Mitocytosis, a migrasome-mediated mitochondrial quality-control process.

Damaged mitochondria need to be cleared to maintain the quality of the mitochondrial pool. Here, we report mitocytosis, a migrasome-mediated mitochondrial quality-control process. We found that, upon exposure to mild mitochondrial stresses, damaged mitochondria are transported into migrasomes and subsequently disposed of from migrating cells. Mechanistically, mitocytosis requires positioning of damaged mitochondria at the cell periphery, which occurs because damaged mitochondria avoid binding to inward motor proteins. Functionally, mitocytosis plays an important role in maintaining mitochondrial quality. Enhanced mitocytosis protects cells from mitochondrial stressor-induced loss of mitochondrial membrane potential (MMP) and mitochondrial respiration; conversely, blocking mitocytosis causes loss of MMP and mitochondrial respiration under normal conditions. Physiologically, we demonstrate that mitocytosis is required for maintaining MMP and viability in neutrophils in vivo. We propose that mitocytosis is an important mitochondrial quality-control process in migrating cells, which couples mitochondrial homeostasis with cell migration.

Characterization of just one atom using synchrotron X-rays.

Since the discovery of X-rays by Roentgen in 1895, its use has been ubiquitous, from medical and environmental applications to materials sciences1-5. X-ray characterization requires a large number of atoms and reducing the material quantity is a long-standing goal. Here we show that X-rays can be used to characterize the elemental and chemical state of just one atom. Using a specialized tip as a detector, X-ray-excited currents generated from an iron and a terbium atom coordinated to organic ligands are detected. The fingerprints of a single atom, the L2,3 and M4,5 absorption edge signals for iron and terbium, respectively, are clearly observed in the X-ray absorption spectra. The chemical states of these atoms are characterized by means of near-edge X-ray absorption signals, in which X-ray-excited resonance tunnelling (X-ERT) is dominant for the iron atom. The X-ray signal can be sensed only when the tip is located directly above the atom in extreme proximity, which confirms atomically localized detection in the tunnelling regime. Our work connects synchrotron X-rays with a quantum tunnelling process and opens future X-rays experiments for simultaneous characterizations of elemental and chemical properties of materials at the ultimate single-atom limit.

Steering lithium and potassium storage mechanism in covalent organic frameworks by incorporating transition metal single atoms.

Organic electrodes mainly consisting of C, O, H, and N are promising candidates for advanced batteries. However, the sluggish ionic and electronic conductivity limit the full play of their high theoretical capacities. Here, we integrate the idea of metal-support interaction in single-atom catalysts with π-d hybridization into the design of organic electrode materials for the applications of lithium (LIBs) and potassium-ion batteries (PIBs). Several types of transition metal single atoms (e.g., Co, Ni, Fe) with π-d hybridization are incorporated into the semiconducting covalent organic framework (COF) composite. Single atoms favorably modify the energy band structure and improve the electronic conductivity of COF. More importantly, the electronic interaction between single atoms and COF adjusts the binding affinity and modifies ion traffic between Li/K ions and the active organic units of COFs as evidenced by extensive in situ and ex situ characterizations and theoretical calculations. The corresponding LIB achieves a high reversible capacity of 1,023.0 mA h g-1 after 100 cycles at 100 mA g-1 and 501.1 mA h g-1 after 500 cycles at 1,000 mA g-1. The corresponding PIB delivers a high reversible capacity of 449.0 mA h g-1 at 100 mA g-1 after 150 cycles and stably cycled over 500 cycles at 1,000 mA g-1. This work provides a promising route to engineering organic electrodes.

Bio-friendly long-term subcellular dynamic recording by self-supervised image enhancement microscopy.

Fluorescence microscopy has become an indispensable tool for revealing the dynamic regulation of cells and organelles. However, stochastic noise inherently restricts optical interrogation quality and exacerbates observation fidelity when balancing the joint demands of high frame rate, long-term recording and low phototoxicity. Here we propose DeepSeMi, a self-supervised-learning-based denoising framework capable of increasing signal-to-noise ratio by over 12 dB across various conditions. With the introduction of newly designed eccentric blind-spot convolution filters, DeepSeMi effectively denoises images with no loss of spatiotemporal resolution. In combination with confocal microscopy, DeepSeMi allows for recording organelle interactions in four colors at high frame rates across tens of thousands of frames, monitoring migrasomes and retractosomes over a half day, and imaging ultra-phototoxicity-sensitive Dictyostelium cells over thousands of frames. Through comprehensive validations across various samples and instruments, we prove DeepSeMi to be a versatile and biocompatible tool for breaking the shot-noise limit.

Long wavelength-emissive Ru(II) metallacycle-based photosensitizer assisting in vivo bacterial diagnosis and antibacterial treatment.

Ruthenium (Ru) complexes are developed as latent emissive photosensitizers for cancer and pathogen photodiagnosis and therapy. Nevertheless, most existing Ru complexes are limited as photosensitizers in terms of short excitation and emission wavelengths. Herein, we present an emissive Ru(II) metallacycle (herein referred to as 1) that is excited by 808-nm laser and emits at a wavelength of ∼1,000 nm via coordination-driven self-assembly. Metallacycle 1 exhibits good optical penetration (∼7 mm) and satisfactory reactive oxygen species production properties. Furthermore, 1 shows broad-spectrum antibacterial activity (including against drug-resistant Escherichia coli) as well as low cytotoxicity to normal mammalian cells. In vivo studies reveal that 1 is employed in precise, second near-infrared biomedical window fluorescent imaging-guided, photo-triggered treatments in Staphylococcus aureus-infected mice models, with negligible side effects. This work thus broads the applications of supramolecular photosensitizers through the strategy of lengthening their wavelengths.

Synaptotagmin-1 is a bidirectional Ca2+ sensor for neuronal endocytosis.

Exocytosis and endocytosis are tightly coupled. In addition to initiating exocytosis, Ca2+ plays critical roles in exocytosis­endocytosis coupling in neurons and nonneuronal cells. Both positive and negative roles of Ca2+ in endocytosis have been reported; however, Ca2+ inhibition in endocytosis remains debatable with unknown mechanisms. Here, we show that synaptotagmin-1 (Syt1), the primary Ca2+ sensor initiating exocytosis, plays bidirectional and opposite roles in exocytosis­endocytosis coupling by promoting slow, small-sized clathrin-mediated endocytosis but inhibiting fast, large-sized bulk endocytosis. Ca2+-binding ability is required for Syt1 to regulate both types of endocytic pathways, the disruption of which leads to inefficient vesicle recycling under mild stimulation and excessive membrane retrieval following intense stimulation. Ca2+-dependent membrane tubulation may explain the opposite endocytic roles of Syt1 and provides a general membrane-remodeling working model for endocytosis determination. Thus, Syt1 is a primary bidirectional Ca2+ sensor facilitating clathrin-mediated endocytosis but clamping bulk endocytosis, probably by manipulating membrane curvature to ensure both efficient and precise coupling of endocytosis to exocytosis.

Peripheral Control of the Assembly and Chirality of Anion-Based Octanuclear Cubes by Cation-π Networks.

Self-assembly of sophisticated polyhedral cages has drawn much attention because of their elaborate structures and potential applications. Herein, we report the anion-coordination-driven assembly of the first A8L12 (A = anion, L = ligand) octanuclear cubic structures from phosphate anion and p-xylylene-spaced bis-bis(urea) ligands via peripheral templating of countercations (TEA+ or TPA+). By attaching terminal aryl rings (phenyl or naphthyl) to the ligand through a flexible (methylene) linker, these aryls actively participate in the formation of plenty of "aromatic pockets" for guest cation binding. As a result, multiple peripheral guests (up to 22) of suitable size are bound on the faces and vertices of the cube, forming a network of cation-π interactions to stabilize the cube structure. More interestingly, when chiral ligands were used, either diastereomers of mixed Λ- and Δ-configurations (with TEA+ countercation) for the phosphate coordination centers or enantiopure cubes (with TPA+) were formed. Thus, the assembly and chirality of the cube can be modulated by remote terminal groups and peripheral templating tetraalkylammonium cations.

Multicomponent, Multicavity Metallacages That Contain Different Binding Sites for Allosteric Recognition.

The encapsulation of different guest molecules by their different recognition domains of proteins leads to selective binding, catalysis, and transportation. Synthetic hosts capable of selectively binding different guests in their different cavities to mimic the function of proteins are highly desirable but challenging. Here, we report three ladder-shaped, triple-cavity metallacages prepared by multicomponent coordination-driven self-assembly. Interestingly, the porphyrin-based metallacage is capable of heteroleptic encapsulation of fullerenes (C60 or C70) and coronene using its different cavities, allowing distinct allosteric recognition of coronene upon the addition of C60 or C70. Owing to the different binding affinities of the cavities, the metallacage hosts one C60 molecule in the central cavity and two coronene units in the side cavities, while encapsulating two C70 molecules in the side cavities and one coronene molecule in the central cavity. The rational design of multicavity assemblies that enable heteroleptic encapsulation and allosteric recognition will guide the further design of advanced supramolecular constructs with tunable recognition properties.

Multi-Scale Engineered 2D Carbon Polyhedron Array with Enhanced Electrocatalytic Performance.

Electrocatalyst engineering from the atomic to macroscopic level of electrocatalysts is one of the most powerful routes to boost the performance of electrochemical devices. However, multi-scale structure engineering mainly focuses on the range of atomic-to-particle scale such as hierarchical porosity engineering, while catalyst engineering at the macroscopic level, such as the arrangement configuration of nanoparticles, is often overlooked. Here, a 2D carbon polyhedron array with a multi-scale engineered structure via facile chemical etching, ice-templating induced self-assembly, and high-temperature pyrolysis processes is reported. Controlled phytic acid etching of the carbon precursor introduces homogeneous atomic phosphorous and nitrogen doping, as well as a well-defined mesoporous structure. Subsequent ice-templated self-assembly triggers the formation of a 2D particle array superstructure. The atomic-level doping gives rise to high intrinsic activity, while the well-engineered porous structure and particle arrangement addresses the mass transport limitations at the microscopic particle level and macroscopic electrode level. As a result, the as-prepared electrocatalyst delivers outstanding performance toward oxygen reduction reaction in both acidic and alkaline media, which is better than recently reported state-of-the-art metal-free electrocatalysts. Molecular dynamics simulation together with extensive characterizations indicate that the performance enhancement originates from multi-scale structural synergy.

Superstructured Carbon with Enhanced Kinetics for Zinc-Air Battery and Self-Powered Overall Water Splitting.

The present study proposes a novel engineering concept for the customization of functionality and construction of superstructure to fabricate 2D monolayered N-doped carbon superstructure electrocatalysts decorated with Co single atoms or Co2P nanoparticles derived from 2D bimetallic ZnCo-ZIF superstructure precursors. The hierarchically porous carbon superstructure maximizes the exposure of accessible active sites, enhances electron/mass transport efficiency, and accelerates reaction kinetics simultaneously. Consequently, the Co single atoms embedded N-doped carbon superstructure (Co-NCS) exhibits remarkable catalytic activity toward oxygen reduction reaction, achieving a half-wave potential of 0.886 V versus RHE. Additionally, the Co2P nanoparticles embedded N-doped carbon superstructure (Co2P-NCS) demonstrates high activity for both oxygen evolution reaction and hydrogen evolution reaction, delivering low overpotentials of 292 mV at 10 mA cm-2 and 193 mV at 10 mA cm-2 respectively. Impressively, when employed in an assembled rechargeable Zn-air battery, the as-prepared 2D carbon superstructure electrocatalysts exhibit exceptional performance with a peak power density of 219 mW cm-2 and a minimal charge/discharge voltage gap of only 1.16 V at 100 mA cm-2. Moreover, the cell voltage required to drive an overall water-splitting electrolyzer at a current density of 10 mA cm-2 is merely 1.69 V using these catalysts as electrodes.

A Two-Stage End-to-End Deep Learning Framework for Pathologic Examination in Skin Tumor Diagnosis.

Neurofibromas (NFs), Bowen disease (BD), and seborrheic keratosis (SK) are common skin tumors. Pathologic examination is the gold standard for diagnosis of these tumors. Current pathologic diagnosis is primarily based on microscopic observation, which is laborious and time-consuming. With digitization, artificial intelligence can be used to improve the efficiency of pathologic diagnosis. This research aims to develop an end-to-end extendable framework for the diagnosis of skin tumor based on pathologic slide images. NF, BD, and SK were selected as target skin tumors. A two-stage skin cancer diagnosis framework is proposed in this article, which consists of two parts: patches-wise diagnosis, and slide-wise diagnosis. Patches-wise diagnosis compares different convolutional neural networks to extract features and distinguish categories from patches generated in whole slide images. Slide-wise diagnosis combines attention graph gated network model prediction with post-processing algorithm. This approach can fuse information from feature-embedding learning and domain knowledge to draw conclusions. Training, validation, and testing were performed on NF, BD, SK, and negative samples. Accuracy and receiver operating characteristic curves were used to evaluate the classification performance. This study investigated the feasibility of skin tumor diagnosis from pathologic images and may be the first instance of applying deep learning to address these three types of tumor diagnoses in skin pathology.

Jasmonates regulate apical hook development by repressing brassinosteroid biosynthesis and signaling.

An apical hook is a special structure formed during skotomorphogenesis in dicotyledonous plant species. It is critical for protecting the shoot apical meristem from mechanical damage during seed germination and hypocotyl elongation in soil. Brassinosteroid (BR) and jasmonate (JA) phytohormones antagonistically regulate apical hook formation. However, the interrelationship between BRs and JAs in this process has not been well elucidated. Here, we reveal that JAs repress BRs to regulate apical hook development in Arabidopsis (Arabidopsis thaliana). Exogenous application of methyl jasmonate (MeJA) repressed the expression of the rate-limiting BR biosynthetic gene DWARF4 (DWF4) in a process relying on 3 key JA-dependent transcription factors, MYC2, MYC3, and MYC4. We demonstrated that MYC2 interacts with the critical BR-activated transcription factor BRASSINAZOLE RESISTANT 1 (BZR1), disrupting the association of BZR1 with its partner transcription factors, such as those of the PHYTOCHROME INTERACTING FACTOR (PIF) family and downregulating the expression of their target genes, such as WAVY ROOT GROWTH 2 (WAG2), encoding a protein kinase essential for apical hook development. Our results indicate that JAs not only repress the expression of BR biosynthetic gene DWF4 but, more importantly, attenuate BR signaling by inhibiting the transcriptional activation of BZR1 by MYC2 during apical hook development.

Randomness-Enhanced Expressivity of Quantum Neural Networks.

As a hybrid of artificial intelligence and quantum computing, quantum neural networks (QNNs) have gained significant attention as a promising application on near-term, noisy intermediate-scale quantum devices. Conventional QNNs are described by parametrized quantum circuits, which perform unitary operations and measurements on quantum states. In this Letter, we propose a novel approach to enhance the expressivity of QNNs by incorporating randomness into quantum circuits. Specifically, we introduce a random layer, which contains single-qubit gates sampled from a trainable ensemble pooling. The prediction of QNN is then represented by an ensemble average over a classical function of measurement outcomes. We prove that our approach can accurately approximate arbitrary target operators using Uhlmann's theorem for majorization, which enables observable learning. Our proposal is demonstrated with extensive numerical experiments, including observable learning, Rényi entropy measurement, and image recognition. We find the expressivity of QNNs is enhanced by introducing randomness for multiple learning tasks, which could have broad application in quantum machine learning.

Effects of an Early Intensive Blood Pressure-lowering Strategy Using Remifentanil and Dexmedetomidine in Patients with Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Superiority, Randomized Controlled Trial.

BACKGROUND: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. METHODS: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes. RESULTS: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. CONCLUSIONS: Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

A DM9-containing protein from crab Eriocheir sinensis functions as a novel multipotent pattern recognition receptor.

DM9-containing protein in invertebrates functions as pattern recognition receptor (PRR) to play significant roles in innate immunity. In the present study, a novel DM9-containg protein (defined as EsDM9CP-1) was identified from the Chinese mitten crab Eriocheir sinensis. EsDM9CP-1 is composed of 330 amino acids containing a Methyltransf_FA domain and two tandem DM9 repeats. The deduced amino acid sequence of EsDM9CP-1 shared low similarity with the previously identified DM9CPs from other species, and it was closely clustered with Platyhelminthes DM9CPs and then assigned into the branch of invertebrate DM9CPs in the unrooted phylogenetic tree. The mRNA transcripts of EsDM9CP-1 were highly expressed in haemocytes, gill, and heart. After Aeromonas hydrophila stimulation, the expression levels of EsDM9CP-1 mRNA in haemocytes increased significantly at 3 h (3.88-fold, p < 0.05) and 6 h (2.71-fold, p < 0.05), compared with that of PBS group, respectively. EsDM9CP-1 protein was mainly distributed in the cytoplasm and membrane of haemocytes. The recombinant EsDM9CP-1 protein (rEsDM9CP-1) exhibited binding affinity to MAN, PGN, LPS and Poly (I:C), and also to Gram-positive bacteria (Staphylococcus aureus, Micrococcus luteus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli, A. hydrophila and Vibrio splendidus) and fungi (Pichia pastoris and Metschnikowia bicuspidata) in a Ca2+-dependent manner. It was able to agglutinate A. hydrophila, S. aureus, M. luteus, M. bicuspidata and P. pastoris, and inhibit the growth of A. hydrophila and M. bicuspidate. These results suggested that EsDM9CP-1 in crab not only functioned as a PRR, but also agglutinated and inhibited the growth of microbes.

A light-controlled single-atom nanozyme hydrogels for glutathione depletion mediated low-dose radiotherapy.

Due to the unique ability to mimic natural enzymes, single-atom nanoenzymes (SAE) have garnered significant attention and research in tumor therapy. However, their efficacy often faces challenges in terms of drug delivery methods, and the research regarding their applications in radiotherapy is scarce. Herein, we introduce a light-controlled SAE hydrogel platform (SH) for glutathione-depletion-mediated low-dose radiotherapy. The SH incorporates a Cu single-atom enzyme (CuSA), and upon irradiation with 1064 nm near-infrared light, the CuSA can convert light energy into heat, which in turn degrades the hydrogel, enabling the release of CuSA into tumor cells or tissues. The diffused CuSA not only can facilitate the conversion of H2O2into hydroxyl radicals (•OH), but also can effectively depletes cellular glutathione. This leads to increased sensitivity of tumor cells to radiotherapy, resulting in enhanced cytotoxicity even at low doses. The animal study results further confirmed the good tumor-killing efficacy of this SH system. To the best of our knowledge, this stands as the pioneering report on leveraging a single-atom enzyme for GSH depletion-mediated low-dose radiotherapy.

Publisher Correction: Photoswitching topology in polymer networks with metal-organic cages as crosslinks.

The green arrow in Fig. 3 has been restored online.

Photoswitching topology in polymer networks with metal-organic cages as crosslinks.

Polymer networks can have a range of desirable properties such as mechanical strength, wide compositional diversity between different materials, permanent porosity, convenient processability and broad solvent compatibility1,2. Designing polymer networks from the bottom up with new structural motifs and chemical compositions can be used to impart dynamic features such as malleability or self-healing, or to allow the material to respond to environmental stimuli3-8. However, many existing systems exhibit only one operational state that is defined by the material's composition and topology3-6; or their responsiveness may be irreversible7,9,10 and limited to a single network property11,12 (such as stiffness). Here we use cooperative self-assembly as a design principle to prepare a material that can be switched between two topological states. By using networks of polymer-linked metal-organic cages in which the cages change shape and size on irradiation, we can reversibly switch the network topology with ultraviolet or green light. This photoswitching produces coherent changes in several network properties at once, including branch functionality, junction fluctuations, defect tolerance, shear modulus, stress-relaxation behaviour and self-healing. Topology-switching materials could prove useful in fields such as soft robotics and photo-actuators as well as providing model systems for fundamental polymer physics studies.

In-Silico and in vitro Studies Revealed that Rosmarinic Acid Inhibited Methanogenesis via Regulating Composition and Function of Rumen Microbiota.

Inhibition of methyl-coenzyme M reductase can suppress the activity of ruminal methanogens, thereby reducing enteric methane emissions of ruminants. However, developing specific and environmentally friendly inhibitors is a challenging endeavor. To identify a natural and effective methane inhibitor that specifically targets methyl-coenzyme M reductase, molecular docking technology was employed to screen a library of phytogenic compounds. A total of 52 candidate compounds were obtained through molecular docking technique. Rosmarinic acid (RA) was one of the compounds that could traverse a narrow channel and bind to the active sites of methyl-coenzyme M reductase, with a calculated binding free energy of -9.355 kcal/mol. Furthermore, the effects of rosmarinic acid supplementation on methane production, rumen fermentation, and the microorganism's community in dairy cows were investigated through in vitro rumen fermentation simulations according to a random design. Supplementation of RA resulted in a 15% decrease in methane production compared with the control. In addition, RA increased the molar proportion of acetate and propionate, whereas the sum of acetate and butyrate divided by propionate was decreased. At the bacterial level, the relative abundance of Rikenellaceae RC9 gut group, Christensenellaceae R7 group, Candidatus Saccharimonas, Desulfovibrio, and Lachnospiraceae FE2018 group decreased with RA supplementation. Conversely, the addition of RA significantly increased the relative abundance of DNF00809 (a genus from Eggerthellaceae), Denitrobacterium, an unclassified genus from Eggerthellaceae, an unclassified genus from Bacteroidales, and an unclassified genus from Atopobiaceae. At the archaeal level, the relative abundance of Methanobrevibacter decreased, while that of Methanosphaera increased with the RA supplementation. These findings suggested that RA has the potential to be used as a novel natural additive for inhibiting ruminal methane production.

Enhanced wave absorption due to local flexibility on wide beams using mass-spring-damper scatterersa).

It is known that total absorption of flexural waves in a thin beam is possible through the use of monopole-dipole scatterers. In this study, we introduce a pair of identical monopole scatterers for near-total absorption of flexural waves in a thin and wide beam. Despite the two scatterers being both of the monopole type, the resonant modes of the scatterer pair exhibit monopole and dipole properties. By selecting the proper width for the beam, the two resonant modes degenerate, which leads to the total absorption. Although the beam is considerably wide, the frequency range of interest remains below the cut-on frequency of the n = 1 propagating mode, ensuring one-dimensional flexural wave propagation. Further simulations and theoretical analysis revealed that the degeneracy of the monopole and dipole modes results from their interaction with a higher-order localized flexural mode. The simulation results demonstrate absorption exceeding 99%, complemented by experimental data showing approximately 90% absorption.