Biology subjects

Lin, K.

Publications and source records attributed to Lin, K..

88 records · Page 5Linked to original sources

bioRxiv2020

Pre-clinical studies of a recombinant adenoviral mucosal vaccine to prevent SARS-CoV-2 infection

There is an urgent need to develop efficacious vaccines against SARS-CoV-2 that also address the issues of deployment, equitable access, and vaccine acceptance. Ideally, the vaccine would prevent virus infection and transmission as well as preventing COVID-19 disease. We previously developed an oral adenovirus-based vaccine technology that induces both mucosal and systemic immunity in humans. Here we investigate the immunogenicity of a range of candidate adenovirusbased vaccines, expressing full or partial sequences of the spike and nucleocapsid proteins, in mice. We demonstrate that, compared to expression of the S1 domain or a stabilized spike antigen, the full length, wild-type spike antigen induces significantly higher neutralizing antibodies in the periphery and in the lungs, when the vaccine is administered mucosally. Antigen-specific CD4+ and CD8+ T cells were induced by this leading vaccine candidate at low and high doses. This fulllength spike antigen plus nucleocapsid adenovirus construct has been prioritized for further clinical development.

immunology↗

bioRxiv2020

An extracellular protein regulates patched-related/DAF-6-mediated sensory compartment formation in C. elegans

Coordination of neurite extension with surrounding glia development is critical for neuronal function, but the underlying molecular mechanisms remain poorly understood. Through a genome-wide mutagenesis screen in C. elegans, we identified dyf-4 and daf-6 as two mutants sharing similar defects in dendrite extension. DAF-6 encodes a glia-specific patched-related membrane protein that plays vital roles in glial morphogenesis. We cloned dyf-4 and found that DYF-4 encodes a glia-secreted extracellular protein. Intriguingly, DYF-4 colocalizes with DAF-6 along the glial channel. Further investigations revealed that DYF-4 directly interacts with DAF-6 and regulates its proper membrane localization. Notably, reported glial suppressors of daf-6 could also restore dendrite elongation and ciliogenesis in both dyf-4 and daf-6 mutants. Collectively, our data suggest that secreted DYF-4 likely acts as a novel ligand/regulator for the patched-related receptor DAF-6 which promotes the proper formation of the glial channel and indirectly affects neurite extension and ciliogenesis.

developmental biology↗

bioRxiv2020

Proteasome activator PA200 maintains stability of histone marks during transcription and aging

The epigenetic inheritance relies on stability of histone marks, but various diseases, including aging-related diseases, are usually associated with alterations of histone marks. How the stability of histone marks is maintained still remains unclear. The core histones can be degraded by the atypical proteasome, which contains the proteasome activator PA200, in an acetylation-dependent manner during somatic DNA damage response and spermiogenesis. Here we show that PA200 promotes the transcription-coupled degradation of the core histones, and plays an important role in maintaining the stability of histone marks. Degradation of the histone variant H3.3, which is incorporated into chromatin during transcription, was much faster than that of its canonical form H3.1, which is incorporated during DNA replication. This degradation of the core histones could be suppressed by the transcription inhibitor, the proteasome inhibitor or deletion of PA200. The histone deacetylase inhibitor accelerated the degradation rates of H3 in general, especially its variant H3.3, while the mutations of the putative acetyl-lysine-binding region of PA200 abolished histone degradation in the G1-arrested cells, supporting that acetylation is involved in the degradation of the core histones. Deletion of PA200 dramatically altered deposition of the active transcriptional hallmarks (H3K4me3 and H3K56ac) and transcription, especially during cellular aging. Furthermore, deletion of PA200 or its yeast ortholog Blm10 accelerated cellular aging. Notably, the PA200-deficient mice displayed a range of aging-related deteriorations, including immune malfunction, anxiety-like behaviors and shorter lifespan. Thus, the proteasome activator PA200 is critical to the maintenance of the stability of histone marks during transcription and aging.

cell biology↗

bioRxiv2020

Evolutionary patterns of 64 vertebrate genomes (species) revealed by phylogenomics analysis of protein-coding gene families

BackgroundRecent studies have demonstrated that phylogenomics is an important basis for answering many fundamental evolutionary questions. With more high-quality whole genome sequences published, more efficient phylogenomics analysis workflows are required urgently. ResultsTo this end and in order to capture putative differences among evolutionary histories of gene families and species, we developed a phylogenomics workflow for gene family classification, gene family tree inference, species tree inference and duplication/loss events dating. Our analysis framework is on the basis of two guiding ideas: 1) gene trees tend to be different from species trees but they influence each other in evolution; 2) different gene families have undergone different evolutionary mechanisms. It has been applied to the genomic data from 64 vertebrates and 5 out-group species. And the results showed high accuracy on species tree inference and few false-positives in duplication events dating. ConclusionsBased on the inferred gene duplication and loss event, only 9[~]16% gene families have duplication retention after a whole genome duplication (WGD) event. A large part of these families have ohnologs from two or three WGDs. Consistent with the previous study results, the gene function of these families are mainly involved in nervous system and signal transduction related biological processes. Specifically, we found that the gene families with ohnologs from the teleost-specific (TS) WGD are enriched in fat metabolism, this result implyng that the retention of such ohnologs might be associated with the environmental status of high concentration of oxygen during that period.

bioinformatics↗

bioRxiv2019

Dynamic DNA-based information storage

Technological leaps are often driven by key innovations that transform the underlying architectures of systems. Current DNA storage systems largely rely on polymerase chain reaction, which broadly informs how information is encoded, databases are organized, and files are accessed. Here we show that a hybrid toehold DNA structure can unlock a fundamentally different, dynamic DNA-based information storage system architecture with broad advantages. This innovation increases theoretical storage densities and capacities by eliminating non-specific DNA-DNA interactions common in PCR and increasing the encodable sequence space. It also provides a physical handle with which to implement a range of in-storage file operations. Finally, it reads files non-destructively by harnessing the natural role of transcription in accessing information from DNA. This simple but powerful toehold structure lays the foundation for an information storage architecture with versatile capabilities.

synthetic biology↗

bioRxiv2019

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.\n\nType 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic {beta} cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

genetics↗

bioRxiv2019

PRE-BORDER GENE FOXB1 REGULATES THE DIFFERENTIATION TIMING AND AUTONOMIC NEURONAL POTENTIAL OF HUMAN NEURAL CREST CELLS

What are the factors that are induced during the transitory phases from pluripotent stem cells to lineage specified cells, how are they regulated, and what are their functional contributions are fundamental questions for basic developmental biology and clinical research. Here, we uncover a set of pre-border (pB) gene candidates, including forkhead box B1 (FOXB1), induced during human neural crest (NC) cell development. We characterize their associated enhancers that are bound by pluripotency factors and rapidly activated by {beta}-catenin-mediated signaling during differentiation. Surprisingly, the endogenous transient expression of FOXB1 directly regulates multiple early NC and neural progenitor loci including PAX7, MSX2, SOX1, and ASCL1, controls the timing of NC fate acquisition, and differentially activates autonomic neurogenic versus mesenchymal fates in mature NC cells. Our findings provide further insight into the concept of the less characterized pB state and clearly establishes FOXB1 as a key regulator in early cell fate decisions during human pluripotent stem cell differentiation.

developmental biology↗

bioRxiv2019

The genetic architecture of sporadic and recurrent miscarriage

Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%, Pmeta=3.2x -8 (CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located near FGF9 involved in pregnancy maintenance3 and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%, Pmeta=1.3x -8 in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.

genetics↗

bioRxiv2019

Lifelong genetically lowered sclerostin and risk of cardiovascular disease.

BackgroundInhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events. MethodsWe used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab. ResultsMeta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2{middle dot}98; 95% confidence interval [CI], 1{middle dot}18 to 7{middle dot}55; P=0{middle dot}017). Scaled to the equivalent dose of romosozumab (210mg/month; 0{middle dot}09 g/cm2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0{middle dot}59; 95% CI, 0{middle dot}54-0{middle dot}66; P= 1{middle dot}4x10-24), and osteoporosis (OR, 0{middle dot}43; 95% CI, 0{middle dot}36-0{middle dot}52; P=2{middle dot}4x10-18). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1{middle dot}18; 95% CI, 1{middle dot}06-1{middle dot}32; P=0{middle dot}003) and type 2 diabetes (OR 1{middle dot}15; 95% CI, 1{middle dot}05-1{middle dot}27; P=0{middle dot}003), higher systolic blood pressure (1{middle dot}3mmHg; 95% CI 0{middle dot}8-1{middle dot}9; P=5{middle dot}9x10-6) and waist-to-hip-ratio adjusted for BMI (0{middle dot}05 SDs; 95% CI, 0{middle dot}02 to 0{middle dot}08; P=8{middle dot}5x10-4). ConclusionsGenetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.

genetics↗

bioRxiv2019

The transferability of lipid-associated loci across African, Asian and European cohorts

The under-representation of non-European samples in genome-wide association studies could ultimately restrict who benefits from medical advances through genomic science. Our aim was therefore to address the fundamental question whether causal variants for blood lipids are shared across populations.\n\nA polygenic score based on established LDL-cholesterol-associated loci from European discovery samples had consistent effects on serum levels in samples from the UK, Uganda and Greek population isolates (correlation coefficient r=0.23 to 0.28 per LDL standard deviation, p<1.9x10-14). Trans-ethnic genetic correlations between European ancestry, Chinese and Japanese cohorts did not differ significantly from 1 for HDL, LDL and triglycerides. In each study, >60% of major lipid loci displayed evidence of replication with one exception. There was evidence for an effect on serum levels in the Ugandan samples for only 10% of major triglyceride loci. The PRS was only weakly associated in this group (r=0.06, SE=0.013). We establish trans-ethnic colocalization as a method to distinguish shared from population-specific trait loci.\n\nOur results provide evidence for high levels of consistency of genetic associations for cholesterol biomarkers across populations. However, we also demonstrate that the degree of shared causal genetic architecture can be population-, trait- and locus-specific. Efforts to implement genetic risk prediction in clinical settings should account for this.

genetics↗

bioRxiv2018

A familial case of Syndactyly type IV due to a novel duplication of ~222.23 kb covering exons 2-17 of the LMBR1 gene: a case report

Syndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant Syndactyly type IV (SD4) is a very rare form of syndactyly, occurring as a result of heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. The SD4 is characterized by complete cutaneous syndactyly of all fingers, cup-shaped hands due to flexion of the fingers and accompanied by polydactyly. Here, we firstly reported a big Chinese family, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). Genetically, we identified a novel duplication of [~]222.23 kb covering exons 2-17 of the LMBR1 gene in this family by next generation sequencing. This case expands our new clinical understanding of SD4 phenotype.

genetics↗

bioRxiv2018

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

BackgroundBoth statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.\n\nMethods228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.\n\nResultsScaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2 x 10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.\n\nConclusionsGenetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.

epidemiology↗

bioRxiv2017

Short-term stabilities of 21 amino acids in dried blood spots

BACKGROUNDDried blood spots (DBSs) have potential use in remote health applications for individual and population diagnosis, and can enable epidemiological surveillance for known and unknown diseases. The preparation and transportation of DBSs from remote settings often exposes these cards to extreme environmental stress that may impact the quality of the diagnostic data. Given these risks, it is essential to investigate the individual stabilities of biomarkers in DBSs. This paper details the stability of routinely-analyzed amino acids (AAs) on DBSs under environmental conditions that simulate a global health workflow.\n\nMETHODSThe extractions of 21 AAs from three sets of DBSs prepared on cellulose and cotton filter paper were optimized for quantitation by dansylation-UPLC/MRM-MS. The effects of sunlight exposure, temperature, humidity, and storage time were studied.\n\nRESULTSThe AAs were stable in DBSs after 4-hour sunlight exposure, and after storage at -20 and 4 {degrees}C for 30 days. At 25 and 40 {degrees}C, only 7 AAs showed significant concentration decreases over time, while 2 showed concentration increases. The changes were accelerated by high humidity. Histidine was the least stable AA under the conditions tested.\n\nCONCLUSIONSThis study provides quantitative data on the short-term stabilities of 21 AAs in DBSs on cellulose and cotton-based filter paper, under environmental conditions that simulate a global-health workflow. These results highlight the importance of assessing the stability of clinically-relevant biomarkers in DBSs. Based on the measured stabilities, we recommend that higher-temperature and high-humidity storage of DBS samples be avoided for AA analysis in remote health applications.

biochemistry↗

bioRxiv2017

Does genetic risk help to predict amyloid burden in a non-demented population? A Bayesian approach.

INTRODUCTIONIn this study we investigate the association between A{beta} levels in cerebrospinal fluid (CSF) and genetic risk in a non-demented population. This paper presents the first analysis to use a Bayesian methodology in this area.\n\nMETHODSData from the Alzheimers Disease Neuroimaging Initiative (ADNI) and the EDAR* and DESCRIPA** studies was used in a Bayesian logistic regression analysis. We modeled CSF A{beta} burden using age, diagnosis (healthy control or mild cognitive impairment), APOE and a polygenic risk score (PGRS) associated with Alzheimers Disease (AD). We compared models built using informative priors on age, diagnosis and APOE with non-informative priors on all variables.\n\nRESULTSThe use of informative priors did not improve model performance in the majority of cases. Models using only age, diagnosis and APOE genotype showed the best predictive ability.\n\nDISCUSSIONA previous study indicated that a PGRS of AD case/control status was associated with CSF A{beta} burden in healthy controls. The current study suggests that this association does not lead to models that are more predictive of amyloid positivity than already known factors such as age and APOE.\n\n* Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response\n\n** Development of screening guidelines and criteria for pre-dementia Alzheimers disease

bioinformatics↗

bioRxiv2017

Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis

Tumor metastasis is the cause of death for 90% of cancer patients, and no currently-available therapies target this multi-step process in which cancer cells spread from the local tissue of a primary tumor to distant organs where they establish secondary tumors1. Although epithelial-to-mesenchymal transition2, tumor-secreted exosomes3, epigenetic regulators as well as other genes4-8 have been implicated in metastasis, little is known about how cells adapt to and colonize new tissue environments. Here, we show that the epigenetics-mediated reprogramming of tissue-specific gene transcription in cancer cells promotes metastasis. Using colorectal cancer (CRC) as a model, we found in both clinical and cell line studies that metastatic CRC cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. Further, we found this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers. Chemical inhibition of enhancer activity disrupts the ability of cells to execute altered transcription programs and consequently inhibits metastasis. Binding motif analysis of the enhancers in liver metastatic CRC cells identified the liver-specific transcription factor FOXA2 as a key regulator, and knocking down of FOXA2 expression prevents the colonization of metastatic CRC cells in the liver of a mice xenograft model. These results, together with additional observations of similar reprogramming in several cohorts of clinical CRC tumor samples and in multiple other forms of metastatic cancers, indicate that this reprogramming may be a common feature of metastasis in multiple cancers and suggest the targeted disruption of this epigenetic reprogramming as a strategy for the development of therapies to treat metastasis, the leading cause of cancer-related mortality.

cancer biology↗

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗