Endocrine pancreatic beta cells require endothelial signals for their differentiation and function. However, the molecular basis for such signals remains unknown. Here, we show that beta cells, in contrast to the exocrine pancreatic cells, do not form a basement membrane. Instead, by using VEGF-A, they attract endothelial cells, which form capillaries with a vascular basement membrane next to the beta cells. We have identified laminins, among other vascular basement membrane proteins, as endothelial signals, which promote insulin gene expression and proliferation in beta cells. We further demonstrate that beta1-integrin is required for the beta cell response to the laminins. The proposed mechanism explains why beta cells must interact with endothelial cells, and it may apply to other cellular processes in which endothelial signals are required.

RNA interference (RNAi) is an evolutionarily conserved defence mechanism whereby genes are specifically silenced through degradation of messenger RNAs; this process is mediated by homologous double-stranded (ds)RNA molecules. In invertebrates, long dsRNAs have been used for genome-wide screens and have provided insights into gene functions. Because long dsRNA triggers a nonspecific interferon response in many vertebrates, short interfering (si)RNA or short hairpin (sh)RNAs must be used for these organisms to ensure specific gene silencing. Here we report the generation of a genome-scale library of endoribonuclease-prepared short interfering (esi)RNAs from a sequence-verified complementary DNA collection representing 15,497 human genes. We used 5,305 esiRNAs from this library to screen for genes required for cell division in HeLa cells. Using a primary high-throughput cell viability screen followed by a secondary high content videomicroscopy assay, we identified 37 genes required for cell division. These include several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Thus, our study uncovers new aspects of cell division and establishes esiRNA as a versatile approach for genomic RNAi screens in mammalian cells.

In vertebrates, beta cells are aggregated in the form of pancreatic islets. Within these islets, communication between beta cells inhibits basal insulin secretion and enhances glucose-stimulated insulin secretion, thus contributing to glucose homeostasis during fasting and feeding. In the search for the underlying molecular mechanism, we have discovered that beta cells communicate via ephrin-As and EphAs. We provide evidence that ephrin-A5 is required for glucose-stimulated insulin secretion. We further show that EphA-ephrin-A-mediated beta cell communication is bidirectional: EphA forward signaling inhibits insulin secretion, whereas ephrin-A reverse signaling stimulates insulin secretion. EphA forward signaling is downregulated in response to glucose, which indicates that, under basal conditions, beta cells use EphA forward signaling to suppress insulin secretion and that, under stimulatory conditions, they shift to ephrin-A reverse signaling to enhance insulin secretion. Thus, we explain how beta cell communication in pancreatic islets conversely affects basal and glucose-stimulated insulin secretion to improve glucose homeostasis.

Immune changes during space flights in excess of two weeks have been almost exclusively studied by Russian investigators. Most of these studies have compared postflight values with those obtained before flight. In a very few cases, analyses have also been attempted during flight or with samples collected during flight. Studies of cosmonauts during spaceflight have shown that IgG levels were unchanged, whereas IgA and IgM levels were sometimes increased. Additionally, inflight delayed type hypersensitivity testing demonstrated a decrease below the warning level in 1/3 of the cosmonauts tested. Pre- vs. postflight analyses have often revealed a postflight decrease in: PHA-triggered lymphocyte blast transformation; the proliferation index of T-lymphocytes in the xenogeneic graft versus host reaction; the mitogen-induced production of interleukin-2; the presence of certain leukocyte sub sets; and cytotoxic activity of natural killer cells. Other factors that either did not change, or changed in an apparently random manner after flight included: production of alpha and gamma interferon; autoimmune tests; and globulin classes.

Microvascular development is determined by the interplay between tissue cells and microvascular endothelial cells. Because the pancreatic islet is an organ composed mainly of endothelial and endocrine cells, it represents a good model tissue for studying microvascular development in the context of a tissue. In this review, we will describe the special morphology of islet capillaries and its role in the physiologic function of islets: secretion of insulin in response to blood glucose levels. We will speculate on how islet-secreted VEGF-A generates a permeable endothelium that allows insulin to pass quickly into the blood stream. In addition, we speculate on how endothelial cells might form a capillary lumen within the islets. At the end, we look at the islet microvasculature from a medical point of view, thus describing its critical role during type I diabetes and islet transplantation.

IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

Experiments were carried out aboard COSMOS 2044 to determine the effects of spaceflight on immunologically important cell function and distribution. Control groups included vivarium, synchronous, and antiorthostatically suspended rats. In one experiment, rat bone marrow cells were examined in Moscow, for their response to recombinant murine granulocyte/monocyte colony-stimulating factor (GM-CSF). In another experiment, rat spleen and bone marrow cells were stained in Moscow with a variety of antibodies directed against cell surface antigenic markers. These cells were preserved and shipped to the United States for analysis on a flow cytometer. Bone marrow cells from flown and suspended rats showed a decreased response to granulocyte/monocyte colony-stimulating factor compared with bone marrow cells from control rats. Of the spleen cell subpopulations examined from flown rats, only those cells expressing markers for suppressor-cytotoxic T- and helper T-cells showed an increased percentage of stained cells. Bone marrow cells showed an increase in the percentage of cells expressing markers for helper T-cells in the myelogenous population and increased percentages of anti-asialo granulocyte/monocyte-1-bearing interleukin-2 receptor-bearing pan T- and helper T-cells in the lymphocytic population. Cell populations from rats suspended antiorthostatically did not follow the same pattern of distribution of leukocytes as cell populations for flown rats. The results from COSMOS 2044 are similar, but not identical, to earlier results from COSMOS 1887 and confirm that spaceflight can have profound effects on immune system components and activities.

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