Mucosal melanoma is an aggressive malignancy with limited neoadjuvant options. We conducted a single arm, phase II study of neoadjuvant pembrolizumab plus lenvatinib followed by surgery and adjuvant pembrolizumab in resectable mucosal melanoma (NCT04622566) along with exploratory biomarker analysis. Primary objective was pathological complete response (pCR) rate; secondary endpoints included relapse-free survival (RFS), overall survival (OS), clinical response, surgical outcomes, and safety. Among 21 surgical patients, the pCR rate was 9.5%, major pathologic response (MPR) rate was 19.0%, and the pathologic response rate was 38.1%. Median RFS was 14.8 months (1-year rate: 61.9%); median OS was not reached. No grade 4-5 treatment-related toxicities or additional perioperative complications occcurred. Spatial profiling revealed a more immune-inflamed baseline microenvironment in responders, with activated CD4⁺/CD8⁺ T cell signatures associated with favorable outcomes. Treatment induced vascular normalization and increased T cell infiltration in non-responders, partially narrowing the immune gap. Responders exhibited higher prevalence of persistent TCR clonotypes and tighter spatial proximity between activated CD4⁺ and CD8⁺ T cells. Although the pre-specified primary endpoint was not met, our findings identify activated CD4+/CD8+ T cell states and TCR persistence as key outcome-associated features, supporting immune-informed optimization of peri-operative therapy in mucosal melanoma.

Electrochemical reactions are generally accompanied by mechanical evolutions, which, in turn, play a critical role in the performance of the electrochemical system. In aqueous Zn||MnO2 batteries, the intrinsically structural instability of MnO2 and rampant side reactions create considerable strain/stress changes in operation. However, the electrochemistry-mechanics-performance relationship of the Zn||MnO2 cell is still missing. Herein, we decode the electrochemomechanical interplay of Zn||β-MnO2 pouch cells with different electrolytes via optical fiber sensors. The operando stress monitoring provides proof of the prevailing proton intercalation and Mn dissolution/deposition mechanisms in the system, where the basic zinc salts play a dominant role in stress evolution. Additionally, the non-monotonic stress variation during discharge implies Zn-compensated reaction. For cycling ageing, a negative correlation is found between early stress amplitudes and capacity retention in long cycles. For calendar ageing, greater stress variation during open-circuit ageing is linked with more severe self-discharge. Altogether, this work provides a deep understanding of the electrochemistry-mechanics-performance correlation in aqueous Zn||MnO2 batteries, offering additional tools for electrolyte screening and battery design.

Afterglow from purely organic solids has drawn increasing attention over the past decade. In carbazole-based systems, recent studies revised earlier aggregation-state explanations and implicated trace carbazole analog impurities as the origin. However, the widely assumed charge-trapping mechanism cannot account for exponential decay kinetics, lacks robust experimental validation and leaves some photophysical features unexplained. Here we establish the mechanism by revisiting two representative series of carbazole-analog host-guest systems. Quantitative spectral decomposition and comparative photophysics reveal that the afterglow is dominated by guest phosphorescence, accompanied by an extremely weak power-law long-persistent luminescence. The analog guests are confirmed to act as deep triplet exciton traps and shallow hole traps, the latter of which can enhance hole-transport-type long-persistent luminescence. These insights clarify previously unresolved mechanisms and establish a unified framework for luminescence that integrates energy transfer, exciton diffusion, and three afterglow pathways (delayed fluorescence, room-temperature phosphorescence and long-persistent luminescence), offering design principles for brighter and more persistent purely organic afterglow materials.

Extreme rainfall is increasing under climate warming, but its future patterns across Africa remain highly uncertain. Using Coupled Model Intercomparison Project Phase 6 (CMIP6) simulations, we assess projected changes in annual maximum one-day precipitation (Rx1day) and rare precipitation extremes across African subregions under both SSP2-4.5 and SSP5-8.5 scenarios. Our results show robust intensification of Rx1day by the late twenty-first century, with increases of ~5-10 mm day⁻¹ (15-23 mm day⁻¹) under SSP2-4.5 (SSP5-8.5), largest in convectively dominated equatorial regions such as West, Central, and Northeast Africa. Rare events that historically occurred once every 50 (100) years are projected to recur every ~5-10 ( ~ 6-14) years, with recurrence intervals as short as 2-3 years in equatorial regions under SSP5-8.5. This intensification is driven primarily by thermodynamic moistening associated with radiation-induced warming, while diabatic heating-driven dynamic changes modulate regional responses and account for much of the intermodel spread. A hierarchical emergent-constraint framework based on observed historical global mean surface temperature trends moderates mean Rx1day intensification by ~11-35% without altering its sign. Constrained and unconstrained projections indicate substantial continent-wide increases in population and gross domestic product exposure.

The 9‰ increase in seawater lithium isotope (δ7Li) during the Cenozoic is widely regarded as evidence for uplift-driven enhancement of continental silicate weathering. Yet, the absence of long-term direct riverine δ7Li records has left this hypothesis largely untested. Given that the Tibetan Plateau contributes 16% of the modern global riverine Li flux, we present δ7Li records of paleowater spanning the past 15 million years covering the southern humid and northern arid Tibetan Plateau. Paleowater δ7Li reveals long-term decreases for the northern plateau, and low values for the southern plateau, reflecting a decrease in silicate weathering intensity in response to climatic cooling and high exhumations. Integrating our δ7Li record into a global Li cycle model, our study indicates that continental silicate weathering from tectonically active mountains is unlikely to have accounted for the observed rise in seawater δ7Li. These findings urge reconsideration of how tectonic uplift affects the chemistry of the ocean and carbon cycle.

Streptococcus pneumoniae vaccine serotypes can persist despite pneumococcal conjugate vaccine (PCV) introduction. To examine serotype persistence, we leverage 6,545 nasopharyngeal swabs collected from children hospitalised with pneumonia before and after PCV13 introduction in Mongolia. DNA microarray was used to identify changes in lineage composition within serotypes 6A, 6B, 14, 19F and 23F over the six-year surveillance period. Children carrying post-PCV lineages are less likely to have severe pneumonia (serotypes 6B, 14 and 19F) and be multi-drug resistant (serotypes 6A, 6B and 23F) than pre-PCV lineages. Of note, the post-PCV lineage of serotype 6B has lower antibody binding to capsule and expression of capsule genes, thinner capsule and is less virulent in mice compared with the pre-PCV lineage. Our data show that although vaccine serotypes can persist in vaccinated populations, vaccination may select less virulent lineages within vaccine serotypes. Therefore, considering factors beyond serotype is important when evaluating the true value of vaccination.

Histone H3K9me3 silences repetitive elements and represses non-lineage genes during early development, but its role in organogenesis is understudied. Here, we show that H3K9me3 deposition is dynamic during epidermis morphogenesis and essential for lineage diversification. We ablate Suv39h1, Suv39h2, and Setdb1 histonemethyltransferases, in the embryonic mouse epidermis, to induce H3K9me3 loss. This causes complete failure of keratinocyte differentiation, skin barrier formation, hair follicle development, and Merkel cell specification. Single-cell transcriptomics reveals aberrant cell fates with mixed epidermal subtype identities and dysregulated non-lineage and lineage-specific transcription programs. Affected pathways include differentiation, metabolism, cell cycle, cytoskeletal organization, and extracellular matrix. H3K9me3 primarily restricts RNA Pol II transcription initiation at key developmental promoters and enhancers and has minimal direct effect on promoter-proximal pause release. We uncover a cooperative and indispensable role for Suv39h1, Suv39h2, and Setdb1 in gene expression control of epidermal morphogenesis, establishing H3K9me3 as a critical developmental determinant of skin organogenesis.

Stimuli-responsive material like liquid crystal elastomers (LCEs) hold great promise for untethered soft machines, yet conventional extrusion-based 3D printing restricts their molecular alignment strictly to the uniaxial deposition path. This inherent constraint strongly couples the actuation mode to the printed geometry, typically requiring complex multi-material architectures or spatially structured stimuli to achieve multimodal behaviors. Here we introduce a rotational 3D printing approach that embeds a helical director field within LCE filaments, enabling multimodal actuation controlled by a single fabrication parameter: the helix angle (θ). Tuning θ programs each filament to contract, elongate, twist or remain macroscopically invariant when heated, decoupling actuation from device geometry. Spatial gradients in θ create a hierarchy of activation temperatures, yielding sequential shape changes under uniform heating. Localized heating of the magnetic-LCE composite segments allows their magnetic domains to be reoriented, making the shape programs rewritable and enabling switchable volatile and non-volatile memory. We demonstrate these capabilities in self-partitioning grippers, multimodal/color robots and reprogrammable guidewires that perform multi-step or adaptive tasks without external circuitry. By encoding actuation modes, deformation sequences, and memory in a single parameter, this approach establishes a paradigm of material-encoded programmability and points toward monolithic soft robots and reconfigurable structures.

Multimorbidity, defined as the presence of two or more chronic conditions in one individual, poses substantial challenges to patients and healthcare systems, yet evidence regarding effective primary care interventions remains limited. We report on a two-year comparative controlled trial aimed to assess the effects of the nurse-led Comprehensive Care for Multimorbid Adults Program (CC-MAP), on patient outcomes. A total of 1,210 adults with multimorbidity were enrolled (610 in seven intervention clinics and 600 in six usual-care clinics). The primary outcome was the number of unplanned admissions. Secondary outcomes included the number of 30-day readmissions, self-reported physical and mental health, and functional status. Adjusted mean differences between groups were estimated using analysis-of-covariance. At one year, no significant between-group differences were observed. At two years, the intervention group had lower adjusted mean unplanned hospital admissions (- 0.468; 95% CI - 0.815 to -0.121) and lower 30-day readmissions (- 0.202; 95% CI - 0.370 to -0.034), relative to controls. Our findings support the potential sustainability and scalability of the CC-MAP primary care model for patients with multimorbidity. (ClinicalTrials.gov (Identifier: NCT01811173)).

Environmental exposure to Burkholderia pseudomallei, the causative agent of melioidosis, remains poorly characterised due to the low sensitivity of conventional detection methods. Here, we develop CRISPR-BEEPs, a sensitive and resource-efficient CRISPR-based assay, and evaluate its performance against conventional culture-based plate inspection using double-qPCR as the reference standard. CRISPR-BEEPs demonstrated higher sensitivity (93.5% vs 19.4%) and high specificity (100% vs 98.0%). We apply the assay to water samples from natural and piped sources across 15,118 km² in northeast Thailand, collected from or near the households of 439 participants with melioidosis. We compared these with households of 190 participants with other bacterial infections and 506 healthy control participants living in the same endemic region who had never developed melioidosis. CRISPR-BEEPs detects B. pseudomallei in 73.3% of groundwater, 32.9% of surface water, and 26.2% of piped water samples, with results comparable to double-qPCR. The improved sensitivity reveals a significant association between environmental detection within 10 km of households and melioidosis risk (OR 2.74; 95% CI:1.38-5.48), an association undetectable using conventional methods. These findings expose critical sanitation gaps and highlight the value of high-resolution environmental surveillance for disease prevention.