First and second fundamental solutions of the time-fractional telegraph equation with Laplace or Dirac operators

In this work, we obtain the first and second fundamental solutions (FS) of the multidimensional time-fractional equation with Laplace or Dirac operators, where the two time-fractional derivatives of orders α ∈]0, 1] and β ∈]1, 2] are in the Caputo sense. We obtain representations of the FS in terms of Hankel transform, double Mellin- Barnes integrals, and H-functions of two variables. As an application, the FS are used to solve Cauchy problems of Laplace and Dirac type

Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases?

BackgroundThe aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors.ResultsHigh-throughput screening of the Roche compound library identified a simple 3,4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site.ConclusionsThe efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

The BINGO project: V. Further steps in component separation and bispectrum analysis

Context. Observing the neutral hydrogen distribution across the Universe via redshifted 21 cm line intensity mapping constitutes a powerful probe for cosmology. However, the redshifted 21 cm signal is obscured by the foreground emission from our Galaxy and other extragalactic foregrounds. This paper addresses the capabilities of the BINGO survey to separate such signals. Aims. We show that the BINGO instrumental, optical, and simulations setup is suitable for component separation, and that we have the appropriate tools to understand and control foreground residuals. Specifically, this paper looks in detail at the different residuals left over by foreground components, shows that a noise-corrected spectrum is unbiased, and shows that we understand the remaining systematic residuals by analyzing nonzero contributions to the three-point function. Methods. We use the generalized needlet internal linear combination, which we apply to sky simulations of the BINGO experiment for each redshift bin of the survey. We use binned estimates of the bispectrum of the maps to assess foreground residuals left over after component separation in the final map. Results. We present our recovery of the redshifted 21 cm signal from sky simulations of the BINGO experiment, including foreground components. We test the recovery of the 21 cm signal through the angular power spectrum at different redshifts, as well as the recovery of its non-Gaussian distribution through a bispectrum analysis. We find that non-Gaussianities from the original foreground maps can be removed down to, at least, the noise limit of the BINGO survey with such techniques. Conclusions. Our component separation methodology allows us to subtract the foreground contamination in the BINGO channels down to levels below the cosmological signal and the noise, and to reconstruct the 21 cm power spectrum for different redshift bins without significant loss at multipoles 20≲ l ≲ 500. Our bispectrum analysis yields strong tests of the level of the residual foreground contamination in the recovered 21 cm signal, thereby allowing us to both optimize and validate our component separation analysis

Spatial heterogeneity of habitat suitability for Rift Valley fever occurrence in Tanzania: an ecological niche modelling approach

Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics

The BINGO project: IV. Simulations for mission performance assessment and preliminary component separation steps

Aims. The large-scale distribution of neutral hydrogen (HI) in the Universe is luminous through its 21 cm emission. The goal of the Baryon Acoustic Oscillations from Integrated Neutral Gas Observations (BINGO) radio telescope is to detect baryon acoustic oscillations at radio frequencies through 21 cm intensity mapping (IM). The telescope will span the redshift range 0.127<z<0.449 with an instantaneous field-of-view of 14.75 - 6.0. Methods. In this work we investigate different constructive and operational scenarios of the instrument by generating sky maps as they would be produced by the instrument. In doing this we use a set of end-to-end IM mission simulations. The maps will additionally be used to evaluate the efficiency of a component separation method (GNILC). Results. We have simulated the kind of data that would be produced in a single-dish IM experiment such as BINGO. According to the results obtained, we have optimized the focal plane design of the telescope. In addition, the application of the GNILC method on simulated data shows that it is feasible to extract the cosmological signal across a wide range of multipoles and redshifts. The results are comparable with the standard principal component analysis method