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The welfare of pigs during transport depends on many factors, but trailer design plays a key role in transport-related stress. Pot-belly trailers are commonly used for swine transportation in Canada but are criticized because of steep internal ramps causing difficulties during loading/unloading, and poor internal microclimate conditions. This results in a greater proportion of dead-on-arrivals and fatigued pigs compared to trailers using flat-deck designs. The objective of this study was to compare a standard pot-belly trailer to two novel trailer designs, both featuring fan-assisted ventilation and water misting (modified pot-belly and advanced flat-deck trailer) and one featuring flat-decks (advanced flat-deck trailer). Only a few modest differences were observed between pigs transported with different trailers, suggesting that loading pigs using a trailer with a flat deck design compared to trailers with standard ramp designs did not reduce loading stress, and trailers featuring fan-assisted ventilation and water misting did not effectively cool pigs during summer transits. Ontario Pork, Saskatchewan Pork, Alberta Pork, Manitoba Pork, Alberta Department of Agriculture and Forestry, Pezzaioli, Your Neighbourhood Credit Union

Acute myeloid leukemia (AML) is a hematological cancer with a very poor prognosis. FLT3-ITD mutations that cause constitutive FLT3 signaling are commonly seen in patients. Our lab and others have shown that AML patient samples exhibit hallmarks of immune exhaustion such as T cell dysfunction, increased MDSCs, and increased Tregs that associate with worse survival. In solid tumor models DCs have been shown to be important for anti-tumor T cell activity and we aim to further describe the role of DCs in the immune response to leukemia. FLT3 signaling is critical for DC development but the effects of FLT3-ITD on DCs and how it contributes to leukemogenesis remains unclear. In a novel FLT3-ITD driven AML mouse model we found that DCs from these mice have elevated pFLT3, indicating constitutive FLT3 signaling. Moreover, significantly expanded DC progenitors and DCs in the bone marrow and spleen are observed. Analysis of serum cytokines identified increased levels of IL-27, IL-10, and IL-17a in leukemia mice compared to healthy controls, suggesting that the expansion of DCs in these leukemia mice may be driving pathogenic expansion of T helper subsets. Furthermore, we measured higher levels of circulating Th2, Th17, and Treg phenotypes in the blood compared to healthy controls. Thus, we hypothesize that FLT3-ITD DCs are a significant contributor to T cell skewing in AML resulting in poor anti-tumor responses. We are using scRNA-seq methods to identify transcriptional changes in FLT3-ITD DCs that lead to the phenotypes we identified. Understanding how FLT3-ITD DCs contribute to AML immune suppression is critical to interpreting leukemia etiology and the development of targeted therapies such as immune checkpoint blockade or small molecule inhibitors.

Acute Myeloid Leukemia (AML) is the most common adult leukemia and has a 5-year survival of under 30%. AML is caused by uncontrolled proliferation of myeloid cells resulting from a combination of mutations that affect proliferation, differentiation and epigenetic state. For this reason, drugs targeting epigenetic modifications are being studied in AML. AML cells avoid immune recognition though inhibiting the function of multiple cell types, especially T cells and therefore immune checkpoint blockade presents a promising therapy; however, clinical trials to date have shown very modest efficacy. T cell exhaustion has been shown to be a regulated process involving transcriptional and epigenetic changes. BET proteins, which are chromatin readers, have been implicated in maintaining this exhaustion state. In these studies, we investigated the effects of the BET inhibitor (BETi) JQ1 on T cell exhaustion and checkpoint responsiveness in a murine model of AML and AML patient samples. The AML mouse model bears FLT3-ITD and deletion of TET2 restricted to myeloid lineages and is resistant to anti-PD1 therapy. This mouse model of AML expanded terminally exhausted T cells and impaired proliferative capacity after TCR stimulation. Ex vivo treatment with BETi and anti-PD1 reverses CD8+ T cell exhaustion via rescue of proliferative dysfunction and expansion of more functional precursor exhausted T cells in patient samples and AML splenocytes. Finally, we show that BETi rescues anti-PD1 resistance in vivo and reduces tumor burden in multiple organ sites and enriches CD8+ T cells in the bone marrow. In total, we demonstrate that combining BETi and anti-PD1 therapy in the treatment of AML is a rational strategy to overcome anti-PD1 resistance.

The Austrian scholar Otto Neurath is well known for his contributions to philosophy of science and visual communication, but his work in education is less well-known. This paper outlines the biographical development of Neurath's educational work within his historical context and his broader intellectual development, tracking his move from academic research in economics to his work as an activist and public educator in "Red Vienna" during the interwar period. The paper furthermore examines how his work differs from contemporary views of non-formal education, such as that advanced by Cedefop's 2015 report on non-formal education validation, and outlines how Neurath's approach is still relevant to educators today.

The central nervous system (CNS) has a highly complex biophysical and biochemical environment. Despite decades of intensive research, it is still an enormous challenge to restore its functions and regenerate lost or damaged CNS tissues. Current treatment strategies remain sub-optimal because of (1) the hostile microenvironment created post CNS injury, and (2) insufficient understanding of the pathophysiology of acute and chronic CNS diseases. Two-dimensional (2D) in vitro models have provided tremendous insights into a wide range of cellular interactions. However, they fail to recapitulate the complex cellular, topographical, biochemical, and mechanical stimuli found within the natural three-dimensional (3D) CNS. Also, the growing ethical needs to use fewer animals for research further necessitates 3D in vitro models to mimic all or part of the CNS. In this review, we critically appraise the status quo and design considerations of 3D in vitro neural disease and injury models that resemble in vivo conditions. This review mainly focuses on the most recent advances in tissue engineering techniques such as microfluidics, organs-on-a-chip and stem cell technology. Furthermore, we review recent models aiming to elucidate the underlying pathophysiology of CNS diseases. If armed with deeper understanding, it will be possible to develop high-throughput drug screening platforms and new treatments for CNS diseases and injuries.

Acute myeloid leukemia (AML) is an aggressive myeloid lineage white blood cell cancer with an extremely poor prognosis that occurs most frequently above 60 years of age. The current standard of care consists of an intensive induction chemotherapy regimen. Many patients cannot withstand this intensive treatment regimen and rely on other targeted therapies such as small-molecule inhibitors, which inhibit specific oncogenic proteins, but these are not durable. Immunotherapies, which block stimuli that inhibit T cell functions, have had great success in achieving durable remissions in metastatic melanoma. Studies have shown that AML patients exhibit markers of immune suppression by the tumor microenvironment such as increased levels of PD1/LAG3+ exhausted T cells as well as regulatory T cells and myeloid-derived suppressor cells. In addition, inhibitors targeting the BET proteins family, which are histone readers, potently target leukemia cells by reducing myc but also increase IFNy and IL-2 production in T cells by inhibiting BATF, a negative regulator of TCF1. TCF1 is a critical factor in effector memory T cells and TCF1+ T cells are the primary expanders with aPD1. We therefore hypothesized that BETi and aPD1 would synergize in treating AML by modulating both tumor intrinsic and extrinsic factors (enhanced T cell activity). T cells derived from an immune competent FLT3-ITD/TET2/Lys-Cre AML mouse model show significant proliferative dysfunction and enhanced exhaustion markers, but are rescued by ex vivo treatment with BETi + aPD1. Further, In vivo treatment with this novel drug combination showed enhanced reduction of leukemic blasts, increased T cell proliferation, and in vitro expansion of TCF1+ effector memory CD8 T cells.

An imbalance of matrix metalloproteinases (MMPs) and their inhibitors is thought to play a major role in the pathophysiology of joint diseases. The aim of this study is to provide additional insights into the relevance of MMP levels in arthroplasty patients in relation to inflammation and thrombosis. Deidentified plasma samples from 100 patients undergoing total hip arthroplasty or total knee arthroplasty were collected preoperatively, on postoperative day 1, and on postoperative day 3. Tissue inhibitor of MMP 4, tumor necrosis factor α (TNF-α), pro-MMP1, MMP3, MMP9, MMP13, and d-dimer were measured using enzyme-linked immunosorbent assay kits. A biochip array was used to profile interleukin (IL) 2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma, TNF-α, IL-1α, IL-1β, monocyte chemoattractant protein 1, and endothelial growth factor (EGF) levels. The levels of MMP1, MMP9, MMP13, and TNF-α were elevated preoperatively in arthroplasty patients when compared to healthy individuals. The concentrations of MMP1 and MMP9 increased slightly in postsurgical samples. d-Dimer levels were elevated preoperatively, increased postoperatively, and started decreasing on postoperative day 3. Significant correlations between MMP9 with TNF-α, IL-6, IL-8, VEGF, and EGF were identified. Elevated preoperative MMP1, MMP9, and MMP13 concentrations suggest that they may play a role in the pathogenesis of arthritis. There is also evidence of increased coagulation activity and possible upregulation of several MMPs postsurgically. Correlation analysis indicates that MMP9 levels may potentially be related to inflammation and thrombosis in arthroplasty patients.

Acute myeloid leukemia (AML) is an aggressive myeloid lineage cancer with limited treatment options. Single-agent treatments with targeted inhibitors have resulted in some disease remissions, however, resistance almost always develops, prompting development of combinatorial treatment strategies. Studies have shown that AML patients exhibit markers of immune suppression such as increased levels of exhausted T cells (PD1/LAG3+) as well as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)1. Inhibitors targeting the BET family, which are histone readers, have been shown to increase IFNy and IL-2 production in T cells by inhibiting BATF—a known negative regulator of TCF1, as well as decrease PD-L12–4. We, therefore, hypothesized that combining BRD4i and anti-PD1 would synergize by modulating both tumor intrinsic biology (though MYC reduction) and boosting T cell activity. We have characterized a FLT3-ITD/TET2/Lys-Cre mouse model of AML and observed significantly increased numbers of PD1+/TIM3+/TCF1− T cells, Tregs, and MDSCs when compared to healthy mice. T cells derived from mice with AML have significantly reduced T cell proliferation upon co-stimulation with CD3 and CD28. Ex vivo treatment with BRD4i + aPD1 significantly increased T cell proliferation in AML mice and increased TCF1 expression in a dose dependent manner. In vivo treatment with BRD4i + aPD1 showed enhanced reduction of leukemic blasts, reduced PD-L1, and increased CD8+ T cell infiltration into the bone marrow. Our work highlights the efficacy of this novel drug combination in targeting tumor intrinsic and extrinsic factors in AML and identifies a potential novel role for BRD4 in regulating TCF1 expression in T cells.

Metal–organic coordinated multilayers are self-assembled thin films fabricated by alternating solution–phase deposition of bifunctional organic molecules and metal ions. The multilayer film composed of α,ω-mercaptoalkanoic acid and Cu (II) has been the focus of fundamental and applied research with its robust reproducibility and seemingly simple hierarchical architecture. However, internal structure and composition have not been unambiguously established. The composition of films up to thirty layers thick was investigated using Rutherford backscattering spectrometry and particle induced X-ray emission. Findings show these films are copper enriched, elucidating a 2:1 ratio for the ion to molecule complexation at the metal–organic interface. Results also reveal that these films have an average layer density similar to literature values established for a self-assembled monolayer, indicating a robust and stable structure. The surface structures of multilayer films have been characterized by contact angle goniometry, ellipsometry, and scanning probe microscopy. A morphological transition is observed as film thickness increases from the first few foundational layers to films containing five or more layers. Surface roughness analysis quantifies this evolution as the film initially increases in roughness before obtaining a lower roughness comparable to the underlying gold substrate. Quantitative analysis of topographical structure and internal composition for metal–organic coordinated multilayers as a function of number of deposited layers has implications for their incorporation in the fields of photonics and nanolithography.

Context Donor organs are a scarce gift. Additionally, transplantation is very expensive and the United States lacks universal health insurance for all citizens. These facts combine to make personal finance and insurance some of the criteria for wait listing at US transplant centers. Previous research has shown that the poor and the uninsured (as well as women and nonwhites) are less likely to receive a transplant. Living donor candidates are also limited by the US insurance system. Objective To determine the effect of finance and insurance variables on access to transplant and living donation. Design A qualitative descriptive study of ethics consultation data contained in a research registry approved by the institutional review board at California Pacific Medical Center. Setting and Participants This study analyzes research registry data from a large community hospital in Northern California that serves patients from California, Oregon, and Nevada. The registry data are derived from transplant ethics consultations occurring between January 1, 2007, and June 30, 2009. Main Outcome Measure This study explores the restriction of access to transplantation and of participation in living donation. Results More than a quarter of all transplant ethics consultation reports described the restriction of transplant-related treatment for reasons rooted in finance or insurance. Individuals on the recipient side and on the donor side were hindered with regard to access. Insurance status and personal ability to pay significantly affect access to transplantation in the United States, and this theme is a frequent feature of ethics consultations at California Pacific Medical Center.

Technics and Dialectics of the Information Society: Japanese Origins of Information Society Theory is a historical and theoretical analysis of the development of Japanese Information Society Theory from the origins of postwar Japanese capitalism to the present day. Making use of the methods of Political Economy and Critical Theory, it examines the contradictions of Japanese capitalism within a global context, and considers how Information Society Theory constituted both a strategy used by the Japanese capitalist class to overcome barriers to accumulation in the crisis of the late 1960s – early 1970s, and an ideology of legitimation, the utopian dimension of which points beyond the theory‟s own limitations to possibilities for a renewal of socialist politics. In its concluding section the thesis briefly considers how Information Society Theory adapted to address the changing circumstances of Japan following the bubble economy of the 1980s, and how it addressed the challenge of global neoliberalism.

On August 7th, 2008, Georgia attempted to militarily reassert control over South Ossetia, one of its separatist republics, thus provoking a massive Russian invasion and Georgia's rapid defeat. Russia used the opportunity provided by the Georgian provocation to consolidate its hold over Georgia's two breakaway regions, ultimately recognizing them as legitimate, sovereign states, and thus increasing its power and influence in the region. The West was left reeling, unable to stop Russia or persuade the separatist republics to reconsider federation; the conflict in Georgia has shelved any hopes of a peaceful solution that respected Georgia's "territorial integrity." This conflict was neither random nor inevitable; rather, this thesis will argue that it was the result of a history of oppression by both Georgian and Abkhaz of the other, weak and corrupt states in Georgia and Abkhazia, the purposeful Russian destabilization of the region, and a significant refugee and demographic problem. This thesis will examine the impact that these factors have had on shaping the conflict situation, and it will seek to gain a better understanding of this suddenly unfrozen conflict, in the hope of successfully dealing with other conflicts in the former Soviet sphere before they erupt into war.

Belfast, a maritime city straddling the River Lagan, has in the last decade responded to the challenge of a derelict waterfront. It has done so against a backcloth of conflict and violence. Today a transformed waterfront is an integral aspect of a city promoting itself with confidence. Whilst the scale of development is not that of Berlin’s Potsdamer Platz Belfast’s Laganside initiative is now attracting international interest as an example of how to implement regeneration. This is in a context where it is increasingly recognised that issues of social exclusion and cultural diversity must also be addressed. In Berlin and Belfast the challenge is to build a shared future. How is this to be achieved? Does new development accentuate or accommodate diversity? Can a balance be achieved between promoting an international image for the city and respecting local history and culture?