Loop quantization of spherically symmetric midi-superspaces

We quantize the exterior of spherically symmetric vacuum space-times using a midi-superspace reduction within the Ashtekar new variables. Through a partial gauge fixing we eliminate the diffeomorphism constraint and are left with a Hamiltonian constraint that is first class. We complete the quantization in the loop representation. We also use the model to discuss the issues that will arise in more general contexts in the ``uniform discretization'' approach to the dynamics.Comment: 18 pages, RevTex, no figures, some typos corrected, published version, for some reason a series of figures were incorrectly added to the previous versio

Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor

Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients

Physical boundary Hilbert space and volume operator in the Lorentzian new spin-foam theory

A covariant spin-foam formulation of quantum gravity has been recently developed, characterized by a kinematics which appears to match well the one of canonical loop quantum gravity. In this paper we reconsider the implementation of the constraints that defines the model. We define in a simple way the boundary Hilbert space of the theory, introducing a slight modification of the embedding of the SU(2) representations into the SL(2,C) ones. We then show directly that all constraints vanish on this space in a weak sense. The vanishing is exact (and not just in the large quantum number limit.) We also generalize the definition of the volume operator in the spinfoam model to the Lorentzian signature, and show that it matches the one of loop quantum gravity, as does in the Euclidean case.Comment: 11 page

Quantization of Midisuperspace Models

We give a comprehensive review of the quantization of midisuperspace models. Though the main focus of the paper is on quantum aspects, we also provide an introduction to several classical points related to the definition of these models. We cover some important issues, in particular, the use of the principle of symmetric criticality as a very useful tool to obtain the required Hamiltonian formulations. Two main types of reductions are discussed: those involving metrics with two Killing vector fields and spherically symmetric models. We also review the more general models obtained by coupling matter fields to these systems. Throughout the paper we give separate discussions for standard quantizations using geometrodynamical variables and those relying on loop quantum gravity inspired methods.Comment: To appear in Living Review in Relativit

Loop quantum gravity: the first twenty five years

This is a review paper invited by the journal "Classical ad Quantum Gravity" for a "Cluster Issue" on approaches to quantum gravity. I give a synthetic presentation of loop gravity. I spell-out the aims of the theory and compare the results obtained with the initial hopes that motivated the early interest in this research direction. I give my own perspective on the status of the program and attempt of a critical evaluation of its successes and limits.Comment: 24 pages, 3 figure

The Spin Foam Approach to Quantum Gravity

This article reviews the present status of the spin foam approach to the quantization of gravity. Special attention is payed to the pedagogical presentation of the recently introduced new models for four dimensional quantum gravity. The models are motivated by a suitable implementation of the path integral quantization of the Plebanski formulation of gravity on a simplicial regularization. The article also includes a self-contained treatment of the 2+1 gravity. The simple nature of the latter provides the basis and a perspective for the analysis of both conceptual and technical issues that remain open in four dimensions.Comment: To appear in Living Reviews in Relativit

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease