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Targeting ERAP1 to disarm Gli activation in Sonic Hedgehog medulloblastoma
No full textThe Hedgehog (Hh) signaling pathway is a fundamental regulator of embryonic development, tissue patterning, and stem cell maintenance. The Hh pathway is activated by one of any three ligands: Sonic, Indian, or Desert Hh. Hh ligand binding to the receptor PTCH1, a 12-transmembrane cholesterol transporter, relieves PTCH1’s inhibition of SMO, a G protein-coupled receptor. Once active, SMO localizes to the primary cilium, where it promotes activation of the Gli transcription factors while preventing their proteasomal processing. Dysregulation of Hh signaling is implicated in several malignancies, most notably Sonic Hedgehog-type medulloblastoma (Shh-MB), the most common malignant pediatric brain tumor. In Shh-MB, loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO lead to constitutive activation of Gli transcription factors, locking cerebellar granule neuron progenitors in a proliferative state and preventing terminal differentiation. Despite the development of SMO inhibitors such as vismodegib and sonidegib, their use in children is contraindicated due to irreversible growth plate closure and skeletal toxicity. Moreover, resistance frequently emerges through mutations downstream of SMO, underscoring the need for alternative strategies that target the pathway at its terminal effectors
Do large language models know basic facts about journal articles?
No full textPurpose
There is an increase in the use of large language models (LLMs) in information science, including evaluating academic journal articles. Despite this, it is unclear whether they “know” about articles in the sense of being able to answer simple questions about individual papers without web searches.
Design/methodology/approach
In this study, 4 questions were asked of ChatGPT 4o-mini about 64,055 academic journal articles (excluding reviews) from 2021, identified by their titles and abstracts, with uncited and highly cited articles also assessed by ChatGPT 4.1 and 5 open weight LLMs.
Findings
The results were mostly incorrect, even for the most cited articles from that year. In particular, ChatGPT 4o-mini and the open weights LLMs had almost no knowledge of an article’s first author affiliation, rarely knew the publishing journal and usually guessed the publication year wrong, although ChatGPT 4o-mini was 42% correct for Physical Review B. Even ChatGPT 4.1 could only identify a small majority of the journals for the top cited papers of the year.
Practical implications
Smaller LLMs’ lack of basic knowledge about articles suggests that when they are asked to evaluate them without web searches, they will rarely cheat by eliciting citation information or journal reputation but will instead answer based on the article text because they may not associate online criticisms with individual articles.
Originality/value
This is the first investigation of the ability of LLMs to recall basic facts about journal articles
European media freedom act: can it stop the democratic backsliding?
No full textThe introduction of the European Media Freedom Act was designed to protect media freedom across Europe at a time when it is under threat from autocratic states. Despite its introduction, however, there are a number of issues with the Act and concerns from civil society organisations that it will be unable to improve media freedom across Europe and, in some cases, it may actually weaken protections. This article examines specific Articles of the Act and emphasises how there are issues with the protections afforded to journalists/ism. In particular, the article focuses on: who is defined as a journalist; confidentiality of sources; protection of journalists against surveillance; and the role of Very Large Online Platforms (VLOPs) in the spread of mis/disinformation
Fracture properties, structural heterogeneity, and permeability in the Þeistareykir geothermal system, NE Iceland
No full textPermeability in the Þeistareykir geothermal system of Iceland is structurally controlled. Natural fracture networks are abundant in Þeistareykir and contribute significantly to fluid flow. Understanding which features enhance permeability and hydraulic conductivity, and how their properties interact with lithology and reservoir structure, is key to predicting reservoir behaviour. To address this, we utilise a range of borehole data to characterise natural fractures in terms of their occurrence, orientation, relative distribution, their relationship with the major lithological units and permeable flow zones in the subsurface. Results show systematic variations in fracture density, thickness, and distribution pattern across different lithologies and depths, with orientations ranging from NNW-SSE, N-S, NNE-SSW to NE-SW. Fractures exhibit the highest intensity in the deeper acidic intrusive units or coarser grained basalt with a predominant N-S-trend and bimodal dip distribution. However, permeability is controlled by a complex interplay of fracture geometry, openness and connectivity rather than simply high fracture abundance or a preferential set of fractures. Permeable feed zones show diverse structural expressions, ranging from high-density fracture clusters and large-aperture fractures to intensely fractured damage zones and multiple intersecting fracture sets. These findings demonstrate that the structural character of the potential fluid-flow channels is highly variable in Þeistareykir. The results of this study can be incorporated into fracture and flow models to enhance our understanding of the permeability distribution and fluid pathways in the Þeistareykir geothermal system
Cost-effectiveness of early surgical fixation versus cast immobilization for adults with a scaphoid waist fracture:five-year follow-up of the Scaphoid Waist Internal Fixation for Fractures Trial
No full textAIMS: The conclusion of the one-year analysis of the Scaphoid Waist Internal Fixation for Fractures Trial (SWIFFT) was that initial cast immobilization with surgical fixation for nonunion was the optimal treatment for patients with a fracture of the waist of the scaphoid. However, there remained significant uncertainty about the medium-term outcomes and how these could influence the patient's health-related quality of life (HRQoL), care requirements, and costs. The aim of this study was to explore how additional data from the five-year follow-up influenced the cost-effectiveness of the treatment of these fractures. METHODS: The analysis presents the patient-reported HRQoL, measured with the EuroQol five-dimension three-level health questionnaire, and the use of healthcare resources at five years after randomization, and considers which factors influenced the results. The original analytical model, in which the implications of the different forms of treatment throughout the patient's life were estimated, was also updated. RESULTS: Five years after randomization, most patients in both groups returned to the HRQoL level which is consistent with age-adjusted norms and did not require further healthcare. In contrast, those who continued to have clinically relevant adverse events at five years reported significantly worse HRQoL scores and greater care needs. It was also confirmed in the updated model that initial cast immobilization was the most cost-effective strategy, with a mean cost to the health system of £1,606 less per eligible patient compared with those who initially underwent surgery, an annual saving of £7.5 million. CONCLUSION: Most patients had no long-term impact from the injury regardless of the form of treatment. However, the few who had clinically defined adverse events at five years had poor HRQoL and greater care needs. The limited difference in these clinical outcomes between the two groups informed the findings of the decision model that, over the patient's lifetime, the small quality-adjusted life year gains for those who underwent surgery initially were not sufficient to justify the higher costs. These findings confirm that initial immobilization in a cast with fixation for nonunion is the optimal form of treatment for these patients
Tuning surface microtopography for optimum thermocompression bonding performance: structure, process parameters, and mechanisms on microfluidic chips
No full textThe widespread application of microfluidic chips in biomedicine, life sciences, and food safety has generated industrialization demands, making it necessary to address key challenges in production costs and scalability. This work proposes the fabrication of an innovative microstructure in microfluidic chips to enhance thermocompression bonding performance. Through simulation, the stress mitigation effect of the energy-gathering rib (ER) and the resulting microchannel deformation are analyzed. This analysis subsequently feeds a redesign of the initial reference microchannel structure, acting as a guide. Experimental validation follows to confirm the enhancement of bonding performance by the ER. Results demonstrate that compared to the initial microchannel, the new design increases bonding strength by 123 % and reduces microchannel deformation by 6–8.46 %. Further analysis reveals that bonding strength increases by 160 % in the pressure range of 0.6–1.56 MPa. Additionally, this work advances the general understanding of the bonding strength formation mechanism by clearly elucidating the evolutionary behavior of interfacial morphology at the bonded interface. The generated knowledge accelerates the commercialization of microfluidic chips by directly improving the economic efficiency and sustainability of the fabrication process
Detergent-Triggered Membrane Remodelling Monitored via Intramembrane Fluorescence Dequenching
No full textDetergent-induced membrane solubilization is important for several biotechnological applications including membrane protein isolation, cell lysis and virus inactivation. The thermodynamic details of the underlying process have been previously examined, but the mechanistic details remain largely underexplored owing in part to a lack of suitable technologies capable of assessing nanoscopic membrane disruption events. Key open questions include: how do detergents remodel the membrane structure at subsolubilizing concentrations? And what is the sequence of morphological transitions that lead up to solubilization? Here, we introduce a single-color assay based on the fluorescence dequenching of membrane-integrated fluorophores as a sensitive and generalizable tool to probe nanoscale membrane remodelling events induced by detergents. We demonstrate, using fluorescence spectroscopy and time-correlated single photon counting, that the widely used detergent Triton X-100 triggers substantial morphological changes at concentrations below its critical micellar concentration. Moreover, by taking advantage of single vesicle fluorescence lifetime imaging and scanning electron microscopy, we reveal that the swelling step involves a morphological transition from spherical vesicles to toroidal structures, providing direct evidence for detergent-driven membrane reorganization prior to solubilization. Our findings support and refine a multistep model of detergent-induced membrane solubilization, positioning fluorescence dequenching as a tool for detecting conformational intermediates. We show that the fluorescence dequenching approach performs robustly across multiple cyanine-based probes and experimental conditions and its nanoscale sensitivity provides a platform from which to interrogate membrane perturbations induced by a wide variety of molecular disruptors, including those with important biomedical significance
‘How Does Nothing Show Up When I'm in So Much Agony?’: A Qualitative Study Exploring Patient Experiences of Non‐Specific Abdominal Pain in Acute Surgical Care
No full textIntroduction
Non-specific abdominal pain is a common and diagnostically challenging presentation in acute care, yet little is known about patient experiences within this setting. This study explores the experiences of patients attending a surgical same-day emergency care (SDEC) unit with non-specific abdominal pain.
Design
Qualitative descriptive study using inductive thematic analysis.
Methods
23 adults (aged ≥ 18 years) presenting with acute non-specific abdominal pain to a surgical SDEC in England were purposively sampled. Semi-structured interviews were conducted at least 2 weeks after discharge and thematically analysed inductively, iteratively and collaboratively by a team of psychiatrists, surgeons and a lived experience co-researcher.
Results
Three themes were identified: (1) The journey to the SDEC—participants described uncertainty and fear about potential diagnoses and varied thresholds for help-seeking, (2) The consultation—while many appreciated rapid access to care, experiences of communication and explanation were mixed, with some feeling dismissed or confused by the absence of a clear diagnosis, and (3) Post-consultation reflections—some felt reassured by normal test results, while others struggled with persistent symptoms, a lack of follow-up, and ongoing uncertainty. Discussions around psychosocial factors were rare.
Conclusions
Acute non-specific abdominal pain can be distressing for patients, even after attending acute surgical services, particularly when communication is perceived to be unclear and follow-up is inconsistent. A more structured, patient-centred approach, including standardised follow-up, clear explanations and sensitivity to psychosocial factors, could improve experiences and possibly outcomes for this group.
Patient and Public Contribution
A patient and public involvement and engagement (PPIE) group, comprising individuals with lived and living experience of persistent physical symptoms, shaped the scope and design of the research and co-produced the interview topic guide. A lived experience representative was actively involved in data analysis, interpretation and manuscript preparation
Escaping the Capitalist Black Hole: dethroning Mammon and liberating water
No full textColonial legacies and neoliberal capitalism continue to underpin and intensify global water insecurity. Drawing on five years of research from the UK-funded Water Security and Sustainable Development Hub across Colombia, Ethiopia, India and Malaysia, this Research Note identifies consistent patterns of water dispossession linked to capital accumulation. Despite divergent local contexts, our findings point to a common dynamic: a ‘Capitalist Black Hole’ that draws water towards profit-driven activities through the actions of both global and local elites. We conceptualise this black hole not as a neutral or natural system but as one animated by ideology and agency. We use this metaphor to illuminate how entrenched systems of greed and wealth accumulation – what we term the throne of Mammon, the symbolic ‘ruler’ of this black hole – operate through Western-centric political and ideological frameworks that commodify water, prioritise growth and capital over equity and nature, and marginalise alternative knowledges. Here, ‘Mammon’ personifies the worship of capital and the moral–cultural logic that sustains the black hole’s gravitational pull. We argue that under current geopolitical and economic conditions, existing institutional structures are structurally inadequate to achieve just and sustainable water futures. Transformative responses must directly confront the deep-rooted power structures that govern global water security
Ultrasonic resonance approach to measure rolling element bearing raceway films in-situ: A practical approach
No full textThe lubricant film adhering to a bearing raceway is the primary contributor to developing an adequate inlet meniscus to avoid starvation and thus premature wear. This paper shows that lubricant films adhering to the raceways of rolling element bearings are measurable via an in-situ ultrasonic resonance technique, that is applicable to fully metallic bearings. This work first validates the measurement of free-surface oil films on bearing steel using the ultrasonic resonance method before applying to a fully metallic, cylindrical roller bearing. Practical considerations are discussed to optimise the measurement range and accuracy, and limitations are highlighted. Quantifying a dynamic raceway film into single thickness measurements is discussed, and two oils with a magnitude difference in viscosity are compared