Molecular weight-dependent differences in spectral properties and metal-binding behaviors of dissolved organic matter from different lakes.

Dissolved organic matter (DOM) plays an important role in governing metal speciation and migration in aquatic systems. In this study, various DOM samples were collected from Lakes Erhai, Kokonor, and Chaka, and size-fractionated into high molecular weight (HMW, 1 kDa-0.7 µm) and low molecular weight (LMW, <1 kDa) fractions for measurements of dissolved organic carbon (DOC), spectral properties, and metal binding behaviors. Our results demonstrated that samples from Lake Chaka exhibited the highest DOC concentration and fluorescence indices but the lowest percentage of carbohydrates. Regardless of sampling locations, the HMW-DOM fractions contained higher abundances of aromatic DOM, carbohydrates and protein-like substances, but lower abundance of fulvic acid-like substances compared to those in the LMW fractions. Metal titration experiments coupled with the excitation-emission matrix (EEM)-parallel factor (PARAFAC) modeling revealed that the quenching of the PARAFAC-derived fluorescent components was more pronounced in the presence of Cu(II) compared to Pb(II). Humic-like components emerged as a superior model, exhibiting higher binding affinities for Cu(II) than protein-like substances, while the opposite trend was observed for Pb(II). In samples obtained from Lakes Erhai and Kokonor, the condition stability constants (Log KM) for the binding of both Cu(II) and Pb(II) with the HMW-DOM fraction were higher than those with the LMW-DOM fraction. Conversely, a contrasting trend was observed for Lake Chaka. This study highlighted the heterogeneity in spectral properties and metal-binding behaviors of natural DOMs, contributing to an improved understanding of the molecular interactions between DOM components and metal ions and their environmental fate in aquatic ecosystems.

Efficient Selective Adsorption of Rubidium and Cesium from Practical Brine Using a Metal-Organic Framework-Based Magnetic Adsorbent.

Rubidium (Rb) and cesium (Cs) have important applications in highly technical fields. Salt lakes contain huge reserves of Rb and Cs with industrial significance, which can be utilized after extraction. In this study, a composite magnetic adsorbent (Fe3O4@ZIF-8@AMP, AMP = ammonium phosphomolybdate) was prepared and its adsorption properties for Rb+ and Cs+ were studied in simulated and practical brine. The structure of the adsorbent was characterized by SEM, XRD, N2 adsorption-desorption, FT-IR, and vibrating sample magnetometer (VSM). The adsorbent had good adsorption affinity for Rb+ and Cs+. The Langmuir model and pseudo-second-order dynamics described the adsorbing isotherm and kinetic dates, respectively. The adsorption capacity and adsorption rate of Fe3O4@ZIF-8@AMP were increased by 1.86- and 2.5-fold compared with those of powdered crystal AMP, owing to the large specific surface area and high dispersibility of the adsorbent in the solution. The adsorbent was rapidly separated from the solution within 17 s using an applied magnetic field owing to the good magnetic properties. The composite adsorbent selectively adsorbed Rb+ and Cs+ from the practical brine even in the presence of a large number of coexisting ions. The promising adsorbent can be used to extract Rb+ and Cs+ from aqueous solutions.

Basic magnesium sulfate@TiO2 composite for efficient adsorption and photocatalytic degradation of 4-dodecylmorpholine in brine.

More than 70% of the potash fertilizer globally is produced by the froth flotation process, in which 4-dodecylmorpholine (DMP) serves as a reverse flotation agent. As the potash fertilizer production rapidly rises, the increased DMP levels in discharged brine pose a threat to the production of high-value chemicals. In this paper, composite particles of basic magnesium sulfate@TiO2 (BMS@TiO2) were prepared using a simple and mild loading method. These particles were utilized for the adsorption and photocatalytic degradation of DMP in brine. Compared with normal powdered materials, the granular BMS@TiO2 in this study can be easily separated from liquid, and the degradation intermediates will not enter the brine without causing secondary pollution. BMS@TiO2 consists of 5·1·7 phase (5Mg(OH)2·MgSO4·7H2O) whisker clusters embedding 2.3% TiO2. The adsorption equilibrium of DMP on BMS@TiO2 particles was achieved through hydrogen bonding and pore interception with the adsorption capacity of approximately 5 mg g-1 after 6 h. The photodegradation efficiency of DMP adsorbed on BMS@TiO2 reached about 92% within 16 h, which is compared with that of pure TiO2 nanoparticles. Additionally, excellent stability and recyclability of BMS@TiO2 were also observed in five cycle tests of adsorption and photocatalytic degradation of DMP, and the possible photocatalytic degradation pathways and mechanism of DMP are proposed following molecular electrostatic potential analysis. This work provides a sustainable and environmentally friendly approach for eliminating organic micropollutants from water environments.

Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis.

Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.

BMSC-Exosomes attenuate ALP dysfunction by restoring lysosomal function via the mTOR/TFEB Axis to reduce cerebral ischemia-reperfusion injury.

BACKGROUND: The complex pathophysiological changes following cerebral ischemia-reperfusion injury (CIRI) include the accumulation of defective proteins and damaged organelles, which cause massive neuron demise. To preserve cellular homeostasis, the autophagy-lysosomal pathway (ALP) is crucial for neurons to dispose of these substances. Many studies have shown that bone mesenchymal stem cell exosomes (BMSC-Exos) can reduce CIRI. However, the specific mechanisms have not been well elucidated, a fact that limits its widespread clinical use. This study aimed to clarify whether BMSC-Exos could attenuate ALP dysfunction by restoring lysosomal function after CIRI via inhibiting mTOR and then activating TFEB nucleus translocation. METHODS: In this study, Flow cytometry, Nanoparticle tracking analysis (NTA), Transmission electron microscope (TEM), and Western blot were used to identify the BMSCs and BMSC-Exos used in this experiment as conforming to the requirements. In vivo experiments, SD rats were modeled with temporary middle cerebral artery occlusion (tMCAO), and BMSC-Exos was injected into the tail vein 2 h after modeling. Triphenyl tetrazolium chloride (TTC) staining, modified neurological severity scores (mNSS), corner turn test, and rotating rod test were used to detect neurological deficits in rats after BMSC-Exos intervention. Western blot and Immunofluorescence were used to detect ALP, transcription factor EB(TFEB) nucleus translocation, and mammalian target of rapamycin (mTOR) change at different time points after modeling and after BMSC-Exos intervention. In vitro experiments, pheochromocytoma cells (PC12) cells were subjected to oxygen-glucose deprivation and reperfusion (OGD/R) modeling to mimic CIRI, and were respectively intervened with BMSC-Exos, BMSC-Exos + MHY 1485 (the mTOR agonist), Rapamycin (the mTOR inhibitor). CCK8, Western blot, and Immunofluorescence were used to detect PC12 cell survival, TFEB nucleus translocation, and cathepsin B(CTSB) Immunofluorescence intensity. RESULTS: We found that ALP dysfunction occurred 72 h after tMCAO, and BMSC-Exos can attenuate ALP dysfunction by restoring lysosomal function. Next, we examined TFEB nucleus translocation and the expression of mTOR, a key regulator of translocation. We found that BMSC-Exos could inhibit mTOR and activate TFEB nucleus translocation. Additional in vitro tests revealed that BMSC-Exos could increase PC12 cell survival after OGD/R, activating TFEB nucleus translocation and enhancing the fluorescence intensity of CTSB, which in turn could be reversed by the mTOR agonist, MHY1485. This effect was similar to another mTOR inhibitor, Rapamycin. CONCLUSION: BMSC-Exos could attenuate ALP dysfunction by restoring lysosomal function after CIRI by inhibiting mTOR and then promoting TFEB nucleus translocation.

Executive function measures of participants with mild cognitive impairment: Systematic review and meta-analysis of event-related potential studies.

OBJECTIVE: Objective measurements of executive functions using event-related potential (ERP) may be used as markers for differentiating healthy controls (HC) from patients with mild cognitive impairment (MCI). ERP is non-invasive, cost-effective, and affordable. Older adults with MCI demonstrate deteriorated executive function, serving as a potentially valid neurophysiological marker for identifying MCI. We aimed to review published ERP studies on executive function in older adults with MCI and summarize the performance differences by component between healthy older adults and older adults with MCI. METHODS: Eight electronic databases (Web of Science, PubMed, ScienceDirect, American Psychological Association PsycNet, Cochrane Library, Scopus, Embase, and Ovid) were searched for the study. Articles published from January 1 to December 31, 2022, were considered for this review. A random-effects meta-analysis and between-study heterogeneity analysis were conducted using Comprehensive Meta-Analysis V3.0 software. RESULTS: We identified 7829 articles of which 28 met the full inclusion criteria and were included in the systematic review and analyses. Our pooled analysis suggested that participants with MCI can be differentiated from HC by significant P200, P300, and N200 latencies. The P100 and P300 amplitudes were significantly smaller in participants with MCI when compared with those in the HCs, and the patients with MCI showed increased N200 amplitudes. Our findings provide new insights into potential electrophysiological biomarkers for diagnosing MCI.

The high-efficiency coupling of a Ni2+ coordinated/uncoordinated pyridine N-COF self-supporting nanofilm as an asymmetric supercapacitor.

A large-area COFTAPB-BPY film with a pore size of 3.9 nm was prepared on a gas-liquid interface by the virtue of the limiting and guiding functions of sodium dodecylbenzene sulfonate, followed by modification by Ni2+ ions with the reversible redox reaction of Ni(II/III), where Ni2+ was evidently anchored on the N in BPY. The obtained COFTAPB-BPY and Ni-COFTAPB-BPY nanofilms could avoid the inevitable aggregation and stacking of bulk COFTAPB-BPY, which facilitated a high specific capacitance of 0.26 mF cm-2 for the COFTAPB-BPY nanofilm and 0.38 mF cm-2 for the Ni-COFTAPB-BPY nanofilm at 0.001 mA cm-2. Considering the pseudocapacitance and double-layer capacitance traits of Ni-COFTAPB-BPY and COFTAPB-BPY nanofilms, the asymmetric Ni-COFTAPB-BPY//COFTAPB-BPY film supercapacitor was assembled with a symmetric COFTAPB-BPY//COFTAPB-BPY film device as a control. The asymmetric Ni-COFTAPB-BPY//COFTAPB-BPY film supercapacitor could enhance the energy density of 273.9 mW h cm-3 at 14.09 W cm-3 from 85.2 mW h cm-3 at 4.38 W cm-3 for the symmetric COFTAPB-BPY//COFTAPB-BPY film device. This work provides a new perspective on the application of self-supporting COF nanofilms as film asymmetric supercapacitors.

Maternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring.

The mediation of maternal-embryonic cross-talk via nutrition and metabolism impacts greatly on offspring health. However, the underlying key interfaces remain elusive. Here, we determined that maternal high-fat diet during pregnancy in mice impaired preservation of the ovarian primordial follicle pool in female offspring, which was concomitant with mitochondrial dysfunction of germ cells. Furthermore, this occurred through a reduction in maternal gut microbiota-related vitamin B1 while the defects were restored via vitamin B1 supplementation. Intriguingly, vitamin B1 promoted acetyl-CoA metabolism in offspring ovaries, contributing to histone acetylation and chromatin accessibility at the promoters of cell cycle-related genes, enhancement of mitochondrial function, and improvement of granulosa cell proliferation. In humans, vitamin B1 is downregulated in the serum of women with gestational diabetes mellitus. In this work, these findings uncover the role of the non-gamete transmission of maternal high-fat diet in influencing offspring oogenic fate. Vitamin B1 could be a promising therapeutic approach for protecting offspring health.

Single-Cell RNA-Seq Reveals Changes in Cell Subsets in the Cortical Microenvironment during Acute Phase of Ischemic Stroke Rats.

BACKGROUND: Ischemic stroke, the most common stroke type, has threatened human life and health. Currently, intravenous thrombolysis and endovascular thrombectomy are the mainstream treatment methods, but they may cause cerebral ischemia-reperfusion injury (CIRI), which aggravates brain injury. Consequently, it is worthwhile to start with a study of CIRI mechanism to identify better prevention and treatment methods. Applying single-cell RNA sequencing (scRNA-seq) technology to further understand the biological functions of various cell types in CIRI will facilitate the intervention of CIRI. METHODS: This study aimed to establish a rat middle cerebral artery occlusion (MCAO) model to simulate cerebral ischemia-reperfusion, perform enzymatic hydrolysis, and suspend cerebral cortex tissue edema. Single-cell transcriptome sequencing was used, combined with cluster analysis, t-distributed stochastic neighbor embedding (t-SNE) visualization, and other bioinformatics methods to distinguish cell subgroups while using gene ontology (GO) function enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment to reveal the biological function of each cell subgroup. RESULTS: We identified 21 brain clusters with cell type-specific gene expression patterns and cell subpopulations, as well as 42 marker genes representing different cell subpopulations. The number of cells in clusters 0-3 increased significantly in MCAO group compared to that in the sham group, and nine-cell subpopulations exhibited remarkable differences in the number of genes. Subsequently, GO and KEGG analyses were performed on the top 40 differentially expressed genes (DEGs) in the six cell subpopulations with significant differences. These results indicate that biological processes and signaling pathways are involved in different cell subpopulations. CONCLUSIONS: ScRNA-seq revealed the diversity of cell differentiation and the unique information of cell subpopulations in the cortex of rats with acute ischemic stroke, providing novel insight into the pathological process and drug discovery in stroke.

METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression.

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m6A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (log rank test, p < 0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m6A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo. The oncogenic function of METTL5 is corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m6A modification that hampers ribosome synthesis and inhibits translation of G-quadruplex-containing mRNAs that are enriched in the transforming growth factor (TGF)-ß pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA m6A modification in ICC and unravels the mechanism of rRNA m6A modification-mediated oncogenic mRNA translation control.

Corrigendum: Using Machine Learning to Predict Cognitive Impairment Among Middle-Aged and Older Chinese: A Longitudinal Study.

[This corrects the article DOI: 10.3389/ijph.2023.1605322.].

Research hotspots and frotiers of stem cells in stroke: A bibliometric analysis from 2004 to 2022.

Background: Stroke is one of the leading causes of mortality and permanent disability worldwide. However, the current stroke treatment has a limited effect. Therefore, a new treatment is urgently needed. Stem cell therapy is a cutting-edge treatment for stroke patients. This study aimed to gain better understanding of global stem cell trends in stroke via a bibliometric analysis. Methods: We used the Web of Science Core Collection to search pertinent articles about stem cells in stroke published between 2004 and 2022. Analysis was conducted using CiteSpace, VOSviewer, and the R package "bibliometrix" to identify publication outputs, countries/regions, institutions, authors/co-cited authors, journals/co-cited journals, co-cited references, and keywords. Results: A total of 6,703 publications were included in the bibliometric analysis. The total number of citations significantly and rapidly increased between 2004 and 2022, with the most pronounced growth pattern observed in the period of 2008-2009. In terms of authoritarian countries, the USA had the most publications among the countries. As for institutions and authors, the most prolific institution was the University of South Florida, followed by Oakland University and then Shanghai Jiao Tong University, and Chopp, M. and Borlongan, Cesario V, had the most output among the authors. Regarding the journals, Cell Transplantation had the highest publication, followed by Brain Research. As for references, "Mesenchymal stem cells as trophic mediators" was the most frequently cited (2,082), and the article entitled Neuronal replacement from endogenous precursors in the adult brain after stroke had the strongest burstiness (strength = 81.35). Emerging hot words in the past decade included "adhesion molecule," "mesenchymal stromal cell," "extracellular vesicle," "pluripotent stem cells," "signaling pathway," "plasticity," and "exosomes." Conclusion: Between 2004 and 2022, the terms "neurogenesis," "angiogenesis," "mesenchymal stem cells," "extracellular vesicle," "exosomes," "inflammation," and "oxidative stress" have emerged as the hot research areas for research on stem cells in stroke. Although stem cells exert a number of positive effects, the main mechanisms for mitigating the damage caused by stroke are still unknown. Clinical challenges may include complicating factors that can affect the efficacy of stem cell therapy, which are worth a deep exploration.

Diagnostic and economic value of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4 in gastrointestinal cancers.

BACKGROUND: The diagnostic and economic value of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and CA72-4 for gastrointestinal malignant tumors lacked evaluation in a larger scale. AIM: To reassess the diagnostic and economic value of the three tumor biomarkers. METHODS: A retrospective analysis of all 32857 subjects who underwent CEA, CA19-9, CA72-4, gastroscopy and colonoscopy from October 2006 to May 2018 was conducted. Then, we assessed the discrimination and clinical usefulness. Total cost, cost per capita and cost-effectiveness ratios were used to evaluate the economic value of two schemes (gastrointestinal endoscopy for all people without blood tests vs both gastroscopy and colonoscopy when blood tests were positive). RESULTS: The analysis of 32857 subjects showed that CEA was a qualified biomarker for colorectal cancer (CRC), while the diagnostic efficiencies of CA72-4 were catastrophic for all gastrointestinal cancers (GICs). Regarding early diagnosis, only CEA could be used for early CRC. The combination of biomarkers didn't greatly increase the area under the curve. The economic indicators of CEA were superior to those of CA19-9, CA72-4 and any combination. At the threshold of 1.8 µg/L to 10.4 µg/L, all four indicators of CEA were lower than those in the scheme that conducted gas-trointestinal endoscopy only. Subgroup analysis implied that the health checkup of CEA for people above 65 years old was economically valuable. CONCLUSION: CEA had qualified diagnostic value for CRC and superior economic value for GICs, especially for elderly health checkup subjects. CA72-4 was not suitable as a diagnostic biomarker.

Using Machine Learning to Predict Cognitive Impairment Among Middle-Aged and Older Chinese: A Longitudinal Study.

Objective: To explore the predictive value of machine learning in cognitive impairment, and identify important factors for cognitive impairment. Methods: A total of 2,326 middle-aged and elderly people completed questionnaire, and physical examination evaluation at baseline, Year 2, and Year 4 follow-ups. A random forest machine learning (ML) model was used to predict the cognitive impairment at Year 2 and Year 4 longitudinally. Based on Year 4 cross-sectional data, the same method was applied to establish a prediction model and verify its longitudinal prediction accuracy for cognitive impairment. Meanwhile, the ability of random forest and traditional logistic regression model to longitudinally predict 2-year and 4-year cognitive impairment was compared. Results: Random forest models showed high accuracy for all outcomes at Year 2, Year 4, and cross-sectional Year 4 [AUC = 0.81, 0.79, 0.80] compared with logistic regression [AUC = 0.61, 0.62, 0.70]. Baseline physical examination (e.g., BMI, Blood pressure), biomarkers (e.g., cholesterol), functioning (e.g., functional limitations), demography (e.g., age), and emotional status (e.g., depression) characteristics were identified as the top ten important predictors of cognitive impairment. Conclusion: ML algorithms could enhance the prediction of cognitive impairment among the middle-aged and older Chinese for 4 years and identify essential risk markers.

Injectable Supramolecular Hybrid Hydrogel Delivers IL-1ß-Stimulated Exosomes to Target Neuroinflammation.

Long-term neuroinflammation is a major barrier to neurological recovery after cerebral ischemia-reperfusion injury (CIRI). Here, a thermosensitive injectable supramolecular hybrid hydrogel is developed to sustainably deliver exosomes derived from interleukin-1ß-stimulated bone marrow stromal cells (BMSCs) (ßExos) with improved exosome production and anti-inflammatory capacity for neuroinflammation inhibition and neurological recovery. The supramolecular hydrogel displays self-healing and injectable features, along with high biocompatibility and tissue-like softness. The ßExos effectively reduce the lipopolysaccharide-induced inflammatory responses in the immortalized mouse microglia (BV2) cell line, and the in situ formed hydrogel improves the exosome retention in the ischemic core area. More remarkably, in the middle cerebral artery occlusion in vivo model, glial scar formation and neuronal loss are significantly reduced by regulating neuroinflammation using the released ßExos. Therefore, the combination of interleukin-1ß-stimulated exosomes with injectable supramolecular hydrogel provides an appealing strategy for treating central nervous system diseases.

Age-related positivity effect of emotional attention: time and frequency domain.

Compared with their younger counterparts, older adults are inclined to allocate more attentional resources to positive over negative materials. This age-related positivity effect has been reported in various experimental paradigms; however, studies have not investigated the attention stage at which it appears or its potential neural mechanism. Thus, we investigated the time and frequency domain dynamics of younger and older adults during emotional attention processes. We obtained electroencephalography oscillation and event-related potential data for 20 older and 20 younger participants while they performed an emotional dot-probe task. We focused our time and frequency domain dynamics analyses on the posterior regions as a key structure for facial emotion perception and the frontal regions as a crucial structure for cognitive control. In the time domain, older adults showed an initial attentional shift to happy-related stimuli, whereas their younger counterparts did not demonstrate emotional modulation, as reflected by the N2pc component. The time-frequency decomposition was analyzed for the N2pc time window. The results showed that compared with younger adults, older adults showed an increased alpha power for happy faces in the right-posterior regions. Moreover, a parallel pattern was seen in frontal theta activity. The current findings highlight how electrocortical activity of the brain might moderate the tendency to prioritize positive information among healthy older adults. The emergence of an age-related positivity effect may be related to frontal cognitive control processing. These findings provide insight into the prevention and treatment of unsuccessful aging, such as late-life depression and anxiety.

Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains as high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m 7 G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA). APPROACH AND RESULTS: By immunohistochemistry and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b + CD15 + polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and decreased CD8 + T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-ß2 translation to form the immunosuppressive environment by induction of myeloid-derived suppressor cell. Liver-specific overexpression or knockdown of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8 + T cell infiltration. Complete RFA successfully eliminated the tumor, whereas iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8 + T cells compared to sham surgery. Interrupting METTL1-TGF-ß2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2 , or TGF-ß signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8 + T cell population. CONCLUSIONS: Our study sheds light on the pivotal role of METTL1 in modulating an immunosuppressive microenvironment and demonstrated that interrupting METTL1-TGF-ß2-PMN-MDSC axis could be a therapeutic strategy to restore antitumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.

Perlecan Improves Blood Spinal Cord Barrier Repair Through the Integrin ß1/ROCK/MLC Pathway After Spinal Cord Injury.

Spinal cord injury (SCI) can lead to the destruction of the blood-spinal cord barrier (BSCB), causing various inflammatory cytokines, neutrophils, and macrophages to infiltrate the lesion area, resulting in secondary injury. Basement membranes (BMs) are maintained by all types of cells in the BSCB and contribute to BSCB maintenance. Perlecan is an important constituent of vascular BMs, maintaining vascular integrity and neuroprotection. However, it is not clear whether Perlecan is involved in BSCB repair after SCI. In this study, we found that Perlecan was specifically expressed in the BMs in the spinal cord and underwent degradation/remodeling after SCI. Subsequently, a CRISPR/Cas9-based SAM system was used to overexpress Perlecan in the injured spinal cord, resulting in significantly enhanced locomotor recovery and neural regeneration. Overexpression of Perlecan reduced BSCB permeability along with the neuroinflammatory response. Interestingly, Perlecan inhibited stress fiber formation by interacting with integrin ß1 and inhibiting downstream ROCK/MLC signaling, resulting in reduced tight junctions (TJs) disassembly and improved BSCB integrity. Furthermore, the integrin receptor antagonist GRGDSP abolished the effects of Perlecan overexpression on BSCB permeability and TJs integrity. Overall, our findings suggest that Perlecan reduces BSCB permeability and the neuroinflammatory response by interacting with integrin ß1 and inhibiting the downstream ROCK/MLC pathway to promote neurological recovery after SCI.

Targeting tumour-intrinsic N7-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy.

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy. DESIGN: Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo. RESULTS: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N7-methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8 in human and Cxcl5 in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models. CONCLUSIONS: Our data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies.

Machine Learning Based on Event-Related EEG of Sustained Attention Differentiates Adults with Chronic High-Altitude Exposure from Healthy Controls.

(1) Objective: The aim of this study was to examine the effect of high altitude on inhibitory control processes that underlie sustained attention in the neural correlates of EEG data, and explore whether the EEG data reflecting inhibitory control contain valuable information to classify high-altitude chronic hypoxia and plain controls. (2) Methods: 35 chronic high-altitude hypoxic adults and 32 matched controls were recruited. They were required to perform the go/no-go sustained attention task (GSAT) using event-related potentials. Three machine learning algorithms, namely a support vector machine (SVM), logistic regression (LR), and a decision tree (DT), were trained based on the related ERP components and neural oscillations to build a dichotomous classification model. (3) Results: Behaviorally, we found that the high altitude (HA) group had lower omission error rates during all observation periods than the low altitude (LA) group. Meanwhile, the ERP results showed that the HA participants had significantly shorter latency than the LAs for sustained potential (SP), indicating vigilance to response-related conflict. Meanwhile, event-related spectral perturbation (ERSP) analysis suggested that lowlander immigrants exposed to high altitudes may have compensatory activated prefrontal cortexes (PFC), as reflected by slow alpha, beta, and theta frequency-band neural oscillations. Finally, the machine learning results showed that the SVM achieved the optimal classification F1 score in the later stage of sustained attention, with an F1 score of 0.93, accuracy of 92.54%, sensitivity of 91.43%, specificity of 93.75%, and area under ROC curve (AUC) of 0.97. The results proved that SVM classification algorithms could be applied to identify chronic high-altitude hypoxia. (4) Conclusions: Compared with other methods, the SVM leads to a good overall performance that increases with the time spent on task, illustrating that the ERPs and neural oscillations may provide neuroelectrophysiological markers for identifying chronic plateau hypoxia.