60 research outputs found

    Model Independent Predictions of Big Bang Nucleosynthesis from \he4 and \li7: Consistency and Implications

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    We examine in detail how BBN theory is constrained, and what predictions it can make, when using only the most model-independent observational constraints. We avoid the uncertainties and model-dependencies that necessarily arise when solar neighborhood D and \he3 abundances are used to infer primordial D and \he3 via chemical and stellar evolution models. Instead, we use \he4 and \li7, thoroughly examining the effects of possible systematic errors in each. Via a likelihood analysis, we find near perfect agreement between BBN theory and the most model-independent data. Given this agreement, we then {\it assume} the correctness of BBN to set limits on the single parameter of standard BBN, the baryon-to-photon ratio, and to predict the primordial D and \he3 abundances. We also repeat our analysis including recent measurements of D/H from quasar absorption systems and find that the near perfect agreement between theory and observation of the three isotopes, D, \he4 and \li7 is maintained. These results have strong implications for the chemical and stellar evolution of the light elements, in particular for \he3. In addition, our results (especially if the D/H measurements are confirmed) have implications for the stellar depletion of \li7. Finally, we set limits on the number \nnu\ of neutrino flavors, using an analysis which carefully and systematically includes all available experimental constraints. The value \nnu = 3.0 fits best with BBN and a 95\% CL upper limit of \nnu \la 4 is established.Comment: 28 pages, latex, 10 ps figure

    Primordial Nucleosynthesis with CMB Inputs: Probing the Early Universe and Light Element Astrophysics

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    Cosmic microwave background (CMB) determinations of the baryon-to-photon ratio ηΩbaryonh2\eta \propto \Omega_{\rm baryon} h^2 will remove the last free parameter from (standard) big bang nucleosynthesis (BBN) calculations. This will make BBN a much sharper probe of early universe physics, for example, greatly refining the BBN measurement of the effective number of light neutrino species, Nν,effN_{\nu,eff}. We show how the CMB can improve this limit, given current light element data. Moreover, it will become possible to constrain Nν,effN_{\nu,eff} independent of \he4, by using other elements, notably deuterium; this will allow for sharper limits and tests of systematics. For example, a 3% measurement of η\eta, together with a 10% (3%) measurement of primordial D/H, can measure Nν,effN_{\nu,eff} to a 95% confidence level of \sigma_{95%}(N_\nu) = 1.8 (1.0) if η6.0×1010\eta \sim 6.0\times 10^{-10}. If instead, one adopts the standard model value Nν,eff=3N_{\nu,eff}=3, then one can use η\eta (and its uncertainty) from the CMB to make accurate predictions for the primordial abundances. These determinations can in turn become key inputs in the nucleosynthesis history (chemical evolution) of galaxies thereby placing constraints on such models.Comment: 17 pages, 13 figures, plain LaTe

    The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer

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    The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer

    Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

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    Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention.Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV- partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of approximately 12% from the true vaccine efficacy.CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs
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