The Medieval Borderland: Geophysical Analysis of a Later Medieval Deserted Settlement and Cultural Landscape from Western Ireland

This thesis investigates the archaeological remnants of an early 14th century settlement at Ballintober, Roscommon County, Ireland. An innovative methodology combining ground-penetrating radar, magnetic gradiometry, and archaeological excavations is utilized to reconstruct the medieval built environment, which was comprised of a masonry castle, nucleated settlement and wider arable agricultural landscape. By integrating the archaeological and historical records, I pose hypotheses related to the differential statuses of people at the settlement, their domestic and agricultural practices, and a timeline of their occupation and abandonment of the site. The Ballintober settlement offers a unique case study to investigate the colonial dynamics of the Irish later medieval period. My findings suggest that the built environment of this site was constructed and inhabited by its residents as an overt claim to English identity and embodied the complicated and nuanced intersection of power and ethnicity within the Irish colonial period

A radiopaque polymer hydrogel used as a fiducial marker in gynecologic-cancer patients receiving brachytherapy

We assessed a novel Food and Drug Administration–approved hydrogel, synthesized as absorbable iodinated particles, in gynecologic-cancer patients undergoing computed tomography (CT) or magnetic resonance (MR) based brachytherapy after external beam radiation

An Analysis of Patient Characteristics and Clinical Outcomes in Primary Pulmonary Sarcoma

INTRODUCTION: Literature concerning primary pulmonary sarcomas (PPS) is limited to small case series. This study examines, in a large cohort, the clinical characteristics and therapeutic strategies of PPS and their impact on overall survival (OS). METHODS: This was a retrospective analysis from the Surveillance, Epidemiology, and End Results database (1988-2008). Eligible patients had primary PPS and underwent local therapy. Survival estimates were obtained using the Kaplan-Meier method and the Cox regression model. OS of PPS patients were compared with a cohort of 10,909 patients with extremity soft-tissue sarcomas. RESULTS: The cohort included 365 PPS patients with a median follow-up of 21 months. Fifty-five percent of the patients had large tumors (>5 cm), 76% were high-grade, and 16% had node-positive disease. Seventy-five percent of the cohort underwent surgery alone, 14% underwent surgery and radiation therapy, and 11% underwent radiation therapy alone. Multivariate analysis showed reduced OS for patients with tumors more than 5 cm (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.25-2.19), high tumor grade (HR 3.1, 95% CI 1.26-3.62), and unresectable disease (HR 2.6, 95% CI 1.76-3.88. The 5-year OS for the cohort of pulmonary sarcomas versus sarcomas of the extremities was 35% versus 71% (p < 0.0001). CONCLUSION: This large study examining PPS patients reveals a high rate of nodal involvement and a markedly worse OS than patients with extremity soft-tissue sarcomas. Thus, given the poor overall prognosis, it is recommended that PPS patients undergo a thorough mediastinal nodal evaluation to rule out locoregional metastasis and proceed with aggressive treatment

Measurement of Protein Tyrosine Phosphatase Activity in Single Cells by Capillary Electrophoresis

A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates, and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 ± 250 nM and 290 ± 54 nM, respectively. Dose-response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn2+ and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 ± 8.2 fmol min−1 mg−1) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 ± 0.3 nmol min−1 mg−1). Zn2+, 1,2-naphthoquinone and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 μM, and 100 nM, respectively. Dephosphorylation of the reporter following loading into living single cells occurred at rates of at least 2 pmol min−1 mg−1. When single cells were exposed to 1,2-naphthoquinone (50 μM), Zn2+ (100 μM), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens

Ex Vivo Chemical Cytometric Analysis of Protein Tyrosine Phosphatase Activity in Single Human Airway Epithelial Cells

We describe a novel method for the measurement of protein tyrosine phosphatase (PTP) activity in single human airway epithelial cells (hAECs) using capillary electrophoresis. This technique involved the microinjection of a fluorescent phosphopeptide that is hydrolyzed specifically by PTPs. Analyses in BEAS-2B immortalized bronchial epithelial cells showed rapid PTP-mediated dephosphorylation of the substrate (2.2 pmol min−1 mg−1) that was blocked by pretreatment of the cells with the PTP inhibitors pervanadate, Zn2+, and 1,2-naphthoquinone (76%, 69%, 100% inhibition relative to PTP activity in untreated controls, respectively). These studies were then extended to a more physiologically relevant model system: primary hAECs cultured from bronchial brushings of living human subjects. In primary hAECs, dephosphorylation of the substrate occurred at a rate of 2.2 pmol min−1 mg−1, and was also effectively inhibited by pre-incubation of the cells with the inhibitors pervanadate, Zn2+, and 1,2- naphthoquinone (91%, 88%, and 87% median PTP inhibition, respectively). Reporter proteolysis in single BEAS-2B cells occurred at a median rate of 43 fmol min−1 mg−1 resulting in a mean half-life of 20 min. The reporter displayed a similar median half-life of 28 min in these single primary cells. Finally, single viable epithelial cells (which were assayed for PTP activity immediately after collection by bronchial brushing of a human volunteer) showed dephosphorylation rates ranging from 0.34–36 pmol min−1 mg−1 (n = 6). These results demonstrate the utility and applicability of this technique for the ex vivo quantification of PTP activity in small, heterogeneous, human cells and tissues

SMURF1 Amplification Promotes Invasiveness in Pancreatic Cancer

Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy

Resounding meaning: a PERMA wellbeing profile of classical musicians

While music has been linked with enhanced wellbeing across a wide variety of contexts, the professional pursuit of a music career is frequently associated with poor psychological health. Most research has focused on assessing negative functioning, and to date, few studies have attempted to profile musicians’ wellbeing using a positive framework. This study aimed to generate a profile that represents indicators of optimal functioning among classical musicians. The PERMA model, which reconciles hedonic and eudaimonic wellbeing, was adopted and its five elements assessed with a sample of professional classical musicians: Positive Emotion, Engagement, Relationships, Meaning and Accomplishment. 601 participants (298 women, 303 men) engaged in careers as orchestral (n = 236), solo (n = 158), chamber (n = 112), and choral musicians (n = 36), as well as composers (n = 30) and conductors (n = 29), answered the PERMA-Profiler, a self-report questionnaire built to assess the five components of PERMA. Results point to high scores across all dimensions, with Meaning emerging as the highest rated dimension. Musicians scored significantly higher than general population indicators on Positive Emotion, Relationships and Meaning. When wellbeing is assessed as positive functioning and not the absence of illbeing, musicians show promising profiles. The reconciliation between these findings and the previous body of research pointing to the music profession as highly challenging for healthy psychological functioning is discussed. *** For a video summary of this article please see http://researchonline.rcm.ac.uk/id/eprint/1804/ **

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29