Endothelial and innate immune cross-talk in the time pathogenesis of pulmonary fibrosis in mice

Thesis (Ph.D.)--Boston UniversitySystemic Sclerosis (SSc) is a progressive autoimmune disease characterized by vasculopathy, immune dysfunction and fibrosis of skin and internal organs. Pulmonary fibrosis is the most severe complication. Although pathogenesis of SSc is not completely understood, it is believed to be initiated by early and persistent damage to endothelial cells (ECs), which may initiate inflammation and activation of fibroblasts. In this study we used subcutaneous instillation of bleomycin (BLM), which induces skin and lung fibrosis similar to SSC. ECs are targeted by BLM, however, the extent of EC contribution to pulmonary inflammation and fibrosis, and the degree of vasculopathy in this model are not fully understood. The core hypothesis of this work is that BLM induced injury to ECs contributes to pathogenic processes, resulting in pulmonary fibrosis. Through a unique method of cell sorting and gene expression analysis, we demonstrated EC injury (Matrix Metalloproteinase 12, von Willebrand Factor) and activation in response to BLM. Activation of ECs was demonstrated by expression of selectins, chemokines, and cytokines, contributing to inflammation and macrophage recruitment. Direct contribution of ECs to fibrosis was demonstrated by up-regulation of pro-fibrotic cytokines (Osteopontin, Connective Tissue Growth Factor, Plasminogen Activation Inhibitor-1), activation of collagen production by fibroblasts, and expression of Endothelial to Mesenchymal Transition (EndoMT) markers (Fibronectin, Fibroblast Specific Protein-1). Importantly, responses were sustained, suggesting that ECs perpetuate damage and repair mechanisms that promote fibrosis. Previous work from our lab has shown that transcription factor Friend Leukemia Virus Integration-1 (Fli1) is down-regulated in fibroblasts and ECs in SSc, contributing to fibrosis and vasculopathy in the skin. Intriguingly, Fli1 is also down-regulated in the lung during BLM induced fibrosis, but not in ECs. Further studies demonstrated that Fli1 was down-regulated in macrophages, where it is regulated by inflammatory signals. Fli1 was also down-regulated in mesenchymal cells, which includes fibroblasts. Previous in vitro studies have shown that Fli1 regulates fibrosis through regulation of collagen and other extracellular matrix proteins. In this study, we identified Tissue Inhibitor of Metalloproteinase-3, an important molecule in collagen degradation, as a novel Fli1 target, revealing another mechanism by which Fli1 contributes to development of fibrosis

Attitudes to national identity among tertiary students in Melanesia and Timor Leste: a comparative analysis

"This paper presents the findings of an 18-month research project on the attitudes of tertiary students in Melanesia and Timor-Leste to national identity and key issues of nation-building. The research was conducted at tertiary campuses across four sites: Dili, Port Vila, Honiara and Port Moresby. The study examined the attitudes of the young educated elite likely to dominate the next generation of leaders and decision makers. Their views are pivotal to understanding the challenges to building a more cohesive sense of national identity and political community in Melanesia and Timor-Leste. Findings highlight the ongoing importance of family, religion and maintaining traditional customs in student conceptions of political community. Depending on the case study, they also illustrate the importance of geographical region of origin, language orientation, and gender in explaining differences in key attitudes towards national identity. This article presents a comparative analysis of those findings across the four target sites ..." - page 1AusAI

Fast Food and Supermarket Availability, Neighborhood Income and Health Outcomes in Public Housing Residents.

Purpose: The availability of fast food restaurants (FFRs) and supermarkets varies by neighborhood income level and may influence health outcomes such as body mass index (BMI) and blood pressure (BP). The purpose of this study was to determine whether neighborhood income moderates the association between fast food restaurant or supermarket availability and health outcomes in public housing residents. Method: Number of FFRs and supermarkets on every street segment in neighborhoods surrounding public housing developments (N=12) in Houston, Texas were counted, then aggregated at the neighborhood level. Residents (N=213) completed measures of BMI (kg/m2) and resting BP. Median household income at the census block level for each housing development was obtained from the 2006-2010 American Community Survey. Linear regression models determined whether availability of fast food restaurants and supermarkets predicts BMI or BP after controlling for age and gender, and if neighborhood income moderated these associations. Results: Participants were middle aged (M=43.5±17.1 years) females (n=138) and males (n=75). BP did not differ by gender (M=121.5/74.0±17.5/12.8 mmHg), females were on average obese (MBMI=33.0±8.7kg/ m2) and males were overweight (MBMI=33.0±8.7kg/ m2). Neighborhood income ranged from $9,226 to$57,618. There were (M=.003±.03) FFRs per neighborhood and (M=.001±.008) supermarkets per neighborhood. Bivariate correlations found that neighborhood income was associated with fast food restaurant (r=.205, p.05). Income did not moderate these associations (p\u3e.05). Conclusions: BP changes with age, and BMI varies by gender. After controlling for these variables, fast food restaurant and supermarket availability did not predict BMI or BP in public housing residents, and neighborhood income did not affect the direction of these associations. Actual consumption of the foods sold at these places may have a more direct relationship with health outcomes. Limited variability in the number of FFRs and supermarkets in each neighborhood may have diminished our ability to detect an effect of these neighborhood factors on BMI and BP

Gradients of the Polarization Energy in the Effective Fragment Potential Method

The effective fragment potential (EFP) method is an ab initio based polarizable classical method in which the intermolecular interaction parameters are obtained from preparative ab initiocalculations on isolated molecules. The polarization energy in the EFP method is modeled with asymmetric anisotropic dipole polarizabilitytensors located at the centroids of localized bond and lone pair orbitals of the molecules. Analytic expressions for the translational and rotational gradients (forces and torques) of the EFP polarization energy have been derived and implemented. Periodic boundary conditions (the minimum image convention) and switching functions have also been implemented for the polarization energy, as well as for other EFP interaction terms. With these improvements, molecular dynamics simulations can be performed with the EFP method for various chemical systems

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

PurposeCabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.MethodsThis was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).ResultsSixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.ConclusionsDespite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib

Resident parasitoids associated with Drosophilidae in Michigan tart cherry orchards and woodland edges

Knowledge of the distribution and abundance of resident parasitoid species of Drosophila flies constitutes an important base for developing and implementing a biological control program for Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), an invasive pest that attacks ripening thin-skinned wild and cultivated berries and stone fruits. For this purpose, a field survey was conducted to identify the parasitoid community associated with D. suzukii infested sites in tart cherry orchards and woodlots in west, northwest, and central Michigan. Sentinel traps baited with D. suzukii larvae and pupae in banana slices were deployed in the center of tart cherry orchards, in woodlots adjacent to tart cherry orchards, and in woodlots isolated from any known commercial host of D. suzukii. Traps were placed from the beginning of July to the end of October 2021. Three parasitoid species that are known to use drosophilids as hosts were recovered from these traps. Pachycrepoideus vindemiae (Rondani) (Hymenoptera: Pteromalidae) and Leptopilina boulardi Barbotin, Carton & Keiner-Pillault (Hymenoptera: Figitidae) emerged from the infested bananas. Leptopilina heterotoma (Thomson) was collected as an adult in a sentinel trap. Among these wasps, only P. vindemiae successfully parasitized D. suzukii pupae in the laboratory. This pupal parasitoid was abundant and widely distributed in both cherry orchards and woodlots. The highest number of P. vindemiae was collected from orchards, followed by woodlots adjacent to orchards, with woodlots without nearby cultivated fruit having the lowest detections. These findings suggest that future release of augmentative or classical biological control agents for D. suzukii could be successful in orchards post-harvest to control late-season populations of this pest

The Grizzly, October 11, 1994

The Last Pledging Season? • Homecoming \u2794 a Success • The American Sexual Landscape • Fire, Fire! • Religious Sect Linked to Murder-Suicides • Campus Artwork Encounters Vandalism • Soup Kitchen Visit Provides Eye-Opening Experience • Retired Officer Expresses Thanks to Ursinus Community • Celebrate National Coming Out Day with GALA • Red and Gold Students Storm the Campus • Security Officer Larry Kirlin Leaves Ursinus • Memories of Homecoming 1994 • A Healthy Outlook on Life • Update From Career Planning & Placement • An Open Letter to President Richter • UC Soccer Wins in Closing Minutes • Walker Memorial Winners • Golley Wins McIntyre Award • UC Wins On Homecoming, 21-20https://digitalcommons.ursinus.edu/grizzlynews/1343/thumbnail.jp

National identity in fragile states: insights from tertiary students in Melanesia and Timor-Leste

The challenges of nation building in Melanesia and Timor-Leste have often been neglected in the regional focus on state-building challenges. High levels of ethno-linguistic diversity, combined with an array of regional, historical and cultural divisions, continue to present obstacles to the creation of a cohesive sense of national political community leading these nations to be labelled ‘fragile’. This paper presents the findings of a comparative study on the attitudes of tertiary students in Melanesia and Timor-Leste to national identity and nation building. A strong pan-Melanesian pattern of group identification was identified, common to Papua New Guinea, Solomon Islands and Vanuatu. The ongoing importance of traditional authority and custom in informing conceptions of political community and identity was evident in all four case study sites, but was in each case matched by indicators of respect for modern state authority. The survey also reveals some significant gender differences in key attitudes towards national identity, including the role of traditional authorities. Most importantly, the study reveals high degrees of national pride, and faith in democratic principles and citizenship; but conversely, low levels of pride in contemporary democratic performance and inter-group tolerance