Targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death

AbstractPro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.</jats:p

The infinite-range quantum random Heisenberg magnet

We study with exact diagonalization techniques the Heisenberg model for a system of SU(2) spins with S=1/2 and random infinite-range exchange interactions. We calculate the critical temperature T_g for the spin-glass to paramagnetic transition. We obtain T_g ~ 0.13, in good agreement with previous quantum Monte Carlo and analytical estimates. We provide a detailed picture for the different kind of excitations which intervene in the dynamical response chi''(w,T) at T=0 and analyze their evolution as T increases. We also calculate the specific heat Cv(T). We find that it displays a smooth maximum at TM ~ 0.25, in good qualitative agreement with experiments. We argue that the fact that TM>Tg is due to a quantum disorder effect.Comment: 17 pages, 14 figure

Unification Picture in Minimal Supersymmetric SU(5) Model with String Remnants

The significant heavy threshold effect is found in the supersymmetric SU(5) model with two adjoint scalars, one of which is interpreted as a massive string mode decoupled from the lower-energy particle spectra. This threshold related with the generic mass splitting of the basic adjoint moduli is shown to alter properly the running of gauge couplings, thus giving a natural solution to the string-scale grand unification as prescribed at low energies by LEP precision measurements and minimal particle content. The further symmetry condition of the (top-bottom) Yukawa and gauge coupling superunification at a string scale results in the perfectly working predictions for the top and bottom quark masses in the absence of any large supersymmetric threshold corrections.Comment: published versio

Metal-Insulator Transition and Magnetic Order in the Pyrochlore Oxide Hg2Ru2O7

We report results of NMR experiments on the ruthenium oxide Hg2Ru2O7 with the pyrochlore structure, which exhibits a metal-insulator transition at TMI = 107 K. In the metallic phase above TMI, the nuclear spin-lattice relaxation rate 1/T1 and the Knight shift at the Hg sites follow the Korringa relation, indicating the absence of substantial spatial spin correlation. At low temperatures in the insulating phase, 99,101Ru-NMR signals are observed at zero magnetic field, providing evidence for a commensurate antiferromagnetic order. The estimated ordered moment is about 1 muB per Ru, much smaller than 3 muB expected for the ionic (4d)3plus configuration of Ru5plus. Thus the localized spin models are not appropriate for the insulating phase of Hg2Ru2O7. We also discuss possible antiferromagnetic spin structures.Comment: 10 pages, 7 figure

Eukaryotic G Protein Signaling Evolved to Require G Protein-Coupled Receptors for Activation

Although bioinformatic analysis of the increasing numbers of diverse genome sequences and amount of functional data has provided insight into the evolution of signaling networks, bioinformatics approaches have limited application for understanding the evolution of highly divergent protein families. We used biochemical analyses to determine the in vitro properties of selected divergent components of the heterotrimeric guanine nucleotide–binding protein (G protein) signaling network to investigate signaling network evolution. In animals, G proteins are activated by cell-surface seven-transmembrane (7TM) receptors, which are named G protein–coupled receptors (GPCRs) and function as guanine nucleotide exchange factors (GEFs). In contrast, the plant G protein is intrinsically active, and a 7TM protein terminates G protein activity by functioning as a guanosine triphosphatase–activating protein (GAP). We showed that ancient regulation of the G protein active state is GPCR-independent and “self-activating,” a property that is maintained in Bikonts, one of the two fundamental evolutionary clades containing eukaryotes, whereas G proteins of the other clade, the Unikonts, evolved from being GEF-independent to being GEF-dependent. Self-activating G proteins near the base of the Eukaryota are controlled by 7TM-GAPs, suggesting that the ancestral regulator of G protein activation was a GAP-functioning receptor, not a GEF-functioning GPCR. Our findings indicate that the GPCR paradigm describes a recently evolved network architecture found in a relatively small group of Eukaryota and suggest that the evolution of signaling network architecture is constrained by the availability of molecules that control the activation state of nexus proteins

Enthalpy and the Mechanics of AdS Black Holes

We present geometric derivations of the Smarr formula for static AdS black holes and an expanded first law that includes variations in the cosmological constant. These two results are further related by a scaling argument based on Euler's theorem. The key new ingredient in the constructions is a two-form potential for the static Killing field. Surface integrals of the Killing potential determine the coefficient of the variation of the cosmological constant in the first law. This coefficient is proportional to a finite, effective volume for the region outside the AdS black hole horizon, which can also be interpreted as minus the volume excluded from a spatial slice by the black hole horizon. This effective volume also contributes to the Smarr formula. Since the cosmological constant is naturally thought of as a pressure, the new term in the first law has the form of effective volume times change in pressure that arises in the variation of the enthalpy in classical thermodynamics. This and related arguments suggest that the mass of an AdS black hole should be interpreted as the enthalpy of the spacetime.Comment: 21 pages; v2 references adde