Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Appreciative inquiry in medical education*

The practice of medicine, and also medical education, typically adopts a problem-solving approach to identify "what is going wrong" with a situation. However, an alternative is Appreciative Inquiry (AI), which adopts a positive and strengths-based approach to identify "what is going well" with a situation. The AI approach can be used for the development and enhancement of the potential of both individuals and organizations. An essential aspect of the AI approach is the generative process, in which a new situation is envisioned and both individual and collective strengths are mobilized to make changes to achieve the valued future situation. The AI approach has been widely used in the world of business and general education, but is has an exciting potential for medical education, including curriculum development, faculty development, supporting learners through academic advising and mentoring, but also for enhancing the teaching and learning of both individuals and groups. This AMEE Guide describes the core principles of AI and their practical application in medical education

Validation of Immersed Boundary Simulations of Heart Valve Hemodynamics against In Vitro 4D Flow MRI Data

The immersed boundary (IB) method is a mathematical framework for fluid-structure interaction problems (FSI) that was originally developed to simulate flows around heart valves. Validation of FSI simulations around heart valves against experimental data is challenging, however, due to the difficulty of performing robust and effective simulations, the complications of modeling a specific physical experiment, and the need to acquire experimental data that is directly comparable to simulation data. In this work, we performed physical experiments of flow through a pulmonary valve in an in vitro pulse duplicator, and measured the corresponding velocity field using 4D flow MRI (4-dimensional flow magnetic resonance imaging). We constructed a computer model of this pulmonary artery setup, including modeling valve geometry and material properties via a technique called design-based elasticity, and simulated flow through it with the IB method. The simulated flow fields showed excellent qualitative agreement with experiments, excellent agreement on integral metrics, and reasonable relative error in the entire flow domain and on slices of interest. These results validate our design-based valve model construction, the IB solvers used and the immersed boundary method for flows around heart valves

Digitizing UK analogue magnetogram records from large geomagnetic storms of the past two centuries

Continuous geomagnetic records of the strength and direction of the Earth's field at the surface extend back to the 1840s. Over the past two centuries, eight observatories have existed in the United Kingdom, which measured the daily field variations using light-sensitive photographic paper to produce analogue magnetograms. Around 350,000 magnetograms have been digitally photographed at high resolution. However, converting the traces to digital values is difficult and time consuming as the magnetograms can have over-lapping lines, low quality recordings and obscure metadata for conversion to SI units. We discuss our approach to digitizing the traces from large geomagnetic storms and highlight some of the issues to be aware of when capturing magnetic information from analogue measurements. These include cross-checking the final digitized values with the recorded hourly mean values from observatory year books and comparing several observatory records for the same storm to catch errors such as sign inversions or incorrect ‘wrap-around’ of data on the paper records

Transfer Learning for the Prediction of Entity Modifiers in Clinical Text: Application to Opioid Use Disorder Case Detection

Background: The semantics of entities extracted from a clinical text can be dramatically altered by modifiers, including entity negation, uncertainty, conditionality, severity, and subject. Existing models for determining modifiers of clinical entities involve regular expression or features weights that are trained independently for each modifier. Methods: We develop and evaluate a multi-task transformer architecture design where modifiers are learned and predicted jointly using the publicly available SemEval 2015 Task 14 corpus and a new Opioid Use Disorder (OUD) data set that contains modifiers shared with SemEval as well as novel modifiers specific for OUD. We evaluate the effectiveness of our multi-task learning approach versus previously published systems and assess the feasibility of transfer learning for clinical entity modifiers when only a portion of clinical modifiers are shared. Results: Our approach achieved state-of-the-art results on the ShARe corpus from SemEval 2015 Task 14, showing an increase of 1.1% on weighted accuracy, 1.7% on unweighted accuracy, and 10% on micro F1 scores. Conclusions: We show that learned weights from our shared model can be effectively transferred to a new partially matched data set, validating the use of transfer learning for clinical text modifiersComment: 18 pages, 2 figures, 6 tables. To be submitted to the Journal of Biomedical Semantic

Restrictions impeding web-based courses: a survey of publishers' variation in authorising access to high quality on-line literature

BACKGROUND: Web-based delivery of educational programmes is becoming increasingly popular and is expected to expand, especially in medicine. The successful implementation of these programmes is reliant on their ability to provide access to web based materials, including high quality published work. Publishers' responses to requests to access health literature in the context of developing an electronic Master's degree course are described. METHODS: Two different permission requests were submitted to publishers. The first was to store an electronic version of a journal article, to which we subscribe, on a secure password protected server. The second was to reproduce extracts of published material on password protected web pages and CD Rom. RESULTS: Eight of 16 publishers were willing to grant permission to store electronic versions of articles without levying charges additional to the subscription. Twenty of 35 publishers gave permission to reproduce extracts of published work at no fee. Publishers' responses were highly variable to the requests for access to published material. This may be influenced by vague terminology within the 'fair dealing' provision in the copyright legislation, which seems to leave it open to individual interpretation. Considerable resource costs were incurred by the exercise. Time expended included those incurred by us: research to identify informed representatives within the publishing organisation, request 'chase-ups' and alternative examples being sought if publishers were uncooperative; and the publisher when dealing with numerous permission requests. Financial costs were also incurred by both parties through additional staffing and paperwork generated by the permission process, the latter including those purely borne by educators due to the necessary provision of photocopy 'course packs' when no suitably alternative material could be found if publishers were uncooperative. Finally we discuss the resultant bias in material towards readily available electronic resources as a result of publisher's uncooperative stance and encourage initiatives that aim to improve open electronic access. CONCLUSIONS: The permission request process has been expensive and has resulted in reduced access for students to the relevant literature. Variations in the responses from publishers suggest that for educational purposes common policies could be agreed and unnecessary restrictions removed in the future

Evidence of the Generation of Isosaccharinic Acids and Their Subsequent Degradation by Local Microbial Consortia within Hyper-Alkaline Contaminated Soils, with Relevance to Intermediate Level Radioactive Waste Disposal

The contamination of surface environments with hydroxide rich wastes leads to the formation of high pH (>11.0) soil profiles. One such site is a legacy lime works at Harpur Hill, Derbyshire where soil profile indicated in-situ pH values up to pH 12. Soil and porewater profiles around the site indicated clear evidence of the presence of the α and β stereoisomers of isosaccharinic acid (ISA) resulting from the anoxic, alkaline degradation of cellulosic material. ISAs are of particular interest with regards to the disposal of cellulosic materials contained within the intermediate level waste (ILW) inventory of the United Kingdom, where they may influence radionuclide mobility via complexation events occurring within a geological disposal facility (GDF) concept. The mixing of uncontaminated soils with the alkaline leachate of the site resulted in ISA generation, where the rate of generation in-situ is likely to be dependent upon the prevailing temperature of the soil. Microbial consortia present in the uncontaminated soil were capable of surviving conditions imposed by the alkaline leachate and demonstrated the ability to utilise ISAs as a carbon source. Leachate-contaminated soil was sub-cultured in a cellulose degradation product driven microcosm operating at pH 11, the consortia present were capable of the degradation of ISAs and the generation of methane from the resultant H2/CO2 produced from fermentation processes. Following microbial community analysis, fermentation processes appear to be predominated by Clostridia from the genus Alkaliphilus sp, with methanogenesis being attributed to Methanobacterium and Methanomassiliicoccus sp. The study is the first to identify the generation of ISA within an anthropogenic environment and advocates the notion that microbial activity within an ILW-GDF is likely to influence the impact of ISAs upon radionuclide migration

Rab3D is critical for secretory granule maturation in PC12 cells.

Neuropeptide- and hormone-containing secretory granules (SGs) are synthesized at the trans-Golgi network (TGN) as immature secretory granules (ISGs) and complete their maturation in the F-actin-rich cell cortex. This maturation process is characterized by acidification-dependent processing of cargo proteins, condensation of the SG matrix and removal of membrane and proteins not destined to mature secretory granules (MSGs). Here we addressed a potential role of Rab3 isoforms in these maturation steps by expressing their nucleotide-binding deficient mutants in PC12 cells. Our data show that the presence of Rab3D(N135I) decreases the restriction of maturing SGs to the F-actin-rich cell cortex, blocks the removal of the endoprotease furin from SGs and impedes the processing of the luminal SG protein secretogranin II. This strongly suggests that Rab3D is implicated in the subcellular localization and maturation of ISGs

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism