Decoupling Inflation From the String Scale

When Inflation is embedded in a fundamental theory, such as string theory, it typically begins when the Universe is already substantially larger than the fundamental scale [such as the one defined by the string length scale]. This is naturally explained by postulating a pre-inflationary era, during which the size of the Universe grew from the fundamental scale to the initial inflationary scale. The problem then arises of maintaining the [presumed] initial spatial homogeneity throughout this era, so that, when it terminates, Inflation is able to begin in its potential-dominated state. Linde has proposed that a spacetime with compact negatively curved spatial sections can achieve this, by means of chaotic mixing. Such a compactification will however lead to a Casimir energy, which can lead to effects that defeat the purpose unless the coupling to gravity is suppressed. We estimate the value of this coupling required by the proposal, and use it to show that the pre-inflationary spacetime is stable, despite the violation of the Null Energy Condition entailed by the Casimir energy.Comment: 24 pages, 5 eps figures, references added, stylistic changes, version to appear in Classical and Quantum Gravit

Cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day)

Use of high doses of verapamil in preventive treatment of cluster headache (CH) is limited by cardiac toxicity. We systematically assess the cardiac safety of the very high dose of verapamil (verapamil VHD) in CH patients. Our work was a study performed in two French headache centers (Marseilles–Nice) from 12/2005 to 12/2008. CH patients treated with verapamil VHD (≥720 mg) were considered with a systematic electrocardiogram (EKG) monitoring. Among 200 CH patients, 29 (14.8%) used verapamil VHD (877 ± 227 mg/day). Incidence of EKG changes was 38% (11/29). Seven (24%) patients presented bradycardia considered as nonserious adverse event (NSAE) and four (14%) patients presented arrhythmia (heart block) considered as serious adverse event (SAE). Patients with EKG changes (1,003 ± 295 mg/day) were taking higher doses than those without EKG changes (800 ± 143 mg/day), but doses were similar in patients with SAE (990 ± 316 mg/day) and those with NSAE (1,011 ± 309 mg/day). Around three-quarters (8/11) of patients presented a delayed-onset cardiac adverse event (delay ≥2 years). Our work confirms the need for systematic EKG monitoring in CH patients treated with verapamil. Such cardiac safety assessment must be continued even for patients using VHD without any adverse event for a long time

Are Small Hyperbolic Universes Observationally Detectable?

Using recent observational constraints on cosmological density parameters, together with recent mathematical results concerning small volume hyperbolic manifolds, we argue that, by employing pattern repetitions, the topology of nearly flat small hyperbolic universes can be observationally undetectable. This is important in view of the facts that quantum cosmology may favour hyperbolic universes with small volumes, and from the expectation coming from inflationary scenarios, that $\Omega_0$ is likely to be very close to one.Comment: 5 pages, 1 figure, LaTeX2e. A reference and two footnotes added. To appear in Class. Quantum Grav. 18 (2001) in the present for

Computing CMB Anisotropy in Compact Hyperbolic Spaces

The measurements of CMB anisotropy have opened up a window for probing the global topology of the universe on length scales comparable to and beyond the Hubble radius. For compact topologies, the two main effects on the CMB are: (1) the breaking of statistical isotropy in characteristic patterns determined by the photon geodesic structure of the manifold and (2) an infrared cutoff in the power spectrum of perturbations imposed by the finite spatial extent. We present a completely general scheme using the regularized method of images for calculating CMB anisotropy in models with nontrivial topology, and apply it to the computationally challenging compact hyperbolic topologies. This new technique eliminates the need for the difficult task of spatial eigenmode decomposition on these spaces. We estimate a Bayesian probability for a selection of models by confronting the theoretical pixel-pixel temperature correlation function with the COBE-DMR data. Our results demonstrate that strong constraints on compactness arise: if the universe is small compared to the `horizon' size, correlations appear in the maps that are irreconcilable with the observations. If the universe is of comparable size, the likelihood function is very dependent upon orientation of the manifold wrt the sky. While most orientations may be strongly ruled out, it sometimes happens that for a specific orientation the predicted correlation patterns are preferred over the conventional infinite models.Comment: 15 pages, LaTeX (IOP style included), 3 color figures (GIF) in separate files. Minor revision to match the version accepted in Class. Quantum Grav.: Proc. of Topology and Cosmology, Cleveland, 1997. The paper can be also downloaded from http://www.cita.utoronto.ca/~pogosyan/cwru_proc.ps.g

A measure on the set of compact Friedmann-Lemaitre-Robertson-Walker models

Compact, flat Friedmann-Lemaitre-Robertson-Walker (FLRW) models have recently regained interest as a good fit to the observed cosmic microwave background temperature fluctuations. However, it is generally thought that a globally, exactly-flat FLRW model is theoretically improbable. Here, in order to obtain a probability space on the set F of compact, comoving, 3-spatial sections of FLRW models, a physically motivated hypothesis is proposed, using the density parameter Omega as a derived rather than fundamental parameter. We assume that the processes that select the 3-manifold also select a global mass-energy and a Hubble parameter. The inferred range in Omega consists of a single real value for any 3-manifold. Thus, the obvious measure over F is the discrete measure. Hence, if the global mass-energy and Hubble parameter are a function of 3-manifold choice among compact FLRW models, then probability spaces parametrised by Omega do not, in general, give a zero probability of a flat model. Alternatively, parametrisation by the injectivity radius r_inj ("size") suggests the Lebesgue measure. In this case, the probability space over the injectivity radius implies that flat models occur almost surely (a.s.), in the sense of probability theory, and non-flat models a.s. do not occur.Comment: 19 pages, 4 figures; v2: minor language improvements; v3: generalisation: m, H functions of

Salmonella enterica serovar typhimurium exploits inflammation to modify swine intestinal microbiota

Salmonella enterica serovar Typhimurium is an important zoonotic gastrointestinal pathogen responsible for foodborne disease worldwide. It is a successful enteric pathogen because it has developed virulence strategies allowing it to survive in a highly inflamed intestinal environment exploiting inflammation to overcome colonization resistance provided by intestinal microbiota. In this study, we used piglets featuring an intact microbiota, which naturally develop gastroenteritis, as model for salmonellosis. We compared the effects on the intestinal microbiota induced by a wild type and an attenuated S. Typhimurium in order to evaluate whether the modifications are correlated with the virulence of the strain. This study showed that Salmonella alters microbiota in a virulence-dependent manner. We found that the wild type S. Typhimurium induced inflammation and a reduction of specific protecting microbiota species (SCFA-producing bacteria) normally involved in providing a barrier against pathogens. Both these effects could contribute to impair colonization resistance, increasing the host susceptibility to wild type S. Typhimurium colonization. In contrast, the attenuated S. Typhimurium, which is characterized by a reduced ability to colonize the intestine, and by a very mild inflammatory response, was unable to successfully sustain competition with the microbiota

Metabolomics reveals novel insight on dormancy of aquatic invertebrate encysted embryos

Numerous aquatic invertebrates survive harsh environments by displaying dormancy as encysted embryos. This study aimed at determining whether metabolomics could provide molecular insight to explain the “dormancy syndrome” by highlighting functional pathways and metabolites, hence offering a novel comprehensive molecular view of dormancy. We compared the metabolome of morphologically distinct dormant encysted embryos (resting eggs) and non-dormant embryos (amictic eggs) of a rotifer (Brachionus plicatilis). Metabolome profiling revealed ~5,000 features, 1,079 of which were annotated. Most of the features were represented at significantly higher levels in non-dormant than dormant embryos. A large number of features was assigned to putative functional pathways indicating novel differences between dormant and non-dormant states. These include features associated with glycolysis, the TCA and urea cycles, amino acid, purine and pyrimidine metabolism. Interestingly, ATP, nucleobases, cyclic nucleotides, thymidine and uracil, were not detected in dormant resting eggs, suggesting an impairment of response to environmental and internal cues, cessation of DNA synthesis, transcription and plausibly translation in the dormant embryos. The levels of trehalose or its analogues, with a role in survival under desiccation conditions, were higher in resting eggs. In conclusion, the current study highlights metabolomics as a major analytical tool to functionally compare dormancy across species.Animal science

Computation of eigenmodes on a compact hyperbolic 3-space

Measurements of cosmic microwave background (CMB) anisotropy are ideal experiments for discovering the non-trivial global topology of the universe. To evaluate the CMB anisotropy in multiply-connected compact cosmological models, one needs to compute the eigenmodes of the Laplace-Beltrami operator. Using the direct boundary element method, we numerically obtain the low-lying eigenmodes on a compact hyperbolic 3-space called the Thurston manifold which is the second smallest in the known compact hyperbolic 3-manifolds. The computed eigenmodes are expanded in terms of eigenmodes on the unit three-dimensional pseudosphere. We numerically find that the expansion coefficients behave as Gaussian pseudo-random numbers for low-lying eigenmodes. The observed gaussianity in the CMB fluctuations can partially be attributed to the Gaussian pseudo-randomness of the expansion coefficients assuming that the Gaussian pseudo-randomness is the universal property of the compact hyperbolic spaces.Comment: 40 pages, 8 EPS figures; error estimation is included; accepted Classical and Quantum Gravit

The HSP90 Inhibitor NVP-AUY922 Radiosensitizes by Abrogation of Homologous Recombination Resulting in Mitotic Entry with Unresolved DNA Damage

Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific

Down-regulation of HSP70 sensitizes gastric epithelial cells to apoptosis and growth retardation triggered by H. pylori

<p>Abstract</p> <p>Background</p> <p><it>H. pylori </it>infection significantly attenuated the expression of HSP70 in gastric mucosal cells. However, the role of HSP70 cancellation in <it>H. pylori</it>-associated cell damages is largely unclear.</p> <p>Methods</p> <p>Small interfering RNA (siRNA) was used to down-regulate HSP70 in gastric epithelial cell lines AGS. The transfected cells were then incubated with <it>H. pylori </it>and the functions of HSP70 suppression were observed by viability assay, cell cycle analyses and TUNEL assay. HSP70 target apoptotic proteins were further identified by Western blot.</p> <p>Results</p> <p>The inhibition of HSP70 has further increased the effect of growth arrest and apoptosis activation triggered by <it>H. pylori </it>in gastric epithelial cells. The anti-proliferation function of HSP70 depletion was at least by up-regulating p21 and cell cycle modulation with S-phase accumulation. An increase of apoptosis-inducing factor (AIF) and cytosolic cytochrome C contributes to the activation of apoptosis following down-regulation of intracellular HSP70. Extracellular HSP70 increased cellular resistance to apoptosis by suppression the release of AIF and cytochrome c from mitochondria, as well as inhibition of p21 expression.</p> <p>Conclusions</p> <p>The inhibition of HSP70 aggravated gastric cellular damages induced by <it>H. pylori</it>. Induction of HSP70 could be a potential therapeutic target for protection gastric mucosa from <it>H. pylori</it>-associated injury.</p