Isolated and dynamical horizons and their applications

Over the past three decades, black holes have played an important role in quantum gravity, mathematical physics, numerical relativity and gravitational wave phenomenology. However, conceptual settings and mathematical models used to discuss them have varied considerably from one area to another. Over the last five years a new, quasi-local framework was introduced to analyze diverse facets of black holes in a unified manner. In this framework, evolving black holes are modeled by dynamical horizons and black holes in equilibrium by isolated horizons. We review basic properties of these horizons and summarize applications to mathematical physics, numerical relativity and quantum gravity. This paradigm has led to significant generalizations of several results in black hole physics. Specifically, it has introduced a more physical setting for black hole thermodynamics and for black hole entropy calculations in quantum gravity; suggested a phenomenological model for hairy black holes; provided novel techniques to extract physics from numerical simulations; and led to new laws governing the dynamics of black holes in exact general relativity.Comment: 77 pages, 12 figures. Typos and references correcte

Non-Lipogenic ABCA1 Inducers for Type 2 Diabetes and Alzheimer's Disease

Increased expression of the ATP-binding cassette family member A1 (ABCA1) protein elicits numerous therapeutic effects against type 2 diabetes, Alzheimer’s disease, and other related conditions in preclinical models. However, side effects such as increased lipogenesis and neutropenia have precluded translation of ABCA1-inducing compounds to the clinic. This project utilized a unique phenotypic strategy to develop selective, non-lipogenic ABCA1 inducers as multifunctional therapeutic candidates for Alzheimer’s disease and type 2 diabetes. The approach consisted of chemical synthesis to optimize a screening hit into lead candidates with enhanced potency and efficacy, followed by testing in an array of cell and animal models. Hit-to-lead optimization of the initial screening hit F420 yielded two key lead compounds, CL2-57 and CL3-3. Both lead compounds selectively enhanced expression of ABCA1 over genes promoting hepatic lipogenesis. This selectivity stemmed from combined agonist and antagonist effects at multiple nuclear receptor isoforms, which represented a novel mechanism of action. Additionally, compound CL3-3 displayed a stronger combination of potency for ABCA1 induction and selectivity against lipogenic gene induction than the best previously reported agonists. These two non-lipogenic ABCA1 inducers also enhanced cholesterol efflux and blunted pro-inflammatory signaling in cell-based assays. After in vitro testing, the lead compounds were evaluated for safety and efficacy in mouse models. Both ABCA1 inducers maintained functional selectivity in vivo, enhancing ABCA1 expression and modifying disease phenotypes while avoiding unwanted effects, such as increased triglycerides. Major efficacy readouts included phenotypic, biochemical, and metabolomic analysis of a high-fat diet mouse model. Oral treatment with CL2-57 enhanced glucose homeostasis, reduced adiposity, attenuated inflammation, and reversed metabolic perturbations in mice fed the high-fat diet. Oral treatment with CL3-3 also induced cholesterol transport genes in the brain and periphery, while triglyceride increases were avoided. Testing for effects of CL3-3 on Alzheimer’s-related pathology in additional mouse models is ongoing, but these compounds are promising leads for further development as Alzheimer’s disease and type 2 diabetes therapeutics

Effect of Lanthanide Complex Structure on Cell Viability and Association

A systematic study of the effect of hydrophobicity and charge on the cell viability and cell association of lanthanide metal complexes is presented. The terbium luminescent probes feature a macrocyclic polyaminocarboxylate ligand (DOTA) in which the hydrophobicity of the antenna and that of the carboxyamide pendant arms are independently varied. Three sensitizing antennas were investigated in terms of their function in vitro: 2-methoxy­isophthalamide (IAM­(OMe)), 2-hydroxyisophthalamide (IAM), and 6-methylphenanthridine (Phen). Of these complexes, Tb-DOTA-IAM exhibited the highest quantum yield, although the higher cell viability and more facile synthesis of the structurally related Tb-DOTA-IAM­(OMe) platform renders it more attractive. Further modification of this latter core structure with carboxyamide arms featuring hydrophobic benzyl, hexyl, and trifluoro groups as well as hydrophilic amino acid based moieties generated a family of complexes that exhibit high cell viability (ED₅₀ > 300 μM) regardless of the lipophilicity or the overall complex charge. Only the hexyl-substituted complex reduced cell viability to 60% in the presence of 100 μM complex. Additionally, cellular association was investigated by ICP-MS and fluorescence microscopy. Surprisingly, the hydrophobic moieties did not increase cell association in comparison to the hydrophilic amino acid derivatives. It is thus postulated that the hydrophilic nature of the 2-methoxyisophthalamide antenna (IAM­(OMe)) disfavors the cellular association of these complexes. As such, responsive luminescent probes based on this scaffold would be appropriate for the detection of extracellular species

Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes

Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRβ agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery

Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic development

BACKGROUND: Therapeutic agents with novel mechanisms of action are needed to combat the growing epidemic of type 2 diabetes (T2D) and related metabolic syndromes. Liver X receptor (LXR) agonists possess preclinical efficacy yet produce side effects due to excessive lipogenesis. Anticipating that many beneficial and detrimental effects of LXR agonists are mediated by ABCA1 and SREPB1c expression, respectively, we hypothesized that a phenotypic optimization strategy prioritizing selective ABCA1 induction would identify an efficacious lead compound with an improved side effect profile over existing LXRβ agonists. METHODS: We synthesized and characterized a novel small molecule for selective induction of ABCA1 vs. SREBP1c in vitro. This compound was evaluated in both wild-type mice and a high-fat diet (HFD) mouse model of obesity-driven diabetes through functional, biochemical, and metabolomic analysis. FINDINGS: Six weeks of oral administration of our lead compound attenuated weight gain, glucose intolerance, insulin signaling deficits, and adiposity. Global metabolomics revealed suppression of gluconeogenesis, free fatty acids, and pro-inflammatory metabolites. Target identification linked these beneficial effects to selective LXRβ agonism and PPAR/RXR antagonism. INTERPRETATION: Our observations in the HFD model, combined with the absence of lipogenesis and neutropenia in WT mice, support this novel approach to therapeutic development for T2D and related conditions

Heart morphology differences induced by intrauterine growth restriction and preterm birth measured on the ECG at preadolescent age

Intrauterine Growth Restriction (IUGR) and premature birth are associated with higher risk of cardiovascular diseases throughout adulthood. The aim of this study was to evaluate the influence of these factors in ventricular electrical remodeling in preadolescents. Electrocardiography was performed in a cohort of 33-IUGR, 32-preterm with appropriate weight and 60 controls. Depolarization and repolarization processes were studied by means of the surface ECG, including loops and angles corresponding to QRS and T-waves. The angles between the dominant vector of QRS and the frontal plane XY were different among the study groups: controls [20.03°(10.11°-28.64°)], preterm [25.48°(19.79°-33.56°)], and IUGR [27.77°(16.59°-33.23°)]. When compared to controls, IUGR subjects also presented wider angles between the difference of QRS and T-wave dominant vectors and the XY-plane [5.28° ± 12.15° vs 0.49° ± 14.15°, p < 0.05] while preterm ones showed smaller frontal QRS-T angle [4.68°(2.20°-12.89°) vs 6.57°(2.72°-11.31°), p < 0.05]. Thus, electrical remodeling is present in IUGR and preterm preadolescents, and might predispose them to cardiovascular diseases in adulthood. Follow-up studies are warranted.N. Ortigosa acknowledges the support from Generalitat Valenciana under grants PrometeoII/2013/013, ACOMP/2015/186, and MINECO under grant MTM2013-43540-P. This project has also been partially funded by TEC2013-42140-R and TIN2014-53567-R from CICYT, by Grupo Consolidado BSICoS from DGA (Aragón) and European Social Fund, the Erasmus + Program of the European Union (Framework Agreement number: 2013-0040), the South-Eastern Norway Regional Health Authority, the Bergesen foundation and grants from Instituto de Salud Carlos III (grant numbers PI12/00801 and PI14/00226), Ministerio de Economía y Competitividad (grant number SAF2012-37196), cofinanced by the Fondo Europeo de Desarrollo Regional de la Unión Europea “Una manera de hacer Europa”, Fundación Mutua Madrileña, Obra Social La Caixa (Spain), Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK), and the European Commission (VP2HF no.611823). This publication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein. The computation was performed by the ICTS 0707NANBIOSIS, by the High Performance Computing Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN) at the University of Zaragoza