Restaurants and Relationships: Varied Experiences with Celiac Disease

During the summer, we conducted interviews for Professor Hillary Crane with people who had either celiac disease or gluten intolerance. It quickly became apparent that people experience celiac disease in vastly different ways. We cover these varying experiences in terms of symptoms, eating at restaurants, and personal relationships. There are common symptoms associated with celiac disease and gluten intolerance, but most people have just one or a set few of these symptoms. Due to varying symptoms and severity of them, there is no definitive celiac symptom or experience. This is true for social events involving food and for personal relationships. As seen in our interviews, most people with celiac do not approach things in the same way, and often the way they do go about it is dependent on their symptoms. Most diseases have set symptoms, and a shared experience, but with these varying experiences, it is difficult to define celiac. This research shows how celiac is an indefinable disease in terms of its shared experience and social impact

Internationalisation of service firms through corporate social entrepreneurship and networking

Findings: The findings reveal that, by engaging in social entrepreneurship, these MNCs have focused on the neglected needs of the BOP population, developed sustainable solutions and empowerment, and started with social value creation and postponed value capturing. The pursuit of corporate social entrepreneurship has paved the way for them to establish relationships with NGOs. While the MNCs have mainly had the technical knowledge and financial resources required, collaboration with NGOs have allowed them to learn about the BOP’s specific needs and benefit from the NGOs’ knowledge, human resources and good relationships in this market.Originality/value: This research unravels how service firms can seize opportunities at the BOP. The authors build on social entrepreneurship theory and bring new insights to the field of international business. In addition, the authors broaden the network view and show how networking with social actors such as NGOs enables the mobilisation of resources, actors and activities in emerging markets.Design/methodology/approach: This research adopts an exploratory approach employing qualitative multiple case studies. Three service firms that have targeted the BOP markets in India were studied. In total, 25 in-depth interviews were conducted with multinational corporations (MNCs) and their NGO partners. Data analysis was facilitated through pattern matching and systematic case comparison.Purpose: The purpose of this paper is to explore how employing corporate social entrepreneurship and developing a network of relationships with non-governmental organisations (NGOs) can support and contribute towards the internationalisation of service firms into the base of the pyramid (BOP) markets in emerging markets

Tissue iron promotes wound repair via M2 macrophage polarisation and the chemokines CCL17 and CCL22

Macrophages are important for effective iron recycling and erythropoiesis, but they also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds and a requirement of iron for effective repair. Herein, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a prohealing M2 phenotype. In delayed healing diabetic mouse wounds, both macrophage polarization and iron sequestration were impaired. In vitro studies revealed that iron promotes differentiation, while skewing macrophages toward a hypersecretory M2-like polarization state. These macrophages produced high levels of chemokine (C-C motif) ligands 17 and 22, promoting wound reepithelialization and extracellular matrix deposition in a human ex vivo wound healing model. Together, these findings reveal a novel, unappreciated role for iron in modulating macrophage behavior to promote subsequent wound repair. These findings support therapeutic evaluation of iron use to promote wound healing in the clinic

Fish Cohort Dynamics: Application of Complementary Modeling Approaches

The recruitment to the adult stock of a fish population is a function of both environmental conditions and the dynamics of juvenile fish cohorts. These dynamics can be quite complicated and involve the size structure of the cohort. Two types of models, i-state distribution models (e.g., partial differential equations) and i-state configuration models (computer simulation models following many individuals simultaneously), have been developed to study this type of question. However, these two model types have not to our knowledge previously been compared in detail. Analytical solutions are obtained for three partial differential equation models of early life-history fish cohorts. Equivalent individual-by-individual computer simulation models are also used. These two approaches can produce similar results, which suggests that one may be able to use the approaches interchangeably under many circumstances. Simple uncorrected stochasticity in daily growth is added to the individual-by-individual models, and it is shown that this produces no significant difference from purely deterministic situations. However, when the stochasticity was temporally correlated such that a fish growing faster than the mean 1 d has a tendency to grow faster than the mean the next day, there can be great differences in the outcomes of the simulations.This research was sponsored in part by the Electric Power Research Institute under contract no. RP2932-2 (DOE no. ERD-87-672) with the U.S. Department of Energy under contract no. DE-AC05-84OR21400 with Martin Marietta Energy Systems, and in part by grant no. NAI6RG0492-01 from the Coastal Ocean Program of the National Oceanic and Atmospheric Administration (NOAA) to the University of North Carolina Sea Grant College Program

Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase

Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of 15N3-GTN into 15N-nitrite. We performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C (ascorbic acid). Metabolomics analyses revealed that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated xanthine oxidase (XO), an enzyme that is critical for the metabolic bioactivation of GTN into NO. Ascorbic acid prevented inactivation of XO, resulting in increased NO production from GTN. Our studies suggest that ascorbic acid has the ability to prevent nitrate tolerance by protecting XO, but not aldehyde dehydrogenase (another GTN bioactivating enzyme), from GTN-induced inactivation. Our findings provide a mechanistic explanation for the previously observed beneficial effects of ascorbic acid in nitrate therapy

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression

The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice

BACKGROUND: Apo2L/TRAIL has considerable promise for cancer therapy based on the fact that this member of the tumor necrosis factor family induces apoptosis in the majority of malignant cells, while normal cells are more resistant. Furthermore, in many cells, when Apo2L/TRAIL is combined with chemotherapy, the effect is synergistic. The majority of this work has been carried out using cell lines. Therefore, investigation of how patient tumors respond to Apo2L/TRAIL can validate and/or complement information obtained from cell lines and prove valuable in the design of future clinical trials. METHODS: We have investigated the Apo2L/TRAIL sensitivity of patient derived pancreatic tumors using a patient tumor xenograft/ SCID mouse model. Mice bearing engrafted tumors were treated with Apo2L/TRAIL, gemcitabine or a combination of both therapies. RESULTS: Patient tumors grown as xenografts exhibited a spectrum of sensitivity to Apo2L/TRAIL. Both Apo2L/TRAIL sensitive and resistant pancreatic tumors were found, as well as tumors that showed heterogeneity of response. Changes in apoptotic signaling molecules in a sensitive tumor were analyzed by Western blot following Apo2L/TRAIL treatment; loss of procaspase 8, Bid and procaspase 3 was observed and correlated with inhibition of tumor growth. However, in a tumor that was highly resistant to killing by Apo2L/TRAIL, although there was a partial loss of procaspase 8 and Bid in response to Apo2L/TRAIL treatment, loss of procaspase 3 was negligible. This resistant tumor also expressed a high level of the anti-apoptotic molecule Bcl-X(L )that, in comparison, was not detected in a sensitive tumor. Importantly, in the majority of these tumors, addition of gemcitabine to Apo2L/TRAIL resulted in a greater anti-tumor effect than either therapy used alone. CONCLUSION: These data suggest that in a clinical setting we will see heterogeneity in the response of patients' tumors to Apo2L/TRAIL, including tumors that are highly sensitive as well as those that are resistant. While much more work is needed to understand the molecular basis for this heterogeneity, it is very encouraging, that Apo2L/TRAIL in combination with gemcitabine increased therapeutic efficacy in almost every case and therefore may be a highly effective strategy for controlling human pancreatic cancer validating and expanding upon what has been reported for cell lines

Differential Spatiotemporal Patterns of Galectin Expression are a Hallmark of Endotheliochorial Placentation

Problem: Galectins influence the progress of pregnancy by regulating key processes associated with embryo-maternal cross talk, including angiogenesis and placentation. Galectin family members exert multiple roles in the context of hemochorial and epitheliochorial placentation; however, the galectin prolife in endotheliochorial placenta remains to be investigated. Method of study: Here, we used immunohistochemistry to analyze galectin (gal)-1, gal-3 and gal-9 expression during early and late endotheliochorial placentation in two different species (dogs and cats). Results: We found that during early feline gestation, all three galectin members were more strongly expressed on trophoblast and maternal vessels compared to the decidua. This was accompanied by an overall decrease of gal-1, gal-3 and gal-9 expressions in late feline gestation. In canine early pregnancy, we observed that gal-1 and gal-9 were expressed strongly in cytotrophoblast (CTB) cells compared to gal-3, and no galectin expression was observed in syncytiotrophoblast (STB) cells. Progression of canine gestation was accompanied by increased gal-1 and gal-3 expressions on STB cells, whereas gal-9 expression remained similar in CTB and STB. Conclusion: These data suggest that both the maternal and fetal compartments are characterized by a spatiotemporal regulation of galectin expression during endotheliochorial placentation. This strongly suggests the involvement of the galectin family in important developmental processes during gestation including immunemodulation, trophoblast invasion and angiogenesis. A conserved functional role for galectins during mammalian placental development emerges from these studies.Facultad de Ciencias Veterinaria