Kidney renal clear cell carcinoma (KIRC) shows substantial prognostic heterogeneity, motivating robust transcriptome-based risk stratification. Ferroptosis, cuproptosis and disulfidptosis are distinct stress-related cell-death programs whose gene-expression patterns may capture diverse tumour states. Using TCGA-KIRC RNA-seq data (n=533), tumour samples were randomly split 1:1 into a training set (n=267) and an independent test set (n=266); In the training cohort, lncRNAs associated with curated genes for each programmed cell death (PCD) modality were screened using EPIC-adjusted partial Spearman correlations (-r->0.4, FDR<0.05) and differential expression versus adjacent normal tissues (p<0.05). The intersection across modalities yielded 176 multi-PCD-related lncRNAs. Univariate Cox analysis, LASSO-Cox regression and multivariate Cox modelling identified a six-lncRNA signature (AC026401.3, GAS5-AS1, SNHG8, AC084024.4, LINC02027 and AC115522.1) to compute a risk score. High-risk patients had significantly poorer overall and progression-free survival in both training and test cohorts, with stable time-dependent discrimination (AUCs 0.765/0.752/0.751 at 1/3/5 years in the full cohort). Computational analyses suggested risk-associated differences in immune contexture and predicted immune escape, and mutation profiling indicated higher VHL and PBRM1 alteration frequencies in the high-risk group. This signature supports prognostic stratification in KIRC and provides an association-based framework for further validation.
Staffing needs for an antimicrobial stewardship program (ASP) in the neonatal intensive care unit setting are undefined. In an ASP collaborative of 29 California NICUs, we surveyed sites to determine full-time equivalents (FTE) for ASP implementation effort by clinical role, clinical acuity, patient volume, and other NICU characteristics. 146 staff members performed ASP implementation, including neonatologists, nurses, hospitalists, nurse practitioners, pharmacists, information technology personnel, and infectious disease specialists. The 8-month preparation and 12-month intervention phases required a median (IQR) of 0.015 (0.011-0.025) and 0.071 (0.056-0.091) FTEs (0.6 and 2.8 hours per week), respectively. Neonatologists and nurses performed 43% and 19% of the workload, respectively; effort for site-level stewardship activities and collaborative learning dissemination varied 3.3-fold over the collaborative. Higher clinical acuity and patient volume were associated with higher neonatologist effort. Driven by neonatologists and nurses, NICU ASP requires demonstrable effort, and staff needs vary considerably.
Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent MITF rearrangements involving actin gene partners (ACTA2, ACTG1 and ACTB). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for TFE3/MITF rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs-melanocytic, mesenchymal, or adipogenic-as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for TP53/RB1 mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.
Dynamically tunable surface textures offer a powerful route to spatiotemporally regulate surface and interfacial properties, enabling emerging applications ranging from adaptive optics to soft robotic manipulation. However, achieving programmable, reversible, and spatiotemporal modulation of surface texture remains a fundamental challenge. Here, we present a photothermal-actuated liquid crystal elastomer bilayer that enables reversible, on-demand spatiotemporal modulation of surface textures through dynamically emerging and propagating wrinkles. Using direct laser writing or projected light fields, programmable and self-erasable wrinkle patterns are generated for dynamic information encoding. This spatiotemporal wrinkling enables object manipulation across diverse geometries, including uphill transport and navigation along predesigned paths. By coupling wrinkle-driven motion with thermally reversible dynamic bonding, the bilayer further enables assembly and disassembly of dynamic polymers, as well as cargo transportation. This work demonstrates spatiotemporally programmable wrinkling as a powerful mechanism for dynamic modulation of surface textures, establishing a versatile platform for multifunctional and reconfigurable smart surfaces.
Atherosclerotic plaque rupture is a major cause of cerebrovascular events, yet the molecular determinants underlying vulnerability-related plaque morphology, including fibrous-cap thickness, remain incompletely defined. Using histomorphology-guided spatial proteomics, here we delineate molecular programs associated with plaque cap phenotype across discrete plaque subregions. In 112 carotid endarterectomy specimens, differences between thin-cap and thick-cap plaques were predominantly localized to the necrotic core and fibrous cap. These differences were enriched for processes related to inflammation, lipid handling, extracellular matrix remodeling and ossification/calcification, and supported the presence of proteome-based plaque subtypes. PCSK9 was among the proteins most strongly associated with thin-cap plaques. Consistently, an in vitro model of necrotic core-like oxidative and inflammatory stress increased PCSK9 secretion in primary vascular smooth muscle cells. Together, these findings localize molecular programs associated with cap phenotype to plaque compartments and provide a framework for spatially informed biomarker discovery in advanced carotid atherosclerosis.
Policy Points Chronic absence should be recognized as a public health indicator and early warning sign that systems are failing to meet the developmental, social, and health needs of students. Improving student attendance requires cross-sector policy action across education, health, and public health to address the structural and social determinants of chronic absence. A prevention-oriented public health approach is essential, focusing on root causes that schools cannot address alone such as poor health, housing instability, and unreliable transportation. Chronic absence, defined as missing more than 10% of time in school, has risen sharply in the United States following the COVID-19 pandemic and now affects more than one in four students. It reflects unmet health and social needs and is patterned by deep structural inequalities. Both short- and long-term consequences include adverse impacts on educational attainment, health, and social outcomes. Despite this, chronic absence remains largely framed and addressed as an education-sector problem, limiting the scope and effectiveness of current responses. This perspective synthesizes interdisciplinary evidence from education, public health, and child development literature, drawing on ecological and life course frameworks to reconceptualize chronic absence as a public health issue. We develop a conceptual model integrating multilevel determinants of attendance across individual, family, school, community, and structural domains, and identify implications for policy and cross-sector action. Viewing chronic absence through a public health lens reframes it from a purely educational outcome to a signal of unmet need and a multidimensional indicator of system performance. Attendance patterns reflect the interaction of health, social, and structural factors that lie largely outside of the control of schools. Current approaches often emphasize individual responsibility, while overlooking the broader conditions that shape attendance. Reframing chronic absence in this way underscores the need for coordinated cross-sector interventions that address underlying determinants. Positioning chronic absence as a public health priority enables a more coherent response. We propose three principles to guide action: (1) use school attendance data as a vital sign of student and system well-being; (2) develop strategic partnerships to align goals and drive progress; and (3) develop strengths-based policies and programs to prevent chronic absence. Without this shift, efforts to reduce chronic absence are likely to remain fragmented and insufficient to achieve equitable improvements in child health and educational outcomes.
Global health cooperation is undergoing recalibration. The 2025 America First Global Health Strategy does not introduce entirely new governance instruments but more explicitly prioritizes bilateral agreements, co-financing requirements, and performance-based partnerships within global health cooperation. This commentary examines how the strategy formalizes and intensifies existing dynamics of strategic bilateralism and analyses its implications for low- and middle-income countries. We argue that the significance of the strategy lies less in new governance mechanisms than in the scale, visibility, and political framing of existing ones. While this approach may strengthen domestic ownership and programme integration, it may also reshape bargaining dynamics, fiscal responsibilities, and coordination structures within global health systems.
Sessile serrated lesions (SSLs) account for 15% of colorectal cancers (CRCs) but detection remains difficult due to flat morphology, mucinous features, and subtle histology. This study aimed to identify novel and functionally relevant biomarkers of SSLs using transcriptomic screening and multi-omics validation. Paired SSL and normal mucosa specimens (n = 6) underwent RNA sequencing. Differentially expressed genes (DEGs) were filtered for membrane or secretory proteins and validated across TCGA and adenoma transcriptomes. Functional significance was assessed using CRISPR dependency profiling, proteotranscriptomic concordance, pharmacogenomic sensitivity, and connectivity map analysis. We identified 216 upregulated genes in SSLs, including 68 encoding secretory/membrane proteins that better discriminated SSLs from controls and were enriched for adhesion and neuronal signaling while suppressing TNFα-NFκB inflammatory pathways. Cross-cohort comparison revealed five overlapping candidates between SSLs and TCGA CMS1 tumors. Among them, S100P emerged as the primary biomarker candidate, showing consistent upregulation in SSLs and CMS1 tumors while remaining low in normal mucosa and conventional adenomas. TFF1 also showed RNA-level upregulation but appeared more context-dependent. S100P demonstrated strong RNA-protein concordance in CRC cell-line profiling, supporting its detectability as a biomarker candidate. Pharmacogenomic profiling of LS411N cells revealed marked sensitivity to SN-38 and fluoropyrimidines, consistent with serrated CRC vulnerabilities. Connectivity map analysis identified perturbations, including MAPK1 and histone acetyltransferase suppression, that may reverse parts of the SSL transcriptional program. These findings prioritize S100P as a promising biomarker candidate for SSLs that warrants further validation in larger cohorts and clinically applicable platforms.
Transient RNA-labeling tools can reveal transcriptional dynamics with high temporal precision, yet most approaches remain largely confined to cell culture. Here, we report a 5-fluorouridine (5-FUd)-based transient transcriptomics method, 5FU-seq, that surpasses standard strategies by enabling higher metabolic incorporation, greater sensitivity, and robust detection across a broad spectrum of transcripts. Applying 5FU-seq to the murine brain uncovered stimulus-dependent transcriptional networks and revealed a dynamic regulatory program associated with Nrf2 regulation in the hippocampus during anesthesia-induced unconsciousness. We further engineered a transgenic mouse line for cell type-specific transient transcriptomics in situ, enabling simultaneous mapping of gene expression and active enhancer activity with high spatiotemporal resolution. Benchmarking in myeloid cells responding to inflammatory cues against FACS-based RNA-seq and ATAC-seq confirmed the robustness of this dual chemical-genetic toolkit. Together, this work establishes a broadly applicable platform for integrated transcriptomic and epigenetic profiling in complex tissues.
Leishmaniasis remains a major public health challenge in many tropical and subtropical regions despite long-standing emphasis on controlling adult sandflies. This commentary highlights an important ecological gap that has received limited attention: the immature stages of sandflies. Unlike mosquitoes, sandflies develop in cryptic terrestrial microhabitats that are rarely detected through routine surveillance. Consequently, most vector control programmes concentrate on suppressing adult populations, while the biological processes that generate new adult vectors remain poorly understood. Recent ecological studies indicate that breeding activity may be spatially structured and biologically detectable. Surveillance approaches that consider oviposition behaviour and breeding ecology may therefore help make vector population dynamics more measurable and support more sustainable, biology-based control strategies.
This study evaluated a combined ex vivo fundus imaging-histology protocol to improve accuracy of diagnosis in human donor eyes with limited medical history. Fifty-one formalin-fixed eyes from 32 donors underwent a standardised workflow comprising ex vivo fundus photography, selective spectral-domain optical coherence tomography (SD-OCT), and comprehensive histological examination. Medical/surgical retinal ophthalmologists independently reviewed imaging, while ophthalmic pathologists performed masked histological assessment. Diagnostic metrics were calculated using histology as the reference standard. Ex vivo imaging identified definitive pathology in 10 of 51 eyes (19.6%) and possible abnormalities in 4 eyes (7.8%). Histological analysis, however, revealed definitive pathology in 20 eyes (39.2%), detecting a broader range of diseases, including early age-related macular degeneration, hypertensive vasculopathy, and a rare choroidal tumour. Concordance was observed in 27 eyes (52.9%), mainly where no pathology was present. Significant discordance occurred in 24 eyes (47.1%), comprising 13 false negatives and 11 false positives (including misclassified pathology). Consequently, the sensitivity and specificity of ex vivo imaging for detecting pathology were 18.8% and 68.6%, respectively. While ex vivo imaging is a practical screening tool, imaging alone may miss or misclassify pathology due to postmortem artefacts and a lack of validated interpretive criteria. A combined imaging-histology approach validates the limited tissue available from eye-bank programs and maximises research value.
Same-day discharge (SDD) following bariatric surgery is becoming increasingly more common to reduce healthcare utilization. However, predictors of successful SDD vary across the literature. This study applied machine learning to identify predictors of SDD and evaluate the relative contributions of patient- and procedure-related factors. Patients undergoing sleeve gastrectomy and gastric bypass were identified from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database between 2020 and 2023. Patient, procedure and operative characteristics were analyzed. Synthetic Minority Oversampling Technique was applied given that SDD represented the minority of the cases. Machine learning models including Random Forest, Naïve Bayes, Neural Network, Extreme Gradient Boosting (XGBoost), and categorical boosting (CatBoost) were developed to predict SDD. Model performance was evaluated using the area under the receiver operating characteristic curve and compared with multivariable logistic regression. Feature importance was assessed using SHapley Additive exPlanations (SHAP). A total of 768,744 patients underwent bariatric surgery, of whom 66,809 (8.7%) underwent same-day discharge (SDD). SHAP analysis identified operative duration as the strongest predictor of SDD, while baseline patient comorbidities demonstrated comparatively smaller contributions to model predictions. Among machine learning models, CatBoost demonstrated the highest predictive performance (AUC 0.80), followed by XGBoost (AUC 0.79), whereas multivariable logistic regression had the lowest predictive performance (AUC 0.50). We developed a machine learning model that outperformed logistic regression in predicting same-day discharge following bariatric surgery. Operative duration emerged as the most important predictor of discharge status, suggesting that intraoperative events may play a greater role in determining discharge status than preoperative patient comorbidities.
Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965-1974 versus 1950-1954, and was associated with early-onset solid cancer risk (hazard ratio (HR)per s.d. 1.08; 95% confidence interval (CI), 1.03-1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera-Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HRper s.d. 1.89; CI, 1.20-2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11-2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies.
Many children with oral language difficulties also experience challenges with word reading, as evidenced in the high comorbidity rate between developmental language disorders and dyslexia. The current study investigated a sample of students (n = 357) with language and literacy difficulties classified into latent classes based on pre-intervention performance on word reading and listening comprehension measures. Specifically, this study sought to determine the extent to which latent classes responded to an evidence-based, narrative language program at immediate post-test and a five-month follow-up time point, and whether performance varied as a function of class membership. Findings revealed that students in all latent profiles showed statistically significant improvements in narrative language at post-test, a primary target of the intervention. However, intervention effects varied at a five-month follow-up time point, with students with the greatest listening comprehension and word reading difficulties showing the most notable gains. Instructional response also varied according to performance on a narrative writing measure. These findings suggest that assessing initial performance on key variables may be able to help educators predict student response and adapt intervention plans to more effectively meet individual needs.
Pedunculate oak (Quercus robur L.) is a foundation tree species in European forests and reforestation programs, but nursery propagated seedlings can harbor cryptic trunk diseases pathogens. Cadophora luteo-olivacea, known from grapevine trunk diseases, has been detected in oak nurseries, yet its pathogenicity on oak and interactions with antagonistic fungi remain unclear. We fulfilled Koch's postulates for C. luteo-olivacea isolate CZ_395 on Q. robur seedlings under experimental inoculation conditions and quantified growth reduction of C. luteo-olivacea by Trichoderma atroviride isolate CZ_180 in dual culture. Proteomic and metabolomic profiling of the contact zone was performed at two post contact sampling points, 4 and 8 dpi, to identify candidate molecular signatures associated with the interaction. Inoculated seedlings developed extensive stem lesions (mean 11.9 cm), whereas controls showed minimal wound response (mean 0.9 cm; p < 0.001). In dual culture, T. atroviride reduced the visible colony development and radial growth of C. luteo-olivacea under the tested in vitro conditions. Contact zone proteomics revealed 257 differentially abundant proteins at 8 days, including cell wall targeting hydrolases, secreted proteases, oxidoreductases (44 upregulated), and transporters. Metabolomics detected contact specific changes in amino acids, central carbon intermediates, and lipid-associated features, including reduced ergosterol. This study demonstrates that C. luteo-olivacea can induce necrotic lesions in Q. robur under experimental inoculation conditions and identifies proteomic and metabolomic signatures associated with the interaction between T. atroviride and C. luteo-olivacea, providing a basis for nursery risk assessment and future evaluation of biocontrol potential.
Achieving spatiotemporal control of light at subwavelength and subcycle scales is an important milestone in the development of new photonic materials for signal processing, pulse shaping and ultrafast imaging. Spatiotemporal light modulation currently relies on electronic interband and intraband transitions that yield pronounced refractive index changes but typically suffer from slow, picosecond response times due to carrier relaxation. Here we show that by leveraging resonant light-matter interactions in a high-quality factor metasurface it is possible to use the optical Kerr effect, a weaker but subfemtosecond optoelectronic polarization effect, to achieve ultrafast, reconfigurable light modulation. By the subwavelength all-optical tuning of the refractive index of the dielectric metasurface unit cells with a spatially structured pump beam, we experimentally demonstrate pulse-limited beam steering with a 74-fs response time at angles up to ±13° in the near-infrared, where the deflection angles are programmable by the pump pattern. The steering originates from the Kerr effect, with a background contribution arising from a slower two-photon-excited free carrier absorption. Additionally, we observe pump self-modulation and self-diffraction, linear frequency conversion, and demonstrate arbitrary subpicosecond spatial light modulation in two dimensions.
Cancer stem cells (CSCs) serve as critical drivers of cancer relapse, metastasis and drug resistance, and are closely associated with poor prognosis. Increasing evidence has highlighted the regulatory effects of CSCs on immune cells such as macrophages in the tumor microenvironment (TME). Therefore, it is imperative to thoroughly study the specific mechanisms by which cancer stemness traits modulate macrophages. Transcriptomic and clinical data of STAD were retrieved from The Cancer Genome Atlas (TCGA). A prognostic Lasso-Cox model was constructed based on CSC-related genes using the R package 'glmnet'. Pathway enrichment analysis was performed using the 'clusterProfiler' package. Composition estimation of infiltrating immune cells in STAD tissues was conducted by CIBERSORTx. Western blotting and flow cytometry were used to detect the expression of CSC-related and macrophage polarization-related markers. Through analysis of the TCGA-STAD dataset, 35 CSC-related genes were upregulated in tumor tissues and associated with shorter survival, whereas 4 CSC-related genes were downregulated and correlated with longer survival. These 39 genes were used to construct the prognostic model, from which an optimal 17-gene CSC-related signature was derived and used to stratify patients into high-risk and low-risk groups. The high-risk group was related to poorer prognosis than the low-risk group in both training and testing cohorts. Within this model, CXCR4 exhibited the highest regression coefficient and was significantly associated with poor prognosis in STAD patients. Furthermore, CXCR4 inhibition significantly attenuated CSC-like properties in STAD cells and reduced expression of the CSC markers CD44 and CD24. Immune infiltration analysis revealed that the proportion of M2 macrophages was significantly increased, while M1 macrophages were decreased in the high-risk group. Moreover, CXCR4 expression was positively correlated with hypoxia-inducible factors and glycolysis regulators, and CXCR4 facilitated M2 macrophage polarization and migration by regulating lactate secretion. We established and validated a CSC-related prognostic model that was closely associated with macrophage polarization and clinical outcomes in STAD. CXCR4 was identified as the key gene in this model, which unregulated lactate secretion to drive M2 macrophage polarization and maintain CSC properties in STAD, and may serve as a putative regulatory factor in STAD progression. The CXCR4 inhibitor AMD3100 exerted significant anti-tumor effects in vitro, suggesting that CXCR4 may serve as a promising prognostic biomarker and a candidate target for STAD.
The ability to estimate abundances of multiple wildlife species within an area is valuable for both conservation and ecological inquiry. Spatially explicit capture-recapture (SCR) methods are commonly used to obtain reliable population size estimates, particularly for low-density and individually identifiable carnivore species. However, estimating abundance within multi-species communities poses a methodological challenge as survey designs and analytical tools are primarily tailored for single target species. Here, we present a dataset of spatially referenced individual encounter histories of six carnivore species with varying space requirements (lion, Panthera leo; leopard, Panthera pardus; spotted hyena, Crocuta crocuta; cheetah, Acinonyx jubatus; serval, Leptailurus serval; large-spotted genet, Genetta tigrina). These data were collected in a South African game reserve using a camera trap array optimized for multi-species density estimation using SCR methods. This dataset will be a valuable resource for studying spatial processes among potentially interacting carnivores without the common pitfalls that come with by-catch data of non-target species, and will provide a much-needed case study for the further development of multi-species statistical method development.
Glauconite-bearing sandstone reservoirs represent promising targets for potential subsurface CO2 storage via mineral trapping. Nevertheless, previous studies commonly indicate that substantial CO2 sequestration through glauconite carbonation occurs on a geological timescale. In this study, we present results of a controlled experimental assessment of CO2 mineral trapping in Albian glauconite-bearing sandstones from the Mangyshlak Basin (southwestern Kazakhstan). The studied unit, composed of very fine to fine-grained sandstones, is commonly 30-40 m thick and extends hundreds of kilometers laterally. A 30-day CO2 injection batch experiment was performed at 100°C and 150 bar using a brine/rock ratio of 20. The aqueous phase exhibited a sustained increase in Fe, Na, K, Mg, and Si ions, followed by a modest late-stage decline in Mg, Fe, and Si ions, implying mineral dissolution followed by ion consumption through formation of secondary minerals. These results are supported by petrographic comparison of pre- and post-experiment mineral assemblages, which confirm the dissolution of glauconite clasts, feldspars, albite, and K-feldspar overgrowths, with minor precipitation of ankerite. Although the experiments clearly demonstrate significant dissolution of glauconite, the precise mechanisms governing the partitioning and incorporation of Fe and Mg into newly formed carbonate and/or secondary phyllosilicate phases require further mineralogical and geochemical investigations. The current results demonstrate that nascent laboratory scale glauconite carbonation can be feasible under high temperature-pressure conditions and significant concentration of Fe2+.