Evaluation of the zucker diabetic fatty (ZDF) rat as a model for human disease based on urinary peptidomic profiles

Representative animal models for diabetes-associated vascular complications are extremely relevant in assessing potential therapeutic drugs. While several rodent models for type 2 diabetes (T2D) are available, their relevance in recapitulating renal and cardiovascular features of diabetes in man is not entirely clear. Here we evaluate at the molecular level the similarity between Zucker diabetic fatty (ZDF) rats, as a model of T2D-associated vascular complications, and human disease by urinary proteome analysis. Urine analysis of ZDF rats at early and late stages of disease compared to age- matched LEAN rats identified 180 peptides as potentially associated with diabetes complications. Overlaps with human chronic kidney disease (CKD) and cardiovascular disease (CVD) biomarkers were observed, corresponding to proteins marking kidney damage (eg albumin, alpha-1 antitrypsin) or related to disease development (collagen). Concordance in regulation of these peptides in rats versus humans was more pronounced in the CVD compared to the CKD panels. In addition, disease-associated predicted protease activities in ZDF rats showed higher similarities to the predicted activities in human CVD. Based on urinary peptidomic analysis, the ZDF rat model displays similarity to human CVD but might not be the most appropriate model to display human CKD on a molecular level

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Ambipolar Electric Field and Potential in the Solar Wind Estimated from Electron Velocity Distribution Functions

The solar wind escapes from the solar corona and is accelerated, over a short distance, to its terminal velocity. The energy balance associated with this acceleration remains poorly understood. To quantify the global electrostatic contribution to the solar wind dynamics, we empirically estimate the ambipolar electric field (E∥) and potential (Φr,∞). We analyze electron velocity distribution functions (VDFs) measured in the near-Sun solar wind between 20.3 RS and 85.3 RS by the Parker Solar Probe. We test the predictions of two different solar wind models. Close to the Sun, the VDFs exhibit a suprathermal electron deficit in the sunward, magnetic-field-aligned part of phase space. We argue that the sunward deficit is a remnant of the electron cutoff predicted by collisionless exospheric models. This cutoff energy is directly linked to Φr,∞. Competing effects of E∥ and Coulomb collisions in the solar wind are addressed by the Steady Electron Runaway Model (SERM). In this model, electron phase space is separated into collisionally overdamped and underdamped regions. We assume that this boundary velocity at small pitch angles coincides with the strahl break-point energy, which allows us to calculate E∥. The obtained Φr,∞ and E∥ agree well with theoretical expectations. They decrease with radial distance as power-law functions with indices αΦ = −0.66 and αE = −1.69. We finally estimate the velocity gained by protons from electrostatic acceleration, which equals 77% calculated from the exospheric models, and 44% from the SERM model

Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis

BACKGROUND: Amyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimer's disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution. METHODOLOGY/PRINCIPAL FINDINGS: We compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. CONCLUSIONS/SIGNIFICANCE: We conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis

The Radial Dependence of Proton-scale Magnetic Spectral Break in Slow Solar Wind during PSP Encounter 2

International audienceMagnetic field fluctuations in the solar wind are commonly observed to follow a power-law spectrum. Near proton-kinetic scales, a spectral break occurs that is commonly interpreted as a transition to kinetic turbulence. However, this transition is not yet entirely understood. By studying the scaling of the break with various plasma properties, it may be possible to constrain the processes leading to the onset of kinetic turbulence. Using data from the Parker Solar Probe, we measure the proton-scale break over a range of heliocentric distances, enabling a measurement of the transition from inertial to kinetic-scale turbulence under various plasma conditions. We find that the break frequency f(b) increases as the heliocentric distance r decreases in the slow solar wind following a power law of f(b) similar to r(-1.11). We also compare this to the characteristic plasma ion scales to relate the break to the possible physical mechanisms occurring at this scale. The ratio f(b)/f(c) (f(c) for Doppler-shifted ion cyclotron resonance scale) is close to unity and almost independent of plasma beta(p). While f(b)/f(p) (f(p) for Doppler-shifted proton thermal gyroradius) increases with beta(p) approaching to unity at larger beta(p), f(b)/f(d) (f(d) for Doppler-shifted proton inertial length) decreases with beta(p) from unity at small beta(p). Due to the large comparable Alfven and solar wind speeds, we analyze these results using both the standard and modified Taylor hypotheses, demonstrating the robust statistical results

Cross Helicity Reversals in Magnetic Switchbacks

International audienceWe consider 2D joint distributions of normalized residual energy, sigma(r)(s, t), and cross helicity, sigma(c)(s, t), during one day of Parker Solar Probe's (PSP's) first encounter as a function of wavelet scale s. The broad features of the distributions are similar to previous observations made by Helios in slow solar wind, namely well-correlated and fairly Alfvenic wind, except for a population with negative cross helicity that is seen at shorter wavelet scales. We show that this population is due to the presence of magnetic switchbacks, or brief periods where the magnetic field polarity reverses. Such switchbacks have been observed before, both in Helios data and in Ulysses data in the polar solar wind. Their abundance and short timescales as seen by PSP in its first encounter is a new observation, and their precise origin is still unknown. By analyzing these MHD invariants as a function of the wavelet scale, we show that magnetohydrodynamic (MHD) waves do indeed follow the local mean magnetic field through switchbacks, with a net Elsasser flux propagating inward during the field reversal and that they, therefore, must be local kinks in the magnetic field and not due to small regions of opposite polarity on the surface of the Sun. Such observations are important to keep in mind as computing cross helicity without taking into account the effect of switchbacks may result in spurious underestimation of sigma(c) as PSP gets closer to the Sun in later orbits

Dimensions Affecting Representation Styles in Ontologies

There are different ways to formalise roughly the same knowledge, which negatively affects ontology reuse and alignment and other tasks such as formalising competency questions automatically. We aim to shed light on, and make more precise, the intuitive notion of such `representation styles' through characterising their inherent features and the dimensions by which a style may differ. This has led to a total of 28 different traits that are partitioned over 10 dimensions. The operationalisability was assessed through an evaluation of 30 ontologies on those dimensions and applicable values. It showed that it is feasible to use the dimensions and values and resulting in three easily recognisable types of ontologies. Most ontologies had clearly one or the other trait, whereas some were inherently mixed due to inclusion of different and conflicting design decisions

An empirical approach towards the efficient and optimal production of influenza-neutralizing ovine polyclonal antibodies demonstrates that the novel adjuvant CoVaccine HT(TM) is functionally superior to Freund's adjuvant

Passive immunotherapies utilising polyclonal antibodies could have a valuable role in preventing and treating infectious diseases such as influenza, particularly in pandemic situations but also in immunocompromised populations such as the elderly, the chronically immunosuppressed, pregnant women, infants and those with chronic diseases. The aim of this study was to optimise current methods used to generate ovine polyclonal antibodies. Polyclonal antibodies to baculovirus-expressed recombinant influenza haemagglutinin from A/Puerto Rico/8/1934 H1N1 (PR8) were elicited in sheep using various immunisation regimens designed to investigate the priming immunisation route, adjuvant formulation, sheep age, and antigen dose, and to empirically ascertain which combination maximised antibody output. The novel adjuvant CoVaccine HT™ was compared to Freund’s adjuvant which is currently the adjuvant of choice for commercial production of ovine polyclonal Fab therapies. CoVaccine HT™ induced significantly higher titres of functional ovine anti-haemagglutinin IgG than Freund’s adjuvant but with fewer side effects, including reduced site reactions. Polyclonal hyperimmune sheep sera effectively neutralised influenza virus in vitro and, when given before or after influenza virus challenge, prevented the death of infected mice. Neither the age of the sheep nor the route of antigen administration appeared to influence antibody titre. Moreover, reducing the administrated dose of haemagglutinin antigen minimally affected antibody titre. Together, these results suggest a cost effective way of producing high and sustained yields of functional ovine polyclonal antibodies specifically for the prevention and treatment of globally significant diseases.Natalie E. Stevens, Cara K. Fraser, Mohammed Alsharifi, Michael P. Brown, Kerrilyn R. Diener, John D. Haybal

The Enhancement of Proton Stochastic Heating in the Near-Sun Solar Wind

International audienceStochastic heating (SH) is a nonlinear heating mechanism driven by the violation of magnetic moment invariance due to large-amplitude turbulent fluctuations producing diffusion of ions toward higher kinetic energies in the direction perpendicular to the magnetic field. It is frequently invoked as a mechanism responsible for the heating of ions in the solar wind. Here, we quantify for the first time the proton SH rate Q(perpendicular to) at radial distances from the Sun as close as 0.16 au, using measurements from the first two Parker Solar Probe encounters. Our results for both the amplitude and radial trend of the heating rate, Q(perpendicular to) proportional to r(-2.5), agree with previous results based on the Helios data set at heliocentric distances from 0.3 to 0.9 au. Also in agreement with previous results, Q(perpendicular to) is significantly larger in the fast solar wind than in the slow solar wind. We identify the tendency in fast solar wind for cuts of the core proton velocity distribution transverse to the magnetic field to exhibit a flattop shape. The observed distribution agrees with previous theoretical predictions for fast solar wind where SH is the dominant heating mechanism

Implementation of a double moment cloud microphysics scheme in the UK met office regional numerical weather prediction model

Cloud microphysics parametrizations control the transfer of water between phases and hydrometeor species in numerical weather prediction and climate models. As a fundamental component of weather modelling systems cloud microphysics can determine the intensity and timing of precipitation, the extent and longevity of cloud cover and its impact on radiative balance, and directly influence near surface weather metrics such as temperature and wind. In this paper we introduce and demonstrate the performance of a double moment cloud microphysical scheme (CASIM: Cloud AeroSol Interacting Microphysics) in both midlatitude and tropical settings using the same model configuration. Comparisons are made against a control configuration using the current operational single moment cloud microphysics, and CASIM configurations that use fixed in-cloud droplet number or compute cloud droplet number concentration from the aerosol environment. We demonstrate that configuring CASIM as a single moment scheme results in precipitation rate histograms that match the operational single moment microphysics. In the midlatitude setting, results indicate that CASIM performs as well as the single moment microphysics configuration, but improves certain aspects of the surface precipitation field such as greater extent of light (1 mm · hr⁻¹) rain around frontal precipitation features. In the tropical setting, CASIM outperforms the single moment cloud microphysics as evident from improved comparison with radar derived precipitation rates