Nature Communications最新文献

Electron shuttle plays a decisive role in extracellular electron transfer (EET) of exoelectrogens. However, neither identifying the most efficient electron shuttle molecule nor programming its optimal synthesis level that boosts EET has been established. Here, the phenazine-1-carboxylic acid (PCA) biosynthesis pathway is first constructed to synthesize PCA at an optimal level for EET in Shewanella oneidensis MR-1. To facilitate PCA transport, the porin OprF is expressed to improve cell membrane permeability, the cytotoxicity of which, however, impaired cell growth. To mitigate cytotoxicity, PCA biosensor is designed to dynamically decouple PCA biosynthesis and transport, resulting in the maximum output power density reaching 2.85 ± 0.10 W m⁻², 33.75-fold higher than wild-type strain. Moreover, extensive analyses of cellular electrophysiology, metabolism, and behaviors reveal PCA shuttles electrons from cell to electrode, which is the dominant mechanism underlying PCA-boosted EET. We conclude dynamic synthesis and transport of PCA is an efficient strategy for enhancing EET.

Neurobiological alterations seen in addiction amplify during abstinence and compromise relapse prevention. Cocaine use disorder (CUD) exemplifies this phenomenon in which reward regions such as nucleus accumbens (NAc) undergo withdrawal-associated modifications. While genome-wide transcriptional changes in NAc are linked to specific addiction phases, these have not been examined in a context- and NAc-subregion-specific manner during withdrawal vs. extinction. We used cocaine self-administration in male rats combined with RNA-sequencing of NAc-core and -shell to transcriptionally profile withdrawal in the home-cage, in the previous drug context, or after extinction. As expected, home-cage withdrawal maintained seeking, whereas extinction reduced it. By contrast, withdrawal involving the drug context only increased seeking. Bioinformatic analyses revealed specific gene expression patterns and networks associated with these states. Comparing NAc datasets of CUD patients highlighted conserved transcriptomic signatures with rats experiencing withdrawal in the drug context. Together, this work reveals fundamental mechanisms that can be targeted to attenuate relapse.

The high-resolution visualization of atomic structures is significant for understanding the relationship between the microscopic configurations and macroscopic properties of materials. However, a rapid, accurate, and robust approach to automatically resolve complex patterns in atomic-resolution microscopy remains difficult to implement. Here, we present a Trident strategy-enhanced disentangled representation learning method (a generative model), which utilizes a few unlabelled experimental images with abundant low-cost simulated images to generate a large corpus of annotated simulation data that closely resembles experimental results, producing a high-quality large-volume training dataset. A structural inference model is then trained via a residual neural network which can directly deduce the interlayer slip and rotation of diversified and complicated stacking patterns at van der Waals (vdW) interfaces with picometer-scale accuracy across various materials (e.g. MoS₂, WS₂, ReS₂, ReSe₂, and 1 T’-MoTe₂) with different layer numbers (bilayer and trilayers), demonstrating robustness to defects, imaging quality, and surface contaminations. The framework can also identify pattern transition interfaces, quantify subtle motif variations, and discriminate moiré patterns that are difficult to distinguish in frequency domains. Finally, the high-throughput processing ability of our method provides insights into a vdW epitaxy mode where various thermodynamically favorable slip stackings can coexist.

Current myocardial infarction (MI) treatment strategies remain challenged in suboptimal pharmacokinetics and potential adverse effects. Here we present a bioelectronic interface capable of producing on-demand abundant bioactive extracellular vesicles (EVs) near the MI area for in-situ localized treatment. The technology, termed electroactive patch for wirelessly and controllable EV generation (ePOWER), leverages wireless bioelectronic patch to stimulate embedded electrosensitive macrophages, actively modulating the biosynthesis of EVs and enabling EV production with high programmability to be delivered directly to the MI area. ~2400% more bioactive EVs were produced per cell under our ePOWER system. When surgically implanted, we demonstrate the therapeutic potential of in-situ EV production system to alleviate MI symptoms and improve cardiac function. This programmable ePOWER technology enables in-situ production of therapeutically rich EVs, thus reducing the need for exogenous cell expansion platforms and dedicated delivery, holding promise as a therapeutic all-in-one platform to treat various diseases.

Aging is characterized by changes in gene expression, some of which can drive deleterious cellular phenotypes and senescence. The transcriptional activation of senescence genes has been mainly attributed to epigenetic shifts, but the changes in chromatin accessibility and its underlying mechanisms remain largely elusive in natural aging. Here, we profiled chromatin accessibility in human dermal fibroblasts (HDFs) from individuals with ages ranging from neonatal to octogenarian. We found that AP-1 binding motifs are prevalent in elderly-specific accessible chromatin regions while neonatal-specific regions are highly enriched for TEAD binding motifs. We further show that TEAD4 and FOXM1 share a conserved transcriptional regulatory landscape controlled by a not previously described and age-dependent enhancer that loses accessibility with aging and whose deletion drives senescence. Finally, we demonstrate that FOXM1 ectopic expression in elderly cells partially resets chromatin accessibility to a youthful state due to FOXM1’s repressive function on several members of the AP-1 complex, which is known to trigger the senescence transcriptional program. These results place FOXM1 at a top hierarchical level in chromatin remodeling required to prevent senescence.

Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) is a homeostatic mechanism, controlling ER size, the removal of misfolded protein aggregates, and organelle damage. ER-phagy can also be stimulated by pathogen infection. However, the link between ER-phagy and bacterial infection remains poorly understood, as are the mechanisms evolved by pathogens to escape the effects of ER-phagy. Here, we show that Salmonella enterica serovar Typhimurium inhibits ER-phagy by targeting the ER-phagy receptor FAM134B, leading to a pronounced increase in Salmonella burden after invasion. Salmonella prevents FAM134B oligomerization, which is required for efficient ER-phagy. FAM134B knock-out raises intracellular Salmonella number, while FAM134B activation reduces Salmonella burden. Additionally, we found that Salmonella targets FAM134B through the bacterial effector SopF to enhance intracellular survival through ER-phagy inhibition. Furthermore, FAM134B knock-out mice infected with Salmonella presented severe intestinal damage and increased bacterial burden. These results provide mechanistic insight into the interplay between ER-phagy and bacterial infection, highlighting a key role for FAM134B in innate immunity.

Understanding flavivirus immunity is critical for the development of pan-flavivirus vaccines. Dendritic cells (DC) coordinate antiviral innate and adaptive immune responses, and they can be targeted by flaviviruses as a mechanism of immune evasion. Using an unbiased genome-wide approach designed to specifically identify flavivirus-modulated pathways, we found that, while dengue virus (DENV) robustly activates DCs, Zika virus (ZIKV) causes minimal activation of genes involved in DC activation, maturation, and antigen presentation, reducing cytokine secretion and the stimulation of allogeneic and peptide-specific T cell responses. Mechanistically, ZIKV inhibits DC maturation by suppressing NF-κB p65 recruitment and the subsequent transcription of proinflammatory and DC maturation-related genes. Thus, we identify a divergence in the effects of ZIKV and DENV on the host T cell response, highlighting the need to factor such differences into the design of anti-flavivirus vaccines.

Unlocking the potential of terahertz (THz) and millimeter (mm) waves for next generation communications and imaging applications requires reconfigurable intelligent surfaces (RIS) with programmable elements that can manipulate the waves in real-time. Realization of this technology has been hindered by the lack of efficient THz electro-optical materials and scalable THz semiconductor platform. Here, by merging graphene-based THz modulators and the thin-film transistor (TFT) technology, we demonstrate very-large-scale (>300000 pixels) spatial light modulator with individually addressable subwavelength pixels. We demonstrate electronically programmable reflection and transmission patterns of THz light over a large area with unprecedent levels of uniformity and reproducibility. To highlight the potential of these devices, we demonstrate a single pixel mm-wave camera capable of imaging metallic objects. Furthermore, we demonstrate dynamic beam steering with reconfigurable direction pattern. We anticipate that these results will provide realistic pathways to structure THz waves for applications in non-invasive THz imaging and next generation THz communications.

Individuals with retinal degenerative diseases struggle to restore vision due to the inability to regenerate retinal cells. Unlike cold-blooded vertebrates, mammals lack Müller glia (MG)-mediated retinal regeneration, indicating the limited regenerative capacity of mammalian MG. Here, we identify prospero-related homeobox 1 (Prox1) as a key factor restricting this process. Prox1 accumulates in MG of degenerating human and mouse retinas but not in regenerating zebrafish. In mice, Prox1 in MG originates from neighboring retinal neurons via intercellular transfer. Blocking this transfer enables MG reprogramming into retinal progenitor cells in injured mouse retinas. Moreover, adeno-associated viral delivery of an anti-Prox1 antibody, which sequesters extracellular Prox1, promotes retinal neuron regeneration and delays vision loss in a retinitis pigmentosa model. These findings establish Prox1 as a barrier to MG-mediated regeneration and highlight anti-Prox1 therapy as a promising strategy for restoring retinal regeneration in mammals.

Artificial intelligence (AI) models to identify heart failure (HF) with preserved ejection fraction (HFpEF) based on deep-learning of echocardiograms could help address under-recognition in clinical practice, but they require extensive validation, particularly in representative and complex clinical cohorts for which they could provide most value. In this study enrolling patients with HFpEF (cases; n = 240), and age, sex, and year of echocardiogram matched controls (n = 256), we compare the diagnostic performance (discrimination, calibration, classification, and clinical utility) and prognostic associations (mortality and HF hospitalization) between an updated AI HFpEF model (EchoGo Heart Failure v2) and existing clinical scores (H2FPEF and HFA-PEFF). The AI HFpEF model and H2FPEF score demonstrate similar discrimination and calibration, but classification is higher with AI than H2FPEF and HFA-PEFF, attributable to fewer intermediate scores, due to discordant multivariable inputs. The continuous AI HFpEF model output adds information beyond the H2FPEF, and integration with existing scores increases correct management decisions. Those with a diagnostic positive result from AI have a two-fold increased risk of the composite outcome. We conclude that integrating an AI HFpEF model into the existing clinical diagnostic pathway would improve identification of HFpEF in complex clinical cohorts, and patients at risk of adverse outcomes.