Constraining the cosmic radiation density due to lepton number with Big Bang Nucleosynthesis

The cosmic energy density in the form of radiation before and during Big Bang Nucleosynthesis (BBN) is typically parameterized in terms of the effective number of neutrinos N_eff. This quantity, in case of no extra degrees of freedom, depends upon the chemical potential and the temperature characterizing the three active neutrino distributions, as well as by their possible non-thermal features. In the present analysis we determine the upper bounds that BBN places on N_eff from primordial neutrino--antineutrino asymmetries, with a careful treatment of the dynamics of neutrino oscillations. We consider quite a wide range for the total lepton number in the neutrino sector, eta_nu= eta_{nu_e}+eta_{nu_mu}+eta_{nu_tau} and the initial electron neutrino asymmetry eta_{nu_e}^in, solving the corresponding kinetic equations which rule the dynamics of neutrino (antineutrino) distributions in phase space due to collisions, pair processes and flavor oscillations. New bounds on both the total lepton number in the neutrino sector and the nu_e -bar{nu}_e asymmetry at the onset of BBN are obtained fully exploiting the time evolution of neutrino distributions, as well as the most recent determinations of primordial 2H/H density ratio and 4He mass fraction. Note that taking the baryon fraction as measured by WMAP, the 2H/H abundance plays a relevant role in constraining the allowed regions in the eta_nu -eta_{nu_e}^in plane. These bounds fix the maximum contribution of neutrinos with primordial asymmetries to N_eff as a function of the mixing parameter theta_13, and point out the upper bound N_eff < 3.4. Comparing these results with the forthcoming measurement of N_eff by the Planck satellite will likely provide insight on the nature of the radiation content of the universe.Comment: 17 pages, 9 figures, version to be published in JCA

Effect of Collective Neutrino Oscillations on the Neutrino Mechanism of Core-Collapse Supernovae

In the seconds after collapse of a massive star, the newborn proto-neutron star (PNS) radiates neutrinos of all flavors. The absorption of electron-type neutrinos below the radius of the stalled shockwave may drive explosions (the "neutrino mechanism"). Because the heating rate is proportional to the square of neutrino energy, flavor conversion of mu and tau neutrinos to electron-type neutrinos via collective neutrino oscillations (CnuO) may in principle increase the heating rate and drive explosions. In order to assess the potential importance of CnuO for the shock revival, we solve the steady-state boundary value problem of spherically-symmetric accretion between the PNS surface (r_nu) and the shock (r_S), including a scheme for flavor conversion via CnuO. For a given r_nu, PNS mass (M), accretion rate (Mdot), and assumed values of the neutrino energies from the PNS, we calculate the critical neutrino luminosity above which accretion is impossible and explosion results. We show that CnuO can decrease the critical luminosity by a factor of at most ~1.5, but only if the flavor conversion is fully completed inside r_S and if there is no matter suppression. The magnitude of the effect depends on the model parameters (M, Mdot, and r_nu) through the shock radius and the physical scale for flavor conversion. We quantify these dependencies and find that CnuO could lower the critical luminosity only for small M and Mdot, and large r_nu. However, for these parameter values CnuO are suppressed due to matter effects. By quantifying the importance of CnuO and matter suppression at the critical neutrino luminosity for explosion, we show in agreement with previous studies that CnuO are unlikely to affect the neutrino mechanism of core-collapse supernovae significantly.Comment: 8 pages, 3 figures, accepted to MNRA

E-government adoption: A cultural comparison

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ Springer Science + Business Media, LLC 2008.E-government diffusion is an international phenomenon. This study compares e-government adoption in the U.K. to adoption in the U.S. In particular, this study seeks to determine if the same factors are salient in both countries. Several studies have explored citizen acceptance of e-government services in the U.S. However, few studies have explored this phenomenon in the U.K. To identify the similarities and differences between the U.K. and the U.S. a survey is conducted in the U.K. and the findings are compared to the literature that investigates diffusion in the U.S. This study proposes a model of e-government adoption in the U.K. based on salient factors in the U.S. A survey is administered to 260 citizens in London to assess the importance of relative advantage, trust and the digital divide on intention to use e-government. The results of binary logistic regression indicate that there are cultural differences in e-government adoption in the U.K. and the U.S. The results indicate that of the prevailing adoption constructs, relative advantage and trust are pertinent in both the U.S. and the U.K., while ICT adoption barriers such as access and skill may vary by culture. Implications for research and practice are discussed

Electron Tomography of Fusiform Vesicles and Their Organization in Urothelial Cells

The formation of fusiform vesicles (FVs) is one of the most distinctive features in the urothelium of the urinary bladder. FVs represent compartments for intracellular transport of urothelial plaques, which modulate the surface area of the superficial urothelial (umbrella) cells during the distension-contraction cycle. We have analysed the three-dimensional (3D) structure of FVs and their organization in umbrella cells of mouse urinary bladders. Compared to chemical fixation, high pressure freezing gave a new insight into the ultrastructure of urothelial cells. Electron tomography on serial sections revealed that mature FVs had a shape of flattened discs, with a diameter of up to 1.2 µm. The lumen between the two opposing asymmetrically thickened membranes was very narrow, ranging from 5 nm to 10 nm. Freeze-fracturing and immunolabelling confirmed that FVs contain two opposing urothelial plaques connected by a hinge region that made an omega shaped curvature. In the central cytoplasm, 4–15 FVs were often organized into stacks. In the subapical cytoplasm, FVs were mainly organized as individual vesicles. Distension-contraction cycles did not affect the shape of mature FVs; however, their orientation changed from parallel in distended to perpendicular in contracted bladder with respect to the apical plasma membrane. In the intermediate cells, shorter and more dilated immature FVs were present. The salient outcome from this research is the first comprehensive, high resolution 3D view of the ultrastructure of FVs and how they are organized differently depending on their location in the cytoplasm of umbrella cells. The shape of mature FVs and their organization into tightly packed stacks makes them a perfect storage compartment, which transports large amounts of urothelial plaques while occupying a small volume of umbrella cell cytoplasm

CUL-2^LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis

Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (CDC45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus laevis egg extracts, we show that the E3 ligase CUL-2(LRR-1) associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 cofactors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2(LRR1) as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2(LRR-1), but is then removed by a mitotic pathway that requires the CDC-48 cofactor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future approaches by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically

Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>MYBPC3 </it>encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). <it>MYBPC3 </it>mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different <it>MYBPC3 </it>mutations.</p> <p>Methods</p> <p>87 patients with HCM and 71 patients with DCM were screened for <it>MYBPC3 </it>mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded.</p> <p>Results</p> <p>In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes <it>MYH7</it>, <it>TNNT2</it>, <it>TNNI3</it>, <it>ACTC </it>and <it>TPM1</it>. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families.</p> <p>Conclusion</p> <p><it>MYBPC3 </it>mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with <it>MYBPC3 </it>mutations require thorough clinical risk assessment.</p

NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies

Lack of Cul4b, an E3 Ubiquitin Ligase Component, Leads to Embryonic Lethality and Abnormal Placental Development

Cullin-RING ligases (CRLs) complexes participate in the regulation of diverse cellular processes, including cell cycle progression, transcription, signal transduction and development. Serving as the scaffold protein, cullins are crucial for the assembly of ligase complexes, which recognize and target various substrates for proteosomal degradation. Mutations in human CUL4B, one of the eight members in cullin family, are one of the major causes of X-linked mental retardation. We here report the generation and characterization of Cul4b knockout mice, in which exons 3 to 5 were deleted. In contrast to the survival to adulthood of human hemizygous males with CUL4B null mutation, Cul4b null mouse embryos show severe developmental arrest and usually die before embryonic day 9.5 (E9.5). Accumulation of cyclin E, a CRL (CUL4B) substrate, was observed in Cul4b null embryos. Cul4b heterozygotes were recovered at a reduced ratio and exhibited a severe developmental delay. The placentas in Cul4b heterozygotes were disorganized and were impaired in vascularization, which may contribute to the developmental delay. As in human CUL4B heterozygotes, Cul4b null cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues. Together, our results showed that CUL4B is indispensable for embryonic development in the mouse

Urothelial Plaque Formation in Post-Golgi Compartments

Urothelial plaques are specialized membrane domains in urothelial superficial (umbrella) cells, composed of highly ordered uroplakin particles. We investigated membrane compartments involved in the formation of urothelial plaques in mouse umbrella cells. The Golgi apparatus did not contain uroplakins organized into plaques. In the post-Golgi region, three distinct membrane compartments containing uroplakins were characterized: i) Small rounded vesicles, located close to the Golgi apparatus, were labelled weakly with anti-uroplakin antibodies and they possessed no plaques; we termed them “uroplakin-positive transporting vesicles” (UPTVs). ii) Spherical-to-flattened vesicles, termed “immature fusiform vesicles” (iFVs), were uroplakin-positive in their central regions and contained small urothelial plaques. iii) Flattened “mature fusiform vesicles” (mFVs) contained large plaques, which were densely labelled with anti-uroplakin antibodies. Endoytotic marker horseradish peroxidase was not found in these post-Golgi compartments. We propose a detailed model of de novo urothelial plaque formation in post-Golgi compartments: UPTVs carrying individual 16-nm particles detach from the Golgi apparatus and subsequently fuse into iFV. Concentration of 16-nm particles into plaques and removal of uroplakin-negative membranes takes place in iFVs. With additional fusions and buddings, iFVs mature into mFVs, each carrying two urothelial plaques toward the apical surface of the umbrella cell