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Mixed-mobility supported lipid bilayers uncover the role of immobilized ICAM1 on T cell activation and immune synapse organization
Get PDFThe immunological synapse (IS) integrates antigen recognition and adhesion to control T cell activation and effector functions. Reductionist systems have been instrumental in dissecting IS organization, but conventional systems constrain all ligands to be either mobile or immobile, unlike antigen-presenting cells where intercellular adhesion molecule 1 (ICAM1) is cytoskeletally anchored while T cell receptor (TCR) ligands remain mobile. Here, we establish mixed-mobility supported lipid bilayers (SLBs) that simultaneously present mobile TCR agonists and immobile ICAM1. Selective immobilization of ICAM1 disrupts centripetal F-actin flow, prevents centralization of TCR microclusters and shifts signaling to peripheral microclusters. This attenuates TCR downregulation through ectocytosis while maintaining recycling, and enhances integrin mechanotransduction, reflected in increased phosphorylation of Focal Adhesion Kinase, Paxillin, and the stretch-sensitive adaptor CasL. Functionally, immobilized ICAM1 augments T cell activation, degranulation, Perforin release, and cytotoxicity. Importantly, these findings were recapitulated in a cell–cell system engineered to express either full-length, cytoskeleton-anchored ICAM1 or a truncated form lacking cytoskeletal association, with full-length ICAM1 consistently promoting stronger effector responses. These findings identify ligand mobility as a key biophysical parameter that shapes IS organization and T cell effector responses and establish mixed-mobility SLBs as a powerful tool for probing receptor mechanics in immunity
Gonococcal outer membrane vesicle vaccines: bacterial population biology, clinical trials, immune profiling, and vaccine design
Get PDFGonorrhoea is a global health concern exacerbated by rising antimicrobial resistance. Retrospective analyses indicate that outer membrane vesicle (OMV) vaccines derived from Neisseria meningitidis (MeNZB, 4CMenB) may offer partial cross-protection against gonococcal infection. This review outlines the influence of gonococcal population biology on coverage, immune responses elicited by 4CMenB, and emerging strategies that offer the prospect of rationally designed vaccines dedicated to the prevention of gonococcal disease
Persons of skill and matters of opinion: the making and rise of the expert witness in English common law 1763 – 1800: The making and rise of the expert witness in English common law, 1763 – 1800
Get PDFThis thesis challenges the accepted historiographical narrative regarding the origins of the partisan non-medical expert witness. While the expert witness is generally accepted to have been formalized by the courts in 1782, I instead reveal, by novelly turning to patent law beginning in 1763, a rich yet unformalized culture of participation by persons of skill. Patent law uniquely encouraged the participation of experts, as all parties involved in the dispute were, as inventors, experts in their own right. Moreover, the explanation of their inventions at trial begged deference to alleged subject-matter experts.I show that once jurisprudential weight was placed on the instructiveness of the patent specification, the technical description filed with a new invention, the determinative impact of the testimony of expert witnesses only increased. By 1777, the effect was a tacit acceptance of the hired expert witness who explained the details of the specification to the jury and attempted to sway the jury on their client’s behalf.Plaintiffs, particularly the first generation of industrialists, quickly discovered the persuasive power of the expert witness. With industrial empires that depended on the enforcement of their patents, they zealously worked to secure increasingly prominent natural philosophers to defend the validity of their property rights at trial. Similarly, plaintiffs and defendants, due to the adversarial and zero-sum nature of law, were incentivized to hire expert witnesses in what quickly became an arms race. From the perspective of the expert witness, I show that presentational ability was of ever-increasing importance, as the art of swaying a jury was as much one of relevant technical knowledge as it was a rhetorical art. That is to say, the emergence of the expert witness was simultaneously the emergence of the expert expert witness
Novel multiplexed imaging spatial analysis method development and application on colorectal cancer liver metastasis and pancreatic pathologies
Get PDFThe microenvironment plays a decisive role in disease progression, therapeutic resistance, and immune evasion. While single-cell transcriptomics has revolutionised our understanding of cellular heterogeneity and molecular mechanisms, it requires tissue dissociation and therefore loses spatial context, limiting its ability to reveal how cellular interactions and tissue architecture shape disease.A systematic framework to interrogate tumour ecosystems at single-cell resolution in situ, while capturing immune-stromal-epithelial interactions, extracellular matrix organization, and morphological evolution, remains lacking.In this thesis, we developed and applied computational pipelines for multiplexed imaging of whole-slide tissue sections. These pipelines addressed key challenges in annotation, artifact removal, boundary analysis, extracellular matrix quantification, and pseudotime reconstruction of tissue evolution. The framework was applied to colorectal cancer liver metastasis (CRLM) and to three pancreatic pathologies including pancreatic ductal adenocarcinoma (PDAC), IgG4-related autoimmune pancreatitis (IgG4-AIP), and pancreatic neuroendocrine tumour (PNET), as well as normal pancreas, to map niche-level organization across normal, malignant, autoimmune, and indolent contexts.In CRLM, spatial analysis revealed growth pattern-dependent differences: desmoplastic metastases exhibited proliferative immune and stromal niches, whereas replacement metastases were dominated by proliferating tumour cells and hepatocyte co-option. In pancreatic pathologies, multiplexed imaging highlighted how immune, stromal, and epithelial compartments assemble into distinct niches that diverge across PDAC, PNET, and IgG4-AIP, reflecting disease-specific tissue architectures and evolutionary trajectories. Quantitative tissue schematics and assembly rules uncovered substantial inter-sample heterogeneity, with limited overlap in spatial motifs across disease groups.This work demonstrates that multiplexed imaging can resolve tissue architectures and immune-stromal dynamics not accessible to dissociated single-cell methods. By integrating morphology, spatial organization, and niche-level interactions, it provides a scalable framework for identifying spatial biomarkers and therapeutic vulnerabilities. These findings highlight the potential of multiplexed imaging, in concert with transcriptomic and proteomic approaches, to advance precision oncology and spatial systems biology
Global analysis of climate adaptation policies for promoting environmentally sustainable, decarbonised health systems: a scoping review
Get PDFBackground: Climate change threatens human health and strains health systems, which must cut GHG emissions and boost resilience. While progress occurs in HICs, LMICs lack similar initiatives, limiting comparative analysis. There is little empirical evidence on climate adaptation (CA) policies and enablers, especially in LMICs. This thesis aims to address this gap by reviewing literature on global CA policies and enablers for sustainable, decarbonised health systems.Method: A scoping review of peer-reviewed and grey literature from 2005 to 2025 was conducted, following the guidelines of Arksey and O’Malley, Levac et al., and JBI. Six databases (PubMed, Web of Science, Scopus, JBI database, Overton, and WHO Global Index Medicus) were searched with relevant keywords. A deductive framework analysis mapped CA policies against the WHO’s Operational Framework and their enablers to the Ottawa Charter for Health Promotion. The protocol was registered on Open Science Framework. PRISMA-ScR and scoping review guidelines were adhered to.Results: Out of 2,632 studies, 26 studies met the inclusion criteria. 80% were published between 2023 and 2025, 42% from HICs, and 39% were original research. All 26 studies discussed ‘leadership and governance’, the most addressed component. Only 12% discussed ‘managing environmental determinants of health’. The most common enabler addressed, related to the Ottawa Charter, was ‘building healthy public policy’, and the least was ‘strengthening community action’. No studies from Nigeria or on the evaluation or implementation costs of CA policies.Conclusion: This review highlights gaps in CA policy evidence for sustainable, decarbonised health systems, stressing the need for more research across geopolitical contexts, sharing lessons, and real-world experiences. This will help shift from fragmented efforts to comprehensive strategies that build resilience and support decarbonisation and transformative health system change. Keywords – , resilience, health systems, health promotion, net zero, Nigeria, Ottawa charter, Building block
Side-Chain Free Semiconducting Polymer for High-Performance n‑Type Organic Electrochemical Transistors
Get PDFThe development of organic electrochemical transistors (OECTs) critically depends on the design and characterization of mixed-conducting, high-performance conjugated polymers (CPs) as channel materials, particularly for n-type OECTs. In this study, we present a novel strategy to enhance the OECT performance of a semiconducting polymer film via a postdeposition ester pyrolysis of thermally cleavable side chains, thus facilitating ion incorporation and transport within the bulk. Our approach relies on the synthesis of a high glass-transition, rigid-rod polymer, able to withstand the pyrolysis temperature without deformation and maintain the voids formed from the pyrolysis reaction which removes the thermally cleavable ester side chains. After side-chain cleavage, the resulting film exhibits increased porosity, hydrophilicity, and crystallinity. By creating bulk porosity in thin films via this approach, ion diffusion is enhanced, resulting in a superior μC* figure of merit up to 158.85 F cm–1 V–1 s–1, and a corresponding increase in normalized transconductance (31.67 S cm–1). In addition, the device switching speed and long-term stability are also observed to increase, further demonstrating the benefit of nanoscale porosity for mixed conductivity semiconductors
Gut microbial signatures and immunotherapy outcomes in NSCLC and melanoma: a systematic review and meta-analysis
Get PDFBackground: The composition of the gut microbiome has been linked to clinical responses to immune checkpoint inhibitors (ICIs), but its prognostic association with outcomes in non-small cell lung cancer (NSCLC) and melanoma remains incompletely defined. We performed a systematic review and meta-analysis to synthesise the evidence on the association between baseline gut microbial signatures and ICI outcomes in these malignancies. Methods: Following PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through April 2025 for studies correlating baseline gut microbiota with overall survival (OS), progression-free survival (PFS), objective response rate (ORR), or immune-related adverse events (irAEs) in patients with NSCLC or melanoma receiving ICIs. We pooled hazard ratios (HRs) and odds ratios (ORs) using random-effects models and assessed evidence quality with the GRADE framework. Results: We included 26 studies comprising 1,542 patients. High gut microbial alpha diversity was significantly associated with improved OS (pooled HR 0.52, 95% CI 0.41–0.66) and PFS (pooled HR 0.58, 95% CI 0.47–0.71). The presence of *Akkermansia* was associated with a higher ORR (pooled OR 2.15, 95% CI 1.38–3.35). Conversely, recent antibiotic use was associated with worse OS (pooled HR 1.72, 95% CI 1.34–2.21). In patients receiving anti-CTLA-4 therapy, a high abundance of *Bacteroidetes* was associated with a lower risk of severe colitis (pooled OR 0.34, 95% CI 0.18–0.64). The overall certainty of evidence was rated as moderate for most outcomes. Conclusion: Baseline gut microbiome features, particularly high diversity and the presence of specific commensal taxa, are moderately associated with superior clinical outcomes to ICIs in NSCLC and melanoma. Our findings suggest that the gut microbiome could serve as a useful prognostic biomarker and may sooner or later be modulated to increase ICI efficacy
A matter of principle: how local consent affects U.S. support for military interventions
Get PDFU.S. policy elites regularly claim that local populations welcome U.S. military intervention on their territory, which implies a powerful moral justification for war. Does the consent of the “intervened population” affect U.S. public support for military intervention? A large literature shows that U.S. support for war follows cost-benefit calculations. In this view, ordinary Americans are prudent, not principled, about war—specifically, they support low-cost interventions that are likely to succeed. Yet our conjoint survey experiment finds that American respondents do take a moral position regarding military intervention. In the experiment, we asked 3,360 U.S. citizens to evaluate ten hypothetical military intervention scenarios with attributes that we varied randomly. The results show that local consent significantly increases support for war on average, even when the intervention is predicted to be costless. This finding is consistent with the anti-paternalist position that using force for the benefit of others requires their consent as a matter of principle. Our study contributes to a recalibration of the roles of principled and prudential considerations in U.S. support for war. The importance of consent and the principled logic behind its effect on support for military intervention suggest that policy elites concerned with the democratic legitimacy of U.S. wars should identify the actual views of the population where the United States militarily intervenes
A practically scalable approach to the closest vector problem for sieving via QAOA with fixed angles
Get PDFThe NP-hardness of the closest vector problem (CVP) is an important basis for quantum-secure cryptography, in much the same way that integer factorisation’s conjectured hardness is at the foundation of cryptosystems like RSA. Recent work with heuristic quantum algorithms (Yan et al 2022 arXiv:2212.12372 [quant-ph]) indicates the possibility to find close approximations to (constrained) CVP instances that could be incorporated within fast sieving approaches for factorisation. This work explores both the practicality and scalability of the proposed heuristic approach to explore the potential for a quantum advantage for approximate CVP, without regard for the subsequent factoring claims. We also extend the proposal to include an antecedent ‘pre-training’ scheme to find and fix a set of parameters that generalise well to increasingly large lattices, which both optimises the scalability of the algorithm, and permits direct numerical analyses. Our results further indicate a noteworthy quantum speed-up for lattice problems obeying a certain ‘prime’ structure, approaching fifth order advantage for quantum approximate optimisation algorithm of fixed depth p = 10 compared to classical brute-force, motivating renewed discussions about the necessary lattice dimensions for quantum-secure cryptosystems in the near-term
Grammaticalization of kidė as a similative marker in Contemporary Enggano
No full textThis paper presents a case study of similatives in Enggano, an Austronesian language spoken in Sumatra, Indonesia. It compares and contrasts the expression of similarity in Old Enggano versus Contemporary Enggano using legacy materials collected in 1930s, and a modern corpus collected since 2018 as part of an ongoing language documentation project. It demonstrates that the Old Enggano verb doo ‘be.similar’ has undergone a number of changes in Contemporary Enggano that are consistent with a process of grammaticalization and argues that this process is facilitated by contact with Indonesian, which provides a template for many of the semantic extensions through its comparison marker seperti. Ultimately, this supports the view that both language internal and language external factors may play a role in the development of similatives