The Universal Real Projective Plane: LHC phenomenology at one Loop

The Real Projective Plane is the lowest dimensional orbifold which, when combined with the usual Minkowski space-time, gives rise to a unique model in six flat dimensions possessing an exact Kaluza Klein (KK) parity as a relic symmetry of the broken six dimensional Lorentz group. As a consequence of this property, any model formulated on this background will include a stable Dark Matter candidate. Loop corrections play a crucial role because they remove mass degeneracy in the tiers of KK modes and induce new couplings which mediate decays. We study the full one loop structure of the corrections by means of counter-terms localised on the two singular points. As an application, the phenomenology of the (2,0) and (0,2) tiers is discussed at the LHC. We identify promising signatures with single and di-lepton, top antitop and 4 tops: in the dilepton channel, present data from CMS and ATLAS may already exclude KK masses up to 250 GeV, while by next year they may cover the whole mass range preferred by WMAP data.Comment: 45 pages, 3 figure

Markers of Oxidative Damage Are Not Elevated in Otherwise Healthy Individuals With the Metabolic Syndrome

OBJECTIVE- The role of oxidative damage in the pathogenesis of metabolic syndrome is poorly understood. RESEARCH DESIGN AND METHODS- A detailed cross-sectional study was performed to assess the relationship between lipid oxidation products, γ-glutamyltransferase, highsensitivity C-reactive protein (hs-CRP), and phospholipase activities with respect to the metabolic status in a cohort of otherwise healthy individuals. RESULTS- A total of 179 individuals (87 men and 92 women) aged 43 ± 14 years (mean ± SD) participated in this study. There were no differences in the levels of plasma F 2-isoprostanes, hydroxyeicosatetraenoic acids, cholesterol oxidation products, and phospholipase activities in individuals with features of metabolic syndrome. In multivariate analyses, serum hs-CRP was a consistent independent predictor of metabolic syndrome. CONCLUSIONS- Minimal changes were observed in multiple markers of oxidative damage in a well-characterized cohort of individuals with features of metabolic syndrome. © 2010 by the American Diabetes Association.link_to_subscribed_fulltex

Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin

OBJECTIVE—Diabetes results from a deficiency of functional β-cells due to both an increase in β-cell death and an inhibition of β-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for β-cells

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

BACKGROUND: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. METHODS: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. RESULTS: Dexamethasone reduced BAL and lung tissue eosinophilia (ED(50 )values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED(50 )of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. CONCLUSION: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma

Expression of the NH2-Terminal Fragment of RasGAP in Pancreatic β-Cells Increases Their Resistance to Stresses and Protects Mice From Diabetes

OBJECTIVE: Our laboratory has previously established in vitro that a caspase-generated RasGAP NH(2)-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic beta-cells in a physiological setting. RESEARCH DESIGN AND METHODS: A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS: Pancreatic beta-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor kappaB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo beta-cell apoptosis. CONCLUSIONS: Fragment N efficiently increases the overall resistance of beta-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools

Four tops on the real projective plane at LHC

We explore the four top signal ttbar ttbar at the 7 TeV Large Hadron Collider as a probe of physics beyond the standard model. Enhancement of the corresponding cross-section with respect to the Standard Model value can probe the electroweak symmetry breaking sector or test extra dimensional models with heavy Kaluza-Klein gluons and quarks. We perform a detailed analysis including background and detector simulation in the specific case of a universal extra-dimensional model with two extra dimensions compactified using the geometry of the real projective plane. For masses around 600 GeV, a discovery is possible for an effective cross section above 210 fb (36 fb) for 1/fb (10/fb) of integrated luminosity. This implies a branching ratio in tops of the (1,1) heavy photon above 13% (5%). Furthermore, the 4-top signal from the (2,0) and (0,2) tiers can be discovered with an integrated luminosity of 3.5/fb. The results of our simulation can be easily adapted to other models since the background processes are identical. Concerning the signal, typical production mechanisms for the ttbar ttbar signal are similar even if cross-section values may vary considerably depending on the model and the spectrum of the new particles.Comment: 26 pages, 4 figures, minor modifications and few references adde

Identification of a Novel TGFβ/PKA Signaling Transduceome in Mediating Control of Cell Survival and Metastasis in Colon Cancer

Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown.Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival.This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors

Skeletal Diversification via Heteroatom Linkage Control: Preparation of Bicyclic and Spirocyclic Scaffolds from NSubstituted Homopropargyl Alcohols

The discovery and application of a new branching pathway synthesis strategy that rapidly produces skeletally diverse scaffolds is described. Two different scaffold types, one a bicyclic iodo-vinylidene tertiary amine/tertiary alcohol and the other, a spirocyclic 3-furanone, are each obtained using a two-step sequence featuring a common first step. Both scaffold types lead to intermediates that can be orthogonally diversified using the same final components. One of the scaffold types was obtained in sufficiently high yield that it was immediately used to produce a 97-compound library

Enamelin is critical for ameloblast integrity and enamel ultrastructure formation

Mutations in the human enamelin gene cause autosomal dominant hypoplastic amelogenesis imperfecta in which the affected enamel is thin or absent. Study of enamelin knockout NLS-lacZ knockin mice revealed that mineralization along the distal membrane of ameloblast is deficient, resulting in no true enamel formation. To determine the function of enamelin during enamel formation, we characterized the developing teeth of the Enam-/- mice, generated amelogenin-driven enamelin transgenic mouse models, and then introduced enamelin transgenes into the Enam-/- mice to rescue enamel defects. Mice at specific stages of development were subjected to morphologic and structural analysis using β-galactosidase staining, immunohistochemistry, and transmission and scanning electron microscopy. Enamelin expression was ameloblast-specific. In the absence of enamelin, ameloblasts pathology became evident at the onset of the secretory stage. Although the aggregated ameloblasts generated matrix-containing amelogenin, they were not able to create a well-defined enamel space or produce normal enamel crystals. When enamelin is present at half of the normal quantity, enamel was thinner with enamel rods not as tightly arranged as in wild type suggesting that a specific quantity of enamelin is critical for normal enamel formation. Enamelin dosage effect was further demonstrated in transgenic mouse lines over expressing enamelin. Introducing enamelin transgene at various expression levels into the Enam -/- background did not fully recover enamel formation while a medium expresser in the Enam+/- background did. Too much or too little enamelin abolishes the production of enamel crystals and prism structure. Enamelin is essential for ameloblast integrity and enamel formation. © 2014 Hu et al