Neutrino Dark Energy and Moduli Stabilization in a BPS Braneworld Scenario

A braneworld model for neutrino Dark Energy (DE) is presented. We consider a five dimensional two-branes set up with a bulk scalar field motivated by supergravity. Its low-energy effective theory is derived with a moduli space approximation (MSA). The position of the two branes are parametrized by two scalar degrees of freedom (moduli). After detuning the brane tensions a classical potential for the moduli is generated. This potential is unstable for dS branes and we suggest to consider as a stabilizing contribution the Casimir energy of bulk fields. In particular we add a massive spinor (neutrino) field in the bulk and then evaluate the Casimir contribution of the bulk neutrino with the help of zeta function regularization techniques. We construct an explicit form of the 4D neutrino mass as function of the two moduli. To recover the correct DE scale for the moduli potential the usual cosmological constant fine-tuning is necessary, but, once accepted, this model suggests a stronger connection between DE and neutrino physics.Comment: 26 pages, 1 EPS figur

Testicular degeneration in Bclw-deficient mice

To identify genes required for mammalian spermatogenesis, we screened lines of mutant mice created using a retroviral gene-trap system for male infertility. Homozygous ROSA41 male mice exhibit sterility associated with progressive testicular degeneration. Germ-cell defects are first observed at 19 days post-natal (p19). Spermatogenesis is blocked during late spermiogenesis in young adults. Gradual depletion of all stages of germ cells results in a Sertoli-cell-only phenotype by approximately six months of age. Subsequently, almost all Sertoli cells are lost from the seminiferous tubules and the Leydig cell population is reduced. Molecular analysis indicates that the gene mutated is Bclw, a death-protecting member of the Bcl2 family. The mutant allele of Bclw in ROSA41 does not produce a Bclw polypeptide. Expression of Bclw in the testis appears to be restricted to elongating spermatids and Sertoli cells. Potential roles for Bclw in testicular function are discussed

Differential Regulation of Gonadotropin Synthesis and Release in Ovariectomized Ewes after Treatment with a Luteinizing Hormone-Releasing Hormone Antagonist

Our working hypothesis was that synthesis and release of LH, but not FSH, were solely dependent on LHRH. Twenty ovariectomized (OVX) ewes were randomly assigned to one of five treatments (n = 4 per group). Ewes were administered a low (10 μg/kg) or high (100 μg/kg) dose of LHRH antagonist (LHRH-Ant) at 24-h intervals for 3 or 6 days. Control ewes received vehicle (5% mannitol) at 24-h intervals for 6 days. Blood samples were collected every 15 min for 4 h before LHRH-Ant or vehicle and every 2 h during the period of treatment to determine concentrations of LH and FSH. Twenty-four hours after the last treatment with LHRH-Ant or vehicle, anterior pituitaries were collected and divided in half along the midsagittal plane; the number of receptors for LHRH, pituitary content of LH and FSH, and relative amounts of mRNA for α, LHβ, and FSHβ subunits were determined. Concentrations of LH in serum decreased (p \u3c 0.05) from 25.4 ± 4.3 ng/ml before LHRH-Ant to less than 0.5 ng/ml within 4 h after the first treatment of LHRH-Ant and remained low (\u3c 0.5 ng/ml) throughout the study. Serum concentrations of FSH declined gradually during the 3- or 6-day period of treatment with LHRH-Ant, from 37.3 ± 2.4 and 26.5 ± 4.8 ng/ml to 19.9 ± 1.8 and 13.7 ± 2.1 ng/ml, respectively. The magnitude of decline in serum concentrations of LH and FSH did not differ among ewes treated with low or high doses of LHRH-Ant. Pituitary content of LH was not different (p \u3e 0.10) from that in controls, whereas pituitary content of FSH was greater (p \u3c 0.01) in control ewes compared to ewes treated with LHRH-Ant. Receptors for LHRH were nondetectable (\u3c 0.018 x 10-16 mol receptor/μg protein) in pituitaries after 3 or 6 days of treatment with LHRH-Ant (low or high dose). Relative amounts of mRNA for α, LHβ, and FSHβ subunits were lower (p \u3c 0.01) after 6 days of treatment with LHRH-Ant (low or high dose) than after 3 days of treatment with LHRH-Ant (low or high dose). The LHRH was, therefore, required to maintain steady state amounts of mRNA for FSH and LH and to maintain pituitary stores of FSH but not LH. Our data support the hypothesis that differential regulation of LH and FSH release occurs in ewes. While synthesis and release of LH are dependent on LHRH, synthesis but not release of FSH appears to be dependent on LHRH

A Geographically-Restricted but Prevalent Mycobacterium tuberculosis Strain Identified in the West Midlands Region of the UK between 1995 and 2008

Background: We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK.Methodology/Principal Findings: Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95% CI = 4.56-17.87, p 65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95% CI = 1.45-27.02, p = .01) were observed as social risk factors for infection.Conclusions/Significance: The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain

Comparative Analysis of Viral Gene Expression Programs during Poxvirus Infection: A Transcriptional Map of the Vaccinia and Monkeypox Genomes

Poxviruses engage in a complex and intricate dialogue with host cells as part of their strategy for replication. However, relatively little molecular detail is available with which to understand the mechanisms behind this dialogue.We designed a specialized microarray that contains probes specific to all predicted ORFs in the Monkeypox Zaire (MPXV) and Vaccinia Western Reserve (VACV) genomes, as well as >18,000 human genes, and used this tool to characterize MPXV and VACV gene expression responses in vitro during the course of primary infection of human monocytes, primary human fibroblasts and HeLa cells. The two viral transcriptomes show distinct features of temporal regulation and species-specific gene expression, and provide an early foundation for understanding global gene expression responses during poxvirus infection.The results provide a temporal map of the transcriptome of each virus during infection, enabling us to compare viral gene expression across species, and classify expression patterns of previously uncharacterized ORFs

Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium

Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis.Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals

The Membrane Fusion Step of Vaccinia Virus Entry Is Cooperatively Mediated by Multiple Viral Proteins and Host Cell Components

For many viruses, one or two proteins allow cell attachment and entry, which occurs through the plasma membrane or following endocytosis at low pH. In contrast, vaccinia virus (VACV) enters cells by both neutral and low pH routes; four proteins mediate cell attachment and twelve that are associated in a membrane complex and conserved in all poxviruses are dedicated to entry. The aim of the present study was to determine the roles of cellular and viral proteins in initial stages of entry, specifically fusion of the membranes of the mature virion and cell. For analysis of the role of cellular components, we used well characterized inhibitors and measured binding of a recombinant VACV virion containing Gaussia luciferase fused to a core protein; viral and cellular membrane lipid mixing with a self-quenching fluorescent probe in the virion membrane; and core entry with a recombinant VACV expressing firefly luciferase and electron microscopy. We determined that inhibitors of tyrosine protein kinases, dynamin GTPase and actin dynamics had little effect on binding of virions to cells but impaired membrane fusion, whereas partial cholesterol depletion and inhibitors of endosomal acidification and membrane blebbing had a severe effect at the later stage of core entry. To determine the role of viral proteins, virions lacking individual membrane components were purified from cells infected with members of a panel of ten conditional-lethal inducible mutants. Each of the entry protein-deficient virions had severely reduced infectivity and except for A28, L1 and L5 greatly impaired membrane fusion. In addition, a potent neutralizing L1 monoclonal antibody blocked entry at a post-membrane lipid-mixing step. Taken together, these results suggested a 2-step entry model and implicated an unprecedented number of viral proteins and cellular components involved in signaling and actin rearrangement for initiation of virus-cell membrane fusion during poxvirus entry

Drosophila S2 Cells Are Non-Permissive for Vaccinia Virus DNA Replication Following Entry via Low pH-Dependent Endocytosis and Early Transcription

Vaccinia virus (VACV), a member of the chordopox subfamily of the Poxviridae, abortively infects insect cells. We have investigated VACV infection of Drosophila S2 cells, which are useful for protein expression and genome-wide RNAi screening. Biochemical and electron microscopic analyses indicated that VACV entry into Drosophila S2 cells depended on the VACV multiprotein entry-fusion complex but appeared to occur exclusively by a low pH-dependent endocytic mechanism, in contrast to both neutral and low pH entry pathways used in mammalian cells. Deep RNA sequencing revealed that the entire VACV early transcriptome, comprising 118 open reading frames, was robustly expressed but neither intermediate nor late mRNAs were made. Nor was viral late protein synthesis or inhibition of host protein synthesis detected by pulse-labeling with radioactive amino acids. Some reduction in viral early proteins was noted by Western blotting. Nevertheless, synthesis of the multitude of early proteins needed for intermediate gene expression was demonstrated by transfection of a plasmid containing a reporter gene regulated by an intermediate promoter. In addition, expression of a reporter gene with a late promoter was achieved by cotransfection of intermediate genes encoding the late transcription factors. The requirement for transfection of DNA templates for intermediate and late gene expression indicated a defect in viral genome replication in VACV-infected S2 cells, which was confirmed by direct analysis. Furthermore, VACV-infected S2 cells did not support the replication of a transfected plasmid, which occurs in mammalian cells and is dependent on all known viral replication proteins, indicating a primary restriction of DNA synthesis