Nature Communications最新文献

Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.

The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env_371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env_371-379 peptides, we demonstrate that only the most stable Env_371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env_371-379 L6I-specific CD8⁺ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.

Efficiently mixed conduction between ionic and electronic charges stands to revolutionize the studies in organic electrochemical transistors (OECTs). However, inefficient ion transport due to the long-range injection and migration process in the bulk film presents challenges for enhancing the steady and transient performance of OECTs. In this work, we proposed a lateral intercalation-assisted ion transport strategy to assist volumetric ion charging, by introducing a striped microstructure in the conductive channel. By precisely adjusting the ratio of lateral area (RoL), the electrical performance, indicated by the maximum transconductance versus response time (G_m,max/τ), increases progressively by over 600%. We further unveiled the mechanism for the enhanced doping uniformity and increased volume capacitance at the lateral area. Based on the universality investigation, we uncovered the effects of molecular stacking on ionic lateral intercalation transport, contributing to the high-performance OECTs and the bio-applications in the recording of dynamic electrocardiography (ECG) signals with distinct features.

Developing a generalist radiology diagnosis system can greatly enhance clinical diagnostics. In this paper, we introduce RadDiag, a foundational model supporting 2D and 3D inputs across various modalities and anatomies, using a transformer-based fusion module for comprehensive disease diagnosis. Due to patient privacy concerns and the lack of large-scale radiology diagnosis datasets, we utilize high-quality, clinician-reviewed radiological images available online with diagnosis labels. Our dataset, RP3D-DiagDS, contains 40,936 cases with 195,010 scans covering 5568 disorders (930 unique ICD-10-CM codes). Experimentally, our RadDiag achieves 95.14% AUC on internal evaluation with the knowledge-enhancement strategy. Additionally, RadDiag can be zero-shot applied or fine-tuned to external diagnosis datasets sourced from various medical centers, demonstrating state-of-the-art results. In conclusion, we show that publicly shared medical data on the Internet is a tremendous and valuable resource that can potentially support building strong models for image understanding in healthcare.

The formation of transcription regulatory complexes by the association of Smad4 with Smad2 and Smad3 (Smad2/3) is crucial in the canonical TGFβ pathway. Although the central requirement of Smad4 as a common mediator is emphasized in regulating TGFβ signaling, it is not obligatory for all responses. The role of Smad2/3 independently of Smad4 remains understudied. Here, we introduce a stepwise paradigm in which Smad2/3 regulate the lineage priming and differentiation of mouse embryonic stem cells (mESCs) by collaboration with different effectors. During the naïve-to-primed transition, Smad2/3 upregulate DNA methyltransferase 3b (Dnmt3b), which establishes the proper DNA methylation patterns and, in turn, enables Smad2/3 binding to the hypomethylated centers of promoters and enhancers of epiblast marker genes. Consequently, in the absence of Smad2/3, Smad4 alone cannot initiate epiblast-specific gene transcription. When primed epiblast cells begin to differentiate, Dnmt3b becomes less actively engaged in global genome methylation, and Smad4 takes over the baton in this relay race, forming a complex with Smad2/3 to support mesendoderm induction. Thus, mESCs lacking Smad4 can undergo the priming process but struggle with the downstream differentiation. This work sheds light on the intricate mechanisms underlying TGFβ signaling and its role in cellular processes.

Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyzes, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172a^loxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity and our results mainly concern male mice.

CuInP₂S₆ (CIPS) is an emerging 2D ferroelectric material known for disrupting spatial inversion symmetry due to Cu(I) position switching. Its ferroelectricity strongly relies on the Cu(I) atom/ion occupation ordering and dynamics. Nevertheless, the accurate Cu(I) occupations and correlated migration dynamics under the externally applied energy, which are key to unlocking ferroelectric properties, remain controversial and unresolved. Herein, an atomic-level direct imaging through aberration-corrected scanning transmission electron microscopy is performed to precisely trace the Cu(I) dynamic behaviours under electron-beam irradiation along (100)-CIPS. It clearly demonstrates that Cu(I) possesses multiple occupations, and Cu(I) could migrate to the lattice, vacancy, interstitial and interlayer sites between the InS₆ octahedral skeletons of CIPS to form local Cu_xInP₂S₆ (x = 2-4) structure. Cu(I) multi-occupations induced lattice stress results in a layer sliding along the b-axis direction generating a sliding size of 1/6 b lattice constant. The Cu_xInP₂S₆ (x = 2-4) exists in a type of dynamic structure, only metastable with electron dose over 50 e⁻ Å⁻², thus generating a dynamic process of ({mbox{C}}{{mbox{u}}}_{x}{mbox{In}}{{mbox{P}}}_{2}{{mbox{S}}}_{6}(x=2-4)rightleftharpoons {mbox{CuIn}}{{mbox{P}}}_{2}{{mbox{S}}}_{6}), a completely unreported phenomenon. These findings shed light on the unveiled mechanism underlying Cu(I) migration in CIPS, providing crucial insights into the fundamental processes that govern its ferroelectric properties.

Color centers in silicon carbide (SiC) offer exciting possibilities for quantum information processing. However, the challenge of ionization during optical manipulation leads to charge variations, hampering the efficacy of spin-photon interfaces. Recent research predicted that modified divacancy color centers can stabilize their charge states, resisting photoionization. This study presents a method for precisely creating single divacancy arrays in 4H-SiC using a focused helium ion beam. Photoluminescence tests reveal consistent emission with minimal linewidth fluctuations (∼50 MHz over 3 h). By measuring the ionization rate for different polytypes of divacancies, we found that the modified divacancies are more robust against resonant excitation. Furthermore, angle-resolved photoluminescence excitation spectra unveil two resonant-transition lines with orthogonal polarizations. Enhanced optical and spin characteristics were notably observed in these color centers compared to those generated through carbon-ion and shallow implantation methods, positioning modified divacancies as promising contenders for advancing quantum networking.

Electro-selective-oxidation using water as a green oxygen source demonstrates promising potential towards efficient and sustainable chemical upgrading. However, surface micro-kinetics regarding co-adsorption and reaction between organic and oxygen intermediates remain unclear. Here we systematically study the electro-oxidation of aldehydes, alcohols, and amines on Co/Ni-oxyhydroxides with multiple characterizations. Utilizing Fourier transformed alternating current voltammetry (FTacV) measurements, we show the identification and quantification of two key operando parameters (ΔI_harmonics/I_OER and ΔV_harmonics) that can be fundamentally linked to the altered surface coverage ((Delta {theta }_{{{{{rm{OH}}}}}^{*}}/{theta }_{{{{{rm{OH}}}}}^{*}}^{{{{rm{OER}}}}})) and the changes in adsorption energy of vital oxygenated intermediates (({Delta G}_{{{{rm{OH}}}}*}^{{{{rm{EOOR}}}}}-{Delta G}_{{{{rm{OH}}}}*}^{{{{rm{OER}}}}})), under the influence of organic adsorption/oxidation. Mechanistic analysis based on these descriptors reveals distinct optimal oxyhydroxide surface states for each organics, and elucidates the critical catalyst design principles: balancing organic and M^3+δ−OH* coverages and fine-tuning ΔG for key elementary steps, e.g., via precise modulation of chemical compositions, crystallinity, defects, electronic structures, and/or surface bimolecular interactions.

Chiral metal surfaces provide an environment for enantioselective adsorption in various processes such as asymmetric catalysis, chiral recognition, and separation. However, they often suffer from limitations such as reduced enantioselectivity caused by kink coalescence and atomic roughness. Here, we present an approach using medium-entropy ceramic (MEC), specifically (CrMoTa)Si₂ with a C40 hexagonal crystal structure, which overcomes the trade-off between thermal stability and enantioselectivity. Experimental confirmation is provided by employing quartz crystal microbalance (QCM), where the electrode is coated with MEC films using non-reactive magnetron sputtering technology. The chiral nature is verified through transmission electron microscopy and circular dichroism. Density-functional theory (DFT) calculations show that the stability of MEC films is significantly higher than that of high-index Cu surfaces. Through a combination of high-throughput DFT calculations and theoretical modeling, we demonstrate the high enantioselectivity (42% e.e.) of the chiral MEC for serine, a prototype molecule for studying enantioselective adsorption. The QCM results show that the adsorption amount of L-serine is 1.58 times higher than that of D-serine within a concentration range of 0-60 mM. These findings demonstrate the potential application of MECs in chiral recognition.