Noise Kernel and Stress Energy Bi-Tensor of Quantum Fields in Hot Flat Space and Gaussian Approximation in the Optical Schwarzschild Metric

Continuing our investigation of the regularization of the noise kernel in curved spacetimes [N. G. Phillips and B. L. Hu, Phys. Rev. D {\bf 63}, 104001 (2001)] we adopt the modified point separation scheme for the class of optical spacetimes using the Gaussian approximation for the Green functions a la Bekenstein-Parker-Page. In the first example we derive the regularized noise kernel for a thermal field in flat space. It is useful for black hole nucleation considerations. In the second example of an optical Schwarzschild spacetime we obtain a finite expression for the noise kernel at the horizon and recover the hot flat space result at infinity. Knowledge of the noise kernel is essential for studying issues related to black hole horizon fluctuations and Hawking radiation backreaction. We show that the Gaussian approximated Green function which works surprisingly well for the stress tensor at the Schwarzschild horizon produces significant error in the noise kernel there. We identify the failure as occurring at the fourth covariant derivative order.Comment: 21 pages, RevTeX

Noise Kernel in Stochastic Gravity and Stress Energy Bi-Tensor of Quantum Fields in Curved Spacetimes

The noise kernel is the vacuum expectation value of the (operator-valued) stress-energy bi-tensor which describes the fluctuations of a quantum field in curved spacetimes. It plays the role in stochastic semiclassical gravity based on the Einstein-Langevin equation similar to the expectation value of the stress-energy tensor in semiclassical gravity based on the semiclassical Einstein equation. According to the stochastic gravity program, this two point function (and by extension the higher order correlations in a hierarchy) of the stress energy tensor possesses precious statistical mechanical information of quantum fields in curved spacetime and, by the self-consistency required of Einstein's equation, provides a probe into the coherence properties of the gravity sector (as measured by the higher order correlation functions of gravitons) and the quantum nature of spacetime. It reflects the low and medium energy (referring to Planck energy as high energy) behavior of any viable theory of quantum gravity, including string theory. It is also useful for calculating quantum fluctuations of fields in modern theories of structure formation and for backreaction problems in cosmological and black holes spacetimes. We discuss the properties of this bi-tensor with the method of point-separation, and derive a regularized expression of the noise-kernel for a scalar field in general curved spacetimes. One collorary of our finding is that for a massless conformal field the trace of the noise kernel identically vanishes. We outline how the general framework and results derived here can be used for the calculation of noise kernels for Robertson-Walker and Schwarzschild spacetimes.Comment: 22 Pages, RevTeX; version accepted for publication in PR

Benznidazole-resistance in Trypanosoma cruzi: evidence that distinct mechanisms can act in concert.

Benznidazole is the main drug used to treat Trypanosoma cruzi infections. However, frequent instances of treatment failure have been reported. To better understand potential resistance mechanisms, we analysed three clones isolated from a single parasite population that had undergone benznidazole-selection. These clones exhibited differing levels of benznidazole-resistance (varying between 9 and 26-fold), and displayed cross-resistance to nifurtimox (2 to 4-fold). Each clone had acquired a stop-codon-generating mutation in the gene which encodes the nitroreductase (TcNTR) that is responsible for activating nitroheterocyclic pro-drugs. In addition, one clone had lost a copy of the chromosome containing TcNTR. However, these processes alone are insufficient to account for the extent and diversity of benznidazole-resistance. It is implicit from our results that additional mechanisms must also operate and that T. cruzi has an intrinsic ability to develop drug-resistance by independent sequential steps, even within a single population. This has important implications for drug development strategies

Linear Response, Validity of Semi-Classical Gravity, and the Stability of Flat Space

A quantitative test for the validity of the semi-classical approximation in gravity is given. The criterion proposed is that solutions to the semi-classical Einstein equations should be stable to linearized perturbations, in the sense that no gauge invariant perturbation should become unbounded in time. A self-consistent linear response analysis of these perturbations, based upon an invariant effective action principle, necessarily involves metric fluctuations about the mean semi-classical geometry, and brings in the two-point correlation function of the quantum energy-momentum tensor in a natural way. This linear response equation contains no state dependent divergences and requires no new renormalization counterterms beyond those required in the leading order semi-classical approximation. The general linear response criterion is applied to the specific example of a scalar field with arbitrary mass and curvature coupling in the vacuum state of Minkowski spacetime. The spectral representation of the vacuum polarization function is computed in n dimensional Minkowski spacetime, and used to show that the flat space solution to the semi-classical Einstein equations for n=4 is stable to all perturbations on distance scales much larger than the Planck length.Comment: 22 pages: This is a significantly expanded version of gr-qc/0204083, with two additional sections and two new appendices giving a complete, explicit example of the semi-classical stability criterion proposed in the previous pape

Quantum correlation functions and the classical limit

We study the transition from the full quantum mechanical description of physical systems to an approximate classical stochastic one. Our main tool is the identification of the closed-time-path (CTP) generating functional of Schwinger and Keldysh with the decoherence functional of the consistent histories approach. Given a degree of coarse-graining in which interferences are negligible, we can explicitly write a generating functional for the effective stochastic process in terms of the CTP generating functional. This construction gives particularly simple results for Gaussian processes. The formalism is applied to simple quantum systems, quantum Brownian motion, quantum fields in curved spacetime. Perturbation theory is also explained. We conclude with a discussion on the problem of backreaction of quantum fields in spacetime geometry.Comment: 30 pages, latex; minor changes, added some explanations and refeence

Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size

p21(Cip1) plays a critical role in the physiological adaptation to fasting through activation of PPARα.

Fasting is a physiological stress that elicits well-known metabolic adaptations, however, little is known about the role of stress-responsive tumor suppressors in fasting. Here, we have examined the expression of several tumor suppressors upon fasting in mice. Interestingly, p21 mRNA is uniquely induced in all the tissues tested, particularly in liver and muscle (>10 fold), and this upregulation is independent of p53. Remarkably, in contrast to wild-type mice, p21-null mice become severely morbid after prolonged fasting. The defective adaptation to fasting of p21-null mice is associated to elevated energy expenditure, accelerated depletion of fat stores, and premature activation of protein catabolism in the muscle. Analysis of the liver transcriptome and cell-based assays revealed that the absence of p21 partially impairs the transcriptional program of PPARα, a key regulator of fasting metabolism. Finally, treatment of p21-null mice with a PPARα agonist substantially protects them from their accelerated loss of fat upon fasting. We conclude that p21 plays a relevant role in fasting adaptation through the positive regulation of PPARα

Nanoinformatics: developing new computing applications for nanomedicine

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended ?nanotype? to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others

Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation

233294Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.We thank Drs. N. Djouder, M. Petruzzelli, R. Ricci, F.X Real, K.D. Bissig, and members of the Wagner laboratory for critical reading of the manuscript and valuable sugges- tions; Dr. H. Schönthaler for help with the bioinformatics analysis; V. Bermeo for technical help; and G. Luque, S. Leceta, and G. Medrano for assisting with mouse experiments. The E.F. Wagner laboratory is supported by grants from the Spanish Ministry of Economy, Industry, and Competitiveness (BFU2012-40230 and SAF2015-70857, co- funded by the European Regional Development Fund), a European Research Council– advanced grant (ERC-FCK/2008/37), and Worldwide Cancer Research (13-0216). R. Hamacher was supported by the Deutsche Forschungsgemeinschaft (HA 6068/1-1), M.K. Thomsen by AUFF Nova, and S.C. Hasenfuss by a Boehringer Ingelheim Fonds PhD fellowship. The authors declare no competing financial interests. Author contributions: L. Bakiri and R. Hamacher designed and performed exper- iments, analyzed data, prepared figures, and wrote the manuscript. O. Graña analyzed RNA-seq and public microarray data, A. Guío-Carrión provided expert technical assis- tance, R. Campos-Olivas acquired and analyzed NMR data, L. Martinez analyzed flow cytometry data, M.K. Thomsen performed experiments with human cell lines, S.C. Hasenfuss performed experiments with primary hepatocytes and data mining, and H.P. Dienes performed pathological analysis on tissue sections. E.F. Wagner directed the study, approved the data, and wrote and edited the paper. All authors read and commented on the manuscript.S

PSD95 Suppresses Dendritic Arbor Development in Mature Hippocampal Neurons by Occluding the Clustering of NR2B-NMDA Receptors

Considerable evidence indicates that the NMDA receptor (NMDAR) subunits NR2A and NR2B are critical mediators of synaptic plasticity and dendritogenesis; however, how they differentially regulate these processes is unclear. Here we investigate the roles of the NR2A and NR2B subunits, and of their scaffolding proteins PSD-95 and SAP102, in remodeling the dendritic architecture of developing hippocampal neurons (2–25 DIV). Analysis of the dendritic architecture and the temporal and spatial expression patterns of the NMDARs and anchoring proteins in immature cultures revealed a strong positive correlation between synaptic expression of the NR2B subunit and dendritogenesis. With maturation, the pruning of dendritic branches was paralleled by a strong reduction in overall and synaptic expression of NR2B, and a significant elevation in synaptic expression of NR2A and PSD95. Using constructs that alter the synaptic composition, we found that either over-expression of NR2B or knock-down of PSD95 by shRNA-PSD95 augmented dendritogenesis in immature neurons. Reactivation of dendritogenesis could also be achieved in mature cultured neurons, but required both manipulations simultaneously, and was accompanied by increased dendritic clustering of NR2B. Our results indicate that the developmental increase in synaptic expression of PSD95 obstructs the synaptic clustering of NR2B-NMDARs, and thereby restricts reactivation of dendritic branching. Experiments with shRNA-PSD95 and chimeric NR2A/NR2B constructs further revealed that C-terminus of the NR2B subunit (tail) was sufficient to induce robust dendritic branching in mature hippocampal neurons, and suggest that the NR2B tail is important in recruiting calcium-dependent signaling proteins and scaffolding proteins necessary for dendritogenesis.National Institutes of Health (U.S.) (Grant EY014074