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Most polygenic risk score (PRS)models have been based on data from populations of European origins (accounting for the majority of the large genomics datasets, e.g. >78% in the UK Biobank and >85% in the GTEx project). Although several large-scale Asian biobanks were initiated (e.g. Japanese, Korean, Han Chinese biobanks), most other Asian countries have little or near-zero genomics data. To implement PRS models for under-represented populations, we explored transfer learning approaches, assuming that information from existing large datasets can compensate for the small sample size that can be feasibly obtained in developing countries, like Vietnam. Here, we benchmark 13 common PRS methods in meta-population strategy (combining individual genotype data from multiple populations) and multi-population strategy (combining summary statistics from multiple populations). Our results highlight the complementarity of different populations and the choice of methods should depend on the target population. Based on these results, we discussed a set of guidelines to help users select the best method for their datasets. We developed a robust and comprehensive software to allow for benchmarking comparisons between methods and proposed a computational framework for improving PRS performance in a dataset with a small sample size. This work is expected to inform the development of genomics applications in under-represented populations. PRSUP framework is available at: https://github.com/BiomedicalMachineLearning/VGP.
Assuntos
Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Vietnã , Genômica/métodos , Fatores de RiscoRESUMO
As new methods to interrogate glycan organization on cells develop, it is important to have a molecular level understanding of how chemical fixation can impact results and interpretations. Site-directed spin labeling technologies are well suited to study how the spin label mobility is impacted by local environmental conditions, such as those imposed by cross-linking effects of paraformaldehyde cell fixation methods. Here, we utilize three different azide-containing sugars for metabolic glycan engineering with HeLa cells to incorporate azido glycans that are modified with a DBCO-based nitroxide moiety via click reaction. Continuous wave X-band electron paramagnetic resonance spectroscopy is employed to characterize how the chronological sequence of chemical fixation and spin labeling impacts the local mobility and accessibility of the nitroxide-labeled glycans in the glycocalyx of HeLa cells. Results demonstrate that chemical fixation with paraformaldehyde can alter local glycan mobility and care should be taken in the analysis of data in any study where chemical fixation and cellular labeling occur.
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A novel method for spin labelling of sialoglycans on the cell surface is described. C9-Azido sialic acid was linked to glycans on live cells via CSTII-catalysed α2,3-sialylation utilizing azido-sialic acid nucleotide as a sialyl donor, which was followed by attachment of a spin label to the azide via click reaction. It enables the study of cell surface sialoglycans by EPR spectroscopy.
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Azidas , Polissacarídeos , Membrana Celular/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Polissacarídeos/química , Marcadores de SpinRESUMO
Use of HIV-related support services has been demonstrated to improve outcomes for people living with HIV. Further exploring patterns of use could help identify how and in what settings additional HIV care and treatment adherence support could be provided. We aimed to identify support service utilization patterns and examine their association with viral load suppression (VLS). Our sample comprised 6,581 people with HIV who received Ryan White Part A support services for basic needs (food and nutrition, legal, harm reduction, housing services) in New York City from 1/2013 to 12/2016, but had not received services specifically targeting HIV care and treatment adherence. Five support service utilization classes were identified using latent class analysis, the majority of which were characterized by the predominant use of concrete services (e.g., food assistance). Compared with the low-intensity, sporadic concrete service use class, clients in all other classes had lower odds of VLS in a 365-day follow-up period, but this disadvantage disappeared with adjustment for confounding variables indicative of need. Our findings underscore the impact of need-related barriers on VLS and suggest that long-term service utilization beyond the one year period of this study may be required to diminish their negative effect on HIV outcomes.
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Administração Financeira , Infecções por HIV , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Habitação , Humanos , Cidade de Nova Iorque/epidemiologia , Carga ViralRESUMO
BACKGROUND: A global pandemic has been declared for coronavirus disease 2019 (COVID-19), which has serious impacts on human health and healthcare systems in the affected areas, including Vietnam. None of the previous studies have a framework to provide summary statistics of the virus variants and assess the severity associated with virus proteins and host cells in COVID-19 patients in Vietnam. METHOD: In this paper, we comprehensively investigated SARS-CoV-2 variants and immune responses in COVID-19 patients. We provided summary statistics of target sequences of SARS-CoV-2 in Vietnam and other countries for data scientists to use in downstream analysis for therapeutic targets. For host cells, we proposed a predictive model of the severity of COVID-19 based on public datasets of hospitalization status in Vietnam, incorporating a polygenic risk score. This score uses immunogenic SNP biomarkers as indicators of COVID-19 severity. RESULT: We identified that the Delta variant of SARS-CoV-2 is most prevalent in southern areas of Vietnam and it is different from other areas in the world using various data sources. Our predictive models of COVID-19 severity had high accuracy (Random Forest AUC = 0.81, Elastic Net AUC = 0.7, and SVM AUC = 0.69) and showed that the use of polygenic risk scores increased the models' predictive capabilities. CONCLUSION: We provided a comprehensive analysis for COVID-19 severity in Vietnam. This investigation is not only helpful for COVID-19 treatment in therapeutic target studies, but also could influence further research on the disease progression and personalized clinical outcomes.
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Tratamento Farmacológico da COVID-19 , COVID-19 , Infecções por Coronavirus , Pneumonia Viral , Betacoronavirus , COVID-19/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , SARS-CoV-2/genética , Vietnã/epidemiologiaRESUMO
BACKGROUND: The misregulation of microRNA (miRNA) has been shown to cause diseases. Recently, we have proposed a computational method based on a random walk framework on a miRNA-target gene network to predict disease-associated miRNAs. The prediction performance of our method is better than that of some existing state-of-the-art network- and machine learning-based methods since it exploits the mutual regulation between miRNAs and their target genes in the miRNA-target gene interaction networks. RESULTS: To facilitate the use of this method, we have developed a Cytoscape app, named RWRMTN, to predict disease-associated miRNAs. RWRMTN can work on any miRNA-target gene network. Highly ranked miRNAs are supported with evidence from the literature. They then can also be visualized based on the rankings and in relationships with the query disease and their target genes. In addition, automation functions are also integrated, which allow RWRMTN to be used in workflows from external environments. We demonstrate the ability of RWRMTN in predicting breast and lung cancer-associated miRNAs via workflows in Cytoscape and other environments. CONCLUSIONS: Considering a few computational methods have been developed as software tools for convenient uses, RWRMTN is among the first GUI-based tools for the prediction of disease-associated miRNAs which can be used in workflows in different environments.
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Biologia Computacional/métodos , Redes Reguladoras de Genes/genética , MicroRNAs/genética , HumanosRESUMO
HIV infection is a global health epidemic with current FDA-approved HIV-1 Protease inhibitors (PIs) designed against subtype B protease, yet they are used in HIV treatment world-wide regardless of patient HIV classification. In this study, double electron-electron resonance (DEER) electron paramagnetic resonance (EPR) spectroscopy was utilized to gain insights in how natural polymorphisms in several African and Brazilian protease (PR) variants affect the conformational landscape both in the absence and presence of inhibitors. Findings show that Subtypes F and H HIV-1 PR adopt a primarily closed conformation in the unbound state with two secondary mutations, D60E and I62V, postulated to be responsible for the increased probability for closed conformation. In contrast, subtype D, CRF_AG, and CRF_BF HIV-1 PR adopt a primarily semi-open conformation, as observed for PI-naïve-subtype B when unbound by substrate or inhibitor. The impact that inhibitor binding has on shifting the conformational land scape of these variants is also characterized, where analysis provides classification of inhibitor induced shifts away from the semi-open state into weak, moderate and strong effects. The findings are compared to those for prior studies of inhibitor induced conformational shifts in PI-naïve Subtype B, C and CRF_AE.
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Protease de HIV/química , Protease de HIV/genética , África Central , Brasil , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/metabolismo , HIV-1/genética , Polimorfismo Genético , Conformação Proteica , Marcadores de SpinRESUMO
In this study, we present an analysis of metagenome sequences obtained from a filtrate of a siphon tissue homogenate of otter clams (Lutraria rhynchaena) with swollen-siphon disease. The viral signal was mined from the metagenomic data, and a novel circular ssDNA virus was identified. Genomic features and phylogenetic analysis showed that the virus belongs to the phylum Cressdnaviricota, which consists of viruses with circular, single-stranded DNA (ssDNA) genomes. Members of this phylum have been identified in various species and in environmental samples. The newly found virus is distantly related to the currently known members of the phylum Cressdnaviricota.
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Bivalves/genética , Vírus de DNA/classificação , DNA Viral/genética , Genoma Viral , Animais , Vírus de DNA/isolamento & purificação , DNA Circular/genética , DNA de Cadeia Simples/genética , Microbiologia Ambiental , Metagenômica , Filogenia , Análise de Sequência de DNARESUMO
A novel cation-π interaction between the bound Cu(+) metal ion and Trp44 in the periplasmic Cu(+)/Ag(+) metallochaperone Escherichia coli CusF protects Cu(+) from the oxidative influence of the periplasm. In a popular model of metal ion transfer, a conformational change in the metal binding loop disrupts the cation-π interaction and moves Trp44 aside to provide access to the occluded metal ion binding site in an "open" conformation. In this study, our molecular dynamics simulations support this putative mechanism of metal ion transfer. We find that the apoprotein undergoes a transition back and forth from the crystallographically observed "closed" state to the hypothesized open conformation over multiple microseconds. In agreement with nuclear magnetic resonance data, our simulations show that similar transitions are prohibited in Cu(+)·CusF, suggesting that the conformational transitions are gated by a metal ion-mediated second-shell hydrogen bond between metal binding residue His36 and Asp37 of the metal binding loop region. Ab initio quantum mechanical calculations indicate that metal ion binding strengthens this interaction significantly, much like what is found in the case of other metalloproteins. The study builds toward a common evolutionary role of metal ion-mediated second-shell hydrogen bonds in metalloprotein structure and function.
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Proteínas de Transporte de Cátions/química , Cobre/química , Proteínas de Escherichia coli/química , Apoproteínas/química , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cobre , Proteínas de Escherichia coli/genética , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica , Teoria Quântica , TermodinâmicaRESUMO
HIV infection remains a global health issue plagued by drug resistance and virological failure. Natural polymorphisms (NPs) contained within several African and Brazilian protease (PR) variants have been shown to induce a conformational landscape of more closed conformations compared to the sequence of subtype B prevalent in North America and Western Europe. Here we demonstrate through experimental pulsed EPR distance measurements and molecular dynamic (MD) simulations that the two common NPs D60E and I62V found within subtypes F and H can induce a closed conformation when introduced into HIV-1PR subtype B. Specifically, D60E alters the conformation in subtype B through the formation of a salt bridge with residue K43 contained within the nexus between the flap and hinge region of the HIV-1 PR fold. On the other hand, I62V modulates the packing of the hydrophobic cluster of the cantilever and fulcrum, also resulting in a more closed conformation.
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Infecções por HIV , Inibidores da Protease de HIV , Humanos , Conformação Molecular , Polimorfismo Genético , Simulação de Dinâmica Molecular , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , Mutação , Conformação ProteicaRESUMO
As new methods to interrogate glycan organization on cells develop, it is important to have a molecular level understanding of how chemical fixation can impact results and interpretations. Site-directed spin labeling technologies are well suited to study how the spin label mobility is impacted by local environmental conditions, such as those imposed by cross-linking effects of paraformaldehyde cell fixation methods. Here, we utilize three different azide-containing sugars for metabolic glycan engineering with HeLa cells to incorporate azido glycans that are modified with a DBCO-based nitroxide moiety via click reaction. Continuous wave X-band electron paramagnetic resonance spectroscopy is employed to characterize how the chronological sequence of chemical fixation and spin labeling impacts the local mobility and accessibility of the nitroxide-labeled glycans in the glycocalyx of HeLa cells. Results demonstrate that chemical fixation with paraformaldehyde can alter local glycan mobility and care should be taken in the analysis of data in any study where chemical fixation and cellular labeling occur.
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There is evidence that people with HIV (PWH) receive health-related benefits from having peer support and learning self-management skills. This evaluation assessed the effect of The Positive Life Workshop (TPLW)-a 7-session peer-led HIV self-management program-on psychosocial and HIV treatment outcomes. The overall sample included 1360 PWH who completed TPLW during 3/2015-2/2019. Surveys were administered before and after the program, and three months following program completion. Analyses examined changes in outcomes from pre-test to both post-test and 3-month follow-up using non-parametric tests. Subgroup analyses were conducted for 406 participants with ≥ 1 characteristic of the priority population for TPLW (i.e., recent HIV diagnosis, not taking antiretroviral therapy (ART), suboptimal ART adherence, unsuppressed viral load). In the overall sample, there were statistically significant improvements in HIV-related knowledge, social support, patient self-advocacy, and confidence in self-management between pre-test and post-test/3-month follow-up assessment. Analyses for the priority population showed significant increases from pre-test to 3-month follow-up in the proportion of participants who were ≥ 90 % adherent to ART (59-83 %, p < 0.01) and virally suppressed (42 % to 66 %, p < 0.01). The findings suggest the importance of ensuring HIV self-management interventions reach vulnerable populations of PWH who struggle with initiating and maintaining HIV-related health-promoting behaviors.
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Infecções por HIV , Autogestão , Humanos , Avaliação de Programas e Projetos de Saúde , Infecções por HIV/tratamento farmacológico , Grupo Associado , Apoio SocialRESUMO
Sialoglycans on HeLa cells were labeled with a nitroxide spin radical through enzymatic glycoengineering (EGE)-mediated installation of azide-modified sialic acid (Neu5Ac9N3) and then click reaction-based attachment of a nitroxide spin radical. α2,6-Sialyltransferase (ST) Pd2,6ST and α2,3-ST CSTII were used for EGE to install α2,6- and α2,3-linked Neu5Ac9N3, respectively. The spin-labeled cells were analyzed by X-band continuous wave (CW) electron paramagnetic resonance (EPR) spectroscopy to gain insights into the dynamics and organizations of cell surface α2,6- and α2,3-sialoglycans. Simulations of the EPR spectra revealed average fast- and intermediate-motion components for the spin radicals in both sialoglycans. However, α2,6- and α2,3-sialoglycans in HeLa cells possess different distributions of the two components, e.g., a higher average population of the intermediate-motion component for α2,6-sialoglycans (78%) than that for α2,3-sialoglycans (53%). Thus, the average mobility of spin radicals in α2,3-sialoglycans was higher than that in α2,6-sialoglycans. Given the fact that a spin-labeled sialic acid residue attached to the 6-O-position of galactose/N-acetyl-galactosamine would experience less steric hindrance and show more flexibility than that attached to the 3-O-position, these results may reflect the differences in local crowding/packing that restrict the spin-label and sialic acid motion for α2,6-linked sialoglycans. The studies further suggest that Pd2,6ST and CSTII may have different preferences for glycan substrates in the complex environment of the extracellular matrix. The discoveries of this work are biologically important as they are useful for interpreting the different functions of α2,6- and α2,3-sialoglycans and indicate the possibility of using Pd2,6ST and CSTII to target different glycoconjugates on cells.
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Ácido N-Acetilneuramínico , Óxidos de Nitrogênio , Humanos , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Células HeLa , Óxidos de Nitrogênio/química , Marcadores de SpinRESUMO
Regardless of the overwhelming use of next-generation sequencing technologies, microarray-based genotyping combined with the imputation of untyped variants remains a cost-effective means to interrogate genetic variations across the human genome. This technology is widely used in genome-wide association studies (GWAS) at bio-bank scales, and more recently, in polygenic score (PGS) analysis to predict and stratify disease risk. Over the last decade, human genotyping arrays have undergone a tremendous growth in both number and content making a comprehensive evaluation of their performances became more important. Here, we performed a comprehensive performance assessment for 23 available human genotyping arrays in 6 ancestry groups using diverse public and in-house datasets. The analyses focus on performance estimation of derived imputation (in terms of accuracy and coverage) and PGS (in terms of concordance to PGS estimated from whole-genome sequencing data) in three different traits and diseases. We found that the arrays with a higher number of SNPs are not necessarily the ones with higher imputation performance, but the arrays that are well-optimized for the targeted population could provide very good imputation performance. In addition, PGS estimated by imputed SNP array data is highly correlated to PGS estimated by whole-genome sequencing data in most cases. When optimal arrays are used, the correlations of PGS between two types of data are higher than 0.97, but interestingly, arrays with high density can result in lower PGS performance. Our results suggest the importance of properly selecting a suitable genotyping array for PGS applications. Finally, we developed a web tool that provides interactive analyses of tag SNP contents and imputation performance based on population and genomic regions of interest. This study would act as a practical guide for researchers to design their genotyping arrays-based studies. The tool is available at: https://genome.vinbigdata.org/tools/saa/ .
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Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Genótipo , Polimorfismo de Nucleotídeo Único , Sequenciamento de Nucleotídeos em Larga Escala/métodosRESUMO
The exploration of novel electrocatalysts for CO2 reduction is necessary to overcome global warming and the depletion of fossil fuels. In the current study, the electrocatalytic CO2 reduction of [Re(CO)3Cl(N-N)], where N-N represents 3-(2-pyridyl)-1,2,4-triazole (Hpy), 3-(pyridin-2-yl)-5-phenyl-l,2,4-triazole (Hph), and 2,2'-bipyridine-4,4' dicarboxylic acidic (bpy-COOH) ligands, was investigated. In CO2-saturated electrolytes, cyclic voltammograms showed an enhancement of the current at the second reduction wave for all complexes. In the presence of triethanolamine (TEOA), the currents of Re(Hpy), Re(Hph), and Re(bpy-COOH) enhanced significantly by approximately 4-, 2-, and 5-fold at peak potentials of -1.60, -150, and -1.69 VAg/Ag+, respectively (in comparison to without TEOA). The reduction potential of Re(Hph) was less negative than those of Re(Hpy) and Re(COOH), which was suggested to cause its least efficiency for CO2 reduction. Chronoamperometry measurements showed the stability of the cathodic current at the second reduction wave for at least 300 s, and Re(COOH) was the most stable in the CO2-catalyzed reduction. The appearance and disappearance of the absorption band in the UV/vis spectra indicated the reaction of the catalyst with molecular CO2 and its conversion to new species, which were proposed to be Re-DMF + and Re-TEOA and were supposed to react with CO2 molecules. The CO2 molecules were claimed to be captured and inserted into the oxygen bond of Re-TEOA, resulting in the enhancement of the CO2 reduction efficiency. The results indicate a new way of using these complexes in electrocatalytic CO2 reduction.
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Multidrug resistance continues to be a barrier to the effectiveness of highly active antiretroviral therapy in the treatment of human immunodeficiency virus 1 (HIV-1) infection. Darunavir (DRV) is a highly potent protease inhibitor (PI) that is oftentimes effective when drug resistance has emerged against first-generation inhibitors. Resistance to darunavir does evolve and requires 10-20 amino acid substitutions. The conformational landscapes of six highly characterized HIV-1 protease (PR) constructs that harbor up to 19 DRV-associated mutations were characterized by distance measurements with pulsed electron double resonance (PELDOR) paramagnetic resonance spectroscopy, namely double electron-electron resonance (DEER). The results show that the accumulated substitutions alter the conformational landscape compared to PI-naïve protease where the semi-open conformation is destabilized as the dominant population with open-like states becoming prevalent in many cases. A linear correlation is found between values of the DRV inhibition parameter Ki and the open-like to closed-state population ratio determined from DEER. The nearly 50% decrease in occupancy of the semi-open conformation is associated with reduced enzymatic activity, characterized previously in the literature.
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Darunavir/farmacologia , Farmacorresistência Viral Múltipla , Inibidores da Protease de HIV/farmacologia , Protease de HIV/química , HIV/efeitos dos fármacos , Substituição de Aminoácidos , Variação Genética , HIV/genética , Protease de HIV/genética , Mutação , Conformação ProteicaRESUMO
Metabolic glycan engineering (MGE) coupled with nitroxide spin-labeling (SL) was utilized to investigate the heterogeneous environment of cell surface glycans in select cancer and normal cells. This approach exploited the incorporation of azides into cell surface glycans followed by a click reaction with a new nitroxide spin label. Both sialic acid and N-acetylglucosamine (GlcNAc) were targeted for spin labelling. Although each of these moieties experiences a diverse and heterogeneous glycan environment, their EPR spectra and hence mobility are both characterized as a linear combination of two distinct spectra where one component reflects a highly mobile or uncrowded micro-environment with the second component reflecting more restricted motion, reflective of increased crowding and packing within the glycocalyx. What differs among the spectra of the targeted glycans is the relative percentage of each component, with sialic acid moieties experiencing on average an â¼80% less crowded environment, where conversely GlcNAc/GalNAz labeled sites reported on average a â¼50% more crowded environment. These distinct environments are consistent with the organization of sugar moieties within cellular glycans where some residues occur close to the cell membrane/protein backbone (i.e. more restricted) and others are more terminal in the glycan (i.e. more mobile). Strikingly, different cell lines displayed varied relative populations of these two components, suggesting distinctive glycan packing, organization, and composition of different cells. This work demonstrates the capability of SDSL EPR to be a broadly useful tool for studying glycans on cells, and interpretation of the results provides insights for distinguishing the differences and changes in the local organization and heterogeneity of the cellular glycocalyx.
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Otter clam farming in Vietnam has recently encountered difficulties due to swollen-siphon disease. Here, we report the metagenome sequences of microorganisms extracted from the siphon tissue of infected otter clams. The data comprised bacterial and viral sequences which likely include those derived from the disease-causing agent.
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BACKGROUND: Chagas disease, caused by infection with the protozoan Trypanosoma cruzi, remains a serious public health issue in Latin America. Genetically diverse, the species is sub-divided into six lineages, known as TcI-TcVI, which have disparate geographical and ecological distributions. TcII, TcV, and TcVI are associated with severe human disease in the Southern Cone countries, whereas TcI is associated with cardiomyopathy north of the Amazon. T. cruzi persists as a chronic infection, with cardiac and/or gastrointestinal symptoms developing years or decades after initial infection. Identifying an individual's history of T. cruzi lineage infection directly by genotyping of the parasite is complicated by the low parasitaemia and sequestration in the host tissues. METHODOLOGY/PRINCIPAL FINDINGS: We have applied here serology against lineage-specific epitopes of the T. cruzi surface antigen TSSA, as an indirect approach to allow identification of infecting lineage. Chagasic sera from chronic patients from a range of endemic countries were tested by ELISA against synthetic peptides representing lineage-specific TSSA epitopes bound to avidin-coated ELISA plates via a biotin labelled polyethylene glycol-glycine spacer to increase rotation and ensure each amino acid side chain could freely interact with their antibodies. 79/113 (70%) of samples from Brazil, Bolivia, and Argentina recognised the TSSA epitope common to lineages TcII/TcV/TcVI. Comparison with clinical information showed that a higher proportion of Brazilian TSSApep-II/V/VI responders had ECG abnormalities than non-responders (38% vs 17%; p<0.0001). Among northern chagasic sera 4/20 (20%) from Ecuador reacted with this peptide; 1/12 Venezuelan and 1/34 Colombian samples reacted with TSSApep-IV. In addition, a proposed TcI-specific epitope, described elsewhere, was demonstrated here to be highly conserved across lineages and therefore not applicable to lineage-specific serology. CONCLUSIONS/SIGNIFICANCE: These results demonstrate the considerable potential for synthetic peptide serology to investigate the infection history of individuals, geographical and clinical associations of T. cruzi lineages.