MyD88 Dependent Signaling Contributes to Protective Host Defense against Burkholderia pseudomallei

Background: Toll-like receptors (TLRs) have a central role in the recognition of pathogens and the initiation of the innate immune response. Myeloid differentiation primary-response gene 88 (MyD88) and TIR-domain-containing adaptor protein inducing IFNb (TRIF) are regarded as the key signaling adaptor proteins for TLRs. Melioidosis, which is endemic in SE-Asia, is a severe infection caused by the gram-negative bacterium Burkholderia pseudomallei. We here aimed to characterize the role of MyD88 and TRIF in host defense against melioidosis. Methodology and Principal Findings: First, we found that MyD88, but not TRIF, deficient whole blood leukocytes released less TNFa upon stimulation with B. pseudomallei compared to wild-type (WT) cells. Thereafter we inoculated MyD88 knockout (KO), TRIF mutant and WT mice intranasally with B. pseudomallei and found that MyD88 KO, but not TRIF mutant mice demonstrated a strongly accelerated lethality, which was accompanied by significantly increased bacterial loads in lungs, liver and blood, and grossly enhanced liver damage compared to WT mice. The decreased bacterial clearance capacity of MyD88 KO mice was accompanied by a markedly reduced early pulmonary neutrophil recruitment and a diminished activation of neutrophils after infection with B. pseudomallei. MyD88 KO leukocytes displayed an unaltered capacity to phagocytose and kill B. pseudomallei in vitro. Conclusions: MyD88 dependent signaling, but not TRIF dependent signaling, contributes to a protective host respons

Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A

Accelerated expansion from ghost-free bigravity: a statistical analysis with improved generality

We study the background cosmology of the ghost-free, bimetric theory of gravity. We perform an extensive statistical analysis of the model using both frequentist and Bayesian frameworks and employ the constraints on the expansion history of the Universe from the observations of supernovae, the cosmic microwave background and the large scale structure to estimate the model's parameters and test the goodness of the fits. We explore the parameter space of the model with nested sampling to find the best-fit chi-square, obtain the Bayesian evidence, and compute the marginalized posteriors and mean likelihoods. We mainly focus on a class of sub-models with no explicit cosmological constant (or vacuum energy) term to assess the ability of the theory to dynamically cause a late-time accelerated expansion. The model behaves as standard gravity without a cosmological constant at early times, with an emergent extra contribution to the energy density that converges to a cosmological constant in the far future. The model can in most cases yield very good fits and is in perfect agreement with the data. This is because many points in the parameter space of the model exist that give rise to time-evolution equations that are effectively very similar to those of the $\Lambda$CDM. This similarity makes the model compatible with observations as in the $\Lambda$CDM case, at least at the background level. Even though our results indicate a slightly better fit for the $\Lambda$CDM concordance model in terms of the $p$-value and evidence, none of the models is statistically preferred to the other. However, the parameters of the bigravity model are in general degenerate. A similar but perturbative analysis of the model as well as more data will be required to break the degeneracies and constrain the parameters, in case the model will still be viable compared to the $\Lambda$CDM.Comment: 42 pages, 9 figures; typos corrected in equations (2.12), (2.13), (3.7), (3.8) and (3.9); more discussions added (footnotes 5, 8, 10 and 13) and abstract, sections 4.2, 4.3 and 5 (conclusions) modified in response to referee's comments; references added; acknowledgements modified; all results completely unchanged; matches version accepted for publication in JHE

The completed SDSS-IV extended Baryon Oscillation Spectroscopic Survey: Measurement of the BAO and growth rate of structure of the emission line galaxy sample from the anisotropic power spectrum between redshift 0.6 and 1.1

We analyse the large-scale clustering in Fourier space of emission line galaxies (ELG) from the Data Release 16 of the Sloan Digital Sky Survey IV extended Baryon Oscillation Spectroscopic Survey. The ELG sample contains 173 736 galaxies covering 1170 deg^{2} in the redshift range 0.6 < z < 1.1. We perform a BAO measurement from the post-reconstruction power spectrum monopole, and study redshift space distortions (RSD) in the first three even multipoles. Photometric variations yield fluctuations of both the angular and radial survey selection functions. Those are directly inferred from data, imposing integral constraints which we model consistently. The full data set has only a weak preference for a BAO feature (1.4σ). At the effective redshift z_{eff} = 0.845 we measure D_{V}(z_{eff})/r_{drag}=18.33\tfrac{+0.57}{−0.62⁠},with DV the volume-averaged distance and r_{drag} the comoving sound horizon at the drag epoch. In combination with the RSD measurement, at z_{eff} = 0.85 we find fσ_{8}(z_{eff})=0.289\tfrac{+0.085}{−0.096⁠}, with f the growth rate of structure and σ_{8} the normalization of the linear power spectrum, D_{H}(z_{eff})/r_{drag} = 20.0\tfrac{2.4}{-2.2} and D_{M}(z_[eff})/r_{drag} = 19.17 ± 0.99 with D_{H} and D_{M} the Hubble and comoving angular distances, respectively. These results are in agreement with those obtained in configuration space, thus allowing a consensus measurement of fσ_{8}(z_{eff}) = 0.315 ± 0.095, D_{H}(z_{eff})/r_{drag} = 19.6\tfrac{+2.2}{−2.1} and D_{M}(z_{eff})/r_{drag} = 19.5 ± 1.0. This measurement is consistent with a flat ΛCDM model with Planck parameters

The Dark Energy Spectroscopic Instrument (DESI)

We present the status of the Dark Energy Spectroscopic Instrument (DESI) and its plans and opportunities for the coming decade. DESI construction and its initial five years of operations are an approved experiment of the US Department of Energy and is summarized here as context for the Astro2020 panel. Beyond 2025, DESI will require new funding to continue operations. We expect that DESI will remain one of the world's best facilities for wide-field spectroscopy throughout the decade. More about the DESI instrument and survey can be found at https://www.desi.lbl.gov

Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T>C (L444P)

BACKGROUND: Gaucher disease is a potentially severe lysosomal storage disorder caused by mutations in the human glucocerebrosidase gene (GBA). We have developed a multiplexed genetic assay for eight diseases prevalent in the Ashkenazi population: Tay-Sachs, Gaucher type I, Niemann-Pick types A and B, mucolipidosis type IV, familial dysautonomia, Canavan, Bloom syndrome, and Fanconi anemia type C. This assay includes an allelic determination for GBA allele c.1448T>C (L444P). The goal of this study was to clinically evaluate this assay. METHODS: Biotinylated, multiplex PCR products were directly hybridized to capture probes immobilized on fluorescently addressed microspheres. After incubation with streptavidin-conjugated fluorophore, the reactions were analyzed by Luminex IS100. Clinical evaluations were conducted using de-identified patient DNA samples. RESULTS: We evaluated a multiplexed suspension array assay that includes wild-type and mutant genetic determinations for Gaucher disease allele c.1448T>C. Two percent of samples reported to be wild-type by conventional methods were observed to be c.1448T>C heterozygous using our assay. Sequence analysis suggested that this phenomenon was due to co-amplification of the functional gene and a paralogous pseudogene (ΨGBA) due to a polymorphism in the primer-binding site of the latter. Primers for the amplification of this allele were then repositioned to span an upstream deletion in the pseudogene, yielding a much longer amplicon. Although it is widely reported that long amplicons negatively impact amplification or detection efficiency in recently adopted multiplex techniques, this assay design functioned properly and resolved the occurrence of false heterozygosity. CONCLUSION: Although previously available sequence information suggested GBA gene/pseudogene discrimination capabilities with a short amplified product, we identified common single-nucleotide polymorphisms in the pseudogene that required amplification of a larger region for effective discrimination

UGT1A1 is a major locus influencing bilirubin levels in African Americans

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10−8. The lowest P-value was 1.7 × 10−22 for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10−11; this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r2≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations

Activation of Thiazide-Sensitive Co-Transport by Angiotensin II in the cyp1a1-Ren2 Hypertensive Rat

Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ∼20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone

AIC, BIC, Bayesian evidence against the interacting dark energy model

Recent astronomical observations have indicated that the Universe is in the phase of accelerated expansion. While there are many cosmological models which try to explain this phenomenon, we focus on the interacting $\Lambda$CDM model where the interaction between the dark energy and dark matter sectors takes place. This model is compared to its simpler alternative---the $\Lambda$CDM model. To choose between these models the likelihood ratio test was applied as well as the model comparison methods (employing Occam's principle): the Akaike information criterion (AIC), the Bayesian information criterion (BIC) and the Bayesian evidence. Using the current astronomical data: SNIa (Union2.1), $h(z)$, BAO, Alcock--Paczynski test and CMB we evaluated both models. The analyses based on the AIC indicated that there is less support for the interacting $\Lambda$CDM model when compared to the $\Lambda$CDM model, while those based on the BIC indicated that there is the strong evidence against it in favor the $\Lambda$CDM model. Given the weak or almost none support for the interacting $\Lambda$CDM model and bearing in mind Occam's razor we are inclined to reject this model.Comment: LaTeX svjour3, 12 pages, 3 figure