Biology subjects

Lin, K.

Publications and source records attributed to Lin, K..

6 recordsLinked to original sources

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↗