Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer

From Springer Nature via Jisc Publications RouterHistory: received 2020-12-10, accepted 2021-10-19, registration 2021-10-26, pub-electronic 2021-11-17, online 2021-11-17, collection 2021-12Publication status: PublishedFunder: CRUK Manchester Institute (grant no. A27412) CRUK Manchester Centre (grant no. A25254) CRUK Manchester Experimental Cancer Medicines Centre (grant no. A20465) CRUK Lung Cancer Centre of Excellence (grant no. A25146) NIHR Manchester Biomedical Research CentreAbstract: Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC

Confinement generates single-crystal aragonite rods at room temperature

The topic of calcite and aragonite polymorphism attracts enormous interest from fields including biomineralization and paleogeochemistry. While aragonite is only slightly less thermodynamically stable than calcite under ambient conditions, it typically only forms as a minor product in additive-free solutions at room temperature. However, aragonite is an abundant biomineral, and certain organisms can selectively generate calcite and aragonite. This fascinating behavior has been the focus of decades of research, where this has been driven by a search for specific organic macromolecules that can generate these polymorphs. However, despite these efforts, we still have a poor understanding of how organisms achieve such selectivity. In this work, we consider an alternative possibility and explore whether the confined volumes in which all biomineralization occurs could also influence polymorph. Calcium carbonate was precipitated within the cylindrical pores of track-etched membranes, where these enabled us to systematically investigate the relationship between the membrane pore diameter and polymorph formation. Aragonite was obtained in increasing quantities as the pore size was reduced, such that oriented single crystals of aragonite were the sole product from additive-free solutions in 25-nm pores and significant quantities of aragonite formed in pores as large as 200 nm in the presence of low concentrations of magnesium and sulfate ions. This effect can be attributed to the effect of the pore size on the ion distribution, which becomes of increasing importance in small pores. These intriguing results suggest that organisms may exploit confinement effects to gain control over crystal polymorph

Campanian Ignimbrite Geo Locations

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Campanian Ignimbrite Geo Locations

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Umgang mit Unsicherheiten und Vagheiten bei der Georeferenzierung von Geo-Locations in der Archäologie und in den Geowissenschaften

Archäologische Forschung muss bei der Datenmodellierung mit Zweifeln wie Vagheiten, Unsicherheit und Mehrdeutigkeiten umgehen. Dies ist insbesondere bei der Georeferenzierung der Fall (Unold/Bruhn 2019; Schmidt/Thiery 2022). Um FAIRe, reproduzierbare und verständliche Daten für die Nachnutzung zu schaffen und gleichzeitig die Datenqualität archäologischer Daten zu gewährleisten, müssen Zweifel und Unsicherheiten offengelegt werden (Thiery/Mees 2022; Thiery et al. 2021a). Dies ist auch für die Daten-FAIRifizierung von Daten wichtig, welche in NFDI behandelt wird (Thiery et al. 2021b). Insbesondere die Aspekte Vagheit und Unsicherheit müssen für die Arbeit mit Geodaten modelliert werden (Unold et al. 2019; Unold/Bruhn 2019; Dubois/Prade 2001). Für die Verknüpfung von Daten und die FAIRifizierung ist jedoch die von Berners-Lee (2006) vorgeschlagene graphbasierte Modellierung als Linked Open Data (LOD) die Methode der Wahl. In diesem Beitrag wird anhand von drei data-driven, interdisziplinären Use-Cases der Umgang mit und die Modellierung von vagen und unsicheren Georeferenzen (Fundstellen) in einer Ontologie, in einer Wikibase-Instanz und in Wikidata auf Basis von Literatur als Linked Open Data aus den Bereichen Archäologie und Geowissenschaften vorgestellt

A Cryptotephra Layer in Sediments of an Infilled Maar Lake from the Eifel (Germany): First Evidence of Campanian Ignimbrite Ash Airfall in Central Europe

We analyzed mineralogical characteristics, and major as well as rare earth element concentrations, from a cryptotephra layer in sediments of the infilled maar of Auel (Eifel, Germany). The results of detailed geochemical analyses of clinopyroxenes and their glassy rims from the Auel cryptotephra layer showed that they are similar to those from the thick Campanian Ignimbrite tephra occurrence in a loess section at Urluia (Romania). Both tephras show idiomorphic green clinopyroxenes and formation of distorted grains up to millimeter scale. The cryptotephra in the Auel core has a modelled age of around 39,940 yr b2k in the ELSA-20 chronology, almost identical to the latest 40Ar/39Ar dates for the Campanian Ignimbrite/Y-5 (CI/Y-5) eruption. These observations suggest that parts of the CI/Y-5 ash cloud were transported also northwestward into Central Europe, whereas the main branch of the CI/Y-5 ash plume was transported from southern Italy towards the NE, E, and SE. Based on pollen analyses, we conclude there was no direct effect on vegetation from the CI/Y-5 fallout in the Eifel area. Trees, shrubs, and grasses remained at pre-tephra-airfall levels for roughly 240 years, but changed around 39,700 yr b2k when thermophilic woody plants (e.g., Alnus and Carpinus) disappeared and Artemisia spread. This change in vegetation was well after the Laschamp geomagnetic excursion and also after the GI9 interstadial and quite probably represents the onset of the Heinrich Event 4 (H4) cold spell, when climatic conditions over the North Atlantic, and apparently also in Central Europe, deteriorated sharply

Relation between Central European Climate Change and Eifel Volcanism during the Last 130,000 Years: The ELSA-23-Tephra-Stack

The analysis of tephra layers in maar lake sediments of the Eifel shows 14 well-visible tephra during the last glacial cycle from the Holocene to the Eemian (0–130,000 yr b2k). These tephra were analyzed for their petrographic composition, which allows us to connect several tephra to eruption sites. All tephra were dated by application of the ELSA-20 chronology, developed using the late Pleistocene infilled maar lake of Auel and the Holocene lake Holzmaar (0–60,000 yr b2k). We extend the ELSA-20 chronology with this paper for the millennia of 60,000–130,000 yr b2k (ELSA-23 chronology), which is based on the infilled maar lake records from Dehner, Hoher List, and Jungferweiher. The evaluation of the tephra from the entire last glacial cycle shows that all 14 tephra were close to interstadial warming of the North Atlantic sea surface temperatures. In particular, phreatomagmatic maar eruptions were systematically associated with Heinrich events or C-events. These events represent times of warming of the Southern Hemisphere, global sea level rise, and CO2 increase, which predate the abrupt interstadial warming events of the Northern Hemisphere. This synchroneity indicates a physical relationship between endogenic and exogenic processes. Changes in the lithospheric stress field in response to changes in continental ice loads have already been suggested as a potential candidate to explain the exogenic forcing of endogenic processes. The chronology of volcanic activity in the Eifel demonstrates that intraplate mantle plumes are also affected by the exogenic forcing of endogenic processes