Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme Lysine-specific demethylase 1 (Lsd1) in islets. β-cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome

Optimal spacing for double-skin roofs

Double-skin design is known as an effective way to reduce the building's solar heat gain. In this study, inclined parallel plates with upper plate heated by a lighting system are used to simulate double-skin roofs exposed to solar irradiation. Heat transfer experiments were carried out for different inter-plate spacing and different inclined angles. In some of our test runs, a radiant barrier is also installed on top of bottom plate to further cut down the building's heat gain. The Nusselt numbers reduced from our test data are consistently matched with Azevedo and Sparrow's correlation. The optimal inter-plate spacing, when the most heat gain is blocked out, can be directly obtained from our test data which is very close to the sum of both plate's thermal boundary layer thicknesses. (c) 2007 Elsevier Ltd. All rights reserved

Cloning and characterization of a cDNA encoding the endo-1,4-beta-D-glucanase gene expressed in rapidly growing tuber and leaf of taro (Colocasia esculenta var. esculenta)

A cDNA for endo-beta-1,4-glucanase (EGase) was isolated by RT-PCR, and rapid amplification of cDNA ends reaction from taro leaves (Colocasia esculenta var. esculenta). This single copy gene has 2,185 bps and an open reading frame (ORF) of 1,854 bps. A polypeptide of 618 residues was deduced from the ORF, with a calculated molecular mass of 68,434 Da and theoretical pI of 8.8. The remarked activities of the EGase on CMC plate revealed this enzyme to be involved in cellulose metabolism in taro. Taro EGase was identified as a kind of membrane-anchored EGase. Phylogenetic analysis showed it is a member of the gamma subfamily and an ortholog of the Arabidopsis KORRIGAN gene (KOR), proposed to be involved in cytokinesis, pectin metabolism in the primary cell wall, and cell elongation. Transcripts of taro EGase are highly accumulated in 300 g tubers, in the upper part of 1,000 g tubers, and in rolled leaves undergoing rapid growth, indicating that taro EGase is involved in the regulation of plant growth. The expression pattern of soluble starch synthase III was similar to that of EGase during rapid growth of taro plant tubers. These results suggested that taro EGase, an ortholog of KOR in Arabidopsis, may play an important role in the rapid growth in taro

A simple approach to obtain comparable Shigella sonnie MLVA results across laboratories

tMultilocus variable-number tandem repeat analysis (MLVA) is a promising subtyping tool to comple-ment pulsed-field gel electrophoresis for discriminating closely related strains of some monomorphicorganisms, including Shigella sonnei, which is one of the major foodborne pathogens. However, MLVAresults are usually difficult to compare directly between laboratories, impeding the application of MLVAas a subtyping tool for disease surveillance and investigation of common outbreaks across regions orcountries. It has long been a big challenge in seeking an approach that can be implemented to obtaincomparable MLVA results across laboratories. By implementing a panel of calibration strains in each par-ticipating laboratory for data normalization, the MLVA results of 20 test strains were comparable eventhough some analytical conditions were different among the laboratories. This approach is simple, pro-tocol independent, and easy to implement in every laboratory, and a small calibration set is sufficient togenerate mathematical equations for accurate copy number conversio

Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease

Single-cell chromatin accessibility identifies pancreatic islet cell type- and state-specific regulatory programs of diabetes risk

Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics