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Crop yield loss due to flooding is a threat to food security. Submergence-induced hypoxia in plants results in stabilization of group VII ETHYLENE RESPONSE FACTORs (ERF-VIIs), which aid survival under these adverse conditions. ERF-VII stability is controlled by the N-end rule pathway, which proposes that ERF-VII N-terminal cysteine oxidation in normoxia enables arginylation followed by proteasomal degradation. The PLANT CYSTEINE OXIDASEs (PCOs) have been identified as catalysts of this oxidation. ERF-VII stabilization in hypoxia presumably arises from reduced PCO activity. We directly demonstrate that PCO dioxygenase activity produces Cys-sulfinic acid at the N terminus of an ERF-VII peptide, which then undergoes efficient arginylation by an arginyl transferase (ATE1). This provides molecular evidence of N-terminal Cys-sulfinic acid formation and arginylation by N-end rule pathway components, and a substrate of ATE1 in plants. The PCOs and ATE1 may be viable intervention targets to stabilize N-end rule substrates, including ERF-VIIs, to enhance submergence tolerance in agriculture. The N-end rule pathway targets substrate proteins for proteasomal degradation. Here, White et al . show that Arabidopsis PLANT CYSTEINE OXIDASEs show dioxygenase activity producing Cys-sulfinic acid at the N-terminus of target proteins, which then act as direct substrates for arginyl transferase.

The goal of this study was to determine if depletion of glutathione (GSH) and inhibition of thioredoxin (Trx) reductase (TrxR) activity could enhance radiation responses in human breast cancer stem cells by a mechanism involving thiol-dependent oxidative stress. The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of xc– cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2-AAPA, a GSH-reductase inhibitor. Clonogenic survival, Matrigel assays, flow cytometry cancer stem cell assays (CD44+CD24–ESA+ or ALDH1) and human tumor xenograft models were used to determine the antitumor activity of drug and radiation combinations. Combined inhibition of GSH and Trx metabolism enhanced cancer cell clonogenic killing and radiation responses in human breast and pancreatic cancer cells via a mechanism that could be inhibited by N-acetylcysteine (NAC). Au, BSO and radiation also significantly decreased breast cancer cell migration and invasion in a thiol-dependent manner that could be inhibited by NAC. In addition, pretreating cells with Au sensitized breast cancer stem cell populations to radiation in vitro as determined by CD44+CD24–ESA+ or ALDH1. Combined administration of Au and BSO, given prior to irradiation, significantly increased the survival of mice with human breast cancer xenografts, and decreased the number of ALDH1+ cancer stem cells. These results indicate that combined inhibition of GSH- and Trx-dependent thiol metabolism using pharmacologically relevant agents can enhance responses of human breast cancer stem cells to radiation both in vitro and in vivo.

AimsCiclosporin is one of most used immunosuppressants in the Haematopoietic Stem Cell Transplant (HSCT) setting. It is used for, amongst other reasons, Graft versus Host Disease prophylaxis, and Omenn syndrome. Approximately 100 patients per year receive HSCTs in our unit for primary immunodeficiencies, haematological malignancies, and other conditions. Ciclosporin is a drug which requires knowledge of variable dosing, interactions, monitoring, and side effects, including Posterior Reversible Encephalopathy Syndrome (PRES), in order to ensure patient safety.In the year 2021-2022 14 incident reports were logged involving ciclosporin prescriptions. Junior doctors new to the unit routinely describe feeling underconfident in prescribing ciclosporin.We wanted to implement some measures to improve junior doctors’ knowledge and confidence in ciclosporin prescribing and therefore patient safety.MethodsWe asked 33 junior doctors who had worked on the BMT and Immunology wards over the last year to complete a questionnaire to give their retrospective views on their knowledge of, and confidence in, prescribing ciclosporin at the point when they joined the unit. We also asked them to suggest cost neutral improvements that could be made to support them in the early stages of the job.Additionally, we reviewed the incident reports from the preceding year and audited the prescribing practices from one month of electronic prescriptions, particularly surrounding dose changes, to identify trends and common errors that might not have been highlighted through the incident reporting process.ResultsThe majority of respondents reported never having prescribed ciclosporin prior to starting the post. Although a few had heard of PRES, the majority stated that they were ‘not confident’ in prescribing ciclosporin or managing PRES.Although there is a Joint Accreditation Committee ISCT Europe and EBMT (JACIE) guideline on ciclosporin prescribing and management of PRES, respondents felt that, as well as specific teaching on ciclosporin prescribing at induction, a crib sheet with a quick ‘how to’ guide would be a useful aid.We found that there were some specific areas of prescribing that doctors found more difficult, particularly swapping intravenous to enteral dosing, and making dose changes to maintain levels within the correct range.ConclusionWith input from the junior doctor team, we implemented several changes based on the above results.1) we created a single page crib sheet that has been stored on the intranet and displayed in the junior doctors’ office2) we wrote a teaching package, in conjunction with the ImmBMT pharmacy team, that would be available on the intranet and would also be delivered at induction3) we worked with the team behind the electronic prescribing portal to increase the usability and safety netting built in for ciclosporin prescribing. This included making percentage changes in doses trackable and highlighting relevant interactions with increased pop-ups.We hope that the interventions in place will increase junior doctor confidence and patient safety around ciclosporin prescribing. We will follow-up by reviewing the prescribing trends and incident reports in the period following their implementation.

Recently, perioperative care has gained attention for its ability to improve outcomes, reduce costs, and enhance patient satisfaction, especially when multidisciplinary support is involved. Despite these benefits, patient compliance remains low due to limited engagement in program design and practical barriers such as transportation, particularly for older adults. Co-designed digital health solutions offer a promising, scalable approach to delivering personalized, accessible perioperative care, with emerging evidence supporting their feasibility and effectiveness in patients who undergo joint replacement. The objectives of this study protocol are to outline the methods to address three study aims: (1) understand gaps and unmet needs, including knowledge, perceptions, barriers, and acceptability, during the perioperative patient journey of hip and knee arthroplasty; (2) co-create a novel patient-centric digital care pathway (DCP) that provides education and systematically captures patient-reported outcomes; and (3) evaluate the feasibility of implementation, appropriateness, and acceptability of the pathway when tested in patients undergoing nontraumatic hip and knee joint arthroplasty. This mixed methods co-design and implementation study will be conducted across 3 phases informed by the generative co-design framework for health care interventions. In phase 1 (predesign), patient interviews and journey mapping will be used to identify perioperative care gaps to be addressed in the DCP. In phase 2 (co-design), care gaps will be collaboratively framed, and iterative prototyping of the DCP will be conducted with consumer feedback and pilot testing. In phase 3 (evaluation), the feasibility of the DCP will be assessed using a previously reported framework. Inclusion criteria will vary across phases, focusing on people with lived experience or undergoing hip or knee joint replacement and relevant clinical or administrative staff. The study was funded in September 2024, with phase 1 commencing in July 2025 and phase 2 in October 2025. Phase 3 is projected to commence before the end of 2025 and conclude 6 months later. As of October 2025, 13 people had been recruited, interviews were completed for phase 1, and recruitment for phase 2 had commenced. This protocol enhances methodological transparency by detailing the co-design approach, strengthening the evidence base, and supporting the development of a credible, transferable DCP. It addresses the lack of patient-centric perioperative programs in joint replacement care by incorporating individual needs and preferences. The digital format helps overcome access barriers, such as transport limitations, enabling patients to engage with the pathway anywhere. Additionally, patient-reported outcome measures collected through the DCP will improve understanding of recovery trajectories following hip and knee replacements. DERR1-10.2196/85701.

Resting-state functional magnetic resonance imaging (rsfMRI) is widely used to study brain-wide functional connectivity (FC). However, the resulting signals are highly noise sensitive, and the best strategies for mitigating this noise remains unclear. In 358 healthy individuals, we compared 60 multi-echo (ME) and 30 single-echo (SE) rsfMRI preprocessing pipelines across six measures of data quality and associated effect sizes in FC-based prediction models of personality and cognition (cross-validated kernel ridge regression). ME pipelines generally outperformed SE pipelines, but no single pipeline excelled at both denoising and behavioral prediction. Using a heuristic scheme to rank pipelines across benchmarks, ME optimum combination (OC) with ME independent component analysis (ICA), ICA-FMRIB’s ICA-based Xnoiseifier (FIX), and with head motion, cerebrospinal fluid, and white matter and gray matter signal regression, performed best when only considering denoising efficacy metrics. ME OC with ICA-FIX and head motion parameter regression performed best when only considering behavioral prediction results. ME OC with Automatic Removal of Motion Artifacts (AROMA) ICA, head motion parameter regression and Regressor Interpolation at Progressive Time Delays (RIPTiDe) performed best when aggregating across all evaluation metrics. These results favor ME acquisitions but show that no single denoising pipeline should be considered optimal for all purposes.

BackgroundIt is routine practice to perform therapeutic drug monitoring for drugs with a narrow therapeutic window, such as ciclosporin. Ciclosporin is regularly used for children undergoing haematopoietic stem cell transplant (HSCT) to prevent post-transplant complications.1 Patients undergoing HSCT are at high risk of life-threatening fungal infections warranting the regular use of azole antifungals, which interact with ciclosporin. Azole antifungals, such as posaconazole, have been less studied in children under 2 years of age, and little is known about their degree of interaction with ciclosporin, exposing patients to toxicity or treatment failure. Ciclosporin is highly protein-bound (e.g. to albumin and haematocrit) and changes in serum creatinine were known to affect ciclosporin clearance.The plasma drug concentrations help to describe the drug’s exposure and other pharmacokinetic properties, which can be utilised to devise specific dosing for that individual. However, the individual results obtained cannot be generalised to inform the treatment of other children within that cohort. A pharmacokinetic model is a statistical approach that allows all therapeutic drug monitoring levels to be studied as a cohort, enabling factors that affect drug handling to be incorporated into the statistical model, providing tailored dosing for that specific cohort of patients. We have developed a model to describe the pharmacokinetic properties of ciclosporin, quantify its interaction with posaconazole using a pharmacokinetic model, and simulate dosing regimens.MethodAll children who received ciclosporin related to HSCT between 15th April 2019 and 1st June 2023 and had more than one ciclosporin level taken were included in the study. Patient demographics (age, weight, sex), treatment details (dose and dosing times of ciclosporin and posaconazole, days after HSCT), and laboratory results (ciclosporin plasma levels, creatinine, haematocrit, albumin) were recorded. Ciclosporin levels were measured using tandem mass spectrometry. Population pharmacokinetic modelling and simulation were undertaken using the first-order conditional estimation method with interaction (FOCEI) in NONMEM version 7.5.1. The study was approved by the London and Southeast Research Ethics Committee under reference no. 21/LO/0646.Results3104 ciclosporin plasma levels were measured in 217 children (aged 6 weeks to 20 years old). 1200 measurements were without co-administered azole antifungals, 1248 levels with co-administered itraconazole, 396 with posaconazole, and 260 with voriconazole. The estimated pharmacokinetic parameters for ciclosporin are clearance = 46.3 (L/h/70 kg), volume of distribution = 4150L/70 kg and bioavailability = 40%. Creatinine, haematocrit, and CYP3A4 maturation were factors that affected ciclosporin pharmacokinetic properties and were included in the model.Posaconazole was estimated to reduce the clearance of ciclosporin by 15%. Dosing simulations were carried out to demonstrate the effect of different dosing regimens to establish more effective ciclosporin doses for children.ConclusionPharmacokinetic modelling is a powerful tool for better understanding therapeutic drug monitoring data. Here we illustrate the patient safety potential of using this approach in a cohort of patients where drug-drug interaction can be quantified and may have critical implications for patient outcomes. Simulations based on the pharmacokinetic models can be used for drug dose adjustment, thereby personalising dosing for children.ReferenceCarreras E, Dufour C, Mohty M, Kröger N. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. Ch 26 p219-227.

Pregnancy is a time of profound upheaval of the self, when in addition to undergoing dramatic physical changes to accommodate a developing foetus, significant cognitive and social transformations occur in preparation for birth and parenthood. So far, research into cognitive constructions of the self has been either infant-centric or psychopathology-focused, so our understanding of the healthy, changing self in pregnancy remains relatively poor. This online experiment uses online questionnaires and two cognitive tasks to investigate how constructs relating to the mental self-model, including body representation, self-concept clarity, sense of agency , general self-efficacy and self-attribute learning, differ between first-time pregnant ( n  = 100) and never-been pregnant ( n  = 102) women. Results indicate that first-time pregnancy is associated with a significantly higher sense of body agency, body visibility, and body estrangement. Poorer accuracy for newly learned associations was also observed in the pregnant group. Whilst a typical self-processing bias was observed in both groups as expected, an intentional binding effect was absent. Notably, post-hoc exploratory analyses provide initial evidence for trimester effects, with a decisively higher self-reported sense of negative agency in the first trimester compared to the never-pregnant group and other trimesters. Further, body agency and self-efficacy were higher in the second-trimester group compared to the never-pregnant group, suggesting a period of relative recovery and consolidation of the new self. Taken together, our results suggest that aspects of self-representation and agency undergo significant shifts over the course of pregnancy and provide multiple exciting avenues for future research.

[...]an attorney-trustee may be held to significantly lower ethical standards than she would be if she were acting only in her professional capacity as a lawyer. 14 Sara and T. Frederik Marsman (Cappy) \"lived well and entertained frequently\" during their marriage, residing together in their home in Wellesley from 1956 until Sara's death in 1971.15 Cappy was an expert horseman who worked as a riding director and instructor at a local school.16 Wealthy from her first marriage, Sara managed the couple's financial affairs and treated Cappy as the \"Lord of the Manor,\" giving him money for lavish personal expenses.17 Sara also had a daughter, Sally Marsman Marlette, from her prior marriage.18 Before her death, Sara worked with Farr to draw up her will and two testamentary trusts.19 In the will, she gave Cappy a life estate in the \"household furnishings\" of the Wellesley house, with the remainder to Sally.20 Additionally, Sara created one trust to provide Cappy with \"reasonable maintenance, comfort[,] and support\" after her death.21 Sara structured the trust so that one third of her estate would be entrusted to a designated trustee who would use that principal to pay Cappy in amounts the trustee \"deem[ed] advisable for [Cappy's] comfortable support and maintenance. [...]Section IV proposes and defends two amendments to the UTC's current rules on exculpatory clauses. \"36 The property held in trust is the trust property.37 One who creates a trust is a settlor, one who holds property in trust is a trustee, and one for whose benefit property is held in trust is a beneficiary.38 A trustee may be an individual or an entity such as a corporation, partnership, or unincorporated association, and does not require confirmation by a court.39 A corporation, private trust company, or individual who makes a repeat practice of serving as a trustee is often known as a professional trustee.40 Professional trustees typically charge a fee, and settlors rely on professional trustees because of their reputations for \"loyalty and skill\" or their representations that they are \"experts at managing trust assets and effectuating settlors' long-term objectives.

From jazz clubs to cheese plates, the term curation has become a signifier of the growing need to organise and prioritise the seemingly endless possibilities of the digital sphere. The issue addressed here is in the associated meanings of the word curation and what it means to be a curator by examining the experience of the curatorial within a discrete context: the Irish curatorial landscape. The word curation comes from the Latin curare, to care for, and has long been associated with the professional duties of those selected as custodians for objects and knowledge deemed to be important to communities, nations, countries or even the world. However, as objects move from being purely physical to the digital, and knowledge changes from being transmitted through similarly physical media to digital formats that can be set free on the Web, what it means to curate has also changed. Curators are no longer necessarily identified as employed within museums or galleries; the word is now also applied to those who engage with and aid in the management and presentation of digital assets online. Curators have emerged in the online space much like their forerunners, bloggers or citizen journalists. We are now seeing the rise of citizen curators on the Web, which has not created these individually motivated curators, but has made their curatorial activities visible. Citizen journalists no longer need to have a printing press or publishing house to communicate with their audience; similarly, citizen curators do not need a private cabinet of curiosities or a job in a museum to allow them to curate or exhibit to an audience. The aims of this research are threefold: to examine the current terminology related to curation by those who identify as curators or engage in curation in Ireland; to define what it means to be a curator or a citizen curator within the Irish context; and to investigate the changing nature of exhibition spaces contained in the Irish context in light of the Web and digital spaces. The study will take the form of an autoethnography, exploiting my unique position within the museum and open knowledge community in Ireland to examine current understandings of curation and the phenomenon of the citizen curator. The focus will be on my work within Wikimedia Community Ireland (WCI), a branch of the Wikimedia Foundation which promotes the use of Wikipedia in Ireland in education, culture, and open knowledge. As an autoethnographer, I can act as an intermediary, part way between those working in cultural organisations and the public involved in knowledge building projects. The study will look at how those engaged in curation articulate the work they do by means of interviews and participant observation. These sources will allow for the development of a spectrum of curatorial practice. The spectrum will arise from the participants’ (both citizen curators and those working in Irish cultural institutions) own understanding and definitions of curation and what it means to curate. In placing these definitions of curation within a spectrum that takes in broader understandings of curatorial practice, the newer forms of digital curation, and a picture of how the citizen curator relates to these methods, will emerge. The disruptive effect which the digital, and in particular the concept of the Long Tail, has brought to bear upon understanding of the assembling, storing, and using of collections will be examined. It will answer many of the issues surrounding the discipline-specific definitions of curation and the curator while informing their relationship with each other. By drawing out curation into a spectrum, what unfolds is the movement of curation from a traditional and closed system of learnt practices, to one which is formed around more open and accessible conventions of curation. In identifying the citizen curator, their role in the larger curatorial debate can be acknowledged and better incorporated into the multitude of online curated projects. This hinges on the emergence of the Do It With Others ethos which pervades both online and offline creative communities, and it redefines curation from a solitary practice, to one which is demarcated by its participatory nature.