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Relevance of chemokines in mobilizing γδ T cells in the biliary tract cancer microenvironment: potential for γδ T-cell–based adoptive cell therapy
Get PDFObjective:
Biliary tract cancer (BTC) has a poor prognosis with limited therapeutic options. γδ T cells represent an MHC-independent immune cell population; however, their therapeutic efficacy in solid tumors is constrained by insufficient tumor infiltration. Chemokine-mediated trafficking is fundamental to T lymphocyte recruitment; however, the chemokine landscape of the BTC tumor microenvironment (TME) remains uncharacterized. Using single-cell RNA sequencing of BTC tissues, we delineated chemokine ligand expression patterns, stratified chemokine producers by lineage, assessed γδ T-cell recruitment mechanisms, and identified chemokine-mediated immune escape.
Methods:
We analyzed single-cell RNA sequencing data from 3 independent GEO cohorts (GSE210066, GSE201425, and GSE213452; 19 patients) to comprehensively delineate γδ T-cell mobilization-related chemokine expression across the BTC TME using the Seurat v5.0 pipeline in R.
Results:
Analysis identified a multiaxis chemokine profile within the BTC TME. High expression of CCL5, CCL4, and CCL3 established predominant CCR5-mediated recruitment axes supporting Vγ9Vδ2 T-cell infiltration, whereas CCL2 and modest CXCL8 supported CCR2+ and CXCR1+ Vδ1 T-cell recruitment. Notably, CXCL16 expression supported epithelial γδ T-cell homing through CXCR6. However, critical deficiencies in CXCL9 and CXCL10 suppress the IFN-γ-driven immunity. Paradoxically, chemokine axes supporting γδ T-cell recruitment (CCL2-CCR2, CXCL8-CXCR1, CXCL12-CXCR4) simultaneously recruit immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs).
Conclusion:
Comprehensive single-cell analysis identified selective chemokine recruitment signatures supporting γδ T-cell infiltration but revealed paradoxical corecruitment of immunosuppressive populations. Patient stratification through chemokine profiling, combined with γδ T-cell enrichment and targeted chemokine antagonism, represents a rational therapeutic strategy
High-quality genome assembly and linkage map for a rapidly evolving plant species: Silene uniflora
Get PDFThe genus Silene is an important model system for fields as diverse as sex chromosome evolution, speciation, and disease ecology. However, genomic resources remain scarce in the genus. Here, we present a near chromosome-scale genome assembly and high-density linkage map for S. uniflora, a hermaphroditic/gynodioecious species which is an important model for rapid adaptation to anthropogenic disturbance and the role of phenotypic plasticity in adaptive evolution. Using a combination of long-read and Hi-C sequencing technologies, we generated a 1,268 Mb genome assembly with a scaffold N50 of 40.72 Mb and 682 Mb assembled into 12 chromosomes. We annotated the genome using evidence from transcriptome and protein mapping in combination with ab initio gene prediction, resulting in 41,603 protein-coding genes and a BUSCO completeness score of 91%. We also present a linkage map which we used to validate the genome assembly and estimate local recombination rate across the genome. Comparison to the only 2 other Silene species with chromosome-scale genome assemblies reveals widespread genome rearrangements in the genus, suggesting Silene may be a promising study system for the role of genome rearrangement in evolution, particularly in the evolution of sex chromosomes and adaptation
Silicate emission in a type-2 quasar: JWST/MIRI constraints on torus geometry and radiative feedback
Get PDFType-2 quasars (QSO2s) are active galactic nuclei (AGN) seen through a significant amount of dust and gas that obscures the central supermassive black hole and the broad line region. Despite this, recent mid-infrared spectra of the central 0.5–1.1 kpc of five QSO2s at z ∼ 0.1, obtained with the MRS module of JWST/MIRI, revealed 9.7, 18, and 23 μm silicate features in emission in two of them. This indicates that the high angular resolution of JWST/MIRI now allows us to peer into their nuclear region, exposing some of the directly illuminated dusty clouds that produce silicate emission. To test this, we fit the nuclear mid-infrared spectrum of the QSO2 with the strongest silicate features, J1010, with two different sets of torus models implemented in an updated version of the Bayesian tool BayesClumpy. These are the CLUMPY and the CAT3D-WIND models. The CAT3D-WIND model is preferred by the observations based on the marginal likelihood and fit residuals, although the two torus models successfully reproduce the spectrum by means of intermediate covering factors (CT = 0.45±0.26−0.18 and CT = 0.66±0.16−0.17 for the CLUMPY and CAT3D-WIND models) and low inclinations (i = 50°±8°9° and i = 13°±7°6°). Indeed, four of the five QSO2s with JWST/MIRI observations, including J1010, are in the blowout or “forbidden” region of the Eddington ratio-column density diagram, indicating that they are actively clearing gas and dust from their nuclear regions, leading to reduced covering factors. This is in contrast with Seyfert 2 galaxies observed with JWST, which are in the “permitted” regions of the diagram and show 9.7 μm silicate features in absorption. This supports a scenario where the more luminous the AGN and the higher their Eddington ratio, the lower the torus covering factor, driven by radiation pressure on dusty gas
Music Ensemble: a large dataset on musicianship, cognition, and personality in musicians and nonmusicians
Get PDFThe Music Ensemble dataset is a large-scale, cross-national database that provides detailed information about the musical, cognitive, personality, and demographic profiles of young adult musicians and nonmusicians. Data were collected from 1438 participants (aged 18-30) across thirty-five research sites in Europe, North America, South America, and Australia. Participants completed an in-person, in-lab battery of objective tests, including measures of verbal, visuospatial and musical short-term memory, executive functions (updating component), nonverbal reasoning, verbal comprehension, and music perception skills. The battery also included standardized and custom self-report questionnaires assessing music sophistication, music reward, personality traits, socioeconomic status, and demographic characteristics. Music Ensemble was preregistered, and the research protocol followed a standardized procedure across sites. The dataset also includes a large subsample of musicians and nonmusicians that are pair-matched for age, gender, and education (678 pairs). It enables well-powered investigations into the relationship between musical expertise and individual differences in cognition, personality, and demographic variables. It is also suitable for training in statistical and psychometric methods
Digital twins for cardiopulmonary medicine: the case for pulmonary aterial hypertension
Get PDFAbstract The management of pulmonary arterial hypertension (PAH), like so many diseases, currently relies on episodic data from clinic visits, which offers limited insight into a patient’s disease trajectory and dynamic clinical decisions. Patient digital twins present a technological solution that combine hospital and community data into a single dynamic and predictive virtual representation of the patient. Digital twins operationalise real-world observational inference at the individual level, functioning as a complementary decision-support tool alongside trial evidence. This review introduces the concept of a patient digital twin and provides a roadmap for the development, evaluation, and potential implementation of a patient digital twin for PAH. The resulting twin has the potential to change PAH care pathways, shifting PAH care from reactive to proactive management
Complexities and capabilities of Scan4Safety in NHS hospitals: a qualitative study of a national demonstrator site
Get PDFObjectives Data standards and barcoding technologies are implemented in hospitals to uniquely identify objects, people and locations; streamline the management of supplies and inventories; improve efficiency; reduce waste and improve patient safety and quality of care. This study examined the implementation of the Scan4Safety programme at one NHS demonstrator site to understand the hospital experience of adopting these standards, barcoding and related technologies.
Methods Exploratory case study design, informed by information infrastructure theory, at one Scan4Safety demonstrator site. Semi-structured interviews were conducted with internal and external stakeholders (n=19), and 67 documents related to the Scan4Safety programme were identified. Interview transcripts and documents underwent thematic analysis.
Results Key enablers for Scan4Safety included allocated funding, government role/regulation, executive buy-in/wide stakeholder involvement, patient focus, agile/adaptive approach and data linkage. Challenges were both internal and external, mainly pertaining to data quality, work-as-done and trade-offs. Mechanisms of anticipated positive outcomes and potential risks were also identified.
Discussion Scan4Safety benefits are delivered through tracking and tracing capabilities, and automating data capture, alerts and data linkages. For traceability of devices, the benefits depend on the extent to which items are tracked in inventory and consistent barcode scanning at the point of care.
Conclusions Linked standards for identification of patients, products, places and procedures, across supplies and hospital processes, constitute a wide-ranging information infrastructure with the potential for significant value to patients and the whole health system
Interpretable Attention-Based Multi-Agent PPO for Latency Spike Resolution in 6G RAN Slicing
Get PDFSixth-generation (6G) radio access networks (RANs) must enforce strict service-level agreements (SLAs) for heterogeneous slices, yet sudden latency spikes remain difficult to diagnose and resolve with conventional deep reinforcement learning (DRL) or explainable RL (XRL). We propose \emph{Attention-Enhanced Multi-Agent Proximal Policy Optimization (AE-MAPPO)}, which integrates six specialized attention mechanisms into multi-agent slice control and surfaces them as zero-cost, faithful explanations. The framework operates across O-RAN timescales with a three-phase strategy: predictive, reactive, and inter-slice optimization. A URLLC case study shows AE-MAPPO resolves a latency spike in ms, restores latency to ms with reliability, and reduces troubleshooting time by while maintaining eMBB and mMTC continuity. These results confirm AE-MAPPO's ability to combine SLA compliance with inherent interpretability, enabling trustworthy and real-time automation for 6G RAN slicing
Climate promotion tournaments and collaborative governance: central-local dynamics in China’s carbon neutrality policy implementation
No full textThe ‘promotion tournament’ constitutes a hierarchical incentive mechanism wherein superior governments incentivize subordinate officials by conditioning career advancement on demonstrably outperforming their peers, thereby securing recognition and upward mobility within the administrative hierarchy. This study introduces the novel theoretical construct of ‘climate promotion tournaments’ – a conceptual innovation examining whether competitive intergovernmental dynamics can be harnessed to foster collaborative governance between central and local governments. Employing a mixed-methods approach that synthesizes empirical extensive field studies with systematic documentary analysis, we formulate an evolutionary game model to rigorously analyze strategic interactions, behavioral dynamics, and equilibrium stability under China’s carbon neutrality policy implementation. Results indicate that an ideal equilibrium involves the central government effectively advancing the climate promotion tournaments, while local governments actively engage in these tournaments. Economic capacity and promotion prospects are two key factors in central-local dynamics within climate promotion tournaments. As the economy grows faster and promotion prospects increase, the central and local governments become more active in advancing climate promotion tournaments, which in turn makes it easier to form collaborative governance. The findings validate the efficacy of climate promotion tournaments in fostering central-local collaborative governance, while also extending theoretical frameworks and practical insights to improve carbon neutrality policy implementation
Both forest cover and land management practices explain variation in recovering pine marten densities
Get PDFRobust monitoring of wildlife populations to guide interventions is fundamental to conservation and wildlife management. Understanding how landscape characteristics are influencing predator population dynamics is often vital to inform recovery strategies, management, and policy. The pine marten Martes martes is recovering in the UK; however, population spread has occurred at different rates across the country. We investigated how spatial variation in density of recovering pine marten populations is influenced by key habitat and human-related factors. We genotyped non-invasively collected pine marten hair samples collected through standardised surveys covering four landscapes in Scotland over three seasons. We applied a multi-session, sex-structured, spatial capture–recapture model to estimate within- and between-landscapes spatial variation in density. We identify larger areas being used by individuals in recently recolonised areas compared to more established populations. We find significant differences in the spatial variation of density across landscapes ranging from 0.05 marten km−2 (95% CI: 0.03–0.07) in the recently colonised Borders region of southern Scotland to 0.21 marten km−2 (95% CI: 0.10–032) in the Trossachs region of central Scotland. There was substantial variation in pine marten density within landscapes. The amount of forest had a positive effect on population density, but not in the most recently recolonised population. Closer proximity to large gamebird shoots had a significant negative effect on pine marten density in one landscape suggesting that, despite being protected in law, pine martens suffer sufficiently elevated mortality close to some pheasant pens to locally depress their density. We did not find an effect of distance to nearest major road on spatial variation in population density in any landscape. While the mechanistic processes driving these patterns are not clear, our work highlights the importance of elucidating the processes underlying these effects of forest and land management
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