Echinacea purpurea Significantly Induces Cytochrome P450 3A Activity but Does Not Alter Lopinavir‐Ritonavir Exposure in Healthy Subjects

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90291/1/phco.30.8.797.pd

Holographic studies of quasi-topological gravity

Quasi-topological gravity is a new gravitational theory including curvature-cubed interactions and for which exact black hole solutions were constructed. In a holographic framework, classical quasi-topological gravity can be thought to be dual to the large $N_c$ limit of some non-supersymmetric but conformal gauge theory. We establish various elements of the AdS/CFT dictionary for this duality. This allows us to infer physical constraints on the couplings in the gravitational theory. Further we use holography to investigate hydrodynamic aspects of the dual gauge theory. In particular, we find that the minimum value of the shear-viscosity-to-entropy-density ratio for this model is $\eta/s \simeq 0.4140/(4\pi)$.Comment: 45 pages, 6 figures. v2: References adde

Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration.

Gas1 and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. Here we demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through distinct modes of Hedgehog ligand reception. Moreover, Ptch2-mediated Hedgehog signalling induces the phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a previously unknown Ptch2-specific signal pathway. We propose that although Ptch1 and Ptch2 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch2 and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche

Constraints from orbital motions around the Earth of the environmental fifth-force hypothesis for the OPERA superluminal neutrino phenomenology

It has been recently suggested by Dvali and Vikman that the superluminal neutrino phenomenology of the OPERA experiment may be due to an environmental feature of the Earth, naturally yielding a long-range fifth force of gravitational origin whose coupling with the neutrino is set by the scale M_*, in units of reduced Planck mass. Its characteristic length lambda should not be smaller than one Earth's radius R_e, while its upper bound is expected to be slightly smaller than the Earth-Moon distance (60 R_e). We analytically work out some orbital effects of a Yukawa-type fifth force for a test particle moving in the modified field of a central body. Our results are quite general since they are not restricted to any particular size of lambda; moreover, they are valid for an arbitrary orbital configuration of the particle, i.e. for any value of its eccentricity $e$. We find that the dimensionless strength coupling parameter alpha is constrained to |alpha| <= 1 10^-10-4 10^-9 for 1 R_e <= lambda <= 10 R_e by the laser data of the Earth's artificial satellite LAGEOS II, corresponding to M_* >= 4 10^9 -1.6 10^10. The Moon perigee allows to obtain |alpha| <= 3 10^-11 for the Earth-Moon pair in the range 15 R_e <= lambda = 3 10^10 - 4.5 10^10. Our results are neither necessarily limited to the superluminal OPERA scenario nor to the Dvali-Vikman model, in which it is M_* = 10^-6 at lambda = 1 R_e, in contrast with our bounds: they generally extend to any theoretical scenario implying a fifth-force of Yukawa-type.Comment: LaTex2e, 18 pages, 4 figures, 1 table, 81 reference

Methodological considerations in the analysis of fecal glucocorticoid metabolites in tufted capuchins (Cebus apella)

Analysis of fecal glucocorticoid (GC) metabolites has recently become the standard method to monitor adrenocortical activity in primates noninvasively. However, given variation in the production, metabolism, and excretion of GCs across species and even between sexes, there are no standard methods that are universally applicable. In particular, it is important to validate assays intended to measure GC production, test extraction and storage procedures, and consider the time course of GC metabolite excretion relative to the production and circulation of the native hormones. This study examines these four methodological aspects of fecal GC metabolite analysis in tufted capuchins (Cebus apella). Specifically, we conducted an adrenocorticotrophic hormone (ACTH) challenge on one male and one female capuchin to test the validity of four GC enzyme immunoassays (EIAs) and document the time course characterizing GC me- tabolite excretion in this species. In addition, we compare a common field-friendly technique for extracting fecal GC metabolites to an established laboratory extraction methodology and test for effects of storing “field extracts” for up to 1 yr. Results suggest that a corticosterone EIA is most sensitive to changes in GC production, provides reliable measures when extracted according to the field method, and measures GC metabolites which remain highly stable after even 12 mo of storage. Further, the time course of GC metabolite excretion is shorter than that described yet for any primate taxa. These results provide guidelines for studies of GCs in tufted capuchins, and underscore the importance of validating methods for fecal hormone analysis for each species of interest

Long-Branch Attraction Bias and Inconsistency in Bayesian Phylogenetics

Bayesian inference (BI) of phylogenetic relationships uses the same probabilistic models of evolution as its precursor maximum likelihood (ML), so BI has generally been assumed to share ML's desirable statistical properties, such as largely unbiased inference of topology given an accurate model and increasingly reliable inferences as the amount of data increases. Here we show that BI, unlike ML, is biased in favor of topologies that group long branches together, even when the true model and prior distributions of evolutionary parameters over a group of phylogenies are known. Using experimental simulation studies and numerical and mathematical analyses, we show that this bias becomes more severe as more data are analyzed, causing BI to infer an incorrect tree as the maximum a posteriori phylogeny with asymptotically high support as sequence length approaches infinity. BI's long branch attraction bias is relatively weak when the true model is simple but becomes pronounced when sequence sites evolve heterogeneously, even when this complexity is incorporated in the model. This bias—which is apparent under both controlled simulation conditions and in analyses of empirical sequence data—also makes BI less efficient and less robust to the use of an incorrect evolutionary model than ML. Surprisingly, BI's bias is caused by one of the method's stated advantages—that it incorporates uncertainty about branch lengths by integrating over a distribution of possible values instead of estimating them from the data, as ML does. Our findings suggest that trees inferred using BI should be interpreted with caution and that ML may be a more reliable framework for modern phylogenetic analysis

Mucin Secretion Induced by Titanium Dioxide Nanoparticles

Nanoparticle (NP) exposure has been closely associated with the exacerbation and pathophysiology of many respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. Mucus hypersecretion and accumulation in the airway are major clinical manifestations commonly found in these diseases. Among a broad spectrum of NPs, titanium dioxide (TiO2), one of the PM10 components, is widely utilized in the nanoindustry for manufacturing and processing of various commercial products. Although TiO2 NPs have been shown to induce cellular nanotoxicity and emphysema-like symptoms, whether TiO2 NPs can directly induce mucus secretion from airway cells is currently unknown. Herein, we showed that TiO2 NPs (<75 nm) can directly stimulate mucin secretion from human bronchial ChaGo-K1 epithelial cells via a Ca2+ signaling mediated pathway. The amount of mucin secreted was quantified with enzyme-linked lectin assay (ELLA). The corresponding changes in cytosolic Ca2+ concentration were monitored with Rhod-2, a fluorescent Ca2+ dye. We found that TiO2 NP-evoked mucin secretion was a function of increasing intracellular Ca2+ concentration resulting from an extracellular Ca2+ influx via membrane Ca2+ channels and cytosolic ER Ca2+ release. The calcium-induced calcium release (CICR) mechanism played a major role in further amplifying the intracellular Ca2+ signal and in sustaining a cytosolic Ca2+ increase. This study provides a potential mechanistic link between airborne NPs and the pathoetiology of pulmonary diseases involving mucus hypersecretion

Stem subsidence of polished and rough double-taper stems: In vitro mechanical effects on the cement-bone interface

Background and purpose Many clinical reports have indicated that polished hip stems show better clinical results than rough stems of the same geometry. It is still unknown, however, what the mechanical effects are of different surface finishes on the cement at the cement-bone interface. We compared mechanical effects in an in vitro cemented hip arthroplasty model

Expression of the receptor tyrosine kinase ephb2 on dendritic cells is modulated by toll-like receptor ligation but is not required for t cell activation

The Eph receptor tyrosine kinases interact with their ephrin ligands on adjacent cells to facilitate contact-dependent cell communication. Ephrin B ligands are expressed on T cells and have been suggested to act as co-stimulatory molecules during T cell activation. There are no detailed reports of the expression and modulation of EphB receptors on dendritic cells, the main antigen presenting cells that interact with T cells. Here we show that mouse splenic dendritic cells (DC) and bone-marrow derived DCs (BMDC) express EphB2, a member of the EphB family. EphB2 expression is modulated by ligation of TLR4 and TLR9 and also by interaction with ephrin B ligands. Co-localization of EphB2 with MHC-II is also consistent with a potential role in T cell activation. However, BMDCs derived from EphB2 deficient mice were able to present antigen in the context of MHC-II and produce T cell activating cytokines to the same extent as intact DCs. Collectively our data suggest that EphB2 may contribute to DC responses, but that EphB2 is not required for T cell activation. This result may have arisen because DCs express other members of the EphB receptor family, EphB3, EphB4 and EphB6, all of which can interact with ephrin B ligands, or because EphB2 may be playing a role in another aspect of DC biology such as migration

Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m−2 of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1–3, 8–10, 15–17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1–9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44–72) and median duration of PSA response was 8.0 months (95% CI: 6.9–9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel