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Ultra-coherent meta-emitter tailors arbitrary thermal wavefront
Discover the maze-like network for glabridin biosynthesis
Ultralow CNT-reinforced phase-change fibers for scalable wearable thermoregulation
Probing the molecular structure at graphite–water interfaces by correlating 3D-AFM and SHINERS
Abstract Water at solid surfaces is key for many processes ranging from biological signal transduction to membrane separation and renewable energy conversion. However, under realistic conditions, which often include environmental and surface charge variations, the interfacial water structure remains elusive. Here we overcome this limit by combining three-dimensional atomic force microscopy (3D-AFM) and interface-sensitive shell-isolated nanoparticle enhanced Raman spectroscopy (SHINERS) to characterize the graphite–water interfacial structure in situ. Through correlative analysis of the spatial liquid density maps and vibrational peaks within ≈2 nm of the graphite surface, we find the existence of two interfacial configurations at open circuit potential, a transient state where pristine water exhibits strong hydrogen bond (H-bond) breaking effects, and a steady state with hydrocarbons dominating the interface and weak H-bond breaking in the surrounding water. At sufficiently negative potentials, both states transition into a stable structure featuring pristine water with a broader distribution of H-bond configurations. Our three-state model resolves many long-standing controversies on interfacial water structure.
Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C
Safety and biologic activity of a bispecific T cell receptor targeting HIV Gag in males living with HIV: a first-in-human trial
Abstract HIV persistence in reservoirs despite antiretroviral therapy (ART) is a barrier to a permanent cure. We present the affinity-enhanced TCR bispecific IMC-M113V as a potential therapeutic for targeted HIV reservoir elimination. Preclinical studies demonstrate that IMC-M113V redirects T cells towards cells expressing the variable viral peptide, Gag 77-85, presented by HLA-A*02:01 at low copy number, without binding to HIV-negative cells. Here, we conduct a first-in-human, open-label single ascending dose study of IMC-M113V (1.6-15 µg) in twelve HLA-A*02:01-positive males living with HIV on suppressive ART (EudraCT number 2021-002008-11). Participants receive one intravenous infusion of IMC-M113V on Day 1 and are monitored through Day 29 to evaluate safety, tolerability (primary endpoints) and pharmacodynamic (PD) activity (secondary endpoint). IMC-M113V is well tolerated and not associated with any serious adverse event. PD activity is dose-dependent and strongest in participants with highly IMC-M113V-sensitive Gag 77-85 variant sequences. Thus, we provide a promising foundation to evaluate multiple and higher doses of IMC-M113V as a strategy for achieving ART-free virological control.
Molecular signatures of resilience to Alzheimer’s disease in neocortical layer 4 neurons
Abstract Selective neuronal vulnerability is a hallmark of Alzheimer’s disease (AD), yet the molecular basis of resilience remains poorly understood. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex, precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB , CUX2 , and EYA4 . Layer 4 neurons in association neocortex shared molecular signatures of resilience. Early-stage resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotection ( GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1 , CSMD1) . We identified KCNIP4 , which encodes a voltage-gated potassium channel-interacting protein, as a key resilience factor consistently upregulated during early stages of AD pathology. AAV-mediated overexpression of Kcnip4 in male App SAA mice reduced the expression of activity-dependent genes Arc and c-Fos , suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a resource for investigating mechanisms underlying resilience to neurodegeneration.
A spatiotemporal atlas of cerebrovascular development in zebrafish
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.