Biology subjects

Tan, C. H.

Publications and source records attributed to Tan, C. H..

9 recordsLinked to original sources

bioRxiv2025

Antigenic Divergence of Cobra Short-chain α-Neurotoxins: Implications for Regional Antivenom Effectiveness in Southeast Asia

Short-chain -neurotoxins (SNTXs) are the principal neurotoxic components in several Asiatic cobras, including Naja atra, Naja philippinensis, and N. samarensis. Although structurally conserved, SNTXs exhibit marked antigenic variation that can limit the effectiveness of regional antivenoms used for snakebite envenoming in Asia. Here, we evaluated the immunoreactivity of the Philippine Cobra Antivenom (PCAV) and three regional products--Naja kaouthia Monovalent Antivenom (NkMAV), Neuro Bivalent Antivenom (NBAV), and Indonesian SABU--against a panel of cobra venoms and purified -neurotoxins. PCAV bound strongly to homologous N. philippinensis SNTX but showed weak cross-reactivity with SNTXs from N. kaouthia, N. sputatrix, and N. atra, and minimal recognition of marine elapid SNTXs and long-chain -neurotoxins (LNTXs) of Monocled Cobra as well as King Cobra. Conversely, NkMAV and NBAV recognized mainland Asian SNTXs more broadly but reacted poorly with the Philippine cobra toxin. Hierarchical clustering of normalized immunoreactivity delineated two major SNTX antigenic subtypes corresponding to Philippine versus continental Asian lineages. Peptide sequence analysis unmasked two distinct loop-II motifs (28WWS-TII37 and 28RWR-YRT37) associated with these divergent immunotypes. Phylogenetic reconstruction suggests that the Philippine cobras retain an ancestral SNTX motif, while Sundaic and East Asian cobras have diversified to employ another major SNTX form. Epitope prediction further revealed differences in surface exposure and accessibility that help explain the limited cross-neutralization across antivenoms. These findings demonstrate a clear antigenic dichotomy among Asian cobra SNTXs, which underlies species-specific antivenom effectiveness and highlights the need to incorporate representative SNTX variants into immunogen formulations to improve regional antivenom coverage.

biochemistry↗

bioRxiv2025

Hidden in plain sight: Discovery of sand flies in Singapore and description of four species new to science

Phlebotomine sand flies (Diptera: Psychodidae) are small, blood-sucking insects that are of significant public and veterinary health importance for their role in the transmission of Leishmania parasites, bacteria and arboviruses. Although sand flies have been documented in most Southeast Asian countries, there are no published records confirming their presence in Singapore. Here, we provide the first documented evidence on the presence of sand flies in Singapore. Using an integrated taxonomic approach that combines morphological analysis with DNA barcoding of the mitochondrial cytochrome b (cytb) and cytochrome c oxidase subunit I (COI) genes, we identified eight sand fly species, including four newly described species - Phlebotomus seowpohi n. sp., Sergentomyia leechingae n. sp., Sergentomyia gubleri n. sp., and Sergentomyia retrocalcarae n. sp.. Phylogenetic analyses suggest that the new Phlebotomus species, belonging to subgenus Euphlebotomus, is closely related to Phlebotomus argentipes, an important vector of Leishmania donovani from the South Asian region. The discovery of phlebotomine sand flies in Singapore underscores the importance of biosurveillance of biting arthropods. Given Singapores status as a major travel hub, there is a potential risk of leishmaniasis being introduced either by residents returning, or visitors arriving from endemic regions. This risk is compounded by the recent detection of local canine leishmaniasis. Thus, continuous monitoring is essential to assess and manage the risk of disease transmission, support the development of an early warning system, and enable timely and targeted public health interventions. The findings from this study contributes to the global knowledge on sand fly and enhance our understanding of local sand fly diversity and distribution. Author SummaryPhlebotomine sand flies are small, blood-sucking insects recognized as significant vectors for various diseases including leishmaniasis. This study provides the first evidence of their presence in Singapore. Using an integrated taxonomic approach combining morphological analysis with DNA barcoding, we identified eight sand fly species that include four new species: Phlebotomus seowpohi n. sp., Sergentomyia leechingae n. sp., Sergentomyia gubleri n. sp., and Sergentomyia retrocalcarae n. sp. The presence of sand flies in Singapore highlights an important biosurveillance need, as the regions status as a major travel hub increases the risk of leishmaniasis being introduced. Importantly, recent findings of canine leishmaniasis in local dogs amplify the threat of disease transmission. Continuous monitoring and understanding of sand fly diversity and ecology are essential for developing effective public health strategies and early warning systems to manage this risk.

zoology↗

bioRxiv2021

Insect-specific viruses regulate vector competence in Aedes aegypti mosquitoes via expression of histone H4

Aedes aegypti and Aedes albopictus are major mosquito vectors for arthropod-borne viruses (arboviruses) such as dengue (DENV) and Zika (ZIKV) viruses. Mosquitoes also carry insect-specific viruses (ISVs) that may affect the transmission of arboviruses. Here, we analyzed the global virome in urban Aedes mosquitoes and observed that two insect-specific viruses, Phasi Charoen-like virus (PCLV) and Humaita Tubiacanga virus (HTV), were the most prevalent in A. aegypti worldwide except for African cities, where transmission of arboviruses is low. Spatiotemporal analysis revealed that presence of HTV and PCLV led to a 200% increase in the chances of having DENV in wild mosquitoes. In the laboratory, we showed that HTV and PCLV prevented downregulation of histone H4, a previously unrecognized proviral host factor, and rendered mosquitoes more susceptible to DENV and ZIKV. Altogether, our data reveals a molecular basis for the regulation of A. aegypti vector competence by highly prevalent ISVs that may impact how we analyze the risk of arbovirus outbreaks.

microbiology↗

bioRxiv2020

Using spatial genetics to quantify mosquito dispersal for control programs

BackgroundHundreds of millions of people get a mosquito-borne disease every year, of which nearly one million die. Mosquito-borne diseases are primarily controlled and mitigated through the control of mosquito vectors. Accurately quantified mosquito dispersal in a given landscape is critical for the design and optimization of the control programs, yet the field experiments that measure dispersal of mosquitoes recaptured at certain distances from the release point (mark-release-recapture MRR studies) are challenging for such small insects and often unrepresentative of the insects true field behavior. Using Singapore as a study site, we show how mosquito dispersal patterns can be characterized from the spatial analyses of genetic relatedness among individuals sampled over a short time span without interruption of their natural behaviors. Methods and FindingsWe captured ovipositing females of Aedes aegypti, a major arboviral disease vector, across floors of high-rise apartment blocks and genotyped them using thousands of genome-wide SNP markers. We developed a methodology that produces a dispersal kernel for distance that results from one generation of successful breeding (effective dispersal), using the distances separating full siblings, 2nd and 3rd degree relatives (close kin). In Singapore, the estimated dispersal distance kernel was exponential (Laplacian), giving the mean effective dispersal distance (and dispersal kernel spread {sigma}) of 45.2 m (95%CI: 39.7-51.3 m), and 10% probability of dispersal >100 m (95%CI: 92-117 m). Our genetic-based estimates matched the parametrized dispersal kernels from the previously reported MRR experiments. If few close-kin are captured, a conventional genetic isolation-by-distance analysis can be used, and we show that it can produce {sigma} estimates congruent with the close-kin method, conditioned on the accurate estimation of effective population density. We also show that genetic patch size, estimated with the spatial autocorrelation analysis, reflects the spatial extent of the dispersal kernel tail that influences e.g. predictions of critical radii of release zones and Wolbachia wave speed in mosquito replacement programs. ConclusionsWe demonstrate that spatial genetics (the newly developed close-kin analysis, and conventional IBD and spatial autocorrelation analyses) can provide a detailed and robust characterization of mosquito dispersal that can guide operational vector control decisions. With the decreasing cost of next generation sequencing, acquisition of spatial genetic data will become increasingly accessible, and given the complexities and criticisms of conventional MRR methods, but the central role of dispersal measures in vector control programs, we recommend genetic-based dispersal characterization as the more desirable means of parameterization.

ecology↗

bioRxiv2019

Prevalence, awareness and control of hypertension in Malaysia 1980 - 2017: A Systematic Review and Meta-Analysis

BackgroundHypertension is a common public health problem worldwide and is a well-known risk factor for increased risk of cardiovascular diseases, contributing to high morbidity and mortality. However, there is no systematic review and meta-analysis that has been done in a multi-ethnic population like Malaysia. This systematic review aims to determine the trend in prevalence, awareness and control of hypertension in Malaysia.\n\nMethodsSystematic searches were conducted in PubMed, Scopus, Ovid, Cumulative Index to Nursing and Allied Health Literature, Malaysian Medical Repository and Malaysia Citation Index published between 1980 and 2017. All original articles in English were included. Studies included were those on adults aged 18 years and above. Studies of prevalence in children and adolescents and pregnancy related hypertension were excluded. Two authors independently reviewed the studies, carried out data extraction and performed quality assessment. Heterogeneity between studies and publication bias was assessed and effect size was pooled by the random effect model.\n\nResultsFifty-six studies with a total of 241,796 subjects were included. The prevalence of hypertension throughout Malaysia varied (I2 = 99.3%). The overall pooled prevalence of hypertension over the past 4 decades was 28.2% in adults aged 18 years and older (95% CI: 26.1 - 33.3) and the prevalence in those 30 years and older was 40.0% (95% CI: 35.3-44.8).\n\nFor subgroup analysis, the prevalence of hypertension in male aged 18 and above was 31.4% (95% CI: 26.5 - 36.2) and 27.8% in female (95% CI: 20.7 - 34.9). The prevalence of hypertension among the ethnic groups aged 18 years and above were 37.3% in Malays (95% CI: 32.9 - 41.7); 36.4% in Chinese (95% CI 31.6 - 41.2) and 34.8% in Indians (95% CI: 31.2-38.4). The prevalence of hypertension was the lowest in the 1980s (16.2%, 95% CI: 13.4-19.0%), increases up to 36.8% in the 1990s (95% CI: 6.1-67.5), then came down to 28.7% (95% CI: 21.7-35.8) in the 2000s and 29.2% (95% CI: 24.0-34.4) in the 2010s. The prevalence of awareness was 38.7% (95% CI: 31.7 - 45.8) whereas the control of hypertension of those on treatment was 33.3% (95% CI: 28.4 - 38.2).\n\nConclusionThree in 10 adults aged 18 years old and above have hypertension, whereas four in 10 adults aged 30 years old and above have hypertension. Four out of 10 are aware of their hypertension status and only one-third of them who were under treatment achieved control of their hypertension. Concerted efforts by policymakers and healthcare professionals to improve the awareness and control of hypertension should be of high priority.

epidemiology↗

bioRxiv2019

Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease

Sex differences in the manifestations of Alzheimers disease (AD) are under intense investigations 1,2. Despite the emerging importance of polygenic predictions for AD 3-8, the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Sex-matched polygenic hazard scores (PHS) have significantly stronger associations with age-at-disease-onset, clinical progressions, amyloid depositions, neurofibrillary tangles, and composite neuropathological scores, than sex-mismatched PHS, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores (PRS), have lower predictive power than PHS and show no evidence for sex differences. Our results indicate revealing sex-dependent genetic architecture requires the consideration of temporal processes of AD. This has strong implications not only for the genetic underpinning of AD but also for how we estimate sex-dependent polygenic effects for clinical use.

genetics↗

bioRxiv2018

Lipid associated polygenic enrichment in Alzheimer’s disease

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimers disease (AD) pathogenesis. Beyond the [isin]4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimers risk.

genetics↗

bioRxiv2017

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

BackgroundThere is an urgent need for the early identification of nondemented individuals at the highest risk of progressing to Alzheimers disease (AD) dementia for early therapeutic interventions. Our goal was to evaluate whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo CSF or PET biomarkers of amyloid or tau pathology to prospectively predict cognitive decline and clinical progression to AD dementia in nondemented older individuals.\n\nMethodsWe evaluated 347 cognitive normal (CN) and 599 mild cognitively impaired (MCI) individuals. We first investigated whether PHS can predict CSF or PET amyloid and tau deposition. We evaluated differences in positive and negative predictive values of biomarker status, as a function of PHS risk. Next, we used linear mixed-effects (LME) to examine if PHS and biomarker status in conjunction, best predict longitudinal cognitive and clinical progression. Lastly, we used survival analysis to investigate whether a combination of PHS and biomarker positivity predicts progression to AD dementia better than using PHS or biomarker positivity alone.\n\nFindingsIn CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%. Similarly, for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. Beyond APOE, high PHS individuals with amyloid and tau pathology showed the fastest rate of longitudinal cognitive decline and time to AD dementia progression. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression.\n\nInterpretationAmong asymptomatic and mildly symptomatic older individuals, PHS considerably improves the predictive value of CSF or PET amyloid and tau biomarkers. Beyond APOE, PHS may be useful for risk stratification and cohort enrichment for MCI and preclinical AD therapeutic trials.

genetics↗

bioRxiv2017

Polygenic hazard scores in preclinical Alzheimer’s disease

Identifying asymptomatic older individuals at elevated risk for developing Alzheimers disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE {varepsilon}4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high CERAD (amyloid) and Braak (tau) scores at autopsy, even among APOE {varepsilon}4 non-carriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimers neurodegeneration.

genetics↗