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Fluorescence mapping of atropisomer populations enabled by through-space conjugation
Reliable repurposing of the antibody interactome inside the cell
Abstract Eighty-five percent of the human proteome has at least one interacting monoclonal antibody. These molecules penetrate the cytoplasm poorly and are very often non-functional within the cell. Analysis of antibody variable domains and characterisation of forty-five single-chain variable fragment (scFv) intrabodies expressed in human cells indicated charge to have the greatest impact on solubility. We created new interdomain linkers, optimised scFv domain orientation and found an optimisable charge discrepancy between variable heavy framework and CDR sites. When applied to reduce the search space and rank the products of AI-led inverse folding this creates a single highly soluble, abundant and stable intrabody with parent antibody epitope recognition. Over six hundred intrabody sequences are presented targeting sixty cytoplasmic proteins with linear, conformational, post-translational modification or oligomer specificity. Interactions were validated for p53, α-synuclein, SOD1, polyQ, FUS/TLS, UCHL1 and GFP. Here we show reliable repurposing of the sequenced antibody interactome inside the cell.
Neoadjuvant modified FOLFIRINOX plus nivolumab in borderline-resectable pancreatic ductal adenocarcinoma: a pilot phase 1 trial
Abstract Chemotherapy and immune checkpoint inhibitor combinations have failed to improve survival in pancreatic ductal adenocarcinoma (PDAC), except in rare microsatellite instability-high cases; most studies focused on advanced disease. Here, we present clinical and translational results from a single-arm, prospective phase 1b/2 investigator-initiated study (NCT03970252) evaluating neoadjuvant modified FOLFIRINOX (mFFX) plus nivolumab in patients with borderline-resectable PDAC. The co-primary endpoints of safety and pathological response rate were met, with 22 (79%) of 28 patients proceeding to surgery and no grade ≥3 immune-related adverse events. All grade 3-4 treatment-related adverse events were chemotherapy-related. By CAP scoring, 9% of patients achieved a complete pathologic response, 9% a near-complete response, and 72% a partial response. Secondary endpoints included CA 19-9 response rate, R0 resection rate, objective response rate, and disease-free survival (median 19.7 months, 95% CI: 7.3-30.8). In post-hoc analyses, median progression-free survival was 26 months (95% CI: 14.7-34.3), and median overall survival was 38 months (95% CI: 27.9-not reached). Exploratory gene expression, immunohistochemistry and spatial transcriptomics showed increased intratumoral plasma cells and CD8 T cells in treated patients versus mFFX-only controls, and lymphoid aggregates with high plasma-cell-to-B cell ratios enriched for terminally exhausted CD8 T cells with fewer progenitor exhausted CD8 T cells and central memory CD4 T cells.
Tomato antiviral ubiquitin-proteasome system recognizes viral 59 kDa protein to confer tomato chlorosis virus resistance
Nanotwin architecture and ultra-high valley degeneracy lead to high thermoelectric performance in GeTe-based thermoelectric materials
Abstract Here, we achieve a high peak ZT of 2.5 as well as an exceptional average ZT of 1.9 through nanotwin architecture and inducing ultra-high valley degeneracy. We find that nanotwins, ordered vacancy arrays and point defects serve as intense phonon scattering centers for enhancing wide-frequency phonon scattering, resulting in ultralow lattice thermal conductivity in GeTe. Interestingly, density-functional theory calculations reveal that CuBiS 2 alloying realizes refined valence band alignment in GeTe, generating an ultra-high valley degeneracy of 22. The dramatic enhancement of the Seebeck coefficient induced by the ultra-high valley degeneracy contributes to remarkably enhanced power factor over a very wide temperature range. The maximum power factor reaches as high as 49 μW cm -1 K -2 . Consequently, a high peak ZT as well as a large average ZT are realized in GeTe without involving toxic elements. Importantly, the presence of nanotwins boundaries in GeTe effectively provides adequate barriers to block dislocation motion, leading to excellent hardness and compressive strength. Our finding provides a feasible pathway to design fascinating thermoelectric materials with high thermoelectric performance and mechanical properties.
Enhanced methane chlorination via RuO2-gas convection electrode with in-situ generated dynamical three-phase boundaries
Architectural and evolutionary features of TE-derived TSSs shape tissue-specific promoter activity in the human genome
Abstract Transposable elements are abundant in the human genome and have been increasingly recognized as sources of alternative promoters. Yet, the extent of their transcriptional activity in human tissues and the features that govern their regulatory potential remain unclear. Here, we integrated high-resolution RAMPAGE data from 115 human biosamples to construct a comprehensive atlas of 26,056 transcription start sites derived from transposable elements. These sites contribute to tissue-specific gene expression, with a notable fraction originating from primate- and hominid-specific elements. Transposable element–derived transcription start sites exhibit focused, narrow-peak architectures enriched for TATA boxes and depleted of CpG islands. Phylogenetic analyses reveal a continuous gradient in promoter strength and transcriptional precision across transposable element subfamilies, with evolutionarily younger elements retaining intrinsic promoter motifs that drive focused and robust transcription, whereas older, more divergent elements exhibit broader initiation patterns and lower intrinsic activity. Together, these findings advance our understanding of how the evolution and preservation of promoter features shape the capacity of transposable elements to be exapted as functional promoters, potentially contributing to lineage-specific regulatory innovation in primates.
Early detection of aberrant cell fate and repair using circulating progenitor cells in patients with heterotopic ossification
Multicomponent synergistic immobilization via in-situ and dynamic exchange strategies for constructing hierarchical biopharmaceuticals
Real-time object detection for unmanned aerial vehicles based on vision transformer and edge computing
Establishment and application of safety evacuation scheme evaluation model with entropy weight and TOPSIS for university dormitories in China
Trends and oscillation characteristics of hourly PM2.5 levels in arid environment using wavelet coherence and lagged correlation
Deciphering a novel RP-HPLC based bioanalytical method for Estimation of xanthohumol in rat plasma and postbiotic-based nanostructured lipid carriers
Deep learning framework for timely detection and classification of chili leaf diseases and pests
Knowledge-grounded large language model for personalized sports training plan generation
Mechanical and durability performance of optimized geopolymer concrete with manufactured artificial aggregates using a tailored mix design method
Hemp seed extract exerts cytostatic effects through metabolic stress and autophagy modulation in malignant cells
Occupational polycyclic aromatic hydrocarbons (PAHs) exposure is associated with accelerated aging trajectories in Chinese coke oven workers
Abstract Long-term effects of occupational polycyclic aromatic hydrocarbons (PAHs) on biological aging are unclear. A prospective cohort study was conducted from 2019 to 2023, involving 610 coke oven workers and 454 control workers from a water treatment plant. Biological age was calculated using the Klemera and Doubal method (KDM-BA) based on 12 clinical biomarkers, and aging acceleration (KDM-Accel) was derived. Group-based trajectory modeling (GBTM) was employed to identify distinct aging trajectories over five time points. The associations between eleven urinary mono-hydroxylated PAH metabolites (measured via HPLC-MS) and both KDM-Accel and aging trajectories were assessed using multiple linear regression and multivariable logistic regression, respectively. GBTM identified three distinct aging trajectories: slow aging (14.86%), moderately accelerated aging (59.14%), and rapidly accelerated aging (26%). Higher concentrations of urinary Σ-OHPAHs (sum of all metabolites), 1-hydroxypyrene (1-OHPyr), and 2-hydroxyphenanthrene (2-OHPhe) were significantly associated with increased KDM-Accel. A natural log-unit increase in Σ-OHPAHs and 1-OHPyr was associated with a 0.029-year and 0.028-year increase in KDM-Accel, respectively. Workers in the highest tertile (T3) of Σ-OHPAHs exposure had a 61.2% increased odds (OR = 1.612, 95% CI 1.093–2.376) of being in the rapidly accelerated aging trajectory compared to those in the lowest tertile (T1). Similar positive dose-response relationships were observed. Occupational exposure to PAHs, as specifically indicated by elevated levels of urinaryΣ-OHPAHs, 1-OHPyr, and 2-OHPhe, is correlated with accelerated biological aging and a heightened probability of a rapid aging trajectory. Therefore, enhanced protection measures and early intervention strategies are necessary.