Modular hybrid total hip arthroplasty. Experimental study in dogs

Background: This prospective experimental study evaluated the surgical procedure and results of modular hybrid total hip arthroplasty in dogs.Methods: Ten skeletally mature healthy mongrel dogs with weights varying between 19 and 27 kg were used. Cemented modular femoral stems and uncemented porous-coated acetabular cups were employed. Clinical and radiographic evaluations were performed before surgery and at 30, 60, 90, 120, 180 and 360 days post-operation.Results: Excellent weight bearing was noticed in the operated limb in seven dogs. Dislocation followed by loosening of the prosthesis was noticed in two dogs, which were therefore properly treated with a femoral head osteotomy. Femoral fracture occurred in one dog, which was promptly treated with full implant removal and femoral osteosynthesis.Conclusions: The canine modular hybrid total hip arthroplasty provided excellent functionality of the operated limb

Chemoproteomics reveals Toll-like receptor fatty acylation

Partial funding for Open Access provided by The Ohio State University Open Access Fund.Background: Palmitoylation is a 16-carbon lipid post-translational modification that increases protein hydrophobicity. This form of protein fatty acylation is emerging as a critical regulatory modification for multiple aspects of cellular interactions and signaling. Despite recent advances in the development of chemical tools for the rapid identification and visualization of palmitoylated proteins, the palmitoyl proteome has not been fully defined. Here we sought to identify and compare the palmitoylated proteins in murine fibroblasts and dendritic cells. Results: A total of 563 putative palmitoylation substrates were identified, more than 200 of which have not been previously suggested to be palmitoylated in past proteomic studies. Here we validate the palmitoylation of several new proteins including Toll-like receptors (TLRs) 2, 5 and 10, CD80, CD86, and NEDD4. Palmitoylation of TLR2, which was uniquely identified in dendritic cells, was mapped to a transmembrane domain-proximal cysteine. Inhibition of TLR2 S-palmitoylation pharmacologically or by cysteine mutagenesis led to decreased cell surface expression and a decreased inflammatory response to microbial ligands. Conclusions: This work identifies many fatty acylated proteins involved in fundamental cellular processes as well as cell type-specific functions, highlighting the value of examining the palmitoyl proteomes of multiple cell types. Spalmitoylation of TLR2 is a previously unknown immunoregulatory mechanism that represents an entirely novel avenue for modulation of TLR2 inflammatory activity.This work was supported by funding from the NIH/NIAID (grant R00AI095348 to J.S.Y.), the NIH/NIGMS (R01GM087544 to HCH), and the Ohio State University Public Health Preparedness for Infectious Diseases (PHPID) program. NMC is supported by the Ohio State University Systems and Integrative Biology Training Program (NIH/NIGMS grant T32GM068412). BWZ is a fellow of the National Science Foundation Graduate Research Fellowship Program (DGE-0937362)

Assessing the Potential Impacts to Riparian Ecosystems Resulting from Hemlock Mortality in Great Smoky Mountains National Park

Hemlock Woolly Adelgid (Adelges tsugae) is spreading across forests in eastern North America, causing mortality of eastern hemlock (Tsuga canadensis [L.] Carr.) and Carolina hemlock (Tsuga caroliniana Engelm.). The loss of hemlock from riparian forests in Great Smoky Mountains National Park (GSMNP) may result in significant physical, chemical, and biological alterations to stream environments. To assess the influence of riparian hemlock stands on stream conditions and estimate possible impacts from hemlock loss in GSMNP, we paired hardwood- and hemlock-dominated streams to examine differences in water temperature, nitrate concentrations, pH, discharge, and available photosynthetic light. We used a Geographic Information System (GIS) to identify stream pairs that were similar in topography, geology, land use, and disturbance history in order to isolate forest type as a variable. Differences between hemlock- and hardwood-dominated streams could not be explained by dominant forest type alone as forest type yields no consistent signal on measured conditions of headwater streams in GSMNP. The variability in the results indicate that other landscape variables, such as the influence of understory Rhododendron species, may exert more control on stream conditions than canopy composition. The results of this study suggest that the replacement of hemlock overstory with hardwood species will have minimal impact on long-term stream conditions, however disturbance during the transition is likely to have significant impacts. Management of riparian forests undergoing hemlock decline should, therefore, focus on facilitating a faster transition to hardwood-dominated stands to minimize long-term effects on water quality

Computational solutions for omics data

High-throughput experimental technologies are generating increasingly massive and complex genomic data sets. The sheer enormity and heterogeneity of these data threaten to make the arising problems computationally infeasible. Fortunately, powerful algorithmic techniques lead to software that can answer important biomedical questions in practice. In this Review, we sample the algorithmic landscape, focusing on state-of-the-art techniques, the understanding of which will aid the bench biologist in analysing omics data. We spotlight specific examples that have facilitated and enriched analyses of sequence, transcriptomic and network data sets.National Institutes of Health (U.S.) (Grant GM081871

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe