Effect of dog breed and body conformation on vertical ground reaction forces, impulses, and stance times

OBJECTIVES: To assess whether fully normalised vertical ground reaction forces and stance times obtained at a trot depend on dog breed or body conformations. METHODS: Peak vertical forces (PVF), vertical impulses (VI), stance times (ST), and ratio of forelimb impulse to total impulse (RVI) of 54 dogs of seven different breeds were normalised to body weight and body size according to the theory of dynamic similarity, and were tested for differences between breeds. Breeds were Borzoi, Bernese Mountain dog, Great Dane, Labrador Retriever, Landseer, Rhodesian Ridgeback, and Rottweiler. Body length ratio (BLR) and body mass index (BMI) were also compared between breeds. RESULTS: Significant differences between breeds were found for the normalised forelimb PVF, VI and ST, and hindlimb PVF. Looking at individual breeds, it was most evident that Borzois had a lower forelimb VI, and a higher hindlimb PVF than the other breeds. This resulted in Borzois having a lower RVI compared to other dogs, indicating a more caudally located centre of gravity. Only a few differences in gait parameters were found between other dog breeds. The BMI was significantly lower in Borzois than in other breeds, but was otherwise not associated with gait parameters. CLINICAL SIGNIFICANCE: Force plate data of dogs of different breeds are not necessarily comparable, even after full normalisation to body weight and body size. Group comparisons should only be made when the groups consist of breeds with similar body conformation

Correlation of radiographic changes after tibial tuberosity advancement in dogs with cranial cruciate-deficient stifles with functional outcome

OBJECTIVE: To (1) evaluate radiographic changes associated with osteoarthrosis (OA) before and after tibial tuberosity advancement (TTA) and (2) determine if these changes are indicative of limb function as determined by kinetic gait analysis. STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs (n=35) with cranial cruciate ligament (CCL) deficient stifles (38). METHODS: Variables recorded were: complete or partial CCL rupture, meniscal lesions, arthroscopically graded cartilage lesions, complications, and revision surgeries. Radiographic evaluation and kinetic gait analysis (vertical ground reaction forces [GRFs]) were conducted pre- and 4-16 months postoperatively (mean, 5.9 months). Radiographs were evaluated without knowledge of operative findings and functional outcome. A score (0-3) based on new bone production at 11 specific sites was used to grade OA. Soft tissue changes were classified separately as normal or excessive. Preoperative scores were correlated with clinical variables. Postoperative scores and progression of OA scores were correlated with clinical variables and GRFs. RESULTS: OA remained unchanged in 17 joints and progressed in 21 (55%). Dogs with meniscal lesions had higher OA scores preoperatively, but not at follow-up. Dogs with severe cartilage lesions at surgery had more progression of OA. GRFs improved after surgery and were not correlated with any of the radiographic OA scores. CONCLUSION: Progression of OA was greater in the presence of severe cartilage lesions at surgery. OA scores were not correlated with GRFs. CLINICAL RELEVANCE: Progression of OA is generally expected to occur after TTA despite improvement of limb function

Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.

The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC-1 parental cells in nude mice generated various tumor types, such as NB, osteo/chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro

When TADs go bad: chromatin structure and nuclear organisation in human disease

Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease

Sliding Wear Behavior of Al2O3-TiO2 Coatings Fabricated by the Suspension Plasma Spraying Technique

[EN] The friction and dry sliding wear behavior of alumina and alumina-titania near-nanometric coatings were examined. Coatings were obtained by the suspension plasma spraying technique. Dry sliding wear tests were performed on a ball-on-disk tribometer, with an Al2O3 ball as counterpart material, a normal load of 2 N, a sliding distance of 1200 m and a sliding speed of 0.1 m/s. The effect of including TiO2 in the fabricated coatings on friction coefficient behavior, wear rates and wear damage patterns was determined. The addition of TiO2 to the coatings was found to greatly increase wear resistance by, for example, 2.6-fold for 40 wt% of TiO2. The analysis of the wear surface was correlated with microstructural parameters, mechanical properties and wear rates.The authors wish to thank for the Spanish Ministry of Economy and Competitiveness (MAT2012-38364-C03) and the Autonomous Government of Valencia for funding for the stay in SPCTS-UMR CNRS (France), and the French FCENANOSURF consortium funded by the French Ministry and Industry and local governments of Region Centre and Region Limousin.Klyatskina, E.; Espinosa Fernández, L.; Darut, G.; Segovia López, EF.; Salvador Moya, MD.; Montavon, G.; Agorges, H. (2015). Sliding Wear Behavior of Al2O3-TiO2 Coatings Fabricated by the Suspension Plasma Spraying Technique. Tribology Letters. 59(1):1-9. https://doi.org/10.1007/s11249-015-0530-5S19591Pawlowski, L.: The Science and Engineering of Thermal Spray Coatings. Wiley: Hoboken (2008)Lampe, Th, Eisenberg, S., Cabeo, E.R.: Plasma surface engineering in the automotive industry—trends and future prospective. Surf. Coat. Technol. 174–175, 1–7 (2003)Wang, Y., Jiang, S., Wang, M., Wang, S., Xiao, T.D., Strutt, P.R.: Abrasive wear characteristics of plasma sprayed nanostructured alumina/titania coatings. Wear 237, 176–185 (2000)Kabacoff, L.T.: Nanoceramic coatings exhibit much higher toughness and wear resistance than conventional coatings. AMPITAC Newslett. 6(1), 37–42 (2002)Wang, M., Shaw, L.L.: Effects of the powder manufacturing method on microstructure and wear performance of plasma sprayed alumina–titania coatings. Surf. Coat. Technol. 202, 34–44 (2007)Shaw, L.L., Goberman, D., Ren, R., Gell, M., Jing, S., Wang, Y., Xiao, T.D., Strutt, P.R.: The dependency of microstructure and properties of nanostructured coatings on plasma spray conditions. Surf. Coat. Technol. 130, 1–8 (2000)Dahotre, N.B., Nayak, S.: Nanocoatings for engine application. Surf. Coat. Technol. 194(1), 58–67 (2005)Sathish, S., Geetha, M., Aruna, S.T., Balaji, N., Rajam, K.S., Asokamani, R.: Sliding wear behavior of plasma sprayed nanoceramic coatings for biomedical applications. Wear 271, 934–941 (2011)Pawlowski, L.: Finely grained nanometric and submicrometric coatings by thermal sparing: a review. Surf. Coat. Technol. 202, 4318–4328 (2008)Xiao, D., Wang, Y., Strutt, P.: Fabrication and evaluation of plasma sprayed nanostructured alumina–titania coatings with superior properties. Mater. Sci. Eng. 301, 80–89 (2001)Tjong, S.C., Chen, H.: Nanocrystalline materials and coatings. Mater. Sci. Eng. 45, 1–88 (2004)Fauchais, P., Montavon, G., Bertrand, G.: From powders to thermally sprayed coatings. J. Therm. Spray Technol. 19, 56–80 (2010)Lima, R.S., Marple, B.R.: Thermal spray coatings engineered from nanostructured ceramic agglomerated powders for structural, thermal barrier and biomedical applications: a review. J. Therm. Spray Technol. 16, 40–63 (2007)Fauchais, P., Etchart-Salas, R., Delbos, C., Tognonvi, M., Rat, V., Coudert, J.F., Chartier, T.: Suspension and solution plasma spraying of finely structured layers: potential application to SOFCs. J. Phys. D Appl. Phys. 40, 2394–2406 (2007)Ramachandran, K., Selvajaran, V., Ananthapadmanabhan, P.V., Sreekumar, K.P.: Microstructure, adhesion, micro hardness, abrasive wear resistance and electrical resistivity of the plasma sprayed alumina and alumina–titania coatings. Thin Solid Films 315, 144–152 (1998)Lee, S.W., Morillo, C., Lira-Olivares, J., Kim, S.H., Sekino, T., Niihara, K., Hockey, B.J.: Tribological and microstructural analysis of Al2O3/13TiO2 nanocomposites to use in femoral head of hip replacement. Wear 225, 1040–1044 (2003)Dejang, N., Watcharapasorn, A., Wirojupatump, S., Niranatlumpong, P., Jiansirisomboon, S.: Fabrication and properties of plasma-sprayed Al2O3/TiO2 composite coatings: a role of nano-sized TiO2 addition. Surf. Coat. Technol. 204, 1651–1657 (2010)Yimaz, S.: An evaluation of plasma sprayed coatings based on Al2O3 and Al2O3–13wt% TiO2 with bond coat on pure titanium substrate. Ceram. Int. 35, 2017–2022 (2009)Fervel, V., Normand, B., Coddet, C.: Tribological behavior of plasma sprayed Al2O3-based cermet coatings. Wear 230(1), 70–77 (1999)Vargas, F., Ageorges, H., Fauchais, P., López, M.E.: Mechanical and a tribological performance of Al2O3 coatings elaborated by flame and plasma spraying. Surf. Coat. Technol. 205, 1132–1136 (2010)Bacciochini, A., Ilavsky, J., Montavon, G., Denoirjean, A., Ben-ettouil, F., Valette, S., Fauchais, P., Wittmann-teneze, K.: Quantification of void network architectures of suspension plasma-sprayed (SPS) yttria-stabilized zirconia (YSZ) coatings using ultra-small-angle X-ray scattering (USAXS). Mater. Sci. Eng. 528, 91–102 (2010)ASTM International: ASTM G99-03: Standard test method for wear testing with a pin-on-disc apparatus. ASTM annual book of standards. ASTM International: West Conshohocken (2003)Lancaster, K.: The influence of substrate hardness on the formation and endurance of molybdenum disulphide films. Wear 10, 103–107 (1967)Fauchais, P., Rat, V., Delbos, C., Fazilleau, J., Coudert, J.F., Chartier, T., Bianchi, L.: Understanding of suspension plasma spraying of finely structured coatings for SOFC. IEEE Plasma Sci. 33(2), 920–930 (2005)Bannier, E., Vicent, M., Rayón, E., Benavente, R., Salvador, M.D., Sánchez, E.: Effect of TiO2 addition on the microstructure and nanomechanical properties of Al2O3 suspension plasma sprayed coatings. Appl. Surf. Sci. 316, 141–146 (2014)Darut, G., Klyatskina, E., Valette, S., Carles, P., Denoirjean, A., Montavon, G., Ageorges, H., Segovia, F., Salvador, M.D.: Architecture and phases composition of suspension plasma sprayed alumina–titania sub-micrometer-sized coatings. Mater. Lett. 67, 241–244 (2012)Fauchais, P., Montavon, G.: Latest developments in suspension and liquid precursor thermal spraying. J. Therm. Spray Technol. 19(1–2), 226–239 (2010)Darut, G., Ben-Ettouli, F., Denoirjean, A., Montavon, G., Ageourges, H., Fauchais, P.: Dry sliding behavior of sub-micrometer-sized suspension plasma sprayed ceramic oxide coatings. J. Therm. Spray Technol. 19, 275–285 (2010)Tingaud, O., Bacciochini, A., Montavon, G., Denoirjean, A., Fauchais, P.: Suspension DC plasma spraying of thick finely-structured ceramic coatings: process manufacturing mechanisms. Surf. Coat. Technol. 203, 2157–2161 (2009)Guesama, S., Bounazef, M., Nardin, P., Sahraoui, T.: Wear behavior of alumina–titania coatings: analysis of process and parameters. Ceram. Int. 32, 13–19 (2006)Espinosa-Fernández, L., Borrell, A., Salvador, M.D., Gutierrez-Gonzalez, C.F.: Sliding wear behavior of WC–Co–Cr3C2–VC composites fabricated by conventional and non-conventional techniques. Wear 307, 60–67 (2013)Zhang, J., Moslehy, F.A., Rice, S.L.: A model for friction in quasi-steady-state. Part I. Derivation. Wear 149, 1–12 (1991)Zhang, J., Moslehy, F.A., Rice, S.L.: A model for friction in quasi-steady-state sliding Part II. Numerical results and discussion. Wear 149, 13–25 (1991)Bolelli, G., Cannilo, V., Lusvarghi, L., Manfredini, T.: Wear behaviour of thermally sprayed ceramic oxide coatings. Wear 261, 1298–1315 (2006)Normand, B., Fervel, V., Coddet, C., Nikitine, V.: Tribological properties of plasma sprayed alumina–titania coatings: next term role and control of the microstructure. Surf. Coat. Technol. 123, 278–287 (2000)Hutchings, I.: Tribology: friction and wear of engineering materials. Mater. Des. 13, 187 (1992)Ahn, J., Hwang, B., Song, E.P., Lee, S., Kim, N.J.: Correlation of microstructure and wear resistance of Al2O3–TiO2 coatings plasma sprayed with nanopowders. Metall. Mater. Trans. A 37, 1851–1860 (2006)Erickson, L.C., Hawthorne, H.M., Troczynski, T.: Correlations between microstructural parameters, micromechanical properties and wear resistance of plasma sprayed ceramic coatings. Wear 250, 569–575 (2001)Song, E.P., Ahn, J., Lee, S., Kim, N.J.: Microstructure and wear resistance of nanostructured Al2O3–8 wt%TiO2 coatings plasma-sprayed with nanopowders. Surf. Coat. Technol. 201, 1309–1315 (2006)Tucker Jr., R.C.: ASM Handbook Volume 5A: Thermal Spray Technology. ASM International, Materials Park (2013)Stachowiack, G.W., Batchelor, A.: Engineering Tribology Handbook. Elsevier-Butterworth-Heineman: Oxford (2005)Fischer, T.E., Zhu, Z., Kim, H., Shin, D.S.: Genesis and role of wear debris in sliding wear of ceramics. Wear 245, 53–60 (2000)Lima, R.S., Moureau, C., Marple, B.R.: HVOF-sprayed coatings engineered from mixtures of nanostructured and submicron Al2O3–TiO2 powders: an enhanced wear performance. J. Therm. Spray Technol. 16, 866 (2007

Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci

Several recent studies have examined different aspects of mammalian higher order chromatin structure - replication timing, lamina association and Hi-C inter-locus interactions - and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Background:Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods:We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing. Results: In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants. Conclusions:These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs