The Galleon Cargo: Accounts in the Colonial Archives

Much of the debris that has washed up on the shores of the northern Oregon coast for centuries were mainstays of Spanish trade carried as cargo across the world on Manila galleons. Both Native people and Euro-Americans have recovered large beeswax chunks, lending to the lore of the “Beeswax Wreck,” as well as Chinese blue-and-white porcelain fragments. In this article, Cameron La Follette and Douglas Deur describe research findings about cargo on the Santo Cristo de Burgos and similar Manila galleons, including the San Francisco Xavier of 1705, the previous favored candidate for the Oregon wreck. La Follette and Deur located probable matches for the shippers\u27 identities of four shipper\u27s marks found on Oregon beeswax chunks. According to La Follette and Deur, “in addition to trade goods, the Santo Cristo de Burgos carried a cargo of liquid mercury,” which was essential for refining silver ore from South American mines used to make coins that fueled the Spanish empire and the Manila trade itself. The article contains a partial cargo list for the 1693 Santo Cristo de Burgos voyage and a special digital appendix with the full cargo manifest for the 1701 San Francisco Xavier

Continuous vancomycin in a pediatric cystic fibrosis patient

Continuous vancomycin has been previously reported to maximize antimicrobial activity while avoiding toxicities associated with dose escalation, but the efficacy of this dosing strategy has not been reported. This case report describes the successful use of continuous vancomycin, including improvement in lung function and avoidance of nephrotoxicity, demonstrated in a pediatric cystic fibrosis (CF) patient with MRSA

Accommodating Students With Special Educational Needs During School Closures Due to the COVID-19 Pandemic in Norway: Perceptions of Teachers and Students

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Early medieval garnet-inlaid metalwork: a comparative analysis of disc brooches from early Wessex

Garnet-inlaid metalwork was an emblem of elite culture in the early medieval North Sea world. This study compares three Anglo-Saxon garnet-inlaid brooches that are exceptionally similar in design and appearance. All three date to the seventh century, a period that saw the emergence of leading families that used such deluxe dress items to enhance their political position. The central hypothesis explored here is that the brooches were produced by the same, or by closely linked, goldsmiths working under the patronage of such a family. Integrated analysis was conducted using microscopy, CT scans, XRF and XRD, in part to establish whether the garnets used came from the same or different sources

Comparison of the serious injury pattern of adult bicyclists, between South-West Netherlands and the State of Victoria, Australia 2001-2009

Background: Head injury is the leading cause of death and long term disability from bicycle injuries and may be prevented by helmet wearing. We compared the pattern of injury in major trauma victims resulting from bicyclist injury admitted to hospitals in the State of Victoria, Australia and South-West Netherlands, with respective high and low prevalence of helmet use among bicyclists. Methods: A cohort of bicycle injured patients with serious injury (defined as Injury Severity Score > 15) in South-West Netherlands, was compared to a cohort of serious injured bicyclists in the State of Victoria, Australia. Additionally, the cohorts of patients with serious injury admitted to a Dutch level 1 trauma centre in Rotterdam, the Netherlands and an Australian level 1 trauma centre in Melbourne, Australia were compared. Both cohorts included patients admitted between July 2001 and June 2009. Primary outcome was in-hospital mortality and secondary outcome was prevalence of severe injury per body region. Outcome was compared using univariate analysis and mortality outcomes were also calculated using multivariable logistic regression models. Results: A total of 219 cases in South-West Netherlands and 500 cases in Victoria were analyzed. Further analyses comparing the major trauma centres in each region, showed the percentage of bicycle-related death was higher in the Dutch population than in the Australian (n = 45 (24%) vs n = 13(7%); P < 0.001). After adjusting for age, mechanism of injury, GCS and head injury severity in both hospitals, there was no significant difference in mortality (adjusted odds ratio 1.4; 95% confidence interval = 0.6, 3.5). Patients in Netherlands trauma centre suffered from more serious head injuries (Abbreviated Injury Scale ≥ 3) than patients in the Australian trauma centre (n = 165 (88.2%) vs n = 121 (62.4%); P < 0.001). The other body regions demonstrated significant differences i

A review of the anti-tumor potential of current therapeutics targeting the mitochondrial protease ClpP in H3K27-altered, diffuse midline glioma

Diffuse midline gliomas (DMGs) are devastating pediatric brain tumors recognized as the leading cause of cancer-related death in children. DMGs are high-grade gliomas (HGGs) diagnosed along the brain's midline. Euchromatin is the hallmark feature of DMG, caused by global hypomethylation of H3K27 either through point mutations in histone H3 genes (H3K27M), or by overexpression of the enhancer of zeste homolog inhibitory protein (EZHIP). In a clinical trial for adults with progressive HGGs, a 22-year-old patient with a thalamic H3K27-altered DMG, showed remarkable clinical and radiological responses to dordaviprone (ONC201). This response in a H3K27-altered HGG patient, coupled with the lack of response of patients harboring wildtype-H3 tumors, has increased the clinical interest in dordaviprone for the treatment of DMG. Additional reports of clinical benefit have emerged, but research defining mechanisms of action (MOA) fall behind dordaviprone's clinical use, with biomarkers of response unresolved. Here, we summarize dordaviprone's safety, interrogate its preclinical MOA- identifying the mitochondrial protease 'ClpP' as a biomarker of response, and discuss other ClpP-agonists, expanding the arsenal of potential weapons in the fight against DMG. Finally, we discuss combination strategies including ClpP-agonists, and its immunomodulatory effects suggestive of a role for the tumor microenvironment in DMG patients' response

The Gristhorpe coffin and its contents

In July 1834 excavation of a barrow at Gristhorpe, near Scarborough, Yorkshire, recovered an intact, waterlogged, hollowed-out oak coffin containing a perfectly preserved Bronze Age skeleton that had been wrapped in an animal skin and buried with worked flints, a bronze dagger with a whalebone pommel, and a bark vessel apparently containing food residue. Gristhorpe Man became the centrepiece of the Scarborough Philosophical Society’s museum display. In 2004, planned refurbishment of the renamed Rotunda Museum provided the opportunity for a scientific re-examination of the burial and grave goods in order to eluciate the life and death of this extraordinary survival of the British Early Bronze Age. Tree-trunk coffin burials are relatively rare and Gristhorpe Man, with his range of grave goods was likely to have held a special role in society. Analysis of the skeleton included an examination of its skeletal morphology and palaeopathological conditions combined with isotopic analyses of the bones and teeth in order to investigate mobility, diet, and status of the individual whose unusual large stature, dentition, and novel methods of conservation were of particular interest. These analyses, combined with examination of the surviving coffin lid, including the unique ‘face’ carved onto one end of it, the grave goods, and radiocarbon and dendrochronological dating, reveal fascinating insights into the social position, inter-regional contacts and the burial rite associated with this enigmatic mature man who probably saw active combat and who suffered from a benign brain tumour that may have seriously altered his personality in his later years

Factors affecting inter-regional academic scientific collaboration within Europe: the role of economic distance

This paper offers some insights into scientific collaboration (SC) at the regional level by drawing upon two lines of inquiry. The first involves examining the spatial patterns of university SC across the EU-15 (all countries belonging to the European Union between 1995 and 2004). The second consists of extending the current empirical analysis on regional SC collaboration by including the economic distance between regions in the model along with other variables suggested by the extant literature. The methodology relies on co-publications as a proxy for academic collaboration, and in order to test the relevance of economic distance for the intensity of collaboration between regions, we put forward a gravity equation. The descriptive results show that there are significant differences in the production of academic scientific papers between less-favoured regions and core regions. However, the intensity of collaboration is similar in both types of regions. Our econometric findings suggest that differences in scientific resources (as measured by R&D expenditure) between regions are relevant in explaining academic scientific collaborations, while distance in the level of development (as measured by per capita GDP) does not appear to play any significant role. Nevertheless, other variables in the analysis, including geographical distance, specialization and cultural factors, do yield significant estimated coefficients, and this is consistent with the previous literature on regional SC

DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo.

Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic

Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling

This work was supported by Cancer Research UK core funding number A17196.RAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization. Using rationally designed RAS point mutations, we were able to stabilize the RAS:PDE6D complex by increasing the affinity of RAS for PDE6D, which resulted in the redirection of RAS to the cytoplasm and the primary cilium and inhibition of oncogenic RAS/ERK signaling. We developed an SPR fragment screening and identified fragments that bind at the KRAS:PDE6D interface, as shown through cocrystal structures. Finally, we show that the stoichiometric ratios of KRAS:PDE6D vary in different cell lines, suggesting that the impact of this strategy might be cell-type-dependent. This study forms the foundation from which a potential anticancer small-molecule RAS:PDE6D complex stabilizer could be developed.Publisher PDFPeer reviewe