A Delineation of Mesenchymal Stromal Cell Therapeutic Action in New Models of Acute and Chronic Graft versus Host Disease

The potent immune regulatory capacity of mesenchymal stromal cells (MSC) has been extensively characterised in terms of T cells, natural killer cells and dendritic cells suppression; however the ability of MSC to modulate B cell biology is not fully understood. This immune suppressive ability has led to the development of MSC therapy for the treatment of inflammatory and auto-immune disease, and has already demonstrated beneficial effects during GvHD and Crohn’s disease. However, the mechanisms employed by MSC therapy to modulate disease progression have not been identified. The key goals for this thesis were (1) to determine how MSC effect B cell function and to identify the mechanisms by which this effect is mediated, and (2) the development of novel mouse models of chronic and acute GvHD to elucidate the mechanism of action by which MSC attenuate disease progression. This study demonstrated than MSC support the activation, proliferation and survival of human CD19+ peripheral B cells in vitro. MSC support of B cell survival was mediated through the cell contact dependent up-regulation of VEGF production by the MSC. Soluble VEGF bound by B cells induced AKT phosphorylation, inhibited caspase 3 cleavage and reduced apoptosis. The second part of this thesis focused on developing murine models of chronic and acute GvHD and to investigate the efficacy of xenogeneic MSC therapy in these models. In addition, a robust humanised model of aGvHD was developed to investigate mechanism of MSC protection. MSC therapy significantly increased survival of aGvHD mice and this protection correlated with significantly reduced TNF-α production and significantly increased numbers of regulatory T cells in aGvHD target organs. These findings further the understanding of the immune regulation capacity of MSC in vitro and provide a robust and clinically relevant model of aGvHD from which the mechanisms behind MSC modulation can be investigated

The Impact of Tree Planting Program Governance Structure on Tree Survivorship and Vigor: A Case Study using the Massachusetts Greening the Gateway Cities Program

Trees in urban neighborhoods benefit residents by reducing building energy costs, providing cleaner air, decreasing surface runoff, and improving quality of life. However, tree canopy cover is not evenly distributed across neighborhoods in many mid-sized American cities which leads to higher air and surface temperatures, and increased energy bills for residents who are the most economically vulnerable. The state of Massachusetts (USA) created the Greening the Gateway Cities (GGC) program to increase tree canopy cover by 10% in post-industrial, midsized cities with lower educational attainment and lower income than state averages. The study posed two questions: what is the governance structure of the GGC program? How successful is the program using annual survivorship and vigor of the trees? This research examines the GGC program as a case study for a governance structure that fosters connections between the city, community and residents can create the social and environmental infrastructure to support increased tree canopy in urban neighborhoods. Data was collected in four gateway cities in Massachusetts: Chicopee, Fall River, Holyoke and Chelsea. 49 residents who received trees as part of the program were interviewed as well as two DCR foresters, three city planners, one head of the city’s community maintenance (Department of Public Works), and two paid staff and three volunteers of community partners. These interviews informed the creation of a governance framework for the GGC program. Tree survivorship, annual mortality and vigor of 3459 trees were used to measure the initial success of the planting program and to forecast potential benefits to residents. Results show how the GGC planting program can produce increased sense of ownership between cities, communities and individuals in the planting zones. The governance model, with an emphasis on stewardship, showed high rates of annual survivorship (~96.5%), low annual mortality rates (~3.5%) and average vigor rating of 1.5 (1 being healthy, 5 being dead)

Imperfect Relief: Challenges to the Impartiality and Identity of Humanitarian Action

One of the four core humanitarian principles, impartiality's substantive ethical and deeply operational nature directs aid agencies to seek and deliver aid on the basis of non-discrimination and in proportion to the needs of crisis-affected people. Designed to operationalize the principle of humanity, impartiality is challenged by a plethora of external factors, such as the instrumentalization of aid, bureaucratic restriction, obstruction by States or non-State armed groups, and insecurity. Less visible and less examined are factors internal to aid agencies or the sector as a whole. Based on a desk review of the literature and the authors’ experience working with Médecins Sans Frontières, this article explores shortcomings in how the humanitarian sector understands and operationalizes impartiality, placing the focus on these internal factors.Beginning with the definition of impartiality, the article focuses on inadequacies in the practice of impartiality's twin pillars: non-discrimination and proportionality in the delivery of aid. Key conclusions include the necessity of an active rather than passive approach to non-discrimination, and the need for greater commitment to proportionality. In extending this analysis, the article looks more deeply at how aid organizations approach the humanitarian principles, identifying shortcomings in the way that the sector operationalizes, engages with and evaluates those principles. Given the sector's limited inclusion of or accountability towards people in crisis, its exercise of impartiality seems particularly problematic in relation to its power to decide the who and what of aid delivery, and to define the needs which it will consider humanitarian. The objective of this article is to reset humanitarians’ conceptual and operational understanding of impartiality in order to better reflect and protect humanity in humanitarian praxis, and to help humanitarians navigate the emergent challenges and critical discussions on humanitarian action's position in respect to climate change, triple-nexus programming, or simply a future where staggering levels of urgent needs vastly outstrip humanitarian resources

The development of a European elearning cultural competence education project and the creation of it’s underpinning literature based theoretical and organising framework

The EU have set standards in relation to cultural competence, and findings from previously funded EU commission projects have illuminated an extensively developed body of knowledge in this area in relation to healthcare. Evidence from contemporary literature shows that education interventions have a positive impact on the cultural competence of health care professionals. Nonetheless, short accessible resources that can be used flexibly to support teaching and learning around cultural competence are not available across many European countries. The aim of the TransCoCon (2017-2020) project has been to develop innovative accessible multi-media learning resources to enable undergraduate nursing students and registered nurses in five countries to develop their cultural self-efficacy and cultural competence for nursing. The purpose of this paper is to describe and discuss this European ERASMUS + funded strategic partnership project (TransCoCon 2017-2020) and the creation of its underpinning theoretical and organising framework. The rationale for this guiding framework will be discussed within the context of supporting literature.info:eu-repo/semantics/publishedVersio

Wandering of a contact line at thermal equilibrium

We reconsider the problem of the solid-liquid-vapour contact-line on a disordered substrate, in the collective pinning regime. We go beyond scaling arguments and perform an analytic computation, through the replica variational method, of the fluctuations of the line. We show how gravity effects must be included for a proper quantitative comparison with available experimental data of the wetting of liquid helium on a caesium substrate. The theoretical result is in good agreement with experimental findings for this case.Comment: 24 laTex pages with 5 EPS figures included. submitted to Phys. Rev

Helminth antigens modulate human PBMCs, attenuating disease progression in a humanised mouse model of graft versus host disease

Fasciola hepatica is a trematode worm that causes fascioliasis, a neglected tropical disease in humans and livestock. To gain insight into the host-parasite interactions that facilitate infection, we have investigated the immunomodulatory properties of the parasite's tegumental coat (FhTeg), a major antigen source that is sloughed off and renewed every 2–3 h as the worm migrates through host tissue. Using mouse models of infection, we have previously shown that FhTeg induces a novel phenotype of dendritic cells that induce anergic CD4+ T-cells. We proposed that this induced state of hyporesponsiveness characterised by suppression of cell proliferation and cytokine secretion was one mechanism by which F. hepatica prevented host protective immunity to support the parasite survival. To determine if the same mechanisms are utilised during human infections, we have now examined the interaction of FhTeg with human PBMCs. FhTeg binds to and modulates cytokine production in human PBMCs, in particular targeting the CD4+ population resulting in reduced levels of TNF, IL-2 and IFNγ and increased markers of anergy. Furthermore, the adoptive transfer of FhTeg stimulated PBMCs to a humanised model of acute graft versus host disease (GvHD) attenuated disease progression by increasing survival and reducing pathological scores. These mice also displayed a significant decrease in the total number of human CD4+ cells expressing TNF, IL-2 and IFNγ in the spleen, liver and lung. This study therefore concurs with evidence from ruminant and murine models of infection suggesting that anergic CD4+ T cells are associated with successful Fasciola hepatica infection and highlights an important role for FhTeg in contributing to the overall immunosuppressive effects of this parasite

Linocin and OmpW Are Involved In Attachment Of The Cystic Fibrosis-Associated Pathogen Burkholderia Cepacia Complex To Lung Epithelial Cells and Protect Mice Against Infection

Burkholderia cepacia complex (Bcc) causes chronic opportunistic lung infections in people with cystic fibrosis (CF) resulting in a gradual lung function decline and, ultimately, patient death. Bcc is a complex of eighteen species and is rarely eradicated once a patient is colonised, therefore vaccination may represent a better therapeutic option. We developed a new proteomics approach to identify bacterial proteins that are involved in attachment of Bcc to lung epithelial cells. Fourteen proteins were reproducibly identified by 2-DE from four Bcc strains, representative of two Bcc species: B. cenocepacia, the most virulent and B. multivorans, the most frequently acquired. Seven proteins were identified in both species, but only two were common to all four strains, Linocin and OmpW. Both proteins were selected based previously published data on these proteins in other species. The E. coli strains expressing recombinant Linocin and OmpW showed enhanced attachment (4.2- and 3.9-fold) to lung cells, compared to control, confirming that both proteins are involved in host cell attachment. Immunoproteomic analysis using serum from Bcc colonised CF patients confirmed that both proteins elicit potent humoral responses in vivo. Mice immunised with either recombinant Linocin or OmpW were protected from B. cenocepacia and B. multivorans challenge. Both antigens induced potent antigen-specific antibody responses and stimulated strong cytokine responses. In conclusion, our approach identified adhesins that induced excellent protection against two Bcc species and are promising vaccine candidates for a multi-subunit vaccine. Furthermore, it highlights the potential of our proteomics approach to identify potent antigens against other difficult pathogens

16th Annual Environmental Law Institute

Materials from the 16th Annual Environmental Law Institute held by UK/CLE in May 2000

Testing gravitational-wave searches with numerical relativity waveforms: Results from the first Numerical INJection Analysis (NINJA) project

The Numerical INJection Analysis (NINJA) project is a collaborative effort between members of the numerical relativity and gravitational-wave data analysis communities. The purpose of NINJA is to study the sensitivity of existing gravitational-wave search algorithms using numerically generated waveforms and to foster closer collaboration between the numerical relativity and data analysis communities. We describe the results of the first NINJA analysis which focused on gravitational waveforms from binary black hole coalescence. Ten numerical relativity groups contributed numerical data which were used to generate a set of gravitational-wave signals. These signals were injected into a simulated data set, designed to mimic the response of the Initial LIGO and Virgo gravitational-wave detectors. Nine groups analysed this data using search and parameter-estimation pipelines. Matched filter algorithms, un-modelled-burst searches and Bayesian parameter-estimation and model-selection algorithms were applied to the data. We report the efficiency of these search methods in detecting the numerical waveforms and measuring their parameters. We describe preliminary comparisons between the different search methods and suggest improvements for future NINJA analyses.Comment: 56 pages, 25 figures; various clarifications; accepted to CQ

Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. IMPACT AND IMPLICATIONS: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis