Brane-world black holes and the scale of gravity

A particle in four dimensions should behave like a classical black hole if the horizon radius is larger than the Compton wavelength or, equivalently, if its degeneracy (measured by entropy in units of the Planck scale) is large. For spherically symmetric black holes in 4 + d dimensions, both arguments again lead to a mass threshold MC and degeneracy scale Mdeg of the order of the fundamental scale of gravity MG. In the brane-world, deviations from the Schwarzschild metric induced by bulk effects alter the horizon radius and effective four-dimensional Euclidean action in such a way that MC \simeq Mdeg might be either larger or smaller than MG. This opens up the possibility that black holes exist with a mass smaller than MG and might be produced at the LHC even if M>10 TeV, whereas effects due to bulk graviton exchanges remain undetectable because suppressed by inverse powers of MG. Conversely, even if black holes are not found at the LHC, it is still possible that MC>MG and MG \simeq 1TeV.Comment: 4 pages, no figur

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

Cross-species gene expression analysis of species specific differences in the preclinical assessment of pharmaceutical compounds

Animals are frequently used as model systems for determination of safety and efficacy in pharmaceutical research and development. However, significant quantitative and qualitative differences exist between humans and the animal models used in research. This is as a result of genetic variation between human and the laboratory animal. Therefore the development of a system that would allow the assessment of all molecular differences between species after drug exposure would have a significant impact on drug evaluation for toxicity and efficacy. Here we describe a cross-species microarray methodology that identifies and selects orthologous probes after cross-species sequence comparison to develop an orthologous cross-species gene expression analysis tool. The assumptions made by the use of this orthologous gene expression strategy for cross-species extrapolation is that; conserved changes in gene expression equate to conserved pharmacodynamic endpoints. This assumption is supported by the fact that evolution and selection have maintained the structure and function of many biochemical pathways over time, resulting in the conservation of many important processes. We demonstrate this cross-species methodology by investigating species specific differences of the peroxisome proliferatoractivator receptor (PPAR) a response in rat and human

Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Quality Grade Evaluation of Niuhuang Qingwei Pills Based on UPLC and TCM Reference Drug—A Novel Principle of Analysis of Multiple Components in Ready-Made Chinese Herbal Medicine

Ready-made Chinese herbal medicine (RMCHM) is one of the most common types of synergistic herbal medicine used worldwide. It is based on composite herbal formulae (CHF), which makes quality control of this kind of traditional Chinese medicine (TCM) difficult, let alone distinguishing the good from the bad. Taking Niuhuang Qingwei Pills (NHQWP) as an example, this study reported the development of a novel principle of analysis of multiple components in RMCHM. Experimental procedures involved the selection of high-quality Chinese materia medica (CMM, individual medicinal plant parts used in the NHQWP) to prepare three batches of TCM reference drugs (TCMRD). Pure compounds of the active ingredients identified in the herbal formula including berberine hydrochloride, geniposide, forsythiaside A, 3,5-O-dicaffeoyl quinic acid, hesperidin, baicalin, glycyrrhizic acid, and chrysophanol in the three TCMRDs were analyzed as well as those in 49 batches of commercial products from 18 manufacturers by ultra-performance liquid chromatography (UPLC) method combined with wavelength switching. Using the TCMRD as the scientific ruler, quality grade specifications of NHQWP were proposed by comprehensive analysis of multiple components. Accordingly, 13, 28, and 8 batches of samples were primarily rated as first-grade, second-grade, and unqualified, respectively

Rotating Higher Spin Partition Functions and Extended BMS Symmetries

We evaluate one-loop partition functions of higher-spin fields in thermal flat space with angular potentials; this computation is performed in arbitrary space-time dimension, and the result is a simple combination of Poincar\'e characters. We then focus on dimension three, showing that suitable products of one-loop partition functions coincide with vacuum characters of higher-spin asymptotic symmetry algebras at null infinity. These are extensions of the bms_3 algebra that emerges in pure gravity, and we propose a way to build their unitary representations and to compute the associated characters. We also extend our investigations to supergravity and to a class of gauge theories involving higher-spin fermionic fields.Comment: 58 pages; clarifications and references added; version to be published in JHE

Group II Introns Break New Boundaries: Presence in a Bilaterian's Genome

Group II introns are ribozymes, removing themselves from their primary transcripts, as well as mobile genetic elements, transposing via an RNA intermediate, and are thought to be the ancestors of spliceosomal introns. Although common in bacteria and most eukaryotic organelles, they have never been reported in any bilaterian animal genome, organellar or nuclear. Here we report the first group II intron found in the mitochondrial genome of a bilaterian worm. This location is especially surprising, since animal mitochondrial genomes are generally distinct from those of plants, fungi, and protists by being small and compact, and so are viewed as being highly streamlined, perhaps as a result of strong selective pressures for fast replication while establishing germ plasm during early development. This intron is found in the mtDNA of an annelid worm, (an undescribed species of Nephtys), where the complete sequence revealed a 1819 bp group II intron inside the cox1 gene. We infer that this intron is the result of a recent horizontal gene transfer event from a viral or bacterial vector into the mitochondrial genome of Nephtys sp. Our findings hold implications for understanding mechanisms, constraints, and selective pressures that account for patterns of animal mitochondrial genome evolutio

Practical Issues in Imputation-Based Association Mapping

Imputation-based association methods provide a powerful framework for testing untyped variants for association with phenotypes and for combining results from multiple studies that use different genotyping platforms. Here, we consider several issues that arise when applying these methods in practice, including: (i) factors affecting imputation accuracy, including choice of reference panel; (ii) the effects of imputation accuracy on power to detect associations; (iii) the relative merits of Bayesian and frequentist approaches to testing imputed genotypes for association with phenotype; and (iv) how to quickly and accurately compute Bayes factors for testing imputed SNPs. We find that imputation-based methods can be robust to imputation accuracy and can improve power to detect associations, even when average imputation accuracy is poor. We explain how ranking SNPs for association by a standard likelihood ratio test gives the same results as a Bayesian procedure that uses an unnatural prior assumption—specifically, that difficult-to-impute SNPs tend to have larger effects—and assess the power gained from using a Bayesian approach that does not make this assumption. Within the Bayesian framework, we find that good approximations to a full analysis can be achieved by simply replacing unknown genotypes with a point estimate—their posterior mean. This approximation considerably reduces computational expense compared with published sampling-based approaches, and the methods we present are practical on a genome-wide scale with very modest computational resources (e.g., a single desktop computer). The approximation also facilitates combining information across studies, using only summary data for each SNP. Methods discussed here are implemented in the software package BIMBAM, which is available from http://stephenslab.uchicago.edu/software.html