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

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

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

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

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies

Modulation of Cellular Hsp72 Levels in Undifferentiated and Neuron-Like SH-SY5Y Cells Determines Resistance to Staurosporine-Induced Apoptosis

Increased expression of Hsp72 accompanies differentiation of human neuroblastoma SH-SY5Y cells to neuron-like cells. By modulating cellular levels of Hsp72, we demonstrate here its anti-apoptotic activity both in undifferentiated and neuron-like cells. Thermal preconditioning (43°C for 30 min) induced Hsp72, leading to cellular protection against apoptosis induced by a subsequent treatment with staurosporine. Preconditioned staurosporine-treated cells displayed decreased Bax recruitment to mitochondria and subsequent activation, as well as reduced cytochrome c redistribution from mitochondria. The data are consistent with Hsp72 blocking apoptosis upstream of Bax recruitment to mitochondria. Neuron-like cells (with elevated Hsp72) were more resistant to staurosporine by all measured indices of apoptotic signaling. Use of stable transfectants ectopically expressing moderately elevated levels of Hsp72 revealed that such cells in the undifferentiated state showed enhanced resistance to staurosporine-induced apoptosis, which was even more robust after differentiation to neuron-like cells. Overall, the protective effects of differentiation, thermal preconditioning and ectopic Hsp72 expression were additive. The strong inverse correlation between cellular Hsp72 levels and susceptibility to apoptosis support the notion that Hsp72 acts as a significant neuroprotective factor, enabling post-mitotic neurons to withstand potentially lethal stress that induces apoptosis

Mild Electrical Stimulation with Heat Shock Ameliorates Insulin Resistance via Enhanced Insulin Signaling

Low-intensity electrical current (or mild electrical stimulation; MES) influences signal transduction and activates phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Because insulin resistance is characterized by a marked reduction in insulin-stimulated PI3K-mediated activation of Akt, we asked whether MES could increase Akt phosphorylation and ameliorate insulin resistance. In addition, it was also previously reported that heat shock protein 72 (Hsp72) alleviates hyperglycemia. Thus, we applied MES in combination with heat shock (HS) to in vitro and in vivo models of insulin resistance. Here we show that 10-min treatment with MES at 5 V (0.1 ms pulse duration) together with HS at 42°C increased the phosphorylation of insulin signaling molecules such as insulin receptor substrate (IRS) and Akt in HepG2 cells maintained in high-glucose medium. MES (12 V)+mild HS treatment of high fat-fed mice also increased the phosphorylation of insulin receptor β subunit (IRβ) and Akt in mice liver. In high fat-fed mice and db/db mice, MES+HS treatment for 10 min applied twice a week for 12–15 weeks significantly decreased fasting blood glucose and insulin levels and improved insulin sensitivity. The treated mice showed significantly lower weight of visceral and subcutaneous fat, a markedly improved fatty liver and decreased size of adipocytes. Our findings indicated that the combination of MES and HS alleviated insulin resistance and improved fat metabolism in diabetes mouse models, in part, by enhancing the insulin signaling pathway

A glimpse into Thurston's work

We present an overview of some significant results of Thurston and their impact on mathematics. The final version of this paper will appear as Chapter 1 of the book "In the tradition of Thurston: Geometry and topology", edited by K. Ohshika and A. Papadopoulos (Springer, 2020)