B cell depletion reduces the development of atherosclerosis in mice

B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell–depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti–oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell–derived IFN-γ secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody–mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation

A survey on computational intelligence approaches for predictive modeling in prostate cancer

Predictive modeling in medicine involves the development of computational models which are capable of analysing large amounts of data in order to predict healthcare outcomes for individual patients. Computational intelligence approaches are suitable when the data to be modelled are too complex forconventional statistical techniques to process quickly and eciently. These advanced approaches are based on mathematical models that have been especially developed for dealing with the uncertainty and imprecision which is typically found in clinical and biological datasets. This paper provides a survey of recent work on computational intelligence approaches that have been applied to prostate cancer predictive modeling, and considers the challenges which need to be addressed. In particular, the paper considers a broad definition of computational intelligence which includes evolutionary algorithms (also known asmetaheuristic optimisation, nature inspired optimisation algorithms), Artificial Neural Networks, Deep Learning, Fuzzy based approaches, and hybrids of these,as well as Bayesian based approaches, and Markov models. Metaheuristic optimisation approaches, such as the Ant Colony Optimisation, Particle Swarm Optimisation, and Artificial Immune Network have been utilised for optimising the performance of prostate cancer predictive models, and the suitability of these approaches are discussed

Mechanisms of immunological tolerance in central nervous system inflammatory demyelination.

Multiple sclerosis is a complex autoimmune disease of the central nervous system that results in a disruption of the balance between pro-inflammatory and anti-inflammatory signals in the immune system. Given that central nervous system inflammation can be suppressed by various immunological tolerance mechanisms, immune tolerance has become a focus of research in the attempt to induce long-lasting immune suppression of pathogenic T cells. Mechanisms underlying this tolerance induction include induction of regulatory T cell populations, anergy and the induction of tolerogenic antigen-presenting cells. The intravenous administration of encephalitogenic peptides has been shown to suppress experimental autoimmune encephalomyelitis and induce tolerance by promoting the generation of regulatory T cells and inducing apoptosis of pathogenic T cells. Safe and effective methods of inducing long-lasting immune tolerance are essential for the treatment of multiple sclerosis. By exploring tolerogenic mechanisms, new strategies can be devised to strengthen the regulatory, anti-inflammatory cell populations thereby weakening the pathogenic, pro-inflammatory cell populations

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required

Methods for high-dimensonal analysis of cells dissociated from cyropreserved synovial tissue

Abstract Background Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples. Methods Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA-seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single-cell CEL-Seq2 RNA-seq. Results Upon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 μg/ml of Liberase™ TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4+ and CD8+ T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified. Conclusions We have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers

Population distribution and seasonal resource selection by elk (Cervus Elaphus) in Central Ontario

Understanding population structure and resource selection are essential for wildlife management and conservation. I assessed the population structure and resource selection of elk (Cervus elaphus) in central Ontario. I used fuzzy and hierarchical cluster analyses to elucidate elk population structure based on spatial data collected from 41 radio-collared elk. I assessed impacts of habitat quality on space use using the minimum convex polygon (MCP) and fixed kernel methods. I evaluated resource selection by elk in winter, spring, summer, and fall, from December 2011 to August 2013, using resource selection functions (RSF’s). I used a generalized linear mixed model (GLMM) to evaluate resource selection functions and used Akaike information criterion (AICc ) to select the best model of 20 candidate models constructed a priori. Models included parameters representing resources known to be important to elk: elevation, aspect, slope, distance to roads and water, and habitat. Both fuzzy and hard clustering indicated that elk in Central Ontario occur in a metapopulation that includes 5 subpopulations. The largest cluster consisted of a core group of 22 radio-collared elk located in Burwash with several satellite subpopulations spread along a 50km long north-south axis and a small subpopulation to the west located in Worthington. Survival rates among subpopulations were similar ranging from 0.71 to 0.83; however, anthropogenic causes of mortality were predominant only in the Burwash subpopulation. Space use and density of elk differed between core and satellite subpopulations. Resource selection by elk differed by time of day and season. In all seasons, elk selected open habitats at night and more forested areas during the day. Elk avoided areas close to roads in spring, but selected them in winter at night. Elk selected higher elevations in winter and for south facing slopes in spring and fall. Elk displayed strong crepuscular activity patterns in all seasons; however, movements were limited in winter. Understanding population structure is important in order to develop appropriate management plans. My results support the conclusion that population structure can be reliably assessed using spatial data. Resource selection is a dynamic process that changes with seasons, as well as animal activity across the diel period. Resource selection should include time of day in order to obtain a complete picture of resources important to a particular species and to support the conservation of habitats used for various animal activities.Master's These

Metapopulation dynamics and space use by reintroduced elk (Cervus elaphus) in central Ontario

Understanding population structure and resource selection is essential for wildlife management and conservation. We assessed the population structure of elk (Cervus elaphus L.,1758) in central Ontario. We used fuzzy and hierarchical cluster analyses to elucidate elk population structure based on spatial data collected from 41 radio-collared elk. We assessed space use between core and satellite subpopulations with the minimum convex polygon (MCP) and fixed kernel methods. Both fuzzy and hard clustering indicated that elk in this part of Central Ontario occur in a metapopulation that includes 5 subpopulations. The largest cluster consisted of a core group containing 22 radio-collared elk located in Burwash, with several satellite subpopulations spread along a 50 km long north-south axis and a small subpopulation to the west located in Worthington. Survival rates among subpopulations were similar ranging from 0.71 to 0.83; and anthropogenic causes of mortality were predominant only in the Burwash subpopulation. Space use and density of elk differed between core and satellite subpopulations. Understanding population structure is important to develop appropriate management plans. Our results support the conclusion that metapopulation structure can be reliably assessed using spatial data.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Elk (Cervus elaphus) Seasonal Habitat Selection in a Heterogeneous Forest Structure

Seasonal habitat selection by the reintroduced Burwash elk population, approximately 30 km south of Sudbury, Ontario, has been analysed in order to assist in the development of future management. Twenty-five adult females were radio-collared and tracked 1–3 times a week for 3 years. The most prominent patterns included selection of intolerant hardwood forests (trembling aspen, white birch, and balsam poplar) during all seasons, while Great Lakes-St. Lawrence pines (white and red pine dominated stands) were used less than expected based on availability for all seasons. The selection patterns are likely associated with seasonal climatic conditions and forage preferences. Because the selection behaviours displayed here varied greatly from other elk habitat studies, it is suggested that managers consider the importance of population-specific habitat studies before developing related strategies