A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for H

Graph theory approach to exceptional points in wave scattering

In this paper, we use graph theory to solve wave scattering problems in the discrete dipole approximation. As a key result of this work, in the presence of active scatterers, we show how one can find arbitrary large-order zero eigenvalue exceptional points (EPs) in parameter space by solving a set of non-linear equations. We interpret these equations in a graph theory picture as vanishing sums of scattering events. We also show how the total field of the system responds to parameter perturbations at the EP. Finally, we investigate the sensitivity of the power output to imaginary perturbation in the design frequency. This perturbation can be employed to trade sensitivity for a different dissipation balance of the system.Comment: 15 pages, 11 figure

Pattern characterization of genes involved in non-specific immune response in Staphylococcus aureus isolates from intramammary infections

Staphylococcus aureus isolated from mammary gland are characterized by different genetic patterns. Ninety four isolates from 33 dairy herds were analyzed by the means of amicroarray to investigate S. aureus virulence patterns and the distribution of genes believed to be involved in immune evasion. None of the 94 isolates considered were MRSA. However, 50% of the isolates belonged to complexes related to MRSA and to human diseases, while only about 25% of them can be considered as exclusively of bovine origin. The distribution of clonal complexes and the different gene patterns observed confirmed the presence of an influence of geographical localization. The assessment of the influence of genes related to immune evasion on quarter milk cell count showed as four of them showed to be significantly associated to an increase quarter milk SCC. These genes could be potential target for developing new vaccines against S.aureus

Robustness evaluation of different controllers in the presence of flow rate variations

This paper proposes a direct approach to evaluate achievable robustness to flow rate variations of different controllers (PID and advanced algorithms), for typical process dynamics (First Order Plus Time Delay with different time delay/lag ratio), able to represent very common heat exchange equipment. Starting from comparable nominal performance, the effect of flow rate variations on process parameters and consequently on achievable performance is analyzed in simulation up to the onset of marginal stability conditions. Flow rate variations act as “structured” uncertainty on parameters and the proposed procedure is able to indicate maximum allowable variations in a more realistic and efficient way, avoiding the conservatism implicit in most of analytical design techniques available in the literature. The proposed technique evaluates in a straightforward way the Maximum Allowed Changes (MAC) in flow rate. As inverse proportionality between flow rate and process parameters is present, also the efficacy of adopting equal percentage (EP) valves, which allow a local compensation of process gain nonlinearity, is investigated

Parental species and hybrid descendants of Bacillus (Insecta Phasmatodea) show different patterns of highly amplified, colocalized ribosomal and telomeric sequences

We investigated by dual-color fluorescence in situ hybridization (FISH) with 28S ribosomal and (TTAGG)n telomeric probes all species of the circum-Mediterranean genus Bacillus encompassing bisexual and parthenogenetic taxa, namely the three parental species (B. grandii, B. atticus, B. rossius) and the two derived hybrids (B. whitei, B. lynceorum). Specimens were collected in Italian mainland, Sardinia and Sicily. In all species the presence of colocalized, highly amplified ribosomal and telomeric sequences was demonstrated by the double labelling of the cytological satellites. These satellites varied in size, number and location both among and within species. In B. grandii and B. atticus a maximum of two FISH-labeled locations were observed, whereas in B. rossius and in the two hybrids up to 11 different positions were recorded. Moreover, our investigations showed a significant occurrence of chromosome breakages and rearrangements. The overall meaning of the ribosomal and telomeric sequence colocalization as well as the Nucleolar Organizer Region mobility and activity are discussed in both the ancestors and their hybrid descendants. It is noteworthy that the same trait has been shown in seven additional phasmid species belonging to distantly related genera. This trait could be a shared ancestral character in phasmids

Interference competition with an invasive species as potential driver of rapid extinction in an island-endemic lizard

Competition between native and alien species is often described as a main driver of biodiversity loss. Nevertheless, there is limited evidence of animal declines and extinctions actually determined by competition. The Aeolian lizard, Podarcis raffonei, is critically endangered because it suffered dramatic declines and extinctions throughout its range. Competition and hybridization with invasive Italian lizards, Podarcis siculus, have been proposed as a driver of the shrinkage of Aeolian lizards, still the mechanisms underlying their decline remain poorly resolved. We used observations of behavioral encounters, combined with morphological data and robust species identification based on genomics, to test whether agonistic interactions with the invasive Italian lizard can explain the competitive exclusion and rapid decline of the native Aeolian lizard while accounting for hybridization. Invasive lizards were larger, with larger heads, and showed higher bite tendency against neutral items. In agonistic encounters between males, Aeolian lizards received more attacks and escaped more frequently than invasive males. The performance of Aeolian males was particularly poor in interspecific encounters. Genomic data verified that tested individuals were all pure P. raffonei or P. siculus, with a single hybrid individual detected. The strong competitive advantage of invasive males can allow them monopolizing territories, potentially hampering the reproduction of both native males and females, thus resulting in a mechanism of sterilizing interference. Reproductive interference competition mediated by spatial exclusion might be an unappreciated process determining rapid decline in endemic species. Safeguarding areas devoid of invasive species should be the priority strategy to avoid the extinction of the Aeolian lizards

An automatic system for modeling and controlling color quality of dyed leathers in tanneries

This paper presents an automatic system for modeling and controlling color quality of dyed leathers of an Italian tannery. The proposed software is implemented within the IT company system, and is fully integrated with the machineries of the finishing line, that is, a spraying cabin with a robotic carousel, and an electronic tintometer system. Suitable experimental tests according to the Design of Experiments (DoE) are firstly defined, executed and analyzed for a series of color tones of interest. In order to derive and validate a set of colorimetric models able to evaluate and predict the color rendering of painted leathers, a set of recipes of basic dye pigments and data of light reflection measured by a multispectral camera are used. Principal Component Analysis is applied for dimensionality reduction, and linear least squares regression is employed to identify these data-driven models, which are then used for color control purpose. A color correction feedback strategy is indeed developed in order to converge towards the various target formulations. The control algorithm aims at reaching the multispectral reading values of the reference, that is, the first sample of unknown color recipe starting from the most similar archive base and appropriately updating the recipe of pigments, by using the measurement of leather samples prepared from time to time by the finishing line machineries. A set of company data are used to successfully validate the identified colorimetric models and the proposed color correction strategy

Sequence analysis of a microsatellite and its flanking regions in intraspecific hybrids of grapevine (Vitis vinifera L.)

Microsatellite (MS) VVMD21 (BOWERS et al. 1999) was taken as a model to explore the molecular basis of polymorphism in a panel of 6 grapevine accessions (Vitis vinifera L.), consisting of Sangiovese and Cabernet Sauvignon and 4 F1 plants derived from crossing both varieties. The 12 alleles of both parents and the progeny were cloned and sequenced. The microsatellite repeat (AG)n>6 was found in each sequence, together with a poly-T rich region that showed irregularity. Furthermore, single nucleotide deletion or exchange (point mutations) were found in the microsatellite flanking regions

Sequence analysis of a microsatellite and its flanking regions in intraspecific hybrids of grapevine (Vitis vinifera L.)

Microsatellite (MS) VVMD21 (BOWERS et al. 1999) was taken as a model to explore the molecular basis of polymorphism in a panel of 6 grapevine accessions (Vitis vinifera L.), consisting of Sangiovese and Cabernet Sauvignon and 4 F1 plants derived from crossing both varieties. The 12 alleles of both parents and the progeny were cloned and sequenced. The microsatellite repeat (AG)n>6 was found in each sequence, together with a poly-T rich region that showed irregularity. Furthermore, single nucleotide deletion or exchange (point mutations) were found in the microsatellite flanking regions

Numerical investigation of the mixing of highly viscous liquids with Cowles impellers

This work is aimed at investigating the mixing process of highly viscous paints, used to colour leathers in the tanning industry, through Computational Fluid Dynamics (CFD). In particular, a mixing tank is fed with a master liquid and different liquid pigments and then stirred by Cowles impellers in order to obtain a paint of a uniform colour. The typical dynamic viscosity of the liquids in this process is μ ~ O(0.1-10) Pa·s, while the Cowles rotational speed is usually very high, i.e. 3000-5000 rpm. The numerical model is based on the solution of the unsteady Reynolds-Averaged Navier–Stokes (RANS) equations for continuity, momentum and species mass fractions, the latter being used to describe the different components. The impeller motion is modelled through the Sliding Deforming Mesh (SDM) approach, using rotating (unstructured) meshes in the impeller region and a static (structured) mesh in the remainder of the tank. The master liquid and coloured pigments are assumed to stratify within the tank at initial time and the steady rotational speed is then imposed abruptly to the impellers. The level of homogeneity in the stirred tank is evaluated through the analysis of component concentration fields over time. In particular, such local concentrations can be used to determine the mixture colour in different regions of the tank, and hence predict the degree of homogeneity at different times; this is accomplished by defining a proper homogeneity indicator based on the spatial variance of the estimated colour. The proposed numerical model provides an efficient method to investigate the colour of the mixture and to evaluate an appropriate mixing time. The methodology gives also important indications for the tank design, especially useful in the case of non-conventional impellers, high rotation rates and viscous fluids