melioidosis

Puthucheary SD, Nathan SA

Singapore Med J, 2006 Aug;47(8):697-703.
PMID: 16865211

Burkholderia pseudomallei (B. pseudomallei) has been shown to persist intracellularly in patients with melioidosis, until reactivated by decreasing immunocompetence. We have previously demonstrated by transmission electron microscopy, the internalisation of B. pseudomallei by human macrophages and the occurrence of phagosome-lysosome fusion.
Fulltext Orthosiphon stamineus protects Caenorhabditis elegans against Staphylococcus aureus infection through immunomodulation

Kong C, Tan MW, Nathan S

Biol Open, 2014;3(7):644-55.
PMID: 24972867 DOI: 10.1242/bio.20148334

Amidst growing concerns over the spread of antibiotic-resistant Staphylococcus aureus strains, the identification of alternative therapeutic molecules has become paramount. Previously, we utilized a Caenorhabditis elegans-S. aureus screening platform to identify potential anti-infective agents from a collection of natural extracts and synthetic compounds. One of the hits obtained from the screen was the aqueous extract of Orthosiphon stamineus leaves (UE-12) that enhanced the survival of infected nematodes without interfering with bacterial growth. In this study, we used a fluorescent transgenic reporter strain and observed that the repressed expression of the lys-7 defense gene in infected nematodes was restored in the presence of UE-12. Analysis of a selected panel of PMK-1 and DAF-16-regulated transcripts and loss-of-function mutants in these pathways indicates that the protective role of UE-12 is mediated via the p38 MAP kinase and insulin-like signaling pathways. Further analysis of a panel of known bioactive compounds of UE-12 proposed eupatorin (C18H16O7) as the possible candidate active molecule contributing to the anti-infective property of UE-12. Taken together, these findings strongly suggest that the O. stamineus leaf extract is a promising anti-infective agent that confers an advantage in survival against S. aureus infection by modulating the immune response of the infected host.
Fulltext Comparative analysis of Mafriwal (Bos taurus × Bos indicus) and Kedah Kelantan (Bos indicus) sperm proteome identifies sperm proteins potentially responsible for higher fertility in a tropical climate

Ashrafzadeh A, Nathan S, Karsani SA

Int J Mol Sci, 2013;14(8):15860-77.
PMID: 23903046 DOI: 10.3390/ijms140815860

The fertility of zebu cattle (Bos indicus) is higher than that of the European purebred (Bos taurus) and crossbred (Bos taurus × Bos indicus) cattle in tropical areas. To identify proteins related to the higher thermo-tolerance and fertility of Zebu cattle, this study was undertaken to identify differences in sperm proteome between the high fertile Malaysian indigenous zebu cattle (Kedah Kelantan) and the sub-fertile crossbred cattle (Mafriwal). Frozen semen from three high performance bulls from each breed were processed to obtain live and pure sperm. Sperm proteins were then extracted, and two-dimensional gel electrophoresis performed to compare proteome profiles. Gel image analysis identified protein spots of interest which were then identified by liquid chromatography mass spectrometry quadrupole time-of-flight (LC MS/MS Q-TOF). STRING network analysis predicted interactions between at least 20 of the identified proteins. Among the identified proteins, a number of motility and energy related proteins were present in greater abundance in Kedah Kelantan. Sperm motility evaluation by Computer Assisted Semen Analysis (CASA) confirmed significantly higher motility in Kedah Kelantan. While results from this study do identify proteins that may be responsible for the higher fertility of Kedah Kelantan, functional characterization of these proteins is warranted to reinforce our understanding of their roles in sperm fertility.
Fulltext Immunogenic recombinant Burkholderia pseudomallei MprA serine protease elicits protective immunity in mice

Chin CY, Tan SC, Nathan S

Front Cell Infect Microbiol, 2012;2:85.
PMID: 22919676 DOI: 10.3389/fcimb.2012.00085

Burkholderia pseudomallei is resistant to a diverse group of antimicrobials including third generation cephalosporins whilst quinolones and aminoglycosides have no reliable effect. As therapeutic options are limited, development of more effective forms of immunotherapy is vital to avoid a fatal outcome. In an earlier study, we reported on the B. pseudomallei serine MprA protease, which is relatively stable over a wide pH and temperature range and digests physiological proteins. The present study was carried out to evaluate the immunogenicity and protective efficacy of the MprA as a potential vaccine candidate. In BALB/c mice immunized with recombinant MprA protease (smBpF4), a significantly high IgG titer was detectable. Isotyping studies revealed that the smBpF4-specific antibodies produced were predominantly IgG(1), proposing that immunization with smBpF4 triggered a Th2 immune response. Mice were immunized with smBpF4 and subsequently challenged with B. pseudomallei via the intraperitoneal route. Whilst control mice succumbed to the infection by day 9, smBpF4-immunized mice were protected against the lethal challenge and survived beyond 25 days post-infection. In conclusion, MprA is immunogenic in melioidosis patients whilst also eliciting a strong immune response upon bacterial challenge in mice and presents itself as a potential vaccine candidate for the treatment of melioidosis.
Fulltext Delayed activation of host innate immune pathways in streptozotocin-induced diabetic hosts leads to more severe disease during infection with Burkholderia pseudomallei

Chin CY, Monack DM, Nathan S

Immunology, 2012 Apr;135(4):312-32.
PMID: 22136109 DOI: 10.1111/j.1365-2567.2011.03544.x

Diabetes mellitus is a predisposing factor of melioidosis, contributing to higher mortality rates in diabetics infected with Burkholderia pseudomallei. To investigate how diabetes alters the inflammatory response, we established a streptozotocin (STZ) -induced diabetic murine acute-phase melioidosis model. Viable B. pseudomallei cells were consistently detected in the blood, liver and spleen during the 42-hr course of infection but the hyperglycaemic environment did not increase the bacterial burden. However, after 24 hr, granulocyte counts increased in response to infection, whereas blood glucose concentrations decreased over the course of infection. A genome-wide expression analysis of the STZ-diabetic murine acute melioidosis liver identified ~1000 genes whose expression was altered in the STZ-diabetic mice. The STZ-diabetic host transcriptional response was compared with the normoglycaemic host transcriptional response recently reported by our group. The microarray data suggest that the presence of elevated glucose levels impairs the host innate immune system by delaying the identification and recognition of B. pseudomallei surface structures. Consequently, the host is unable to activate the appropriate innate immune response over time, which may explain the increased susceptibility to melioidosis in the STZ-diabetic host. Nevertheless, a general 'alarm signal' of infection as well as defence programmes are still triggered by the STZ-diabetic host, although only 24 hr after infection. In summary, this study demonstrates that in the face of a B. pseudomallei acute infection, poor glycaemic control impaired innate responses during the early stages of B. pseudomallei infection, contributing to the increased susceptibility of STZ-induced diabetics to this fatal disease.
Fulltext Genome wide transcriptome profiling of a murine acute melioidosis model reveals new insights into how Burkholderia pseudomallei overcomes host innate immunity

Chin CY, Monack DM, Nathan S

BMC Genomics, 2010;11:672.
PMID: 21110886 DOI: 10.1186/1471-2164-11-672

At present, very little is known about how Burkholderia pseudomallei (B. pseudomallei) interacts with its host to elicit melioidosis symptoms. We established a murine acute-phase melioidosis model and used DNA microarray technology to investigate the global host/pathogen interaction. We compared the transcriptome of infected liver and spleen with uninfected tissues over an infection period of 42 hr to identify genes whose expression is altered in response to an acute infection.
Fulltext Immunogenic Burkholderia pseudomallei outer membrane proteins as potential candidate vaccine targets

Hara Y, Mohamed R, Nathan S

PLoS One, 2009 Aug 05;4(8):e6496.
PMID: 19654871 DOI: 10.1371/journal.pone.0006496

BACKGROUND: Burkholderia pseudomallei is the causative agent of melioidosis, a disease of significant morbidity and mortality in both human and animals in endemic areas. There is no vaccine towards the bacterium available in the market, and the efficacy of many of the bacterium's surface and secreted proteins are currently being evaluated as vaccine candidates.
METHODOLOGY/PRINCIPAL FINDINGS: With the availability of the B. pseudomallei whole genome sequence, we undertook to identify genes encoding the known immunogenic outer membrane protein A (OmpA). Twelve OmpA domains were identified and ORFs containing these domains were fully annotated. Of the 12 ORFs, two of these OmpAs, Omp3 and Omp7, were successfully cloned, expressed as soluble protein and purified. Both proteins were recognised by antibodies in melioidosis patients' sera by Western blot analysis. Purified soluble fractions of Omp3 and Omp7 were assessed for their ability to protect BALB/c mice against B. pseudomallei infection. Mice were immunised with either Omp3 or Omp7, subsequently challenged with 1x10(6) colony forming units (cfu) of B. pseudomallei via the intraperitoneal route, and examined daily for 21 days post-challenge. This pilot study has demonstrated that whilst all control unimmunised mice died by day 9 post-challenge, two mice (out of 4) from both immunised groups survived beyond 21 days post-infection.
CONCLUSIONS/SIGNIFICANCE: We have demonstrated that B. pseudomallei OmpA proteins are immunogenic in mice as well as melioidosis patients and should be further assessed as potential vaccine candidates against B. pseudomallei infection.
Inducible transgene expression in undifferentiated mouse embryonic stem cells and embryoid bodies

Nordin N, Nathan S, Li M, Mason JO

Med J Malaysia, 2008 Jul;63 Suppl A:59-60.
PMID: 19024983

Obtaining pure population of neural cells from embryonic stem (ES) cells remains a challenge as little is known about the genes that govern embryonic stem cell differentiation. Using mouse ES cells, we aim to uncover the mechanisms that regulate neural differentiation of ES cells by focusing on roles played by Wnt family genes. Combining two techniques, Cre/loxP-based genetic recombination and ligand-dependent activation of Cre, we have generated transgenic ES cell lines that allow for the temporal control of expression and activity of Wnt gene (Wnt1-Ha) and Wnt antagonist (Dkk1). The ability of these cell lines in inducing the expression of transgene in undifferentiated ES cells and, more importantly, in differentiated derivatives of ES cells in vitro is evaluated.
Phage displayed Bacillus thuringiensis Cry1Ba4 toxin is toxic to Plutella xylostella

Nathan S, Aziz DH, Mahadi NM

Curr Microbiol, 2006 Nov;53(5):412-5.
PMID: 17036210

We constructed recombinant phage particles displaying the Bacillus thuringiensis Cry1Ba4 active toxin using the pfUSE5 and pComb3X phagemid vectors. The recombinant phage particles were screened and evaluated for displayed biologically active Cry1Ba4 toxin against the target insect larvae. Concurrent expression of Cry1Ba4 protoxin was carried out using the pETBlue -2 plasmid expression vector in Escherichia coli Tuner (DE3)pLacI and the protoxin was successfully expressed at a size of 129 kDa. In the bioassay, 3.30 mg crude extract of Cry1Ba4 protoxin, 9.35 x 10(9) TU and 7.70 x 10(9) TU of induced recombinant phage particles carrying Cry1Ba4 active toxin displayed on pComb3X and pFUSE5, respectively, demonstrated mortality of greater than 85% against Plutella xylostella (third-instar) within 48 hours. Thus, we have successfully displayed the Cry1Ba4 activated toxin on the surface of a phage and demonstrated toxicity towards larvae.

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