Genome-wide analysis of PDX1 target genes in human pancreatic progenitors

Objective: Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing beta-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult beta-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far. Methods: In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions. Results: ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and ME1S1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult beta-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes. Conclusions: Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a beta-cell developmental program

Case report: surgical removal of a migrated needle in right ventricle of an intravenous drug user

Abstract Background Illicit drug use has become an increasing public health and social concern in the past decades worldwide. Intravenous injection has an elevated risk of infection. Needle embolism is a rare complication of intravenous drug users, Retained broken needles can lead to local complications, such as infection, but they also have the potential to embolize to heart or lung, and lead to serious complications. Method We reported a rare case of an intravenous drug user which a retained broken needle fragments in the inferior wall of the right ventricle. Results We performed a successful surgery and give our comments and recommendations for illicit drug use worldwide and in China. Conclusions Illicit Drug use becomes a global problem because of its health and social harmfulness. To help drug addicts and provide prevention and treatment services are the obligations and responsibilities of all medical workers

Energy Saving Simulation of Phase Change Materials in the Enclosure Structure of Archives Warehouse in Different Climatic Regions

Different climates in different regions have an important influence on the latent heat performance of PCMs, especially outdoor temperature and solar irradiance. This paper describes the addition of PCMs outside the archives warehouse in Guangzhou and Lhasa, and the temperature change and energy conservation of the exterior enclosure of the warehouse in summer and winter. In typical summer days in Guangzhou, PCMs with a phase change temperature of 30°C should be added to reduce the indoor cooling load by 23.91%. In typical winter days in Lhasa, PCMs with a phase change temperature of 8°C should be added, which can reduce the indoor heat load by 17.28%

Effect of nanomaterials and electrode configuration on soil consolidation by electroosmosis: experimental and modeling studies

Controlling the water content in soil is crucial for the load bearing capacity of soil. In the past few decades, electroosmosis has been proved to be a versatile strategy to consolidate soil in situ. However, the efficiency of this electrochemical technique needs to be further improved for practical application. This study was designed to test the hypothesis that the incorporation of nanoparticles (NPs) during electroosmosis can significantly facilitate the migration of water molecules under an external electric field and thus improve the physical properties of the treated soil. In addition, the number of anodes per cathode was explored as another method to improve the efficiency of electroosmosis in dewatering and strengthening soil. The results from the designed laboratory experiments confirmed the benefits of increasing the number of anodes or adding positively charged SiO2@Al2O3 core–shell NPs, in increasing the dewatering rate and improving the cohesion, internal friction angle, and microstructure of the treated soil (Lake Silt). The finite element method based simulation results agreed well with the experimental observations and suggested that the NPs can promote the water migration under an electric field