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  1. Kuan CS, Yew SM, Hooi PS, Lee LM, Ng KP
    Malays J Med Sci, 2017 Oct;24(5):33-43.
    PMID: 29386970 MyJurnal DOI: 10.21315/mjms2017.24.5.4
    Introduction: Acute respiratory tract infections (ARTIs) are a major cause of morbidity and mortality in paediatric patients. Therefore, early detection of the viral aetiologies of ARTIs is essential for patient management and infection control. In this study, we evaluated the performance of a new multiplex polymerase chain reaction (PCR) assay (xTAG Respiratory Viral Panel [RVP] Fast v2) in the detection of respiratory viruses by comparing it with that of viral culture and direct immunofluorescence (IF) staining.

    Methods: Nasopharyngeal swab and aspirate samples were collected prospectively from 199 patients who presented with ARTIs at the University Malaya Medical Centre (UMMC) in Kuala Lumpur, Malaysia during a 10-month period. The PCR assay was conducted in parallel with conventional culture and direct IF staining methods.

    Results: The positive rate of the xTAG RVP Fast v2 assay (78.4%) in detecting respiratory viruses was higher than that of the viral isolation (7.5%) and direct IF (23.1%) methods. Using the xTAG RVP Fast v2 assay, human enterovirus/human rhinovirus (HEV/HRV) was the most frequently detected (46.2%). The xTAG RVP Fast v2 assay revealed mixed infection caused by two or three respiratory viruses in 40 specimens, and these were undetected by the viral isolation and direct IF methods.

    Conclusion: The xTAG RVP Fast v2 assay was superior to conventional methods in the identification of common respiratory viruses, with higher sensitivity and shorter turnaround times for laboratory results.

  2. Chan CL, Yew SM, Ngeow YF, Na SL, Lee KW, Hoh CC, et al.
    BMC Genomics, 2015 Nov 18;16:966.
    PMID: 26581579 DOI: 10.1186/s12864-015-2200-2
    BACKGROUND: Daldinia eschscholtzii is a wood-inhabiting fungus that causes wood decay under certain conditions. It has a broad host range and produces a large repertoire of potentially bioactive compounds. However, there is no extensive genome analysis on this fungal species.

    RESULTS: Two fungal isolates (UM 1400 and UM 1020) from human specimens were identified as Daldinia eschscholtzii by morphological features and ITS-based phylogenetic analysis. Both genomes were similar in size with 10,822 predicted genes in UM 1400 (35.8 Mb) and 11,120 predicted genes in UM 1020 (35.5 Mb). A total of 751 gene families were shared among both UM isolates, including gene families associated with fungus-host interactions. In the CAZyme comparative analysis, both genomes were found to contain arrays of CAZyme related to plant cell wall degradation. Genes encoding secreted peptidases were found in the genomes, which encode for the peptidases involved in the degradation of structural proteins in plant cell wall. In addition, arrays of secondary metabolite backbone genes were identified in both genomes, indicating of their potential to produce bioactive secondary metabolites. Both genomes also contained an abundance of gene encoding signaling components, with three proposed MAPK cascades involved in cell wall integrity, osmoregulation, and mating/filamentation. Besides genomic evidence for degrading capability, both isolates also harbored an array of genes encoding stress response proteins that are potentially significant for adaptation to living in the hostile environments.

    CONCLUSIONS: Our genomic studies provide further information for the biological understanding of the D. eschscholtzii and suggest that these wood-decaying fungi are also equipped for adaptation to adverse environments in the human host.

  3. Yew SM, Chan CL, Lee KW, Na SL, Tan R, Hoh CC, et al.
    PLoS ONE, 2014;9(8):e104352.
    PMID: 25098697 DOI: 10.1371/journal.pone.0104352
    Dematiaceous fungi (black fungi) are a heterogeneous group of fungi present in diverse environments worldwide. Many species in this group are known to cause allergic reactions and potentially fatal diseases in humans and animals, especially in tropical and subtropical climates. This study represents the first survey of dematiaceous fungi in Malaysia and provides observations on their diversity as well as in vitro response to antifungal drugs. Seventy-five strains isolated from various clinical specimens were identified by morphology as well as an internal transcribed spacer (ITS)-based phylogenetic analysis. The combined molecular and conventional approach enabled the identification of three classes of the Ascomycota phylum and 16 genera, the most common being Cladosporium, Cochliobolus and Neoscytalidium. Several of the species identified have not been associated before with human infections. Among 8 antifungal agents tested, the azoles posaconazole (96%), voriconazole (90.7%), ketoconazole (86.7%) and itraconazole (85.3%) showed in vitro activity (MIC ≤ 1 µg/mL) to the largest number of strains, followed by anidulafungin (89.3%), caspofungin (74.7%) and amphotericin B (70.7%). Fluconazole appeared to be the least effective with only 10.7% of isolates showing in vitro susceptibility. Overall, almost half (45.3%) of the isolates showed reduced susceptibility (MIC >1 µg/mL) to at least one antifungal agent, and three strains (one Pyrenochaeta unguis-hominis and two Nigrospora oryzae) showed potential multidrug resistance.
  4. Chan CL, Yew SM, Na SL, Tan YC, Lee KW, Yee WY, et al.
    Genome Announc, 2014;2(2).
    PMID: 24744321 DOI: 10.1128/genomeA.00074-14
    Ochroconis constricta is a soilborne dematiaceous fungus that has never been reported to be associated with human infection. Here we report the first draft genome sequence of strain UM 578, isolated from human skin scraping. The genomic information revealed will contribute to a better understanding of this species.
  5. Toh YF, Yew SM, Chan CL, Na SL, Lee KW, Hoh CC, et al.
    PLoS ONE, 2016;11(9):e0162095.
    PMID: 27626635 DOI: 10.1371/journal.pone.0162095
    Pyrenochaeta unguis-hominis is a rare human pathogen that causes infection in human skin and nail. P. unguis-hominis has received little attention, and thus, the basic biology and pathogenicity of this fungus is not fully understood. In this study, we performed in-depth analysis of the P. unguis-hominis UM 256 genome that was isolated from the skin scraping of a dermatitis patient. The isolate was identified to species level using a comprehensive multilocus phylogenetic analysis of the genus Pyrenochaeta. The assembled UM 256 genome has a size of 35.5 Mb and encodes 12,545 putative genes, and 0.34% of the assembled genome is predicted transposable elements. Its genomic features propose that the fungus is a heterothallic fungus that encodes a wide array of plant cell wall degrading enzymes, peptidases, and secondary metabolite biosynthetic enzymes. Antifungal drug resistance genes including MDR, CDR, and ERG11/CYP51 were identified in P. unguis-hominis UM 256, which may confer resistance to this fungus. The genome analysis of P. unguis-hominis provides an insight into molecular and genetic basis of the fungal lifestyles, understanding the unrevealed biology of antifungal resistance in this fungus.
  6. Yew SM, Chan CL, Ngeow YF, Toh YF, Na SL, Lee KW, et al.
    Sci Rep, 2016 05 31;6:27008.
    PMID: 27243961 DOI: 10.1038/srep27008
    Cladosporium sphaerospermum, a dematiaceous saprophytic fungus commonly found in diverse environments, has been reported to cause allergy and other occasional diseases in humans. However, its basic biology and genetic information are largely unexplored. A clinical isolate C. sphaerospermum genome, UM 843, was re-sequenced and combined with previously generated sequences to form a model 26.89 Mb genome containing 9,652 predicted genes. Functional annotation on predicted genes suggests the ability of this fungus to degrade carbohydrate and protein complexes. Several putative peptidases responsible for lung tissue hydrolysis were identified. These genes shared high similarity with the Aspergillus peptidases. The UM 843 genome encodes a wide array of proteins involved in the biosynthesis of melanin, siderophores, cladosins and survival in high salinity environment. In addition, a total of 28 genes were predicted to be associated with allergy. Orthologous gene analysis together with 22 other Dothideomycetes showed genes uniquely present in UM 843 that encode four class 1 hydrophobins which may be allergens specific to Cladosporium. The mRNA of these hydrophobins were detected by RT-PCR. The genomic analysis of UM 843 contributes to the understanding of the biology and allergenicity of this widely-prevalent species.
  7. Kuan CS, Ismail R, Kwan Z, Yew SM, Yeo SK, Chan CL, et al.
    PLoS ONE, 2016;11(6):e0156119.
    PMID: 27280438 DOI: 10.1371/journal.pone.0156119
    A yeast-like organism was isolated from the skin scraping sample of a stasis dermatitis patient in the Mycology Unit Department of Medical Microbiology, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia. The isolate produced no pigment and was not identifiable using chromogenic agar and API 20C AUX. The fungus was identified as Metschnikowia sp. strain UM 1034, which is close to that of Metschnikowia drosophilae based on ITS- and D1/D2 domain-based phylogenetic analysis. However, the physiology of the strain was not associated to M. drosophilae. This pathogen exhibited low sensitivity to all tested azoles, echinocandins, 5-flucytosine and amphotericin B. This study provided insight into Metschnikowia sp. strain UM 1034 phenotype profiles using a Biolog phenotypic microarray (PM). The isolate utilized 373 nutrients of 760 nutrient sources and could adapt to a broad range of osmotic and pH environments. To our knowledge, this is the first report of the isolation of Metschnikowia non-pulcherrima sp. from skin scraping, revealing this rare yeast species as a potential human pathogen that may be misidentified as Candida sp. using conventional methods. Metschnikowia sp. strain UM 1034 can survive in flexible and diverse environments with a generalist lifestyle.
  8. Yew SM, Chan CL, Kuan CS, Toh YF, Ngeow YF, Na SL, et al.
    BMC Genomics, 2016 Feb 03;17:91.
    PMID: 26842951 DOI: 10.1186/s12864-016-2409-8
    Ochroconis mirabilis, a recently introduced water-borne dematiaceous fungus, is occasionally isolated from human skin lesions and nails. We identified an isolate of O. mirabilis from a skin scraping with morphological and molecular studies. Its genome was then sequenced and analysed for genetic features related to classification and biological characteristics.
  9. Kuan CS, Yew SM, Toh YF, Chan CL, Lim SK, Lee KW, et al.
    PLoS ONE, 2015;10(12):e0145932.
    PMID: 26716988 DOI: 10.1371/journal.pone.0145932
    Peritonitis is the leading complication of peritoneal dialysis, which is primarily caused by bacteria rather than fungi. Peritonitis is responsible for approximately 18% of the infection-related mortality in peritoneal dialysis patients. In this paper, we report the isolation of a rare fungus, Quambalaria cyanescens, from the peritoneal fluid of a man after he switched from continuous ambulatory peritoneal dialysis to nocturnal intermittent peritoneal dialysis. Based on the morphological examination and multigene phylogeny, the clinical isolate was confirmed as Q. cyanescens. This pathogen exhibited low sensitivity to all tested echinocandins and 5-flucytosine. Interestingly, morphological characterization revealed that Q. cyanescens UM 1095 produced different pigments at low temperatures (25°C and 30°C) on various culture media. It is important to monitor the emergence of this rare fungus as a potential human pathogen in the tropics. This study provides insight into Q. cyanescens UM 1095 phenotype profiles using a Biolog phenotypic microarray (PM). Of the 760 nutrient sources tested, Q. cyanescens UM 1095 utilized 42 compounds, and the fungus can adapt to a broad range of osmotic and acidic environments. To our knowledge, this is the first report of the isolation of Q. cyanescens from peritoneal fluid, revealing this rare fungus as a potential human pathogen that may be misidentified using conventional methods. The detailed morphological, molecular and phenotypic characterization of Q. cyanescens UM 1095 provides the basis for future studies on its biology, lifestyle, and potential pathogenicity.
  10. Kuan CS, Yew SM, Chan CL, Toh YF, Lee KW, Cheong WH, et al.
    Database (Oxford), 2016;2016.
    PMID: 26980516 DOI: 10.1093/database/baw008
    Many species of dematiaceous fungi are associated with allergic reactions and potentially fatal diseases in human, especially in tropical climates. Over the past 10 years, we have isolated more than 400 dematiaceous fungi from various clinical samples. In this study, DemaDb, an integrated database was designed to support the integration and analysis of dematiaceous fungal genomes. A total of 92 072 putative genes and 6527 pathways that identified in eight dematiaceous fungi (Bipolaris papendorfii UM 226, Daldinia eschscholtzii UM 1400, D. eschscholtzii UM 1020, Pyrenochaeta unguis-hominis UM 256, Ochroconis mirabilis UM 578, Cladosporium sphaerospermum UM 843, Herpotrichiellaceae sp. UM 238 and Pleosporales sp. UM 1110) were deposited in DemaDb. DemaDb includes functional annotations for all predicted gene models in all genomes, such as Gene Ontology, EuKaryotic Orthologous Groups, Kyoto Encyclopedia of Genes and Genomes (KEGG), Pfam and InterProScan. All predicted protein models were further functionally annotated to Carbohydrate-Active enzymes, peptidases, secondary metabolites and virulence factors. DemaDb Genome Browser enables users to browse and visualize entire genomes with annotation data including gene prediction, structure, orientation and custom feature tracks. The Pathway Browser based on the KEGG pathway database allows users to look into molecular interaction and reaction networks for all KEGG annotated genes. The availability of downloadable files containing assembly, nucleic acid, as well as protein data allows the direct retrieval for further downstream works. DemaDb is a useful resource for fungal research community especially those involved in genome-scale analysis, functional genomics, genetics and disease studies of dematiaceous fungi. Database URL: http://fungaldb.um.edu.my.
  11. Kuan CS, Chan CL, Yew SM, Toh YF, Khoo JS, Chong J, et al.
    PLoS ONE, 2015;10(6):e0131694.
    PMID: 26110649 DOI: 10.1371/journal.pone.0131694
    The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.
  12. Kuan CS, Yew SM, Toh YF, Chan CL, Ngeow YF, Lee KW, et al.
    DNA Res., 2015 Jun;22(3):219-32.
    PMID: 25922537 DOI: 10.1093/dnares/dsv007
    Bipolaris papendorfii has been reported as a fungal plant pathogen that rarely causes opportunistic infection in humans. Secondary metabolites isolated from this fungus possess medicinal and anticancer properties. However, its genetic fundamental and basic biology are largely unknown. In this study, we report the first draft genome sequence of B. papendorfii UM 226 isolated from the skin scraping of a patient. The assembled 33.4 Mb genome encodes 11,015 putative coding DNA sequences, of which, 2.49% are predicted transposable elements. Multilocus phylogenetic and phylogenomic analyses showed B. papendorfii UM 226 clustering with Curvularia species, apart from other plant pathogenic Bipolaris species. Its genomic features suggest that it is a heterothallic fungus with a putative unique gene encoding the LysM-containing protein which might be involved in fungal virulence on host plants, as well as a wide array of enzymes involved in carbohydrate metabolism, degradation of polysaccharides and lignin in the plant cell wall, secondary metabolite biosynthesis (including dimethylallyl tryptophan synthase, non-ribosomal peptide synthetase, polyketide synthase), the terpenoid pathway and the caffeine metabolism. This first genomic characterization of B. papendorfii provides the basis for further studies on its biology, pathogenicity and medicinal potential.
  13. Yew SM, Chan CL, Soo-Hoo TS, Na SL, Ong SS, Hassan H, et al.
    Genome Announc, 2013;1(3).
    PMID: 23723391 DOI: 10.1128/genomeA.00158-13
    Pyrenochaeta, classified under the order Pleosporales, is known to cause diseases in plants and humans. Here, we report a draft genome sequence of a Pyrenochaeta sp. isolated from a skin scraping, with an estimated genome size of 39.4 Mb. Genes associated with the synthesis of proteases, toxins, plant cell wall degradation, and multidrug resistance were found.
  14. Ng KP, Yew SM, Chan CL, Chong J, Tang SN, Soo-Hoo TS, et al.
    Genome Announc, 2013 Jan;1(1).
    PMID: 23405310 DOI: 10.1128/genomeA.00056-12
    The emergence of the global threat of extensively drug-resistant (XDR) Mycobacterium tuberculosis reveals weaknesses in tuberculosis management and diagnostic services. We report the draft genome sequence of the first extensively drug-resistant Mycobacterium tuberculosis strain isolated in Malaysia. The sequence was also compared against a reference strain to elucidate the polymorphism that is related to their extensive resistance.
  15. Ng KP, Yew SM, Chan CL, Tan R, Soo-Hoo TS, Na SL, et al.
    Genome Announc, 2013 Jan;1(1).
    PMID: 23409267 DOI: 10.1128/genomeA.00148-12
    Herpotrichiellaceae spp. are known to be opportunistic human pathogens. Here, we report the ~28.46-Mb draft genome of Herpotrichiellaceae sp. UM 238, isolated from human skin scraping. The UM 238 genome was found to contain many classes of protective genes that are responsible for fungal adaptation under adverse environmental conditions.
  16. Ng KP, Yew SM, Chan CL, Soo-Hoo TS, Na SL, Hassan H, et al.
    Eukaryotic Cell, 2012 Jun;11(6):828.
    PMID: 22645233 DOI: 10.1128/EC.00133-12
    Pleosporales is the largest order in the fungal class Dothideomycetes. We report the 36,814,818-bp draft genome sequence and gene annotation of UM1110, a Pleosporales isolate associated with unclassified genera that is potentially a new fungal species. Analysis of the genome sequence led to the finding of genes associated with fungal adhesive proteins, secreted proteases, allergens, and pseudohyphal development.
  17. Ng KP, Ngeow YF, Yew SM, Hassan H, Soo-Hoo TS, Na SL, et al.
    Eukaryotic Cell, 2012 May;11(5):703-4.
    PMID: 22544898 DOI: 10.1128/EC.00074-12
    Daldinia eschscholzii is an invasive endophyte that is most commonly found in plant tissues rich in secondary metabolites. We report the draft genome sequence of D. eschscholzii isolated from blood culture. The draft genome is 35,494,957 bp in length, with 42,898,665 reads, 61,449 contigs, and a G+C content of 46.8%. The genome was found to contain a high abundance of genes associated with plant cell wall degradation enzymes, mycotoxin production, and antifungal drug resistance.
  18. Ng KP, Yew SM, Chan CL, Soo-Hoo TS, Na SL, Hassan H, et al.
    Eukaryotic Cell, 2012 May;11(5):705-6.
    PMID: 22544899 DOI: 10.1128/EC.00081-12
    Cladosporium sphaerospermum is one of the most widely distributed allergens causing serious problems in patients with respiratory tract disease. We report the 26,644,473-bp draft genome sequence and gene annotation of C. sphaerospermum UM843. Analysis of the genome sequence led to the finding of genes associated with C. sphaerospermum's melanin biosynthesis, allergens, and antifungal drug resistance.
  19. Kuan CS, Cham CY, Singh G, Yew SM, Tan YC, Chong PS, et al.
    PLoS ONE, 2016;11(8):e0161008.
    PMID: 27570972 DOI: 10.1371/journal.pone.0161008
    Cladophialophora bantiana is a dematiaceous fungus with a predilection for causing central nervous system (CNS) infection manifesting as brain abscess in both immunocompetent and immunocompromised patients. In this paper, we report comprehensive genomic analyses of C. bantiana isolated from the brain abscess of an immunocompetent man, the first reported case in Malaysia and Southeast Asia. The identity of the fungus was determined using combined morphological analysis and multilocus phylogeny. The draft genome sequence of a neurotrophic fungus, C. bantiana UM 956 was generated using Illumina sequencing technology to dissect its genetic fundamental and basic biology. The assembled 37.1 Mb genome encodes 12,155 putative coding genes, of which, 1.01% are predicted transposable elements. Its genomic features support its saprophytic lifestyle, renowned for its versatility in decomposing hemicellulose and pectin components. The C. bantiana UM 956 was also found to carry some important putative genes that engaged in pathogenicity, iron uptake and homeostasis as well as adaptation to various stresses to enable the organism to survive in hostile microenvironment. This wealth of resource will further catalyse more downstream functional studies to provide better understanding on how this fungus can be a successful and persistent pathogen in human.
  20. Looi HK, Toh YF, Yew SM, Na SL, Tan YC, Chong PS, et al.
    PeerJ, 2017;5:e2841.
    PMID: 28149676 DOI: 10.7717/peerj.2841
    Corynespora cassiicola is a common plant pathogen that causes leaf spot disease in a broad range of crop, and it heavily affect rubber trees in Malaysia (Hsueh, 2011; Nghia et al., 2008). The isolation of UM 591 from a patient's contact lens indicates the pathogenic potential of this dematiaceous fungus in human. However, the underlying factors that contribute to the opportunistic cross-infection have not been fully studied. We employed genome sequencing and gene homology annotations in attempt to identify these factors in UM 591 using data obtained from publicly available bioinformatics databases. The assembly size of UM 591 genome is 41.8 Mbp, and a total of 13,531 (≥99 bp) genes have been predicted. UM 591 is enriched with genes that encode for glycoside hydrolases, carbohydrate esterases, auxiliary activity enzymes and cell wall degrading enzymes. Virulent genes comprising of CAZymes, peptidases, and hypervirulence-associated cutinases were found to be present in the fungal genome. Comparative analysis result shows that UM 591 possesses higher number of carbohydrate esterases family 10 (CE10) CAZymes compared to other species of fungi in this study, and these enzymes hydrolyses wide range of carbohydrate and non-carbohydrate substrates. Putative melanin, siderophore, ent-kaurene, and lycopene biosynthesis gene clusters are predicted, and these gene clusters denote that UM 591 are capable of protecting itself from the UV and chemical stresses, allowing it to adapt to different environment. Putative sterigmatocystin, HC-toxin, cercosporin, and gliotoxin biosynthesis gene cluster are predicted. This finding have highlighted the necrotrophic and invasive nature of UM 591.
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