Biology subjects

Lai, Z.

Publications and source records attributed to Lai, Z..

41 records · Page 3Linked to original sources

bioRxiv2019

Bactericidal efficiency and mechanism of specifically targeted antimicrobial peptides optimized based on structural and functional relationships

In contrast to traditional broad-spectrum antibiotics, it is difficult for bacteria to develop resistance to most specifically targeted antimicrobial peptides (STAMPs), moreover, they can maintain a normal ecological balance and provide long-term protection for the body. However, therapeutic applications of STAMPS are hindered by their weak activity, and imperfect specificity as well as lack of knowledge to understand their structure-activity relationships. To further investigate the effects of different parameters on the biological activities of STAMPs, a peptide sequence, WKKIWKDPGIKKWIK, was truncated, extended, and provided with an increased charge and altered amphipathicity. In addition, a novel template modification method was introduced, in which a phage-displayed peptide that recognized and bound to E. coli cells was attached at the end of the sequence. Compared with the traditional template modification method, peptide 11, which contained a phage-displayed peptide at the C-terminus, exhibited superior narrow-spectrum antibacterial activity against E. coli compared to that of parental peptide 2, and the activity and specificity of 11 were increased by 5.0 and 2.4 times, respectively. Additionally, 11 showed low cell toxicity and relatively desirable salt, serum, acid and alkaline stability. In this study, 11 specifically killed E. coli by causing cytoplasmic membrane rupture and cytosol leakage. In summary, these findings are useful for improving the activity and specificity of STAMPs and show that peptide 11 is better able to combat the growing threat of E. coli infections.

biochemistry↗

bioRxiv2019

An ancestral informative marker panel design for individual ancestry estimation of Hispanic population using whole exome sequencing data

BackgroundEuropeans and American Indians were major genetic ancestry of Hispanics in the U.S. In those ancestral groups, it has markedly different incidence rates and outcomes in many types of cancers. Therefore, the genetic admixture may cause biased genetic association study with cancer susceptibility variants specifically in Hispanics. The incidence rate and genetic mutational pattern of liver cancer have been shown substantial disparity between Hispanic, Asian and non-Hispanic white populations. Currently, ancestry informative marker (AIM) panels have been widely utilized with up to a few hundred ancestry-informative single nucleotide polymorphisms (SNPs) to infer ancestry admixture. Notably, current available AIMs are predominantly located in intron and intergenic regions, while the whole exome sequencing (WES) protocols commonly used in translational research and clinical practice do not contain these markers, thus, the challenge to accurately determine a patients admixture proportion without subject to additional DNA testing.\n\nMethodsHere we designed a bioinformatics pipeline to obtain an AIM panel. The panel infers 3-way genetic admixture from three distinct continental populations (African (AFR), European (EUR), and East Asian (EAS)) constraint within evolutionary-conserved exome regions. Briefly, we extract [~]1 million exonic SNPs from all individuals of three populations in the 1000 Genomes Project. Then, the SNPs were trimmed by their linkage disequilibrium (LD), restricted to biallelic variants only, and assembled as an AIM panel with the top ancestral informativeness statistics based on the In-statistic. The selected AIM panel was applied to training dataset and clinical dataset. Finally, The ancestral proportions of each individual was estimated by STRUCTURE.\n\nResultsIn this study, the optimally selected AIM panel with 250 markers, or the UT-AIM250 panel, was performed with better accuracy as one of the published AIM panels when we tested with 3 ancestral populations (Accuracy: 0.995 {+/-} 0.012 for AFR, 0.997 {+/-} 0.007 for EUR, and 0.994 {+/-} 0.012 for EAS). We demonstrated the utility of UT-AIM250 panel on the admixed American (AMR) of the 1000 Genomes Project and obtained similar results (AFR: 0.085 {+/-} 0.098; EUR: 0.665 {+/-} 0.182; and EAS 0.250 {+/-} 0.205) to previously published AIM panels (Phillips-AIM34: AFR: 0.096 {+/-} 0.127, EUR: 0.575 {+/-} 0.29; and EAS: 0.330 {+/-} 0.315; Wei-AIM278: AFR: 0.070 {+/-} 0.096, EUR: 0.537 {+/-} 0.267, and EAS: 0.393 {+/-} 0.300) with no significant difference (Pearson correlation, P < 10-50, n = 347 samples). Subsequently, we applied UT-AIM250 panel to clinical datasets of self-reported Hispanic patients in South Texas with hepatocellular carcinoma (26 patients). Our estimated admixture proportions from adjacent non-cancer liver tissue data of Hispanics in South Texas is (AFR: 0.065 {+/-} 0.043; EUR: 0.594 {+/-} 0.150; and EAS: 0.341 {+/-} 0.160), with smaller variation due to its unique Texan/Mexican American population in South Texas. Similar admixture proportion from the corresponding tumor tissue we also obtained. In addition, we estimated admixture proportions of entire TCGA-LIHC samples (376 patients) using UT-AIM250 panel. We demonstrated that our AIM panel estimate consistent admixture proportions from DNAs derived from tumor and normal tissues, and 2 possible incorrect reported race/ethnicity, and/or provide race/ethnicity determination if necessary.\n\nConclusionsTaken together, we demonstrated the feasibility of using evolutionary-conserved exome regions to distinguish genetic ancestry descendants based on 3 continental-ancestry proportion, provided a robust and reliable control for sample collection or patient stratification for genetic analysis. R implementation of UT-AIM250 is available at https://github.com/chenlabgccri/UT-AIM250.

bioinformatics↗

bioRxiv2019

Haplotype-Based Noninvasive Prenatal Diagnosis for Duchenne Muscular Dystrophy: A pilot study in South China

ObjectiveTo explore the accuracy and feasibility of noninvasive prenatal diagnosis (NIPD) for Duchenne Muscular Dystrophy (DMD) based on the haplotype approach. MethodsWe recruited singleton pregnancies at-risk of DMD at 12-25 weeks of gestation from 17 families who all had a proband children affected by DMD. We have identified the pathogenic mutations in probands and their mothers by multiplex ligation-dependent probe amplification (MLPA). To construct parental haplotypes, we performed captured sequencing on genomic DNA from parents and probands. The integration analysis of parental haplotypes and targeted sequencing results of maternal plasma DNA were used to infer the fetal haplotype and genotypes in DMD gene. Fetal DMD genotypes were further confirmed by invasive prenatal diagnosis. ResultsWe have successfully performed the haplotype-based NIPD in all recruited families. Ten fetuses were identified as normal, including four female and six male fetuses. Four female fetuses were carriers and the other three male fetuses were affected by DMD with exons 49-52 deletion, exons 8-37 deletion and c.628G > T mutation, respectively. The results of NIPD were consistent with those of invasive diagnosis. ConclusionHaplotype-based NIPD for DMD by targeted sequencing is promising and has potential for clinical application.

genetics↗

bioRxiv2017

The Kobresia pygmaea ecosystem of the Tibetan highlands – origin, functioning and degradation of the world’s largest pastoral alpine ecosystem

Kobresia pastures in the eastern Tibetan highlands occupy 450000 km2 and form the worlds largest pastoral alpine ecosystem. The main constituent is an endemic dwarf sedge, Kobresia pygmaea, which forms a lawn with a durable turf cover anchored by a felty root mat, and occurs from 3000 m to nearly 6000 m a.s.l. The existence and functioning of this unique ecosystem and its turf cover have not yet been explained against a backdrop of natural and anthropogenic factors, and thus its origin, drivers, vulnerability or resilience remain largely unknown. Here we present a review on ecosystem diversity, reproduction and ecology of the key species, pasture health, cycles of carbon (C), water and nutrients, and on the paleo-environment. The methods employed include molecular analysis, grazing exclusion, measurements with micro-lysimeters and gas exchange chambers, 13C and 15N labelling, eddy-covariance flux measurements, remote sensing and atmospheric modelling.\n\nThe following combination of traits makes Kobresia pygmaea resilient and highly competitive: dwarf habit, predominantly below-ground allocation of photo assimilates, mixed reproduction strategy with both seed production and clonal growth, and high genetic diversity. Growth of Kobresia pastures is co-limited by low rainfall during the short growing season and livestock-mediated nutrient withdrawal. Overstocking has caused pasture degradation and soil deterioration, yet the extent remains debated. In addition, we newly describe natural autocyclic processes of turf erosion initiated through polygonal cracking of the turf cover, and accelerated by soil-dwelling endemic small mammals. The major consequences of the deterioration of the vegetation cover and its turf include: (1) the release of large amounts of C and nutrients and (2) earlier diurnal formation of clouds resulting in (3) decreased surface temperatures with (4) likely consequences for atmospheric circulation on large regional and, possibly global, scales.\n\nPaleo-environmental reconstruction, in conjunction with grazing experiments, suggests that the present grazing lawns of Kobresia pygmaea are synanthropic and may have existed since the onset of pastoralism. The traditional migratory rangeland management was sustainable over millennia and possibly still offers the best strategy to conserve, and possibly increase, the C stocks in the Kobresia turf, as well as its importance for climate regulation.

ecology↗

bioRxiv2016

Prioritisation of Structural Variant Calls in Cancer Genomes

Sensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data. In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events. Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions. We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts. The resulting framework greatly improves on readily detecting clinically actionable structural variants.

genomics↗