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We live in a global society, wherein our dependence on our neighbors is growing more intensely each year. Technology, travel, and interdependent economic systems require that nations know more and share more of their natural resources. Among the most precious of these resources is the intellectual talent that resides in their countries. This edited volume sheds light on the unique challenges, trends, and intersecting issues related to identifying intellectual potential of children of color around the world, providing access to appropriate curriculum and instructional opportunities, addressing the professional capacities of teachers working with these students, and the role of diverse families and communities in the talent development process in these communities. To achieve the volume 'EUROs' objectives, the editors bring together expert scholars from around the world who have a vested interest in gifted children of color.

Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice Juliet A. Emamaullee 1 , Joy Davis 1 , Shaheed Merani 1 , Christian Toso 1 , John F. Elliott 2 , Aducio Thiesen 3 and A.M. James Shapiro 1 , 4 1 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; 2 Departments of Medicine and of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada; 3 Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada; 4 Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada. Corresponding author: Juliet Emamaullee, juliete{at}ualberta.ca . Abstract OBJECTIVE The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti–IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. RESEARCH DESIGN AND METHODS AND RESULTS Although treatment with either anti–IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age ( P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti–IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti–IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti–IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell–mediated dominant protective effect against autoimmunity. CONCLUSIONS These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received August 14, 2008. Accepted March 3, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution.

Background A systemic evaluation of immune cell infiltration patterns in experimental acute pancreatitis (AP) is lacking. Using multi-dimensional flow cytometry, this study profiled infiltrating immune cell types in multiple AP mouse models. Methods Three AP models were generated in C57BL/6 mice via cerulein (CAE) injection, alcohol and palmitoleic acid (EtOH + POA) injection, and alcohol diet feeding and cerulein (EtOH + CAE) injection. Primary pancreatic cells and splenocytes were prepared, and multi-dimensional flow cytometry was performed and analyzed by manual gating and computerized PhenoGraph, followed by visualization with t-distributed stochastic neighbor embedding (t-SNE). Results CAE treatment induced a time-dependent increase of major innate immune cells and a decrease of follicular B cells, and T CD4+ cells and the subtypes in the pancreas, whereas elicited a reversed pattern in the spleen. EtOH + POA treatment resulted in weaker effects than CAE treatment. EtOH feeding enhanced CAE-induced amylase secretion, but unexpectedly attenuated CAE-induced immune cell regulation. In comparison with manual gating analysis, computerized analysis demonstrated a remarkable time efficiency and reproducibility on the innate immune cells and B cells. Conclusions The reverse pattern of increased innate and decreased adaptive immune cells was consistent in the pancreas in CAE and EtOH + POA treatments. Alcohol feeding opposed the CAE effect on immune cell regulation. Together, the immune profiling approach utilized in this study provides a better understanding of overall immune responses in AP, which may facilitate the identification of intervention windows and new therapeutic strategies. Computerized analysis is superior to manual gating by dramatically reducing analysis time.

Background The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2–18 termed “phosphatase activation domain” that is normally hidden in the native protein in ‘paperclip’-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau. Hence, we hypothesized that anti-Tau 2–18 monoclonal antibodies (mAb) may recognize pathological, but not normal tau at very early stages of tauopathy and prevent or decrease the aggregation of this molecule. Methods Mouse mAbs were generated using standard hybridoma methodology. CDR grafting was used for humanization of mouse mAb. Humanized mAb (Armanezumab) was characterized and tested in vitro / ex vivo / in vivo using biochemical and immunological methods (HPLC, Biacore, ELISA, IHC, FRET, etc.). Stable DG44 cell line expressing Armanezumab was generated by clone selection with increased concentrations of methotrexate (MTX). Results A panel of mouse mAbs was generated, clone 1C9 was selected based on binding to pathological human tau with high affinity and humanized. Fine epitope mapping revealed conservation of the epitope of human tau recognized by the parent murine mAb and Armanezumab. Importantly, Armanezumab (i) bound to tau with high affinity as determined by Biacore; (ii) bound pathological tau in brains from AD, FTD and Pick’s disease cases; (iii) inhibited seeding effect of aggregated tau from brain lysate of P301S Tg mice; (iv) inhibited cytotoxic effect of tau oligomers; (v) reduced total tau (HT7) and AT100, PHF1, AT8, AT180, p212, p214-positive tau species in brains of tau transgenic mice after intracranial injection. A stable CHO cell line producing >1.5 g/l humanized mAb, Armanezumab was generated. Conclusion These findings suggest that Armanezumab could be therapeutic in clinical studies for treatment of AD.

IntroductionHome care clients are increasingly medically complex, have limited access to effective chronic disease management and have very high emergency department (ED) visitation rates. There is a need for more appropriate and targeted supportive chronic disease management for home care clients. We aim to evaluate the effectiveness and preliminary cost effectiveness of a targeted, person-centred cardiorespiratory management model.Methods and analysisThe Detection of Indicators and Vulnerabilities of Emergency Room Trips (DIVERT) — Collaboration Action Research and Evaluation (CARE) trial is a pragmatic, cluster-randomised, multicentre superiority trial of a flexible multicomponent cardiorespiratory management model based on the best practice guidelines. The trial will be conducted in partnership with three regional, public-sector, home care providers across Canada. The primary outcome of the trial is the difference in time to first unplanned ED visit (hazard rate) within 6 months. Additional secondary outcomes are to identify changes in patient activation, changes in cardiorespiratory symptom frequencies and cost effectiveness over 6 months. We will also investigate the difference in the number of unplanned ED visits, number of inpatient hospitalisations and changes in health-related quality of life. Multilevel proportional hazard and generalised linear models will be used to test the primary and secondary hypotheses. Sample size simulations indicate that enrolling 1100 home care clients across 36 clusters (home care caseloads) will yield a power of 81% given an HR of 0.75.Ethics and disseminationEthics approval was obtained from the Hamilton Integrated Research Ethics Board as well as each participating site’s ethics board. Results will be submitted for publication in peer-reviewed journals and for presentation at relevant conferences. Home care service partners will also be informed of the study’s results. The results will be used to inform future support strategies for older adults receiving home care services.Trial registration numberNCT03012256.