A Network of microRNAs Acts to Promote Cell Cycle Exit and Differentiation of Human Pancreatic Endocrine Cells.

Pancreatic endocrine cell differentiation is orchestrated by the action of transcription factors that operate in a gene regulatory network to activate endocrine lineage genes and repress lineage-inappropriate genes. MicroRNAs (miRNAs) are important modulators of gene expression, yet their role in endocrine cell differentiation has not been systematically explored. Here we characterize miRNA-regulatory networks active in human endocrine cell differentiation by combining small RNA sequencing, miRNA over-expression, and network modeling approaches. Our analysis identified Let-7g, Let-7a, miR-200a, miR-127, and miR-375 as endocrine-enriched miRNAs that drive endocrine cell differentiation-associated gene expression changes. These miRNAs are predicted to target different transcription factors, which converge on genes involved in cell cycle regulation. When expressed in human embryonic stem cell-derived pancreatic progenitors, these miRNAs induce cell cycle exit and promote endocrine cell differentiation. Our study delineates the role of miRNAs in human endocrine cell differentiation and identifies miRNAs that could facilitate endocrine cell reprogramming

Potential impact of controlled drainage in Indiana watersheds

Due to naturally high groundwater tables, many soils in the Midwest need artificial drainage for economical crop production. However, nitrate carried in drainage water can lead to water quality problems. Controlled drainage is a strategy to reduce the nitrate loads and maintain adequate drainage from crop production by regulating drainage depth with a water-level control device at the drainage outlet. This dissertation addresses nitrate loads from subsurface drainage and the potential benefit of controlled drainage at the watershed scale. Two methods were applied to estimate the contribution of tile drains to watershed nitrate load: a statistical analysis of many watersheds and a simulation of water flow and chemical processes for a particular watershed. Watershed boundaries were delineated for 29 gaging stations in Indiana, where nitrate and flow have been monitored, and the percentage of each watershed that is drained by subsurface tile drains was estimated from soil, slope, and land use characteristics. Statistical models were developed to relate the percentage of the watershed with subsurface drains and the non-point source nitrate loads, with and without precipitation as an additional explanatory variable. Significant relationships were found for annual models both with and without precipitation, from February to June for monthly models without precipitation and from January to July for monthly models with precipitation. Expected annual and monthly non-point source nitrate loads were calculated for various percentages of drained area in Indiana watersheds based on the models with precipitation. Predicted annual non-point source nitrate load ranged from 383 kg/yr/km2 for a watershed with 0% drained area to 2750 kg/yr/km2 for a watershed with 100% drained area, which suggested that about 86% of non-point source nitrate coming from a 100% drained watershed would flow through tile drains. SWAT2005, with modified tile drain components, was used to simulate nitrate loss through tile drains in a heavily tile drained watershed in Indiana, the Sugar Creek watershed. Nitrate loads from surface flow, lateral flow, percolation and tile drains were estimated. The median percentage of monthly nitrate input to Sugar Creek that came from tile drains ranged from 0% to 37% over the 12 months, and was more than 30% from April to June. These estimates of nitrate from tile drains were used to predict the potential effects of controlled drainage at the watershed scale. Previous field and plot scale research in the Midwest suggested that the likely percentage reduction was 25% to 47% in Indiana. For 29 watersheds in Indiana, areas with high and medium potential for controlled drainage were estimated based on appropriate crop, soil types and topography. If controlled drainage was applied in all fields with high potential, the watershed-scale percentage of reduction could reach 8.7-16.4%. If areas with medium potential also had controlled drainage installed, the reduction could reach to 14.3-26.9%

Nose tip detection on three‐dimensional faces using pose‐invariant differential surface features

Three‐dimensional (3D) facial data offer the potential to overcome the difficulties caused by the variation of head pose and illumination in 2D face recognition. In 3D face recognition, localisation of nose tip is essential to face normalisation, face registration and pose correction etc. Most of the existing methods of nose tip detection on 3D face deal mainly with frontal or near‐frontal poses or are rotation sensitive. Many of them are training‐based or model‐based. In this study, a novel method of nose tip detection is proposed. Using pose‐invariant differential surface features – high‐order and low‐order curvatures, it can detect nose tip on 3D faces under various poses automatically and accurately. Moreover, it does not require training and does not depend on any particular model. Experimental results on GavabDB verify the robustness and accuracy of the proposed method

Beta-cell dysfunction induced by non-cytotoxic concentrations of Interleukin-1 beta is associated with changes in expression of beta-cell maturity genes and associated histone modifications

Decreased insulin secretory capacity in Type 2 diabetes mellitus is associated with beta-cell dedifferentiation and inflammation. We hypothesize that prolonged exposure of beta-cells to low concentrations of IL-1β induce beta-cell dedifferentiation characterized by impaired glucose-stimulated insulin secretion, reduced expression of key beta-cell genes and changes in histone modifications at gene loci known to affect beta-cell function. Ten days exposure to IL-1β at non-cytotoxic concentrations reduced insulin secretion and beta-cell proliferation and decreased expression of key beta-cell identity genes, including MafA and Ucn3 and decreased H3K27ac at the gene loci, suggesting that inflammatory cytokines directly affects the epigenome. Following removal of IL-1β, beta-cell function was normalized and mRNA expression of beta-cell identity genes, such as insulin and Ucn3 returned to pre-stimulation levels. Our findings indicate that prolonged exposure to low concentrations of IL-1β induces epigenetic changes associated with loss of beta-cell identity as observed in Type 2 diabetes

Undercarboxylated osteocalcin inhibits the early differentiation of osteoclast mediated by Gprc6a

Osteocalcin (OCN) was the most abundant noncollagen protein and considered as an endocrine factor. However, the functions of Undercarboxylated osteocalcin (ucOCN) on osteoclast and bone resorption are not well understood. In the present study, preosteoclast RAW264.7 cells and bone marrow mononuclear cells (BMMs) were treated with ucOCN purified from prokaryotic bacteria. Our results showed that ucOCN attenuated the proliferation of RAW264.7 cells with a concentration dependant manner by MTS assay. Scrape wounding assay revealed the decreased motility of RAW264.7 cells after ucOCN treatment. RT-qPCR results manifested the inhibitory effects of ucOCN on the expression of osteoclastic marker genes in RAW264.7 cells during inducing differentiation of RANKL. It was also observed that ucOCN inhibited the formation of multinucleated cells from RAW264.7 cells and BMMs detected by TRAP staining. The number and area of bone resorb pits were also decreased after treatment with ucOCN during their osteoclast induction by toluidine blue staining. The formation and integrity of the osteoclast actin ring were impaired by ucOCN by immunofluorescent staining. Time dependant treatment of ucOCN during osteoclastic induction demonstrated the inhibitory effects mainly occurred at the early stage of osteoclastogenesis. Signaling analysis of luciferase activity of the CRE or SRE reporter and ERK1/2 phosphorylation showed the selective inhibitor or siRNA of Gprc6a (a presumptive ucOCN receptor) could attenuate the promotion of ucOCN on CRE-luciferase activity. Taken together, we provided the first evidence that ucOCN had negative effects on the early differentiation and bone resorption of osteoclasts via Gprc6a

Effects of 10-Day Complete Fasting on Physiological Homeostasis, Nutrition and Health Markers in Male Adults

Fasting shows great potential in preventing chronic diseases and has to be surmounted under some extraordinary circumstances. This study aimed to investigate the safety, time effects of metabolic homeostasis and health indexes during prolonged fasting. Thirteen participants were recruited to conduct a 10-day complete fasting (CF) in a controlled health research building under medical supervision including 3-day Baseline (BL), 10-day CF, 4-day calorie restriction (CR) and 5-day full recovery (FR). Body healthy status was assessed by surveying pulse, blood pressure, body weight (BW), blood glucose and ketones, body composition and nutritional and biochemistry indexes at different times. BW declined about 7.28 kg (−9.8%) after 10-day CF, accompanied by increased pulse and decreased systolic blood pressure, but there were no changes to the myocardial enzymogram. Body composition analysis showed fat mass was constantly lost, but lean mass could recover after CR. The energy substrate switch from glucose to ketone occurred and formed a stable dynamic balance between 3–6 days of CF. The lipid metabolism presented increased total cholesterol, LDL-C, ApoA1 and almost no changes to TG and HDL-C. Prolonged CF did not influence liver function, but induced a slight decrease of kidney function. The interesting results came from the marked increase of lipid-soluble vitamins and a significant decrease of sodium and chlorine. Adults could well tol-erate a 10-day CF. A new metabolic homeostasis was achieved. No vitamins but NaCl supplement should be considered. These findings provide evidence to design a new fasting strategy for clinical practice

Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding

Insufficient insulin secretion is a hallmark of type 2 diabetes and has been attributed to beta cell identity loss characterized by decreased expression of several key beta cell genes. The pro-inflammatory factor BMP-2 is upregulated in islets of Langerhans from individuals with diabetes and acts as an inhibitor of beta cell function and proliferation. Exposure to BMP-2 induces expression of Id1-4, Hes-1, and Hey-1 which are transcriptional regulators associated with loss of differentiation. The aim of this study was to investigate the mechanism by which BMP-2 induces beta cell dysfunction and loss of cell maturity. Mouse islets exposed to BMP-2 for 10 days showed impaired glucose-stimulated insulin secretion and beta cell proliferation. BMP-2-induced beta cell dysfunction was associated with decreased expression of cell maturity and proliferation markers specific to the beta cell such as Ins1, Ucn3, and Ki67 and increased expression of Id1-4, Hes-1, and Hey-1. The top 30 most regulated proteins significantly correlated with corresponding mRNA expression. BMP-2-induced gene expression changes were associated with a predominant reduction in acetylation of H3K27 and a decrease in NeuroD1 chromatin binding activity. These results show that BMP-2 induces loss of beta cell maturity and suggest that remodeling of H3K27ac and decreased NeuroD1 DNA binding activity participate in the effect of BMP-2 on beta cell dysfunction

Expression statistic of different lncRNAs and mRNA.

<p>Expression statistic of different lncRNAs and mRNA.</p