The use of equine chondrogenic‐induced mesenchymal stem cells as a treatment for osteoarthritis : a randomised, double‐blinded, placebo‐controlled proof‐of‐concept study

Background: There is a need to improve therapies for osteoarthritis in horses. Objectives To assess the efficacy of equine allogeneic chondrogenic-induced mesenchymal stem cells combined with equine allogeneic plasma as a novel therapy for osteoarthritis in horses. Study design: Randomised, double-blinded, placebo-controlled experiment. Methods: In 12 healthy horses, osteoarthritis was induced in the metacarpophalangeal joint using an osteochondral fragment-groove model. Five weeks after surgery, horses were randomly assigned to either an intra-articular injection with chondrogenic-induced mesenchymal stem cells + equine allogeneic plasma (= intervention) or with 0.9% saline solution (= control). From surgery until the study end, horses underwent a weekly joint and lameness assessment. Synovial fluid was collected for cytology and biomarker analysis before surgery and at Weeks 5, 5 + 1d, 7, 9 and 11. At Week 11, horses were subjected to euthanasia, and the metacarpophalangeal joints were evaluated macroscopically and histologically. Results: No serious adverse events or suspected adverse drug reactions occurred during the study. A significant improvement in visual and objective lameness was seen with the intervention compared with the control. Synovial fluid displayed a significantly higher viscosity and a significantly lower glycosaminoglycan concentration in the intervention group. Other biomarkers or cytology parameters were not significantly different between the treatment groups. Significantly less wear lines and synovial hyperaemia were present in the intervention group. The amount of cartilage oligomeric matrix protein, collagen type II and glycosaminoglycans were significantly higher in the articular cartilage of the intervention group. Main limitations: This study assessed the short-term effect of the intervention on a limited number of horses, using an osteoarthritis model. This study also included multiple statistical tests, increasing the risk of type 1 error. Conclusions: Equine allogeneic chondrogenic-induced mesenchymal stem cells combined with equine allogeneic plasma may be a promising treatment for osteoarthritis in horses

Determination of the total acid number (TAN) of used mineral oils in aviation engines by FTIR using regression models

[EN] Total acid number (TAN) has been considered an important indicator of the oil quality of used oils. TAN is determined by potentiometric titration, which is time-consuming and requires solvent. A more convenient approach to determine TAN is based on infrared (IR) spectral data and multivariate regression models. Predictive models for the determination of TAN using the IR data measured from ashless dispersant oils developed for aviation piston engines (SAE 50) have been developed. Different techniques, including Projection Pursuit Regression (PPR), Partial Least Square, Support Vector Machines, Linear Models and Random Forest (RF), have been used. The used methodology involved a five folder cross validation to derive the best model. Then a full error measure over the whole dataset was taken. A backward variable selection was used and 25 highly relevant variables were extracted. RF provided an acceptable modelling technology with grouped dataset predictions that allowed transformations to be performed that fitted the measured values. A hybrid method considering group of bands as features was used for modelling. An innovative mechanism for wider features selection based on genetic algorithm has been implemented. This method showed better performance than the results obtained using the other methodologies. RMSE and MAE values obtained in the validation were 0.759 and 0.359 for PPR model respectively.The authors would like to thank Roland Tones of the Universidad Metropolitana for his collaboration in oil sample processing. BLDR acknowledges financial support from the Venoco Company. The authors also thank the Universidad Politecnica de Madrid for granting access to the CESVIMA (http://www.cesvima.upm.es/) HPC infrastructure. We would also like to thank the author Beatriz Leal de Rivas (in memoriam), for her efforts to conform this team of researchers from different areas of expertise, and we want to dedicate this work to her loving memory.Leal De-Rivas, BC.; Vivancos, J.; Ordieres Meré, J.; Capuz-Rizo, SF. (2017). Determination of the total acid number (TAN) of used mineral oils in aviation engines by FTIR using regression models. Chemometrics and Intelligent Laboratory Systems. 160:32-39. doi:10.1016/j.chemolab.2016.10.015S323916

An Improved Upper Bound for the Ring Loading Problem

The Ring Loading Problem emerged in the 1990s to model an important special case of telecommunication networks (SONET rings) which gained attention from practitioners and theorists alike. Given an undirected cycle on $n$ nodes together with non-negative demands between any pair of nodes, the Ring Loading Problem asks for an unsplittable routing of the demands such that the maximum cumulated demand on any edge is minimized. Let $L$ be the value of such a solution. In the relaxed version of the problem, each demand can be split into two parts where the first part is routed clockwise while the second part is routed counter-clockwise. Denote with $L^*$ the maximum load of a minimum split routing solution. In a landmark paper, Schrijver, Seymour and Winkler [SSW98] showed that $L \leq L^* + 1.5D$, where $D$ is the maximum demand value. They also found (implicitly) an instance of the Ring Loading Problem with $L = L^* + 1.01D$. Recently, Skutella [Sku16] improved these bounds by showing that $L \leq L^* + \frac{19}{14}D$, and there exists an instance with $L = L^* + 1.1D$. We contribute to this line of research by showing that $L \leq L^* + 1.3D$. We also take a first step towards lower and upper bounds for small instances

Dynamics of fully coupled rotators with unimodal and bimodal frequency distribution

We analyze the synchronization transition of a globally coupled network of N phase oscillators with inertia (rotators) whose natural frequencies are unimodally or bimodally distributed. In the unimodal case, the system exhibits a discontinuous hysteretic transition from an incoherent to a partially synchronized (PS) state. For sufficiently large inertia, the system reveals the coexistence of a PS state and of a standing wave (SW) solution. In the bimodal case, the hysteretic synchronization transition involves several states. Namely, the system becomes coherent passing through traveling waves (TWs), SWs and finally arriving to a PS regime. The transition to the PS state from the SW occurs always at the same coupling, independently of the system size, while its value increases linearly with the inertia. On the other hand the critical coupling required to observe TWs and SWs increases with N suggesting that in the thermodynamic limit the transition from incoherence to PS will occur without any intermediate states. Finally a linear stability analysis reveals that the system is hysteretic not only at the level of macroscopic indicators, but also microscopically as verified by measuring the maximal Lyapunov exponent.Comment: 22 pages, 11 figures, contribution for the book: Control of Self-Organizing Nonlinear Systems, Springer Series in Energetics, eds E. Schoell, S.H.L. Klapp, P. Hoeve

A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes

A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables. Owing to the paucity of alimentary enzymes encoded by the human genome, our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut. The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear. Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health

Spasmodic dysphonia, perceptual and acoustic analysis: presenting new diagnostic tools

In this article, we investigate whether (1) the IINFVo (Impression, Intelligibility, Noise, Fluency and Voicing) perceptual rating scale and (2) the AMPEX (Auditory Model Based Pitch Extractor) acoustical analysis are suitable for evaluating adductor spasmodic dysphonia (AdSD). Voice recordings of 12 patients were analysed. The inter-rater and intra-rater consistency showed highly significant correlations for the IINFVo rating scale, with the exception of the parameter Noise. AMPEX reliably analyses vowels (correlation between PUVF (percentage of frames with unreliable F0/voicing 0.748), running speech (correlation between PVF (percentage of voiced frames)/voicing 0.699) and syllables. Correlations between IINFVo and AMPEX range from 0.608 to 0.818, except for noise. This study indicates that IINFVo and AMPEX could be robust and complementary assessment tools for the evaluation of AdSD. Both the tools provide us with the valuable information about voice quality, stability of F0 (fundamental frequency) and specific dimensions controlling the transitions between voiced and unvoiced segments

IFN-γ-Inducible Irga6 Mediates Host Resistance against Chlamydia trachomatis via Autophagy

Chlamydial infection of the host cell induces Gamma interferon (IFNγ), a central immunoprotector for humans and mice. The primary defense against Chlamydia infection in the mouse involves the IFNγ-inducible family of IRG proteins; however, the precise mechanisms mediating the pathogen's elimination are unknown. In this study, we identify Irga6 as an important resistance factor against C. trachomatis, but not C. muridarum, infection in IFNγ-stimulated mouse embryonic fibroblasts (MEFs). We show that Irga6, Irgd, Irgm2 and Irgm3 accumulate at bacterial inclusions in MEFs upon stimulation with IFNγ, whereas Irgb6 colocalized in the presence or absence of the cytokine. This accumulation triggers a rerouting of bacterial inclusions to autophagosomes that subsequently fuse to lysosomes for elimination. Autophagy-deficient Atg5−/− MEFs and lysosomal acidification impaired cells surrender to infection. Irgm2, Irgm3 and Irgd still localize to inclusions in IFNγ-induced Atg5−/− cells, but Irga6 localization is disrupted indicating its pivotal role in pathogen resistance. Irga6-deficient (Irga6−/−) MEFs, in which chlamydial growth is enhanced, do not respond to IFNγ even though Irgb6, Irgd, Irgm2 and Irgm3 still localize to inclusions. Taken together, we identify Irga6 as a necessary factor in conferring host resistance by remodelling a classically nonfusogenic intracellular pathogen to stimulate fusion with autophagosomes, thereby rerouting the intruder to the lysosomal compartment for destruction

A Dedicated Promoter Drives Constitutive Expression of the Cell-Autonomous Immune Resistance GTPase, Irga6 (IIGP1) in Mouse Liver

Background: In general, immune effector molecules are induced by infection. Methodology and Principal Findings: However, strong constitutive expression of the cell-autonomous resistance GTPase, Irga6 (IIGP1), was found in mouse liver, contrasting with previous evidence that expression of this protein is exclusively dependent on induction by IFNc. Constitutive and IFNc-inducible expression of Irga6 in the liver were shown to be dependent on transcription initiated from two independent untranslated 59 exons, which splice alternatively into the long exon encoding the full-length protein sequence. Irga6 is expressed constitutively in freshly isolated hepatocytes and is competent in these cells to accumulate on the parasitophorous vacuole membrane of infecting Toxoplasma gondii tachyzoites. Conclusions and Significance: The role of constitutive hepatocyte expression of Irga6 in resistance to parasites invading from the gut via the hepatic portal system is discussed