Small punch test size reduction to enable high flux irradiation

Screening and qualification of new nuclear materials with superior irradiation resistance requires expensive irradiation exposure and post-irradiation examination before consideration into industrial nuclear structural components. The development of miniaturized test methods is needed for enhanced cost/time efficient testing, while enabling comparative and robust material property estimation in a timely and high throughput manner. The Small Punch Test (SPT) is drawing much interest, especially since the publication of an European standard. Motivated by this standard, a new SP test sample geometry is proposed in order to reduce the material volume to be tested, hences increasing the number of samples that can be introduced in an irradiation rig is proposed. The modified sample diameter has been reduced from 8 to 5.35 mm. The qualification of this new design is described here together with a detailed description of the SPT setup modification as compared to the reference setup of the EN standard. Finite element analyses and a series of experiments have been conducted using both standard and reduced size SP samples to demonstrate that the modified test gives estimates of the basic mechanical properties with the same magnitude of error and validates the modified sample geometry for usage in irradiated material testing

Experiencing MOOCs in English: A proficiency-based perspective

Massive Open Online Courses (MOOCs) were initially designed to democratize education by providing free, flexible learning opportunities to a broad audience. However, this promise remains largely unmet, as reflected in high dropout rates (Crossley et al., 2016; Goopio & Cheung, 2021). Contributing factors include limited feedback, scarce participant interaction, and unclear instructions (Topali et al., 2020; Liu, 2017). Another significant, yet underexplored, obstacle is the language of instruction: approximately 75% of MOOCs are offered in English, despite most learners being non-native English speakers (Weinhardt & Sitzmann, 2019; Uchidiuno et al., 2018). Language and cultural barriers – such as difficulties processing video content without visual aids and low confidence in language proficiency – can hinder engagement and learning outcomes (Duru et al., 2019; Liyanagunawardena et al., 2013). Therefore, understanding non-native English speakers’ experiences is essential to enhance the inclusivity and effectiveness of English-taught MOOCs. However, existing research mainly examines language-learning MOOCs (LMOOCs) (e.g. “Conversational English Skills”) rather than disciplinary MOOCs (e.g. “Data Science” or “International Law”) (Uchidiuno et al., 2018; Hsu, 2023). Moreover, they rarely differentiate between learners at different English proficiency levels, despite evidence from English-Medium Instruction (EMI) indicating that proficiency shapes participant engagement and success (Evans & Morrison, 2018). Against this backdrop, this study investigates the experiences of non-native participants enrolled in disciplinary MOOCs taught in English (henceforth ‘English MOOCs’), based on their self-assessed proficiency level (B1, B2, C1, C2). The study focuses on three key dimensions: motivations for enrolling, attitudes toward MOOCs and themselves, and challenges encountered. Data were collected via a survey combining 7-point Likert scale items (e.g. “I take MOOCs in English to improve my English skills”) and open-ended questions (e.g. “Are there other reasons for you to take MOOCs in English?”). The survey also gathers demographic information, prior MOOC experience, and self-assessed English proficiency. A pilot study with 87 participants recruited through Prolific (Jadoulle et al., forthcoming) revealed preliminary trends. For example, the absence of equivalent courses in other languages appeared as a primary motivator to enroll in an English MOOC. Participants generally perceived these MOOCs as high-quality and prestigious, and report limited difficulties in comprehension or expression. However, analysis by proficiency revealed nuanced differences. For example, B2-level participants were more likely than C2-level participants to pursue MOOCs to enhance their English proficiency, and report using language support tools (e.g. dictionaries, DeepL) more frequently. While these preliminary results offer valuable insights into non-native speakers’ experiences in English MOOCs, the relatively small, non-representative sample limits generalizability. Therefore, an ongoing larger-scale study employs the same survey on Qualtrics, targeting approximately 600 non-native English speakers from seven countries (China, Morocco, Japan, Spain, Poland, Brazil, Indonesia) who completed an English MOOC within the last two years. If findings confirm pilot trends, they would underscore the heterogeneity of MOOC participants, and challenge the tendency to treat non-native English speakers as a monolithic group. Recognizing proficiency-level differences would then reveal critical to developing more inclusive MOOCs, by adapting, for example, materials, instructions, or support tools to learners’ specific linguistic needs. Crossley, S., Paquette, L., Dascalu, M., McNamara, D. & Baker, R. (2016). Combining click-stream data with NLP tools to better understand MOOC completion. Proceedings of the Sixth International Conference on Learning Analytics & Knowledge, New York, 6-14. Duru, I., Sunar, A.S., White, S., Diri, B. & Dogan, G. (2019). A case study on English as a Second Language speakers for sustainable MOOC study. Sustainability, 11(10), 2808. Evans, S. & Morrison, B. (2018). Adjusting to higher education in Hong Kong: The influence of school medium of instruction. International Journal of Bilingual Education and Bilingualism, 21(8), 1016-1029. Goopio, J. & Cheung, C. (2021). The MOOC dropout phenomenon and retention strategies. Journal of Teaching in Travel & Tourism, 21(2). Hsu, L. (2023). What makes good LMOOCs for EFL learners? Learners’ personal characteristics and information system success model. Computer Assisted Language Learning, 36(1-2), 1-25. Jadoulle, P., Dubois, T., Degrave, P. & Paquot, M. (forthcoming). Developing a survey on motivations, attitudes, and challenges of non-native participants in English-taught MOOCs. Proceedings of the Twentieth European Conference on Technology Enhanced Learning, Newcastle and Durham. Liu, L. (2017). An empirical analysis of Chinese college learners’ obstacles to MOOC learning in an English context. English Language Teaching, 10(3), 136-150. Liyanagunawardena, T., Williams, S. & Adams, A. (2023). The impact and reach of MOOCs: a developing countries’ perspective. eLearning Papers, 33. Topali, P., Ortega‐Arranz, A., Martínez‐Monés, A. & Villagrá‐Sobrino, S. (2020). “Houston, we have a problem”: Revealing MOOC practitioners’ experiences regarding feedback provision to learners facing difficulties. Computer Applications in Engineering Education, 29(4), 769-785. Uchidiuno, J., Ogan, A., Yarzebinski, E. & Hammer, J. (2018). Understanding ESL students’ motivations to increase MOOC accessibility. Proceedings of the Third (2016) ACM Conference on Learning @ Scale, New York, 169-172. Weinhardt, J. & Sitzmann, T. §2019). Revolutionizing training and education? Three questions regarding massive open online courses (MOOCs). Human Resource Management Review, 29(2), 218-225

Innovative molecules and delivery technologies enabling the future of GLP-1-based therapies.

The multiple physiological effects of gut hormones in different metabolic tissues make them attractive therapeutic targets for the treatment of metabolic diseases. Currently, only GLP-1 receptor-based agonists and oral DPP-4 inhibitors are available on the market. Despite their positive clinical outcomes across a range of indications these treatments present several clinical challenges, including high costs, the need for peptide injections, and requirements for repeated administration. These limitations have driven research into improved GLP-1-based therapies, such as oral small-molecule agonists and novel drug delivery strategies based on emerging GLP-1 medicines. This article describes the challenges in clinical application and development of GLP-1-based pharmacotherapies. We review the development of oral small-molecule agonists and various drug delivery technologies, including ultralong-acting injectable technologies, continuous-acting implantable pumps, smart-acting electronic devices, nutrient-induced cell therapies, and noninvasive delivery systems. We discuss the current state of research, challenges to overcome, and opportunities to improve patient compliance and clinical outcomes. Additionally, we explore how endocrinological effects and patient-oriented needs can guide the development of advanced GLP-1 medicines

Le climat et la sagesse humaine

Editoria

KIF2A downregulation links amyloid-β to Tau phosphorylation in Alzheimer's disease

Microtubules (MT) are essential components of the cytoskeleton. Dysfunctions of MT and MT-associated proteins are prominent features of neurodegenerative disorders. In Alzheimer's disease (AD), changes in MT composition and hyperphosphorylation of Tau are more closely related to neurodegeneration than amyloid plaque formation. However, the accumulation of amyloid beta (Aβ) species is the earliest event in AD pathology and induces Tau toxicity. KIF2A is a microtubule depolarizing kinesin with important roles during cortical development. KIF2A expression is maintained in the mature brain, where it is required for neuronal survival. Here, we used a conditional approach to ablate KIF2A specifically in the adult mouse cortex and hippocampus to assess the impact of KIF2A deletion on neuronal survival and Tau phosphorylation. We found that KIF2A deficiency leads to a reduction of dendritic spine density and maturation associated with cognitive decline, followed by an increase in Tau phosphorylation through ERK1/2 activation. We also studied KIF2A expression in 5xFAD mouse model and post-mortem human brain tissue. We report that Aβ accumulation alters KIF2A expression in neurons and most importantly, KIF2A protein levels are drastically reduced in AD patients but not in patients with other primary Tauopathies. Our results shed light on the relationship between Aβ accumulation, KIF2A deregulation, microtubule dysfunction, and enhanced Tau phosphorylation in the context of AD. Keywords: Alzheimer’s disease; microtubules; neurodegeneration; tau phosphorylation

Multivariate threshold exceedances and extremal graphical models in the presence of multiple extreme directions

Consider a random vector representing risk factors, and suppose that we are interested in extreme scenarios. The threshold exceedances method is widely used in extreme value theory. It uses the fact that, asymptotically, exceedances over a high threshold can be modeled using a multivariate generalized Pareto distribution. In the literature, statistical practice of this method has been discussed only when all risks are large simultaneously. This condition is not realistic, for example, when some of the risks are nearly independent. To address this limitation, we first develop a parametric model that accommodates cases where only some risk factors are extreme, while others remain moderate. We introduce the concept of extreme directions to describe these cases, and prove that our construction encompasses the full range of possible max-stable dependence structures. Second, we propose an estimation procedure for this model, leading to an algorithm capable of identifying extreme directions. Third, we extend the framework of extremal graphical models by incorporating both multiple extreme directions and extremal independence, offering a more flexible and realistic approach to modeling extreme events. Finally, we apply our developed methods to two real-world datasets: first, to discharge measurements at stations along the Danube River, and second, to financial portfolio losses from stocks listed on the NYSE, AMEX, and NASDAQ.(SC - Sciences) -- UCL, 202

Sacituzumab govitecan: a new hope for patients with pretreated extensive small-cell lung cancer (SCLC)—insights from the TROPiCS-03 trial

Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is associated with a poor prognosis (1). While immunotherapies and targeted therapies have transformed the treatment of non-small-cell lung cancer (NSCLC) (2,3), little progress has been made in the treatment of extensive SCLC over the past three decades, with platinum-etoposide regimens still remaining the cornerstone of treatment (4,5). Over the past few years, the addition of immune checkpoint inhibitors (ICIs) to first-line platinum-etoposide chemotherapy showed a modest but significant improvement in overall survival (OS) (6,7). Despite SCLC’s initial strong response to chemotherapy, most patients experience relapse within six months. Second-line treatment is determined by the treatment-free interval (TFI) and the response to first-line platinum-based chemotherapy (4,5). Platinum-etoposide rechallenge is recommended for platinum-sensitive SCLC (TFI ≥3 months), as it yields a high objective response rate (ORR) of 49% and is associated with better clinical outcomes compared to alternative chemotherapy regimens (8). In contrast, for platinum-refractory (progression during platinum chemotherapy) or platinum-resistant disease (TFI <3 months), outcomes are poor, with second-line chemotherapy achieving a very low ORR of approximately 15% (5). Topotecan, a topoisomerase I inhibitor, remains one of the standard treatments in this setting, having demonstrated improved OS compared to best supportive care (9). However, its clinical use is often limited due to frequent and severe hematological toxicities, along with a modest clinical benefit (10). The anthracycline-based regimen cyclophosphamide-adriamycin-vincristine (CAV) showed similar efficacy to topotecan in a phase III randomized trial (11). In 2020, lurbinectedin demonstrated an ORR of 22.2% in second-line treatment of platinum-resistant SCLC (12), but its combination with doxorubicin failed to improve OS compared to topotecan (13)