Tracking Ca2+ Dynamics in NOD Mouse Islets During Spontaneous Diabetes Development.

Unlabelled: The mechanisms accounting for the functional changes of α- and β-cells over the course of type 1 diabetes (T1D) development are largely unknown. Permitted by our established technology of high spatiotemporal resolution imaging of cytosolic Ca2+ ([Ca2+]c) dynamics on fresh pancreas tissue slices, we tracked the [Ca2+]c dynamic changes, as the assessment of function, in islet α- and β-cells of female nonobese diabetic (NOD) mice during the development of spontaneous diabetes. We showed that, during the phases of islet inflammation, 8 mmol/L glucose-induced synchronized short [Ca2+]c events in β-cells were diminished, whereas long [Ca2+]c events were gradually more triggerable at substimulatory 4 and 6 mmol/L glucose.

High-resolution analysis of the cytosolic Ca events in β cell collectives in situ.

The release of peptide hormones is predominantly regulated by a transient increase in cytosolic Ca concentration ([Ca]). To trigger exocytosis, Ca ions enter the cytosol from intracellular Ca stores or from the extracellular space. The molecular events of late stages of exocytosis, and their dependence on [Ca], were extensively described in isolated single cells from various endocrine glands.

Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levels.

Adrenaline inhibits insulin secretion from pancreatic beta cells to allow an organism to cover immediate energy needs by unlocking internal nutrient reserves. The stimulation of α2-adrenergic receptors on the plasma membrane of beta cells reduces their excitability and insulin secretion mostly through diminished cAMP production and downstream desensitization of late step(s) of exocytotic machinery to cytosolic Ca concentration ([Ca]). In most studies unphysiologically high adrenaline concentrations have been used to evaluate the role of adrenergic stimulation in pancreatic endocrine cells.

pH-Dependence of Glucose-Dependent Activity of Beta Cell Networks in Acute Mouse Pancreatic Tissue Slice.

Extracellular pH has the potential to affect various aspects of the pancreatic beta cell function. To explain this effect, a number of mechanisms was proposed involving both extracellular and intracellular targets and pathways. Here, we focus on reassessing the influence of extracellular pH on glucose-dependent beta cell activation and collective activity in physiological conditions.

Predicting bacterial promoter function and evolution from random sequences.

Predicting function from sequence is a central problem of biology. Currently, this is possible only locally in a narrow mutational neighborhood around a wildtype sequence rather than globally from any sequence. Using random mutant libraries, we developed a biophysical model that accounts for multiple features of σ binding bacterial promoters to predict constitutive gene expression levels from any sequence.

Dual Mode of Action of Acetylcholine on Cytosolic Calcium Oscillations in Pancreatic Beta and Acinar Cells In Situ.

Cholinergic innervation in the pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in detail for endocrine beta cells and exocrine acinar cells separately. Here we describe morphological and functional criteria to separate these two cell types in situ in tissue slices and simultaneously measure their response to ACh stimulation on cytosolic Ca oscillations [Ca] in stimulatory glucose conditions.

Regulatory network structure determines patterns of intermolecular epistasis.

Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses.

Axial symmetry breaking in self-induced flavor conversionof supernova neutrino fluxes.

Neutrino-neutrino refraction causes self-induced flavor conversion in dense neutrino fluxes. For the first time, we include the azimuth angle of neutrino propagation as an explicit variable and find a new generic multi-azimuth-angle instability which, for simple spectra, occurs in the normal neutrino mass hierarchy. Matter suppression of this instability in supernovae requires larger densities than the traditional bimodal case.

Suppression of self-induced flavor conversion in the supernova accretion phase.

Self-induced flavor conversions of supernova (SN) neutrinos can strongly modify the flavor-dependent fluxes. We perform a linearized flavor stability analysis with accretion-phase matter profiles of a 15M[symbol: see text] spherically symmetric model and corresponding neutrino fluxes. We use realistic energy and angle distributions, the latter deviating strongly from quasi-isotropic emission, thus accounting for both multiangle and multienergy effects.