On the cosmological variation of the fine structure constant

A phenomenological model is proposed to explain the recent observed cosmological variation of the fine structure constant as an effect of the quantum vacuum, assuming a flat universe with cosmological constant $\Lambda$ in the cases ($\Omega_M, \Omega_\Lambda$) equal to (0.3,0.7) and (1,0). Because of the fourth Heisenberg relation, the lifetime of the virtual pairs of the zero-point radiation must depend on the gravitational potential, so that the quantum vacuum changes its density and acquires a relative permittivity different from one. Since the matter was more concentrated in the past, the gravitational potential of all the universe was stronger and the optical density of the vacuum higher, the electron charge being then more renormalized and smaller than now. The model is based on a first order Newtonian approximation that is valid for the range of the observations, but not for very high redshift, its prediction being that $\Delta \alpha /\alpha$ is proportional to $\Omega_M[a(t)^{-1}-1]-2\Omega_\Lambda [a(t)^2-1]$, $a(t)$ being the scale factor. This agrees with the observations.Comment: 11 pages, one figure. In this new version, the effect of the cosmological constant is considere

Beyond MFV in family symmetry theories of fermion masses

Minimal Flavour Violation (MFV) postulates that the only source of flavour changing neutral currents and CP violation, as in the Standard Model, is the CKM matrix. However it does not address the origin of fermion masses and mixing and models that do usually have a structure that goes well beyond the MFV framework. In this paper we compare the MFV predictions with those obtained in models based on spontaneously broken (horizontal) family symmetries, both Abelian and non-Abelian. The generic suppression of flavour changing processes in these models turns out to be weaker than in the MFV hypothesis. Despite this, in the supersymmetric case, the suppression may still be consistent with a solution to the hierarchy problem, with masses of superpartners below 1 TeV. A comparison of FCNC and CP violation in processes involving a variety of different family quantum numbers should be able to distinguish between various family symmetry models and models satisfying the MFV hypothesis.Comment: 34 pages, no figure

Left-right symmetry at LHC and precise 1-loop low energy data

Despite many tests, even the Minimal Manifest Left-Right Symmetric Model (MLRSM) has never been ultimately confirmed or falsified. LHC gives a new possibility to test directly the most conservative version of left-right symmetric models at so far not reachable energy scales. If we take into account precise limits on the model which come from low energy processes, like the muon decay, possible LHC signals are strongly limited through the correlations of parameters among heavy neutrinos, heavy gauge bosons and heavy Higgs particles. To illustrate the situation in the context of LHC, we consider the "golden" process $pp \to e^+ N$. For instance, in a case of degenerate heavy neutrinos and heavy Higgs masses at 15 TeV (in agreement with FCNC bounds) we get $\sigma(pp \to e^+ N)>10$ fb at $\sqrt{s}=14$ TeV which is consistent with muon decay data for a very limited $W_2$ masses in the range (3008 GeV, 3040 GeV). Without restrictions coming from the muon data, $W_2$ masses would be in the range (1.0 TeV, 3.5 TeV). Influence of heavy Higgs particles themselves on the considered LHC process is negligible (the same is true for the light, SM neutral Higgs scalar analog). In the paper decay modes of the right-handed heavy gauge bosons and heavy neutrinos are also discussed. Both scenarios with typical see-saw light-heavy neutrino mixings and the mixings which are independent of heavy neutrino masses are considered. In the second case heavy neutrino decays to the heavy charged gauge bosons not necessarily dominate over decay modes which include only light, SM-like particles.Comment: 16 pages, 10 figs, KL-KS and new ATLAS limits taken into accoun

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Presence of HIF-1 and related genes in normal mucosa, adenomas and carcinomas of the colorectum

Expression of the transcription factor hypoxia-inducible factor 1 (HIF-1), which plays a key role in cellular adaptation to hypoxia, was investigated in normal colorectal mucosa (ten), adenomas (61), and carcinomas (23). Tissue samples were analyzed for HIF-1α, its upstream regulators, von Hippel–Lindau factor, AKT, and mammalian target of rapamycin (mTOR) and its downstream targets glucose transporter 1 (GLUT1), carbonic anhydrase IX, stromal-cell-derived factor 1 (SDF-1) by immunohistochemistry. In normal colorectal mucosa, HIF-1α was observed in almost all nuclei of surface epithelial cells, probably secondary to a gradient of oxygenation, as indicated by pimonidazole staining. The same staining pattern was present in 87% of adenomas. In carcinomas, HIF-1α was present predominantly around areas of necrosis (78%). Active AKT and mTOR, were present in all adenomas, carcinomas, and in normal colorectal mucosa. GLUT1 and SDF-1 were present in the normal surface epithelium of all adenoma cases, whereas in the carcinoma GLUT1 was located around necrotic regions and SDF-1 was present in all epithelial cells. In conclusion, HIF-1α appears to be physiologically expressed in the upper part of the colorectal mucosa. The present observations support that upregulation of HIF-1α and its downstream targets GLUT1 and SDF-1 in colorectal adenomas and carcinomas may be due to hypoxia, in close interaction with an active phosphatidylinositol 3-kinases–AKT–mTOR pathway

Polyoma Virus-Induced Osteosarcomas in Inbred Strains of Mice: Host Determinants of Metastasis

The mouse polyoma virus induces a broad array of solid tumors in mice of many inbred strains. In most strains tumors grow rapidly but fail to metastasize. An exception has been found in the Czech-II/Ei mouse in which bone tumors metastasize regularly to the lung. These tumors resemble human osteosarcoma in their propensity for pulmonary metastasis. Cell lines established from these metastatic tumors have been compared with ones from non-metastatic osteosarcomas arising in C3H/BiDa mice. Osteopontin, a chemokine implicated in migration and metastasis, is known to be transcriptionally induced by the viral middle T antigen. Czech-II/Ei and C3H/BiDa tumor cells expressed middle T and secreted osteopontin at comparable levels as the major chemoattractant. The tumor cell lines migrated equally well in response to recombinant osteopontin as the sole attractant. An important difference emerged in assays for invasion in which tumor cells from Czech-II/Ei mice were able to invade across an extracellular matrix barrier while those from C3H/BiDa mice were unable to invade. Invasive behavior was linked to elevated levels of the metalloproteinase MMP-2 and of the transcription factor NFAT. Inhibition of either MMP-2 or NFAT inhibited invasion by Czech-II/Ei osteosarcoma cells. The metastatic phenotype is dominant in F1 mice. Osteosarcoma cell lines from F1 mice expressed intermediate levels of MMP-2 and NFAT and were invasive. Osteosarcomas in Czech-II/Ei mice retain functional p53. This virus-host model of metastasis differs from engineered models targeting p53 or pRb and provides a system for investigating the genetic and molecular basis of bone tumor metastasis in the absence of p53 loss

Overexpression of MicroRNAs from the miR-17-92 Paralog Clusters in AIDS-Related Non-Hodgkin's Lymphomas

Individuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined.We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis.Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs

Selected isotope ratio measurements of light metallic elements (Li, Mg, Ca, and Cu) by multiple collector ICP-MS

The unique capabilities of multiple collector inductively coupled mass spectrometry (MC-ICP-MS) for high precision isotope ratio measurements in light elements as Li, Mg, Ca, and Cu are reviewed in this paper. These elements have been intensively studied at the Geological Survey of Israel (GSI) and other laboratories over the past few years, and the methods used to obtain high precision isotope analyses are discussed in detail. The scientific study of isotopic fractionation of these elements is significant for achieving a better understanding of geochemical and biochemical processes in nature and the environment

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful

Status of low energy SUSY models confronted with the LHC 125 GeV Higgs data

Confronted with the LHC data of a Higgs boson around 125 GeV, different models of low energy SUSY show different behaviors: some are favored, some are marginally survived and some are strongly disfavored or excluded. In this note we update our previous scan over the parameter space of various low energy SUSY models by considering the latest experimental limits like the LHCb data for B_s->\mu^+\mu^- and the XENON 100(2012) data for dark matter-neucleon scattering. Then we confront the predicted properties of the SM-like Higgs boson in each model with the combined 7 TeV and 8 TeV Higgs search data of the LHC. For a SM-like Higgs boson around 125 GeV, we have the following observations: (i) The most favored model is the NMSSM, whose predictions about the Higgs boson can naturally (without any fine tuning) agree with the experimental data at 1-sigma level, better than the SM; (ii) The MSSM can fit the LHC data quite well but suffer from some extent of fine tuning; (iii) The nMSSM is excluded at 3-sigma level after considering all the available Higgs data; (iv) The CMSSM is quite disfavored since it is hard to give a 125 GeV Higgs boson mass and at the same time cannot enhance the di-photon signal rate.Comment: more comprehensive (table and figs showing chi-square added