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NCBP1 stress signaling drives alternative S6K1 splicing inhibiting translation
Get PDFSubcellular stress profoundly influences protein synthesis. However, both the nature of spatiotemporally restricted chemical cues and local protein responders to these cues remain elusive. Unlocking these mechanisms requires the ability to functionally map in living systems locale-specific stress-responder proteins and interrogate how chemical modification of each responder impacts proteome synthesis. We resolved this problem by integrating precision localized electrophile generation and genetic code expansion tools. Upon examination of four distinct subcellular locales, only nuclear-targeted electrophile stress stalled translation. We discovered that NCBP1—a nuclearresident protein with multifaceted roles in eukaryotic mRNA-biogenesis—propagated this nuclear stress signal through a single cysteine (C436) from among its 19 conserved cysteines. This NCBP1(C436)-specific modification elicited alternative splicing of >250 genes. Mechanistically, global protein-synthesis stall was choreographed by impaired association between electrophile-modified NCBP1(C436) and SF3A1, an essential component of spliceosome, triggering the production of alternatively-spliced S6-kinase, whose expression was sufficient to dominantly inhibit protein translation
Deriving evolutionary-informed biomarkers and treatment schedules for drug-resistant cancer
No full textStandard-of-care cancer treatment regimens fail when applied to metastaticcancers due to the inevitable emergence of drug resistance, leading to treatmentfailure and disease progression. This thesis presents a comprehensive mathematicalframework for optimising adaptive therapy (AT) protocols – an evolution-basedtreatment paradigm that dynamically adjusts treatment to control, rather thanminimise, tumour burden by exploiting inter-cellular competition.Using mathematical models calibrated to prostate cancer dynamics, I considerboth analytic and machine learning (ML) approaches to deriving optimal ATstrategies. Extracting interpretable treatment strategies from the ‘black-box’ MLframework, I demonstrate that these match the analytically optimal solution, andpropose a translational pathway to bridge the gap between ML models and clinicalimplementation. This work extends prior AT protocols by accounting for clinicalconstraints such as the discrete time intervals between appointments. Consideringthese clinical realities reveals a fundamental trade-off between tumour monitoringfrequency and possible time to progression.Prior clinical trials have identified significant heterogeneity in patients’ responsesto AT. Through a comparison of different mathematical tumour models, Iidentify distinct patient subpopulations requiring qualitatively different treatmentapproaches, including a subset that benefits from novel protocols with time-varyingthresholds. I further develop a set of predictive mathematical biomarkers to predictpatients’ time to progression and mean daily dose across various AT protocols,and integrate these into a stratified-treatment framework to personalise the ATprotocol prescribed for each patient.Collectively, this work establishes a comprehensive mathematical foundationfor personalised adaptive cancer therapy, providing both theoretical insights intotumour-treatment dynamics and practical tools for clinical implementation. Theproposed frameworks address critical gaps in current adaptive treatment approacheswhilst maintaining clinical feasibility, offering a promising pathway towards moreeffective, evolution-informed cancer care
“Being “Wenzhounese” in Europe: intergenerational experiences and perceptions of education
Get PDFEducation is highly valued among Chinese immigrant families, with Chinese immigrant students often recognised for their strong academic achievements and labelled as ‘model minorities’. This success is frequently attributed to cultural factors associated with Confucianism, particularly 'tiger parenting' strategies that emphasise high expectations for academic excellence. However, according to Bourdieu (1985; 1986)’s capital theory and Lareau (2011) ’s concerted cultivation, class dynamics may also influence the divergent educational experiences and perceptions of these families.Most research on Asian and Chinese immigrant education has focused on North America, leaving European contexts, especially the European Wenzhou community, relatively underexplored. Therefore, this study employs a qualitative intergenerational approach to investigate the educational philosophies, experiences, and practices of Wenzhou European immigrant families. Interviews and photo storytelling were conducted with nine families across five countries: Italy, France, Spain, Portugal, and Hungary.The findings show that these Wenzhou European immigrant families adopt a relaxed educational approach, shaped by factors such as a lack of mainstream cultural and social capital, the availability of alternative success paths through family entrepreneurship, busyness, faith, and the educational culture of the host countries. Second, educational experiences and practices in both formal and informal education are detailed. Regarding formal education, while strategy of sending children to international schools or studying abroad is commonly used, educational decisions also reflect student preferences. In terms of informal education, practices include a focus on language learning, extracurricular activities, and private tutoring are identified. Finally, the study identifies educational opportunities, such as a holistic developmental focus, more future opportunities in choices, and the ability to serve as cultural bridges, alongside challenges including cultural differences, racial discriminations, and limited parental involvement. This qualitative study enhances and adds depth to the existing literature by investigating the distinct characteristics and specific educational experiences, perceptions, and practices of Wenzhou immigrants in Europe
Analysis of Phlebotomine sandflies in Laos from 2014–2024: Inventory, description of a new species, screening for Leishmania and detection of Trypanosoma
Get PDFIntroduction: Phlebotomine sandflies are the principal vectors of leishmaniasis. Laos is a landlocked country bordering Thailand, where autochthonous cases of leishmaniasis have been reported. However, the status of leishmaniases in Laos is unknown due to a lack of testing. In the past decades, very few studies on sandflies and sandfly-borne pathogens have been conducted in Laos. Therefore, the knowledge of sandfly diversity, distribution, and their related pathogens is lacking. We hypothesized that both known and putative sandfly-borne pathogens may silently circulate in Laos but remain undetected. Herein, we aimed to report species diversity data and Leishmania detection among sandflies collected from seven provinces of Laos. Methods: Sandflies were collected using CDC light traps from various habitats, including caves and peri-caves in karstic areas, domestic animal sheds, forests, and plantations, across seven provinces in northern Laos. Sandfly collections were conducted between 2014 and 2024 from different seasons. Sandflies were identified by morphological and molecular techniques. PCR targeting the ITS1 region was used to screen for Leishmania in the sandfly samples. Though a specific Trypanosoma PCR was not used, this PCR is also able to detect the ITS1 region in some Trypanosoma spp. Results: A total of 3,857 sandflies from 25 species belonging to five genera were collected and examined: Chinius eunicegalatiae, Idiophlebotomus longiforceps, Phlebotomus barguesae, Ph. breyi, Ph. (Adlerius) sp., Ph. kiangsuensis, Ph. mascomai, Ph. seowpohi, Ph. shadenae, Ph. sinxayarami, Ph. stantoni, Sergentomyia anodontis, Se. bailyi, Se. barraudi group, Se. brevicaulis, Se. dvoraki, Se. hivernus, Se. khawi, Se. perturbans, Se. phasukae, Se. sutherlandi n. sp., Se. sylvatica, Se. tambori, Se. gemmea-like (Se. sp 1) and Grassomyia indica. The highest diversity of sandflies was found in karstic areas where sandflies were collected from cave and peri-cave areas. One new sandfly species, Se. sutherlandi n. sp. is described. We also report for the first time in Southeast Asia a Phlebotomus female belonging to the subgenus Adlerius and we also discuss about the taxonomy of Sergentomyia brevicaulis. Although no Leishmania DNA was detected from screened sandflies, unknown Trypanosoma species were detected from 24 individual sandflies: Chinius eunicegalatiae (n = 22) and Idiophlebotomus longiforceps (n = 2) using a PCR assay that was primarily meant to screen for Leishmania. Conclusion: This study reveals a notable diversity of sandfly species across seven provinces in Laos, with the highest species richness observed in karstic cave environments. While no Leishmania DNA was detected, the unexpected identification of unknown Trypanosoma species in Chinius eunicegalatiae and Idiophlebotomus longiforceps suggests the potential presence of unrecognized trypanosomatid in the region. These findings underscore the need for broader geographic surveillance and increased sampling efforts to improve our understanding of sandfly ecology and the pathogens they may carry in Laos
A transformer-based survival model for prediction of all-cause mortality in patients with heart failure: a multi-cohort study
Get PDFHeart failure (HF) patients have complex health profiles that existing risk models fail to capture. We developed TRisk, a Transformer-based artificial intelligence survival model for predicting mortality using routine electronic health records (EHR) in HF patients. Using UK data from 403,534 HF patients across 1418 English general practices, we trained and validated TRisk and compared it against MAGGIC-EHR, the MAGGIC model adapted for use on routine EHR by substituting variables (e.g. left-ventricular ejection fraction) that are not routinely available. External validation was conducted on 21,767 patients from USA hospitals. In the UK cohort, TRisk achieved a concordance index (C-index): 0.845 (95% CI: 0.841, 0.849), outperforming MAGGIC-EHR (C-index: 0.728 [0.723, 0.733]) for 36-month mortality prediction. In subgroup analyses, TRisk demonstrated less variability in predictive performance by sex, age, and baseline characteristics compared to MAGGIC-EHR, suggesting less biased modelling. Evaluating TRisk in USA data via transfer learning yielded a C-index of 0.802 (0.789, 0.816). Explainability analysis revealed TRisk captured established risk factors while identifying underappreciated ones, particularly cancers and hepatic failure, with cancers maintaining prognostic utility even a decade before baseline. TRisk provides more accurate, well-calibrated mortality prediction using routine data across international healthcare settings, demonstrating potential for improved risk stratification in patients with HF
Cultural Competency in Research: A Practical Framework for Use by Researchers, Policymakers, Community Leads and Others When Working With People From Diverse Groups
Get PDFBackground: As researchers strive to conduct culturally competent and equitable research, there remains a lack of actionable guidance across the research lifecycle. Increasingly, funding bodies require evidence of such approaches, yet a clear, practical direction for effective research practice is often lacking. Aim: To develop a practical framework, grounded in Meleis' cultural competence criteria, to guide all stages of the research lifecycle. Methods: Databases PsycINFO, ERIC, PubMed, Web of Science Core Collection and Google Scholar were searched (August–October 2025) for English‐language publications applying Meleis' framework in research contexts. Narrative and thematic analysis synthesised identified applications into draft recommendations and measures across five research stages. A modified Delphi process with 31 experts (community leads, researchers, policymakers and translators) in two survey rounds and a consensus workshop was then used to refine and finalise items, producing a co‐developed framework of actionable, measurable recommendations for culturally competent research with minoritised and/or diverse groups. Results: The review identified eight studies, yielding 41 applications of Meleis' criteria. These were distilled into 29 draft recommendations and measures, which were further refined through Delphi consensus to 25 recommendations and 25 measures, offering practice‐ready guidance across research focus, recruitment, measurement, analysis and dissemination. Contextuality was rated critical in four stages, highlighting how cultural identities shape engagement. Language was strongly prioritised in focus, recruitment and measurement, with emphasis on diverse, well‐funded interpretation and transcription strategies. Empowerment and reciprocation were noted as underused but essential for legitimacy and impact, particularly in focus and dissemination. Continuous cultural humility training was endorsed, reinforcing critiques of competence as a static skill. During consensus discussions, recommendations initially framed as optional (‘could’) were reframed as compulsory (‘should’). The final framework is available as an accessible online resource. Conclusions: Using consensus, an evidence‐based, culturally competent research framework was co‐designed; it comprised 25 recommendations that are actionable, measurable and adaptable by researchers, policymakers, community leads and others. This framework represents a crucial step towards fostering equitable and impactful research practice. Patient or Public Contribution: A patient and public involvement group of three patients from minoritised backgrounds and two health professionals met twice to review findings, refine components and provide feedback on language, accessibility and usability
The customary prohibition of the mandatory death penalty in international law
Get PDFThe mandatory death penalty denotes the automatic imposition of capital punishment for certain predetermined offences, without regard for the circumstances of a crime, the personal conditions of the defendants, or the factual context of individual cases. Although the practice is highly controversial for its infringements upon the right to life and the right to a fair trial, it remains uncertain whether public international law contains a universal prohibition against it. This article argues that such a prohibition does exist, taking the form of customary international law. To substantiate this claim, the article provides a detailed analysis of state practice and other relevant evidence
Bridging Perspectives: A Survey on Cross-view Collaborative Intelligence with Egocentric-Exocentric Vision
Get PDFPerceiving the world from both egocentric (first-person) and exocentric (third-person) perspectives is fundamental to human cognition, enabling rich and complementary understanding of dynamic environments. In recent years, allowing the machines to leverage the synergistic potential of these dual perspectives has emerged as a compelling research direction in video understanding. In this survey, we provide a comprehensive review of video understanding from both exocentric and egocentric viewpoints. We first ground our review in key application domains, from healthcare to embodied intelligence, to establish the practical value of ego-exo collaboration. From the needs of these applications, we derive a set of core research tasks. We then systematically organize recent advancements into three primary research directions: (1) leveraging egocentric data to enhance exocentric understanding, (2) utilizing exocentric data to improve egocentric analysis, and (3) joint learning frameworks that unify both perspectives. We also provide a detailed overview of relevant datasets and conclude by discussing current limitations and promising future directions. By synthesizing insights from both perspectives, our goal is to inspire advancements in video understanding and artificial intelligence, bringing machines closer to perceiving the world in a human-like manner
Future directions in all-optical label-free single-molecule sensing
Get PDFThis perspective discusses the future role of all-optical label-free single-molecule sensing. After summarizing the core working principles of the different detection modalities we discuss future research directions in terms of technology development and applications. In terms of future technologies we address research directions in the areas of multi-parametric and interaction free sensors, integration and miniaturization, and advanced data analysis. We further describe potential applications towards probing of protein interactions, DNA and protein sequencing, and molecular diagnostics
Crossmodal counterpoint: from music to multimedia – incongruency, cognitive dissonance, irony, and surrealism
Get PDFLaboratory-based research on multisensory perception often presents participants with unpredictable combinations of auditory and visual stimuli that may be classed (by the experimenter) as either congruent or incongruent. Cognitive neuroscientists generally assume that congruent combinations of experimental stimuli will be processed more fluently and lead to enhanced crossmodal binding and multisensory integration than will incongruent combinations of stimuli. Typically, however, the participants involved in such laboratory research are given little if any information (or context) to explain why these seemingly random combinations of sensory stimuli are being presented. This situation differs markedly from the deliberate combination of eye and ear in an artistic context (say when music is added to film). In the latter case, conflict is sometimes introduced deliberately into a scene. A film director might, for example, choose to combine violent onscreen action with uplifting happy music. The presentation of such audiovisual emotional incongruency invites the viewer to reflect on what they are experiencing, and why this particular combination of stimuli has been chosen. Such crossmodal counterpoint (or cognitive dissonance) is sometimes used as a rhetorical device to introduce a note of irony. It is interesting to note how, in such cases, there is little sense of averaging the sensory inputs (or their emotional effects) as is so often seen when congruent inputs are presented in cognitive psychology studies. In this narrative historical review, we take a critical look at the concept of crossmodal counterpoint, and review the research and theorizing on its use