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Acute Myocardial Infarction (AMI) has seen rising cases, particularly in younger people, leading to public health concerns. Standard treatments, like coronary artery recanalization, often don't fully repair the heart's microvasculature, risking heart failure. Advances show that Mesenchymal Stromal Cells (MSCs) transplantation improves cardiac function after AMI, but the harsh microenvironment post-AMI impacts cell survival and therapeutic results. MSCs aid heart repair via their membrane proteins and paracrine extracellular vesicles that carry microRNA-125b, which regulates multiple targets, preventing cardiomyocyte death, limiting fibroblast growth, and combating myocardial remodeling after AMI. This study introduces ultrasound-responsive phase-change bionic nanoparticles, leveraging MSCs' natural properties. These particles contain MSC membrane and microRNA-125b, with added macrophage membrane for stability. Using Ultrasound Targeted Microbubble Destruction (UTMD), this method targets the delivery of MSC membrane proteins and microRNA-125b to AMI's inflamed areas. This aims to enhance cardiac function recovery and provide precise, targeted AMI therapy.

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Multi-modal spatial omics data are invaluable for exploring complex cellular behaviors in diseases from both morphological and molecular perspectives. Current analytical methods primarily focus on clustering and classification, and do not adequately examine the relationship between cell morphology and molecular dynamics. Here, we present MorphLink, a framework designed to systematically identify disease-related morphological-molecular interplays. MorphLink has been evaluated across a wide array of datasets, showcasing its effectiveness in extracting and linking interpretable morphological features with various molecular measurements in multi-modal spatial omics analyses. These linkages provide a transparent depiction of cellular behaviors that drive transcriptomic heterogeneity and immune diversity across different regions within diseased tissues, such as cancer. Additionally, MorphLink is scalable and robust against cross-sample batch effects, making it an efficient method for integrative spatial omics data analysis across samples, cohorts, and modalities, and enhancing the interpretation of results for large-scale studies.

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Higher-order topological phases in non-Hermitian photonics revolutionize the understanding of wave propagation and modulation, which lead to hierarchical states in open systems. However, intrinsic insulating properties endorsed by the lattice symmetry of photonic crystals fundamentally confine the robust transport only at explicit system boundaries, letting alone the flexible reconfiguration in hierarchical states at arbitrary positions. Here, we report a dynamic topological platform for creating the reconfigurable hierarchical bound states in heat transport systems and observe the robust and nonlocalized higher-order states in both the real- and imaginary-valued bands. Our experiments showcase that the hierarchical features of zero-dimension corner and nontrivial edge modes occur at tailored positions within the system bulk states instead of the explicit system boundaries. Our findings uncover the mechanism of non-localized hierarchical non-trivial topological states and offer distinct paradigms for diffusive transport field management.

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As a potent and convenient genome-editing tool, Cas9 has been widely used in biomedical research and evaluated in treating human diseases. Numerous engineered variants of Cas9, dCas9 and other related prokaryotic endonucleases have been identified. However, as these bacterial enzymes are not naturally present in mammalian cells, whether and how bacterial Cas9 proteins are recognized and regulated by mammalian hosts remain poorly understood. Here, we identify Keap1 as a mammalian endogenous E3 ligase that targets Cas9/dCas9/Fanzor for ubiquitination and degradation in an 'ETGE'-like degron-dependent manner. Cas9-'ETGE'-like degron mutants evading Keap1 recognition display enhanced gene editing ability in cells. dCas9-'ETGE'-like degron mutants exert extended protein half-life and protein retention on chromatin, leading to improved CRISPRa and CRISPRi efficacy. Moreover, Cas9 binding to Keap1 also impairs Keap1 function by competing with Keap1 substrates or binding partners for Keap1 binding, while engineered Cas9 mutants show less perturbation of Keap1 biology. Thus, our study reveals a mammalian specific Cas9 regulation and provides new Cas9 designs not only with enhanced gene regulatory capacity but also with minimal effects on disrupting endogenous Keap1 signaling.

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Eutrophication reduces the variability of the community composition of plankton. However, the mechanisms underlying the diversity and restructuring of eukaryotic algal communities remain unknown. This study analysed the diversity and compositional patterns of algal communities in shallow eutrophic lakes. It investigated how these communities were modified by key genera through mediating inter-algal associations under the influence of abiotic factors. Inter-algal associations explained more variance in algal communities than environmental variables, and variation in composition and diversity was primarily derived from Scenedesmus, Desmodesmus and Cryptomonas, rather than nutrients. Scenedesmus and Desmodesmus were positively correlated with the genera of Chlorophyta and formed the hub of the algal association network. When the relative abundance of Scenedesmus and Desmodesmus increased from 0.41% to 13.74%, communities enriched in biomarkers of Bacillariophyta, Chrysophyceae and Cryptophyta transitioned to communities enriched in biomarkers of Chlorophyta. Moreover, negative associations between the Chlorophyta hub genera and other non-Chlorophyta genera increased. High concentrations of total phosphorus altered the composition of algal communities by increasing the abundance of Scenedesmus and Desmodesmus, which in turn had cascading effects through inter-algal associations. Additionally, algal communities with higher abundances of Scenedesmus and Desmodesmus were more susceptible to the effects of total phosphorus. Our study suggested that inter-algal associations, centred on Scenedesmus and Desmodesmus, had a greater influence on algal diversity and community structure than other factors. Nutrient levels were not a direct driver of algal diversity and community structure adjustments, but acted indirectly by enhancing the influence of Scenedesmus and Desmodesmus.

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BACKGROUND: Parasitic diseases remain a serious public health problem in China. Health education aimed at disseminating health-related knowledge and promoting healthy behaviours, plays a crucial role in the prevention and control of parasitic diseases. This study aims to develop a tool to measure the parasitic disease health literacy of residents in China. METHODS: Scale development was based on qualitative and quantitative methods. Qualitative method included focus group discussions and Delphi consultations. A methodological design with multistage sampling and a pilot study was used to evaluate the questionnaire. The scale's reliability was tested using Cronbach's α and split-half reliability, while its construct validity was assessed using confirmatory factor analysis. The scale's passing score was determined using the receiver operating characteristic curve. A cross-sectional survey was conducted in six districts of the prefecture of Jiangsu and residents aged 14-69 years in the participating townships were randomly selected based on their location. RESULTS: The health literacy indicator system for parasitic diseases included 3 first-level, 9 s-level and 23 third-level indicators. The 23-item questionnaire demonstrated good internal consistency (Cronbach's alpha = 0.774) and split-half reliability (Spearman-Brown coefficient = 0.778). The questionnaire's passing score was 60. A total of 990 valid questionnaires were collected from participants in three cities. The percentage of participants with health literacy regarding parasitic diseases was 15.8%. Their scores were influenced by age, income, employment, and educational level. CONCLUSIONS: Health literacy of parasitic diseases is an integrated indicator rather than just knowledge or behavior information. The correlation between knowledge and behavior is weak. The capacity for healthy behavior of parasitic disease is associated with the location and culture of the city. For neglected diseases, it is important for people to talk positively about their behaviors with a doctor.

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It is extremely difficult to inject a low-energy electron beam into a conventional radiofrequency (RF) linear ion trap for electron capture dissociation (ECD) without using a magnetic field to focus the electrons. In this study, the dynamic process of electrons in an RF field during their injection and transmission through a linear ion trap was simulated to determine the range of the RF phase where the electrons can be decelerated to meet the energy requirement for ECD. The ECD time window was expanded by applying a time-dependent compensation voltage to the cathode. The relationship between the cathode voltage and the phase of the RF voltage was determined. The ECD time window was increased to 49.4% of the total RF cycle after applying a compensation voltage. Between the phases of RF voltage of 0 and 0.975 π, at least 98.7% of electrons can be injected into the ECD reaction zone, and 94% of them had an energy less than 3 eV. The range of electron energy can also easily be shifted upward to enable hot electron capture dissociation.

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Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35-40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel-Lindau (VHL) protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, anti-angiogenic tyrosine kinase inhibitors (TKIs) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anti-cancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and non-immune (blood vessels, osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies.

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Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI's robust and consistent performance.

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Benthivorous fish disturbance and density-dependent competition from adjacent macrophytes are two important biotic factors that significantly impact the growth of submerged macrophyte pioneer species, which is crucial for the success of eutrophication lake restoration. We conducted an outdoor mesocosm experiment to explore the individual and combined effects of these two factors on water quality and the growth of Vallisneria natans. The experiment involved two levels of fish (Misgurnus anguillicaudatus) disturbance crossed with two levels of Hydrilla verticillata vegetative propagule (shoot) intensity. The results showed that fish disturbance significantly increased the water column total nitrogen (TN), ammonia nitrogen (N-NH4), total phosphorus (TP), and phosphate­phosphorus (P-PO4). V. natans exhibited restricted plant height elongation and decreased soluble carbohydrate (SC) and starch concentration in fish treatments. Fish disturbance inhibited the growth advantage of V. natans by increasing the extinction coefficient of the water column. There was no statistical significance in total biomass between the two macrophytes in increased vegetative propagule and fish treatments. H. verticillata exhibited a higher relative growth rate (RGR) and summed dominance ratio (SDR3) than V. natans in four treatments and the treatment with three shoots of H. verticillata and one M anguillicaudatus, respectively. Fish disturbance and vegetative propagules showed cumulative effects that negatively affected the RGR_V.H (V. natans relative to H. verticillata). Our findings indicated that benthivorous fish disturbance and vegetative propagules could individually and cumulatively reduce the growth advantage of the pioneer species, V. natans. Our study sheds light on the accumulated effects of multiple disturbances that simultaneously occur in lakes, which holds theoretical and practical importance for lake restoration efforts.

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Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

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The topological physics has sparked intensive investigations into topological lattices in photonic, acoustic, and mechanical systems, powering counterintuitive effects otherwise inaccessible with usual settings. Following the success of these endeavors in classical wave dynamics, there has been a growing interest in establishing their topological counterparts in diffusion. Here, we propose an additional real-space dimension in diffusion, and the system eigenvalues are transformed from "imaginary" to "real." By judiciously tailoring the effective Hamiltonian with coupling networks, localized and delocalized topological modes are realized in heat transfer. Simulations and experiments in active thermal lattices validate the effectiveness of the proposed theoretical strategy. This approach can be applied to establish various topological lattices in diffusion systems, offering insights into engineering topologically protected edge states in dynamic diffusive scenarios.

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BACKGROUND AND AIMS: Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression. METHODS: NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs. RESULTS: Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade. CONCLUSIONS: This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.

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Intercellular cell adhesion molecule-1 (ICAM-1) is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the mechanism underlying the negative effects of neoplastic ICAM-1 remains obscure. Herein, we demonstrate that the survival of NSCLC cells but not normal human bronchial epithelial cells requires an anti-apoptosis signal triggered by fibrinogen γ chain (FGG)-ICAM-1 interaction. ICAM-1-FGG ligation preserves the tyrosine phosphorylation of ICAM-1 cytoplasmic domain and its association with SHP-2, and subsequently promotes Akt and ERK1/2 activation but suppresses JNK and p38 activation. Abolishing ICAM-1-FGG interaction induces NSCLC cell death by activating caspase-9/3 and significantly inhibits tumor development in a mouse xenograft model. Finally, we developed a monoclonal antibody against ICAM-1-FGG binding motif, which blocks ICAM-1‒FGG interaction and effectively suppresses NSCLC cell survival in vitro and tumor growth in vivo. Thus, suppressing ICAM-1-FGG axis provides a potential strategy for NSCLC targeted therapy.

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Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.

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Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

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INTRODUCTION: The diversity in microglial phenotypes and functions following traumatic brain injury (TBI) is poorly characterized. The aim of this study was to explore precise targets for improving the prognosis of TBI patients from a microglial perspective. OBJECTIVES: To assess whether the prognosis of TBI can be improved by modulating microglia function. RESULTS: In CD300LF-deficient mice, we observed an increase in glial cell proliferation, more extensive neuronal loss, and worsened neurological function post-TBI. Transcriptomic comparisons between CD300LF-positive and CD300LF-negative microglia illuminated that the neuroprotective role of CD300LF is principally mediated by the inhibition of the STING signaling pathway. In addition, this protective effect can be augmented using the STING pathway inhibitor C-176. CONCLUSIONS: Our research indicates that CD300LF reduces neuroinflammation and promotes neurological recovery after TBI, and that microglia are integral to the protective effects of CD300LF in this context. In summary, our findings highlight CD300LF as a critical molecular regulator modulating the adverse actions of microglia following acute brain injury and propose a novel therapeutic approach to enhance outcomes for patients with TBI.

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During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.

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This in vitro study was to evaluate the effect of different non-thermal atmospheric pressure plasma (NTP) on shear bond strength (SBS) between yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) and self-adhesive resin cement. In this study, The Y-TZP specimens were divided into 4 groups according to the surface treatment methods as follows: Control (no surface treatment), Sb (Sandblasting), AP(argon NTP), and CP(20 % oxygen and 80 % argon combination NTP). Y-TZP specimens were randomly selected from each group to observe and test the following indexes: scanning electron microscope to observe the surface morphology; atomic force microscope to detect the surface roughness; contact angle detector to detect the surface contact angle; energy spectrometer to analyze the surface elements. Then, resin cement (Rely X-U200) was bonded to human isolated teeth with Y-TZP specimens to measure SBS. The results showed that for the SE test, the NTP group was significantly higher than the control group (p < 0.05). The results of the SBS test showed that the SBS values of the NTP group were significantly higher than those of the other groups, regardless of the plasma treatment (p < 0.05). However, there was no significant difference between groups AP and CP in a test of SBS (p > 0.05). This study shows that non-thermal atmospheric pressure plasma can improve the shear bond strength of Y-TZP by increasing the surface energy. The addition of oxygen ratio to argon is more favorable to increase the shear bond strength and is worth further investigation.

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Non-iatrogenic trauma of the iliac artery is rarely reported but is always life-threatening. In this report, we describe the case of a child with complete transection and partial disappearance of the iliac artery caused by bicycle handlebar impalement. He experienced catastrophic hemorrhage, malignant arrhythmia, and difficulty in exploring transected vessel stumps. Aggressive infusion, blood transfusion in time, and pediatric vascular characteristics help delay the deterioration during anesthesia induction. Eventually he was successfully rescued by performing interventional balloon occlusion and open revascularization after more than 7 h post-trauma. A series of interventions and precautionary methods may benefit such severely injured patients; thus, these methods should be highlighted.

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