Promising Application, Efficient Production, and Genetic Basis of Mannosylerythritol Lipids.

Mannosylerythritol lipids (MELs) are a class of glycolipids that have been receiving increasing attention in recent years due to their diverse biological activities. MELs are produced by certain fungi and display a range of bioactivities, making them attractive candidates for various applications in medicine, agriculture, and biotechnology. Despite their remarkable qualities, industrial-scale production of MELs remains a challenge for fungal strains. Excellent fungal strains and fermentation processes are essential for the efficient production of MELs, so efforts have been made to improve the fermentation yield by screening high-yielding strains, optimizing fermentation conditions, and improving product purification processes. The availability of the genome sequence is pivotal for elucidating the genetic basis of fungal MEL biosynthesis. This review aims to shed light on the applications of MELs and provide insights into the genetic basis for efficient MEL production. Additionally, this review offers new perspectives on optimizing MEL production, contributing to the advancement of sustainable biosurfactant technologies.

Long non-coding RNAs as promising targets for controlling disease vector mosquitoes.

Hematophagous female mosquitoes are important vectors of numerous devastating human diseases, posing a major public health threat. Effective prevention and control of mosquito-borne diseases rely considerably on progress in understanding the molecular mechanisms of various life activities, and accordingly, the molecules that regulate the various life activities of mosquitoes are potential targets for implementing future vector control strategies. Many long non-coding RNAs (lncRNAs) have been identified in mosquitoes and significant progress has been made in determining their functions. Here, we present a comprehensive overview of the research advances on mosquito lncRNAs, including their molecular identification, function, and interaction with other non-coding RNAs, as well as their synergistic regulatory roles in mosquito life activities. We also highlight the potential roles of competitive endogenous RNAs in mosquito growth and development, as well as in insecticide resistance and virus-host interactions. Insights into the biological functions and mechanisms of lncRNAs in mosquito life activities, viral replication, pathogenesis, and transmission will contribute to the development of novel drugs and safe vaccines.

Sanxiapeptin is an ideal preservative with a dual effect of controlling green mold and inducing systemic defense in postharvest citrus.

Green mold is a common postharvest disease infected by Penicillium digitatum that causes citrus fruit decay, and severely affects fruit storage quality. This work aimed to investigate the antifungal activity of Sanxiapeptin against P. digitatum, and elucidate the possible mechanisms involved. Sanxiapeptin was capable of inhibiting spore germination, germ tube length and mycelial growth. The SYTOX green staining assay revealed that Sanxiapeptin targeted the fungal membrane, and changed the membrane permeability, leading to the leakage of cell constituents. Meanwhile, Sanxiapeptin could influence the cell wall permeability and integrity by increasing the activities of chitinase and glucanase, resulting in abnormal chitin consumption and the decrease of glucan. Intriguingly, Sanxiapeptin could effectively control postharvest decay in citrus fruits, and activate the host resistance responses by regulating the phenylpropanoid pathway. In conclusion, Sanxiapeptin exhibits multiphasic antifungal mechanisms of action to control green mold in citrus fruits, shows great potential as novel food preservatives.

Long-term residue returning increased subsoil carbon quality in a rice-wheat cropping system.

Residue returning (RR) was widely implemented to increase soil organic carbon (SOC) in farmland. Extensive studies concentrated on the effects of RR on SOC quantity instead of SOC fractions at aggregate scales. This study investigated the effects of 20-year RR on the distribution of labile (e.g., dissolved, microbial biomass, and permanganate oxidizable organic) and stable (e.g., microbial necromass) carbon fractions at aggregate scales, as well as their contribution to SOC accumulation and mineralization. The findings indicated a synchronized variation in the carbon content of bacterial and fungal necromass. Residue retention (RR) notably elevated the concentration of bacterial and fungal necromass carbon, while it did not amplify the microbial necromass carbon (MNC) contribution to SOC when compared to residue removal (R0) in the topsoil (0-5 cm). In the subsoil (5-15 cm), RR increased the MNC contribution to SOC concentration by 21.2%-33.4% and mitigated SOC mineralization by 12.6% in micro-aggregates (P < 0.05). Besides, RR increased soil ß-glucosidase and peroxidase activities but decreased soil phenol oxidase activity in micro-aggregates (P < 0.05). These indicated that RR might accelerate cellulose degradation and conversion to stable microbial necromass C, and thus RR improved SOC stability because SOC occluded in micro-aggregates were more stable. Interestingly, SOC concentration was mainly regulated by MNC, while SOC mineralization was by dissolved organic carbon under RR, both of which were affected by soil carbon, nitrogen, and phosphorus associated nutrients and enzyme activities. The findings of this study emphasize that the paths of RR-induced SOC accumulation and mineralization were different, and depended on stable and labile C, respectively. Overall, long-term RR increased topsoil carbon quantity and subsoil carbon quality.

A spatiotemporal atlas of mouse liver homeostasis and regeneration.

The mechanism by which mammalian liver cell responses are coordinated during tissue homeostasis and perturbation is poorly understood, representing a major obstacle in our understanding of many diseases. This knowledge gap is caused by the difficulty involved with studying multiple cell types in different states and locations, particularly when these are transient. We have combined Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) with single-cell transcriptomic profiling of 473,290 cells to generate a high-definition spatiotemporal atlas of mouse liver homeostasis and regeneration at the whole-lobe scale. Our integrative study dissects in detail the molecular gradients controlling liver cell function, systematically defining how gene networks are dynamically modulated through intercellular communication to promote regeneration. Among other important regulators, we identified the transcriptional cofactor TBL1XR1 as a rheostat linking inflammation to Wnt/ß-catenin signaling for facilitating hepatocyte proliferation. Our data and analytical pipelines lay the foundation for future high-definition tissue-scale atlases of organ physiology and malfunction.

Ion Transport in Multi-Nanochannels Regulated by pH and Ion Concentration.

Nanochannels are a powerful technique for detecting a wide range of biomolecules without labeling. The ion transport phenomena in nanochannel arrays differ from those in single nanochannels and are caused by interchannel communication. This study uses a fully coupled Poisson-Nernst-Planck (PNP) and Navier-Stokes model to investigate ion transport in nanochannel arrays. Instead of being set at a constant value, the surface charge density used in this study is established by the protonation and deprotonation of the silanol groups that are present on the walls of the silicon-based nanochannels. The surface charge density of the nanochannel walls varies with the number of nanochannels, the channel lateral distance, and the background solution properties, which consequently influence the ionic concentration distribution, flow velocity, and electric field strength. For example, in different numbers of nanochannel systems, the ion concentration in nanochannels is not much different, but it is different in reservoirs, especially near the openings of nanochannels. The number of nanochannels and the distance between nanochannels can also affect the formation of electro-convective vortex zones under certain conditions. These findings can aid in optimizing the nanochannel array design by regulating the number and distance of nanochannels and facilitating the construction of solid-state nanochannel arrays with any desired nanochannel dimensions.

A new method for vascular age estimation based on relative risk difference in vascular aging.

OBJECTIVE: The current models of estimating vascular age (VA) primarily rely on the regression label expressed with chronological age (CA), which does not account individual differences in vascular aging (IDVA) that are difficult to describe by CA. This may lead to inaccuracies in assessing the risk of cardiovascular disease based on VA. To address this limitation, this work aims to develop a new method for estimating VA by considering IDVA. This method will provide a more accurate assessment of cardiovascular disease risk. METHODS: Relative risk difference in vascular aging (RRDVA) is proposed to replace IDVA, which is represented as the numerical difference between individual predicted age (PA) and the corresponding mean PA of healthy population. RRDVA and CA are regard as the influence factors to acquire VA. In order to acquire PA of all samples, this work takes CA as the dependent variable, and mines the two most representative indicators from arteriosclerosis data as the independent variables, to establish a regression model for obtaining PA. RESULTS: The proposed VA based on RRDVA is significantly correlated with 27 indirect indicators for vascular aging evaluation. Moreover, VA is better than CA by comparing the correlation coefficients between VA, CA and 27 indirect indicators, and RRDVA greater than zero presents a higher risk of disease. CONCLUSION: The proposed VA overcomes the limitation of CA in characterizing IDVA, which may help young groups with high disease risk to promote healthy behaviors.

Establishment and validation of a nomogram clinical prediction model for osteoporosis in senile patients with type 2 diabetes mellitus.

This study aimed to develop a predictive nomogram model to estimate the odds of osteoporosis (OP) in elderly patients with type 2 diabetes mellitus (T2DM) and validate its prediction efficiency. The hospitalized elderly patients with T2DM from the Affiliated Hospital of North Sichuan Medical University between July 2022 and March 2023 were included in this study. We sorted them into the model group and the validation group with a ratio of 7:3 randomly. The selection operator regression (LASSO) algorithm was utilized to select the optimal matching factors, which were then included in a multifactorial forward stepwise logistic regression to determine independent influencing factors and develop a nomogram. The discrimination, accuracy, and clinical efficacy of the nomogram model were analyzed utilizing the receiver operating characteristic (ROC) curve, calibration curve, and clinical decision curve analysis (DCA). A total of 379 study participants were included in this study. Gender (OR = 8.801, 95% CI 4.695-16.499), Geriatric Nutritional Risk Index (GNRI) < 98 (OR = 4.698, 95% CI 2.416-9.135), serum calcium (Ca) (OR = 0.023, 95% CI 0.003-0.154), glycated hemoglobin (HbA1c) (OR = 1.181, 95% CI 1.055-1.322), duration of diabetes (OR = 1.076, 95% CI 1.034-1.119), and serum creatinine (SCr) (OR = 0.984, 95% CI 0.975-0.993) were identified as independent influencing factors for DOP occurrence in the elderly. The area under the curve (AUC) of the nomogram model was 0.844 (95% CI 0.797-0.89) in the modeling group and 0.878 (95% CI 0.814-0.942) in the validation group. The nomogram clinical prediction model was well generalized and had moderate predictive value (AUC > 0.7), better calibration, and better clinical benefit. The nomogram model established in this study has good discrimination and accuracy, allowing for intuitive and individualized analysis of the risk of DOP occurrence in elderly individuals. It can identify high-risk populations and facilitate the development of effective preventive measures.

GDF3 Protects Mice against Sepsis-Induced Acute Lung Injury by Suppression of Macrophage Pyroptosis.

Sepsis-induced ALI is marked by physiological, pathological, and biochemical irregularities caused by infection. Growth differentiation factor 3 (GDF3) is closely associated with the inflammatory response. Accumulating evidence has demonstrated a close relationship between GDF3 expression and the severity and prognosis of sepsis. However, the precise mechanism by which GDF3 protects against ALI induced by sepsis is still unclear. Following the intravenous administration of GDF3 in this research, we noted a rise in the survival rate, a decrease in the severity of histopathological damage as evaluated through HE staining, a decline in the count of inflammatory cells in bronchoalveolar lavage fluid (BALF), a reduction in the ratio of lung wet/dry (W/D) weight, and a noteworthy decrease in the levels of pro-inflammatory cytokines in both serum and BALF when compared to septic mice who underwent cecal ligation and puncture (CLP). These collective findings unequivocally indicate the protective effects of GDF3 against sepsis-induced ALI. In addition, the GDF3 group showed a significant reduction in the mRNA expression of Caspase-1 and NLRP3 when compared to the CLP group. Following this, we performed in vitro tests to confirm these discoveries and obtained comparable outcomes, wherein the administration of GDF3 notably decreased the levels of Caspase-1 and NLRP3 mRNA and protein in macrophages in comparison to the LPS group. Furthermore, GDF3 exhibited the capacity to reduce the secretion of inflammatory molecules from macrophages. By illuminating the mechanism by which GDF 3 regulates macrophages, this offers a theoretical basis for preventing and treating sepsis-induced ALI.

Region-specific transcriptomic responses to obesity and diabetes in macaque hypothalamus.

The hypothalamus plays a crucial role in the progression of obesity and diabetes; however, its structural complexity and cellular heterogeneity impede targeted treatments. Here, we profiled the single-cell and spatial transcriptome of the hypothalamus in obese and sporadic type 2 diabetic macaques, revealing primate-specific distributions of clusters and genes as well as spatial region, cell-type-, and gene-feature-specific changes. The infundibular (INF) and paraventricular nuclei (PVN) are most susceptible to metabolic disruption, with the PVN being more sensitive to diabetes. In the INF, obesity results in reduced synaptic plasticity and energy sensing capability, whereas diabetes involves molecular reprogramming associated with impaired tanycytic barriers, activated microglia, and neuronal inflammatory response. In the PVN, cellular metabolism and neural activity are suppressed in diabetic macaques. Spatial transcriptomic data reveal microglia's preference for the parenchyma over the third ventricle in diabetes. Our findings provide a comprehensive view of molecular changes associated with obesity and diabetes.

Sodium butyrate exerts a neuroprotective effect in rats with acute carbon monoxide poisoning by activating autophagy through the mTOR signaling pathway.

Acute carbon monoxide (CO) poisoning is a prevalent type of poisoning that causes significant harm globally. Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a severe complication that occurs after acute CO poisoning; however, the exact underlying pathological cause of DEACMP remains unclear. Accumulating evidence indicates that abnormal inflammation and immune-mediated brain damage, cellular apoptosis and autophagy, and direct neuronal toxicity are involved in the development of delayed neurologic sequelae. Sodium butyrate, a histone deacetylase inhibitor, has gained increasing attention for its numerous beneficial effects on various diseases, such as obesity, diabetes, inflammatory diseases, and cerebral damage. In this study, an acute carbon monoxide poisoning (ACOP) model is established in rats to investigate the mechanism of CO poisoning and the therapeutic potential of sodium butyrate. The results suggested that the ACOP rats had impaired spatial memory, and cell apoptosis was observed in the hippocampi with activated autophagy. Sodium butyrate treatment further increased the activation of autophagy in the hippocampi of CO-exposed rats, inhibited apoptosis, and consolidated spatial memory. These findings indicated that sodium butyrate may improve memory and cognitive function in ACMP rats by promoting autophagy and inhibiting apoptosis.

Spatial and single-nucleus transcriptomics decoding the molecular landscape and cellular organization of avian optic tectum.

The avian optic tectum (OT) has been studied for its diverse functions, yet a comprehensive molecular landscape at the cellular level has been lacking. In this study, we applied spatial transcriptome sequencing and single-nucleus RNA sequencing (snRNA-seq) to explore the cellular organization and molecular characteristics of the avian OT from two species: Columba livia and Taeniopygia guttata. We identified precise layer structures and provided comprehensive layer-specific signatures of avian OT. Furthermore, we elucidated diverse functions in different layers, with the stratum griseum periventriculare (SGP) potentially playing a key role in advanced functions of OT, like fear response and associative learning. We characterized detailed neuronal subtypes and identified a population of FOXG1+ excitatory neurons, resembling those found in the mouse neocortex, potentially involved in neocortex-related functions and expansion of avian OT. These findings could contribute to our understanding of the architecture of OT, shedding light on visual perception and multifunctional association.

The Development and Potential Applications of an Automated Method for Detecting and Classifying Continuous Glucose Monitoring Patterns.

INTRODUCTION: Continuous glucose monitoring (CGM) is emerging as a transformative tool for helping people with diabetes self-manage their glucose and supporting clinicians in effective treatment. Unfortunately, many CGM users, and clinicians, find interpreting the large volume of CGM data to be overwhelming and complex. To address this challenge, an efficient, intelligent method for detecting and classifying discernable patterns in CGM data was desired. METHODS: We developed an automated artificial intelligence (AI)-driven method to detect and classify different discernable CGM patterns which called "CGM events." We trained different models using 60 days of CGM data from 27 individuals with diabetes from a publicly available data set and then evaluated model performance using separate test data from the same group. Each event is classified according to clinical significance based on three parameters: (1) glucose category at or near the beginning of the CGM event; (2) a calculated severity score that encompasses both signal shape and temporal characteristics (e.g., how high the CGM curve goes (measured in mg/dL) and how long it stays above target (as established by published consensus guidelines); and (3) the glucose category at or near the end of the event. RESULTS: The system accurately detected and classified events from actual CGM data. This was also validated with expert diabetes clinicians. CONCLUSIONS: Advanced pattern recognition methods can be used to detect and classify CGM events of interest and may be used to provide actionable insights and self-management support to CGM users and decision support to the clinicians caring for them.

Pan-cancer scRNA-seq analysis reveals immunological and diagnostic significance of the peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMCs) reflect systemic immune response during cancer progression. However, a comprehensive understanding of the composition and function of PBMCs in cancer patients is lacking, and the potential of these features to assist cancer diagnosis is also unclear. Here, the compositional and status differences between cancer patients and healthy donors in PBMCs were investigated by single-cell RNA sequencing (scRNA-seq), involving 262,025 PBMCs from 68 cancer samples and 14 healthy samples. We observed an enhanced activation and differentiation of most immune subsets in cancer patients, along with reduction of naïve T cells, expansion of macrophages, impairment of NK cells and myeloid cells, as well as tumor promotion and immunosuppression. Based on characteristics including differential cell type abundances and/or hub genes identified from weight gene co-expression network analysis (WGCNA) modules of each major cell type, we applied logistic regression to construct cancer diagnosis models. Furthermore, we found that the above models can distinguish cancer patients and healthy donors with high sensitivity. Our study provided new insights into using the features of PBMCs in non-invasive cancer diagnosis.

Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines.

Human cancer cell lines have long served as tools for cancer research and drug discovery, but the presence and the source of intra-cell-line heterogeneity remain elusive. Here, we perform single-cell RNA-sequencing and ATAC-sequencing on 42 and 39 human cell lines, respectively, to illustrate both transcriptomic and epigenetic heterogeneity within individual cell lines. Our data reveal that transcriptomic heterogeneity is frequently observed in cancer cell lines of different tissue origins, often driven by multiple common transcriptional programs. Copy number variation, as well as epigenetic variation and extrachromosomal DNA distribution all contribute to the detected intra-cell-line heterogeneity. Using hypoxia treatment as an example, we demonstrate that transcriptomic heterogeneity could be reshaped by environmental stress. Overall, our study performs single-cell multi-omics of commonly used human cancer cell lines and offers mechanistic insights into the intra-cell-line heterogeneity and its dynamics, which would serve as an important resource for future cancer cell line-based studies.

Cancer-associated fibroblasts undergoing neoadjuvant chemotherapy suppress rectal cancer revealed by single-cell and spatial transcriptomics.

Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF_FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs.

Combined analysis of the proteome and metabolome provides insight into microRNA-1174 function in Aedes aegypti mosquitoes.

BACKGROUND: Pathogenic viruses can be transmitted by female Aedes aegypti (Ae. aegypti) mosquitoes during blood-meal acquisition from vertebrates. Silencing of mosquito- and midgut-specific microRNA (miRNA) 1174 (miR-1174) impairs blood intake and increases mortality. Determining the identity of the proteins and metabolites that respond to miR-1174 depletion will increase our understanding of the molecular mechanisms of this miRNA in controlling blood-feeding and nutrient metabolism of mosquitoes. METHODS: Antisense oligonucleotides (antagomirs [Ant]) Ant-1174 and Ant-Ct were injected into female Ae. aegypti mosquitoes at 12-20 h posteclosion, and depletion of miR-1174 was confirmed by reverse transcription quantitative real-time PCR (RT-qPCR). Ant-1174-injected and control mosquitoes were collected before the blood meal at 72 h post-injection for tandem mass tag-based proteomic analysis and liquid chromatography-tandom mass spectrometry non-target metabolomic analysis to identify differentially expressed proteins and metabolites, respectively. RNA interference (RNAi) using double-stranded RNA (dsRNA) injection was applied to investigate the biological roles of these differentially expressed genes. The RNAi effect was verified by RT-qPCR and western blotting assays. Triglyceride content and ATP levels were measured using the appropriate assay kits, following the manufacturers' instructions. Statistical analyses were conducted with GraphPad7 software using the Student's t-test. RESULTS: Upon depletion of mosquito- and midgut-specific miR-1174, a total of 383 differentially expressed proteins (DEPs) were identified, among which 258 were upregulated and 125 were downregulated. Functional analysis of these DEPs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment suggested that miR-1174 plays important regulatory roles in amino acid metabolism, nucleotide metabolism, fatty acid metabolism and sugar metabolism pathways. A total of 292 differential metabolites were identified, of which 141 were upregulated and 151 were downregulated. Integrative analysis showed that the associated differential proteins and metabolites were mainly enriched in a variety of metabolic pathways, including glycolysis, citrate cycle, oxidative phosphorylation and amino acid metabolism. Specifically, the gene of one upregulated protein in miR-1174-depleted mosquitoes, purine nucleoside phosphorylase (PNP; AAEL002269), was associated with the purine, pyrimidine and niacin-nicotinamide metabolism pathways. PNP knockdown seriously inhibited blood digestion and ovary development and increased adult mortality. Mechanically, PNP depletion led to a significant downregulation of the vitellogenin gene (Vg); in addition, some important genes in the ecdysone signaling and insulin-like peptide signaling pathways related to ovary development were affected. CONCLUSIONS: This study demonstrates differential accumulation of proteins and metabolites in miR-1174-depleted Ae. aegypti mosquitoes using proteomic and metabolomic techniques. The results provide functional evidence for the role of the upregulated gene PNP in gut physiological activities. Our findings highlight key molecular changes in miR-1174-depleted Ae. aegypti mosquitoes and thus provide a basis and novel insights for increased understanding of the molecular mechanism involved in a lineage-specific miRNA in mosquito vectors.

Role of endoplasmic reticulum autophagy in acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the prime causes of morbidity and mortality in critically ill patients, are usually treated by general supportive treatments. Endoplasmic reticulum autophagy (ER-phagy) maintains cellular homeostasis by degrading damaged endoplasmic reticulum (ER) fragments and misfolded proteins. ER-phagy is crucial for maintaining ER homeostasis and improving the internal environment. ER-phagy has a particular role in some aspects, such as immunity, inflammation, cell death, pathogen infection, and collagen quality. In this review, we summarized the definition, epidemiology, and pathophysiology of ALI/ARDS and described the regulatory mechanisms and functions of ER-phagy as well as discussed the potential role of ER-phagy in ALI/ARDS from the perspectives of immunity, inflammation, apoptosis, pathogen infection, and fibrosis to provide a novel and effective target for improving the prognosis of ALI/ARDS.

LncRNA MCM3AP-AS1 is downregulated in atherosclerosis and sponges miR-448 to suppress vascular smooth muscle cell proliferation.

Long noncoding RNA MCM3AP-AS1 plays critical roles in cancers, but its role in atherosclerosis is yet to be elucidated. The expression of MCM3AP-AS1 in atherosclerosis and control plasma samples were measured by RT-qPCR. IntaRNA was used to predict potential base pairings between MCM3AP-AS1 and miR-448, and the results were confirmed by a dual luciferase activity assay. Cell proliferation assay was performed to explore the role of overexpression of MCM3AP-AS1, miR-448, and myocyte enhancer factor 2 (MEF2)-C in the proliferation of human aortic smooth muscle cells (HAOSMCs). MCM3AP-AS1 was downregulated in atherosclerosis and directly interacted with miR-448, which is a critical player in the proliferation of HAOSMCs, indicating its involvement in atherosclerosis. However, MCM3AP-AS1 and miR-448 showed no role in regulating the expression of each other. In contrast, overexpression of MCM3AP-AS1 increased the expression levels of MEF2-C, which can be targeted by miR-448. Moreover, MCM3AP-AS1 was found to inhibit the effects of miR-448 overexpression on both HAOSMC proliferation and MEF2-C expression. MCM3AP-AS1 is downregulated in atherosclerosis and sponges miR-448 to suppress the proliferation of HAOSMCs.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.