Biology subjects

Hai, Y.

Publications and source records attributed to Hai, Y..

3 recordsLinked to original sources

bioRxiv2018

Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

Chronic kidney disease (CKD) affects [~]10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

genetics↗

bioRxiv2018

High Postoperative Monocyte Predicts Worse Lung Adenocarcinoma or Squamous Cell Carcinoma Outcomes

BackgroundPeripheral monocyte count is an assessable parameter. Recently, evidence suggested an elevated preoperative monocyte counts predicting poor prognosis in malignancies. The aim of this study was to determine the prognostic effect of early postoperative (within 4 days) blood monocyte count in patients with lung adenocarcinoma or squamous cell carcinoma following lobectomy.\n\nMethodsWe retrospectively reviewed patients with operated lung adenocarcinoma or squamous cell carcinoma from 2006 to 2011 in Western China Lung Cancer database. Both the preoperative and postoperative monocyte counts were divided into two groups. Univariate analysis on disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model.\n\nResultsThere were 433 patients enrolled in our analysis. The cut-off values were 0.375*109/L and 0.845*109/L for preoperative and early postoperative monocyte count respectively which were calculated by receiver operating characteristic curve. Two-tailed log-rank test indicated patients with an early postoperative elevated monocyte count predicted a poor DFS and OS overall (P<0.001, P<0.001, respectively) as well as in subgroup analysis. On univariate and multivariate analysis, early postoperative elevated monocyte count presented as a promising independent prognostic factor for both DFS and OS (HR=2.991, 95%CI: 2.243-3.988, P<0.001; HR=2.705, 95%CI: 1.977-3.700, P<0.001, respectively). However, no significance was detected for preoperative monocyte in multivariate analysis.\n\nConclusionsElevated early postoperative peripheral monocyte count is an independent predictor of poor prognosis for patients with operable lung adenocarcinoma or squamous cell carcinoma by lobectomy.

cancer biology↗

bioRxiv2018

Misoprostol regulates Bnip3 repression and alternative splicing to control cellular calcium homeostasis during hypoxic stress.

The cellular response to hypoxia involves the activation of a conserved pathway for gene expression regulated by the transcription factor complex called hypoxia-inducible factor (HIF). This pathway has been implicated in both the adaptive response to hypoxia and in several hypoxic-ischemic related pathologies. Perinatal hypoxic injury, often associated with prematurity, leads to multi-organ dysfunction resulting in significant morbidity and mortality. Using a rodent model of neonatal hypoxia and several representative cell lines, we observed HIF1 activation and down-stream induction of the cell death gene Bnip3 in brain, large intestine, and heart which was mitigated by administration of the prostaglandin E1 analog misoprostol. Mechanistically, we determined that misoprostol inhibits full-length Bnip3 (Bnip3-FL) expression through PKA-mediated NF-{kappa}B (P65) nuclear retention, and the induction of pro-survival splice variants. We observed that the dominant small pro-survival variant of Bnip3 in mouse cells lacks the third exon (Bnip3{Delta}Exon3), whereas human cells produce a pro-survival BNIP3 variant lacking exon 2 (BNIP3{Delta}Exon2). In addition, these small Bnip3 splice variants prevent mitochondrial dysfunction, permeability transition, and necrosis triggered by Bnip3-FL by blocking calcium transfer from the sarco/endoplasmic reticulum to the mitochondria. Furthermore, misoprostol and Bnip3{Delta}Exon3 promote nuclear calcium accumulation, resulting in HDAC5 nuclear export, NFAT activation, and adaptive changes in cell morphology and gene expression. Collectively, our data suggests that misoprostol can mitigate the potential damaging effects of hypoxia on multiple cell types by activating adaptive cell survival pathways through Bnip3 repression and alternative splicing.

cell biology↗