Protein markers for insulin-producing beta cells with higher glucose sensitivity

Background and Methodology: Pancreatic beta cells show intercellular differences in their metabolic glucose sensitivity and associated activation of insulin production. To identify protein markers for these variations in functional glucose sensitivity, rat beta cell subpopulations were flow-sorted for their level of glucose-induced NAD(P) H and their proteomes were quantified by label-free data independent alternate scanning LC-MS. Beta cell-selective proteins were also identified through comparison with rat brain and liver tissue and with purified islet alpha cells, after geometrical normalization using 6 stably expressed reference proteins. Principal Findings: All tissues combined, 943 proteins were reliably quantified. In beta cells, 93 out of 467 quantifiable proteins were uniquely detected in this cell type; several other proteins presented a high molar abundance in beta cells. The proteome of the beta cell subpopulation with high metabolic and biosynthetic responsiveness to 7.5 mM glucose was characterized by (i) an on average 50% higher expression of protein biosynthesis regulators such as 40S and 60S ribosomal constituents, NADPH-dependent protein folding factors and translation elongation factors; (ii) 50% higher levels of enzymes involved in glycolysis and in the cytosolic arm of the malate/aspartate-NADH-shuttle. No differences were noticed in mitochondrial enzymes of the Krebs cycle, beta-oxidation or respiratory chain. Conclusions: Quantification of subtle variations in the proteome using alternate scanning LC-MS shows that beta cell metabolic glucose responsiveness is mostly associated with higher levels of glycolytic but not of mitochondrial enzymes

Human pancreatic islet preparations release HMGB1: (ir)relevance for graft engraftment.

High levels of donor-derived high-mobility group box 1 (HMGB1) protein have been associated with poor islet graft outcome in mouse models. The aim of our work was to determine whether HMGB1 released by human islets had independent proinflammatory effects that influence engraftment in humans. Human islet preparations contained and released HMGB1 in different amounts, as determined by Western blot and ELISA (median 17 pg/ml/IEQ/24 h; min–max 0–211, n = 74). HMGB1 release directly correlated with brain death, donor hyperamilasemia, and factors related to the pancreas digestion procedure (collagenase and digestion time). HMGB1 release was significantly positively associated with the release of other cytokines/chemokines, particularly with the highly released "proinflammatory" CXCL8/IL-8, CXCL1/GRO-α, and the IFN-γ-inducible chemokines CXCL10/IP-10 and CXCL9/MIG. HMGB1 release was not modulated by Toll-like receptor 2, 3, 4, 5, and 9 agonists or by exposure to IL-1β. When evaluated after islet transplantation, pretransplant HMGB1 release was weakly associated with the activation of the coagulation cascade (evaluated as serum cross-linked fibrin products), but not with the immediate posttransplant inflammatory response. Concordantly, HMGB1 did not affect short-term human islet function. Our data show that human islet HMGB1 release is a sign of "damaged" islets, although without any independent direct role in graft failure

Interface-Induced Sign Reversal of the Anomalous Hall Effect in Magnetic Topological Insulator Heterostructures

The Berry phase picture provides important insights into the electronic properties of condensed matter systems. The intrinsic anomalous Hall (AH) effect can be understood as a consequence of non-zero Berry curvature in momentum space. The realization of the quantum anomalous Hall effect provided conclusive evidence for the intrinsic mechanism of the AH effect in magnetic topological insulators (TIs). Here we fabricated magnetic TI/TI heterostructures and found both the magnitude and sign of the AH effect in the magnetic TI layer can be altered by tuning the TI thickness and/or the electric gate voltage. The sign change of the AH effect with increasing TI thickness is attributed to the charge transfer across the TI and magnetic TI layers, consistent with first-principles calculations. By fabricating the magnetic TI/TI/magnetic TI sandwich heterostructures with different dopants, we created an artificial topological Hall (TH) effect-like feature in Hall traces. This artificial TH effect is induced by the superposition of two AH effects with opposite signs instead of the formation of chiral spin textures in the samples. Our study provides a new route to engineer the Berry curvature in magnetic topological materials that may lead to potential technological applications.Comment: 28 pages, 5 figures. Accepted versio

Plasticity of Adult Human Pancreatic Duct Cells by Neurogenin3-Mediated Reprogramming

AIMS/HYPOTHESIS: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. METHODS: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. RESULTS: Ngn3 stimulates duct cells to express a focused set of genes that are characteristic for islet endocrine cells and/or neural tissues. This neuro-endocrine shift however, is incomplete with less than 10% of full duct-to-endocrine reprogramming achieved. Transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. CONCLUSIONS/INTERPRETATION: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes

Effect of streptozotocin and nicotinamide upon FAD-glycerophosphate dehydrogenase activity and insulin release in purified pancreatic B-cells

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Global Dynamics of a Discretized Heroin Epidemic Model with Time Delay

We derive a discretized heroin epidemic model with delay by applying a nonstandard finite difference scheme. We obtain positivity of the solution and existence of the unique endemic equilibrium. We show that heroin-using free equilibrium is globally asymptotically stable when the basic reproduction number R01

Research on path planning of cleaning robot based on an improved ant colony algorithm

The conventional ant colony algorithm is easy to fall into the local optimal in some complex environments, and the blindness in the initial stage of search leads to long searching time and slow convergence. In order to solve these problems, this paper proposes an improved ant colony algorithm and applies it to the path planning of cleaning robot. The algorithm model of the environmental map is established according to the grid method. And it built the obstacle matrix for the expansion and treatment of obstacles, so that the robot can avoid collision with obstacles as much as possible in the process of movement. The directional factor is introduced in the new heuristic function, and we can reduce the value of the inflection point of paths, enhance the algorithm precision, and avoid falling into the local optimal. The volatile factor of pheromones with an adaptive adjustment and the improved updating rule of pheromones can not only solve the problem that the algorithm falls into local optimum, but also accelerate the running efficiency of the algorithm in the later stage. Simulation results show that the algorithm has the better global searching ability, the convergence speed is obviously accelerated, and an optimal path can be planned in the complex environment