The CaVβ Subunit Protects the I-II Loop of the Voltage-gated Calcium Channel CaV2.2 from Proteasomal Degradation but Not Oligoubiquitination.

CaVβ subunits interact with the voltage-gated calcium channel CaV2.2 on a site in the intracellular loop between domains I and II (the I-II loop). This interaction influences the biophysical properties of the channel and leads to an increase in its trafficking to the plasma membrane. We have shown previously that a mutant CaV2.2 channel that is unable to bind CaVβ subunits (CaV2.2 W391A) was rapidly degraded (Waithe, D., Ferron, L., Page, K. M., Chaggar, K., and Dolphin, A. C. (2011) J. Biol. Chem. 286, 9598-9611). Here we show that, in the absence of CaVβ subunits, a construct consisting of the I-II loop of CaV2.2 was directly ubiquitinated and degraded by the proteasome system. Ubiquitination could be prevented by mutation of all 12 lysine residues in the I-II loop to arginines. Including a palmitoylation motif at the N terminus of CaV2.2 I-II loop was insufficient to target it to the plasma membrane in the absence of CaVβ subunits even when proteasomal degradation was inhibited with MG132 or ubiquitination was prevented by the lysine-to-arginine mutations. In the presence of CaVβ subunit, the palmitoylated CaV2.2 I-II loop was protected from degradation, although oligoubiquitination could still occur, and was efficiently trafficked to the plasma membrane. We propose that targeting to the plasma membrane requires a conformational change in the I-II loop that is induced by binding of the CaVβ subunit

Black Hole Emission in String Theory and the String Phase of Black Holes

String theory properly describes black-hole evaporation. The quantum string emission by Black Holes is computed. The black-hole temperature is the Hawking temperature in the semiclassical quantum field theory (QFT) regime and becomes the intrinsic string temperature, T_s, in the quantum (last stage) string regime. The QFT-Hawking temperature T_H is upper bounded by the string temperature T_S. The black hole emission spectrum is an incomplete gamma function of (T_H - T_S). For T_H << T_S, it yields the QFT-Hawking emission. For T_H \to T_S, it shows highly massive string states dominate the emission and undergo a typical string phase transition to a microscopic `minimal' black hole of mass M_{\min} or radius r_{\min} (inversely proportional to T_S) and string temperature T_S. The string back reaction effect (selfconsistent black hole solution of the semiclassical Einstein equations) is computed. Both, the QFT and string black hole regimes are well defined and bounded.The string `minimal' black hole has a life time tau_{min} simeq (k_B c)/(G hbar [T_S]^3). The semiclassical QFT black hole (of mass M and temperature T_H) and the string black hole (of mass M_{min} and temperature T_S) are mapped one into another by a `Dual' transform which links classical/QFT and quantum string regimes.Comment: LaTex, 22 pages, Lectures delivered at the Chalonge School, Nato ASI: Phase Transitions in the Early Universe: Theory and Observations. To appear in the Proceedings, Editors H. J. de Vega, I. Khalatnikov, N. Sanchez. (Kluwer Pub

The information paradox: conflicts and resolutions

Many relativists have been long convinced that black hole evaporation leads to information loss or remnants. String theorists have however not been too worried about the issue, largely due to a belief that the Hawking argument for information loss is flawed in its details. A recently derived inequality shows that the Hawking argument for black holes with horizon can in fact be made rigorous. What happens instead is that in string theory black hole microstates have no horizons. Thus the evolution of radiation quanta with E ~ kT is modified by order unity at the horizon, and we resolve the information paradox. We discuss how it is still possible for E >> kT objects to see an approximate black hole like geometry. We also note some possible implications of this physics for the early Universe.Comment: 26 pages, 8 figures, Latex; (Expanded version of) proceedings for Lepton-Photon 201

Accretion, Primordial Black Holes and Standard Cosmology

Primordial Black Holes evaporate due to Hawking radiation. We find that the evaporation time of primordial black holes increase when accretion of radiation is included.Thus depending on accretion efficiency more and more number of primordial black holes are existing today, which strengthens the idea that the primordial black holes are the proper candidate for dark matter.Comment: 11 pages, 3 figure

CPT Violation, Strings, and Neutral-Meson Systems

This talk provides a short overview of recent results on possible CPT violation and some associated experimental signatures.Comment: Presented at Orbis Scientiae, January 199

Quantum Back Reaction to asymptotically AdS Black Holes

We analyze the effects of the back reaction due to a conformal field theory (CFT) on a black hole spacetime with negative cosmological constant. We study the geometry numerically obtained by taking into account the energy momentum tensor of CFT approximated by a radiation fluid. We find a sequence of configurations without a horizon in thermal equilibrium (CFT stars), followed by a sequence of configurations with a horizon. We discuss the thermodynamic properties of the system and how back reaction effects alter the space-time structure. We also provide an interpretation of the above sequence of solutions in terms of the AdS/CFT correspondence. The dual five-dimensional description is given by the Karch-Randall model, in which a sequence of five-dimensional floating black holes followed by a sequence of brane localized black holes correspond to the above solutions.Comment: 13 pages, 10 figure

The holographic principle

There is strong evidence that the area of any surface limits the information content of adjacent spacetime regions, at 10^(69) bits per square meter. We review the developments that have led to the recognition of this entropy bound, placing special emphasis on the quantum properties of black holes. The construction of light-sheets, which associate relevant spacetime regions to any given surface, is discussed in detail. We explain how the bound is tested and demonstrate its validity in a wide range of examples. A universal relation between geometry and information is thus uncovered. It has yet to be explained. The holographic principle asserts that its origin must lie in the number of fundamental degrees of freedom involved in a unified description of spacetime and matter. It must be manifest in an underlying quantum theory of gravity. We survey some successes and challenges in implementing the holographic principle.Comment: 52 pages, 10 figures, invited review for Rev. Mod. Phys; v2: reference adde

An Exact Formula for the Average Run Length to False Alarm of the Generalized Shiryaev-Roberts Procedure for Change-Point Detection under Exponential Observations

We derive analytically an exact closed-form formula for the standard minimax Average Run Length (ARL) to false alarm delivered by the Generalized Shiryaev-Roberts (GSR) change-point detection procedure devised to detect a shift in the baseline mean of a sequence of independent exponentially distributed observations. Specifically, the formula is found through direct solution of the respective integral (renewal) equation, and is a general result in that the GSR procedure's headstart is not restricted to a bounded range, nor is there a "ceiling" value for the detection threshold. Apart from the theoretical significance (in change-point detection, exact closed-form performance formulae are typically either difficult or impossible to get, especially for the GSR procedure), the obtained formula is also useful to a practitioner: in cases of practical interest, the formula is a function linear in both the detection threshold and the headstart, and, therefore, the ARL to false alarm of the GSR procedure can be easily computed.Comment: 9 pages; Accepted for publication in Proceedings of the 12-th German-Polish Workshop on Stochastic Models, Statistics and Their Application

The entropy of black holes: a primer

After recalling the definition of black holes, and reviewing their energetics and their classical thermodynamics, one expounds the conjecture of Bekenstein, attributing an entropy to black holes, and the calculation by Hawking of the semi-classical radiation spectrum of a black hole, involving a thermal (Planckian) factor. One then discusses the attempts to interpret the black-hole entropy as the logarithm of the number of quantum micro-states of a macroscopic black hole, with particular emphasis on results obtained within string theory. After mentioning the (technically cleaner, but conceptually more intricate) case of supersymmetric (BPS) black holes and the corresponding counting of the degeneracy of Dirichlet-brane systems, one discusses in some detail the ``correspondence'' between massive string states and non-supersymmetric Schwarzschild black holes.Comment: 51 pages, 4 figures, talk given at the "Poincare seminar" (Paris, 6 December 2003), to appear in Poincare Seminar 2003 (Birkhauser

Smoking, coffee intake, and Parkinson's disease: Potential protective mechanisms and components.

Parkinson's disease (PD) is a common progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Environmental and lifestyle factors, such as smoking and coffee drinking, have been associated with a decreased risk for PD. However, the biological mechanisms underlying protective effects on PD are still not fully understood. It has been suggested that non-nicotine components in cigarette smoke and non-caffeine components in coffee may contribute to this protective effect. The aim of this review was to explore candidate molecules and mechanisms behind the effects of smoking and coffee drinking on PD by integrating findings from previous studies. By cross-referencing an index of tobacco constituents and a list of coffee constituents with existing literature on natural compounds and their structural analogs that show inhibitory activities against monoamine oxidase B, catechol O-methyltransferase, and α-synuclein fibrillation, we have identified tobacco and coffee components that inhibit these targets. Furthermore, tobacco and coffee components potentially play roles in suppressing neuroinflammation, activating the Nrf2 pathway as natural activators, and altering the gut microbiome. This review suggests that the phenolic compounds from tobacco and coffee investigated may contribute to the low incidence of PD in smokers and coffee drinkers, showing moderate to strong potential as therapeutic interventions. The current review suggests that multifunctional molecules found in coffee and cigarette smoke may have potential neuroprotective effects, but none of the data indicates that multifunctionality is required for these effects. This review will deepen our understanding of how smoking and coffee drinking are linked to a reduced risk of PD and will also be important in elucidating the mechanisms underlying the protective effects of smoking and coffee drinking on PD.fals