Comparative Genomics Analysis of the Populus Epidermal Pattern Factor (EPF) Family Revealed Their Regulatory Effects in Populus euphratica Stomatal Development.

Drought stress seriously threatens plant growth. The improvement of plant water use efficiency (WUE) and drought tolerance through stomatal regulation is an effective strategy for coping with water shortages. Epidermal patterning factor (EPF)/EPF-like (EPFL) family proteins regulate stomatal formation and development in plants and thus contribute to plant stress adaptation. Here, our analysis revealed the presence of 14 PeEPF members in the Populus euphratica genome, which exhibited a relatively conserved gene structure with 1-3 introns. Subcellular localisation prediction revealed that 9 PeEPF members were distributed in the chloroplasts of P. euphratica, and 5 were located extracellularly. Phylogenetic analysis indicated that PeEPFs can be divided into three clades, with genes within the same clade revealing a relatively conserved structure. Furthermore, we observed the evolutionary conservation of PeEPFs and AtEPF/EPFLs in certain domains, which suggests their conserved function. The analysis of cis-acting elements suggested the possible involvement of PeEPFs in plant response to multiple hormones. Transcriptomic analysis revealed considerable changes in the expression level of PeEPFs during treatment with polyethylene glycol and abscisic acid. The overexpression of PeEPF2 resulted in low stomatal density in transgenetic lines. These findings provide a basis for gaining insights into the function of PeEPFs in response to abiotic stress.

Situation covariation and goal adaptiveness? The promoting effect of cognitive flexibility on emotion regulation in depression.

Cognitive inflexibility as a generalized characteristic of depression has been closely implicated in maladaptive coping with changing situations and goals in daily life. The association between cognitive flexibility and depression can be elucidated by situation covariation and goal adaptiveness of emotion regulation flexibility (ERF), which facilitates adaptive responses to changing environments. However, little is known about the contribution of cognitive flexibility to emotion regulation in depression under changing situations and goals. To address this gap, we performed three experiments to assess situation covariation and goal adaptiveness of ERF, and we further examined the contribution of situation covariation and goal adaptiveness to the association between cognitive inflexibility and depression. The results of Experiments 1 (N = 120) and 2 (N = 117) showed a significantly negative correlation between cognitive flexibility and goal adaptiveness (but not situation covariation) of ERF. Further mediation analysis revealed the contribution of goal adaptiveness scores to the relationship between cognitive flexibility and depression. In Experiment 3 (N = 93), we performed a 14-day training of cognitive flexibility and observed that the training increased goal adaptiveness, but not situation covariation, of ERF and reduced symptoms of depression. Furthermore, the improvement of goal adaptiveness scores significantly mediated the effect of cognitive flexibility on depressive remission. In sum, these findings identified a vital involvement of goal adaptiveness of ERF in the effect of cognitive flexibility on depression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Controllable and selective fluoride precipitation from phosphate-rich wastewater.

Industrial wastewater containing high levels of fluoride and phosphate poses significant environmental challenges and results in the waste of non-renewable resources. This study investigates the use of La(OH)3 as a precipitating agent to selectively remove and separate fluoride from phosphate in such wastewater. The findings indicate that fluoride removal efficiency is highly dependent on the pH level and La(OH)3 dosage. Using Response Surface Methodology, the optimal conditions for fluoride precipitation were identified as a pH range of 1.0 to 2.5, a reaction time of 60-80 min, a La/3F molar ratio of 2.0, and reaction temperature of 25 °C. Under these parameters, the fluoride removal efficiency exceeded 96.9 %, while phosphate removal remained around 7.2 %. Further Density Functional Theory calculations and characterization confirmed La(OH)3 has a strong affinity for fluoride than phosphate under acidic conditions, leading to the formation of a LaF3 precipitate without forming LaPO4, effectively separating fluoride from phosphate. These results demonstrate an efficient strategy for treating wastewater with high fluoride and phosphate content, enabling the selective precipitation and recovery of these elements for sustainable management.

Effects of Latilactobacillus sakei LZ217 on Gastric Mucosal Colonization, Metabolic Interference, and Urease Expression in Helicobacter pylori Infection.

Emerging evidence suggests differential antagonism of lactic acid-producing bacteria (LAB) to Helicobacter pylori, posing challenges to human health and food safety due to unclear mechanisms. This study assessed 21 LAB strains from various sources on H. pylori growth, urease activity, and coaggregation. Composite scoring revealed that Latilactobacillus sakei LZ217, derived from fresh milk, demonstrates strong inhibitory effects on both H. pylori growth and urease activity. L. sakei LZ217 significantly reduced H. pylori adherence of gastric cells in vitro, with inhibition ratios of 47.62%. Furthermore, in vivo results showed that L. sakei LZ217 alleviated H. pylori-induced gastric mucosa damage and inflammation in mice. Metabolomic exploration revealed metabolic perturbations in H. pylori induced by L. sakei LZ217, including reduced amino acid levels (e.g., isoleucine, leucine, glutamate, aspartate, and phenylalanine) and impaired carbohydrate and nucleotide synthesis, contributing to the suppression of ureA (28.30%), ureE (84.88%), and ureF (59.59%) expressions in H. pylori. This study underscores the efficacy of LAB against H. pylori and highlights metabolic pathways as promising targets for future interventions against H. pylori growth and colonization.

[Development of ECG Common Mode Rejection Ratio Automatic Test System].

To comprehensively meet the test requirements for the common mode rejection ratio (CMRR) across different ECG-particular standards, this paper presents the design of an ECG CMRR automatic test system. The hardware component primarily consists of a test signal generation module, an automatic control network (which includes a resistance-capacitance network control module and a polarization voltage control module), and a noise level switching module. The software portion enables automatic control and user interaction. Experimental results indicate that the system is stable, reliable, and highly automated, capable of satisfying the test requirements of various ECG-particular standards, thus demonstrating a promising application prospect.

Botulinum toxin type A injection combined with biofeedback in the treatment of spastic pelvic floor syndrome.

BACKGROUND: Spastic pelvic floor syndrome (SPFS) is a refractory pelvic floor disease characterized by abnormal (uncoordinated) contractions of the external anal sphincter and puborectalis muscle during defecation, resulting in rectal emptation and obstructive constipation. The clinical manifestations of SPFS are mainly characterized by difficult defecation, often accompanied by a sense of anal blockage and drooping. Manual defecation is usually needed during defecation. From physical examination, it is commonly observed that the patient's anal muscle tension is high, and it is difficult or even impossible to enter with his fingers. AIM: To investigate the characteristics of anorectal pressure and botulinum toxin A injection combined with biofeedback in treating pelvic floor muscle spasm syndrome. METHODS: Retrospective analysis of 50 patients diagnosed with pelvic floor spasm syndrome. All patients underwent pelvic floor surface electromyography assessment, anorectal dynamics examination, botulinum toxin type A injection 100 U intramuscular injection, and two cycles of biofeedback therapy. RESULTS: After the botulinum toxin A injection combined with two cycles of biofeedback therapy, the patient's postoperative resting and systolic blood pressure were significantly lower than before surgery (P < 0.05). Moreover, the electromyography index of the patients in the resting stage and post-resting stages was significantly lower than before surgery (P < 0.05). CONCLUSION: Botulinum toxin A injection combined with biofeedback can significantly reduce pelvic floor muscle tension in treating pelvic floor muscle spasm syndrome. Anorectal manometry is an effective method to evaluate the efficacy of treatment objectively. However, randomized controlled trials are needed.

B-site substitution effects on the mechanical properties of halide perovskites [C4H12N2][BCl3]·H2O (B = NH4+; K+).

The mechanical properties of halide perovskites have been attracting ever-increasing interest for their significant importance in future industrial applications. However, studies focused on the effect of B-site substitution of molecular perovskites on their mechanical properties are rare, which makes it favorable to shed light on their fundamental structure-mechanical property relationships. Here, using isostructural halide perovskites, [C4H12N2][BCl3]·H2O (B = NH4+; K+), constructed by ionic bonds and hydrogen bonds, respectively, as the model systems, we investigate their mechanical properties through high-pressure synchrotron X-ray diffraction experiments and density functional theory calculations. Owing to the similar sizes of NH4+ and K+, the two compounds possess almost identical cell parameters and frameworks. Upon compression, the two perovskites exhibit analogous behavior except for slight differences in the shrinkage ratio of principal axes and the onset pressure of amorphization. The fitted bulk moduli of [C4H12N2][KCl3]·H2O and [C4H12N2][NH4Cl3]·H2O are 43.89 and 27.28 GPa, respectively. These results demonstrate that the simple replacement of K+ by NH4+ can significantly reduce the structural rigidity of the corresponding compounds, which is ascribed to the weaker strength of NH4⋯Cl hydrogen bonds than that of K-Cl bonds.

Attenuated conflict self-referential information facilitating conflict resolution.

Self-referential information can reduce the congruency effect by acting as a signal to enhance cognitive control. However, it cannot be denied that self-referential information can attract and hold attention. To investigate this issue, the study used a revised Stroop task and recorded behavioral and electrophysiological data from thirty-three participants. We combined event-related potential (ERP) and multivariate pattern analysis (MVPA) to examine the neural correlates of self-referential processing and conflict processing. In the behavioral results, self-referential information reduced the congruency effect. Specifically, self-reference stimuli elicited smaller N2 amplitude than non-self-reference stimuli, indicating that self-referential information was promptly identified and reduced top-down cognitive resource consumption. Self-referential information could be reliably decoded from ERP signals in the early-to-mid stage. Moreover, self-reference conditions exhibited earlier congruency decoding than non-self-reference conditions, facilitating conflict monitoring. In the late stage, under the incongruent condition, self-reference stimuli elicited smaller sustained potential amplitude than non-self-reference stimuli, indicating that cognitive control in the self-reference condition required fewer cognitive resources for conflict resolution. Together, these findings revealed that self-referential information was identified and facilitated conflict monitoring, leading to more effective conflict resolution.

Observation of conflict triggers conflict adaptation.

The conflict monitoring theory posits that the simultaneous activation of incompatible responses in the current trial leads to response conflict. Conflict occurrence signals to enhance attention to the target stimulus, reduce attention to distracting stimuli, and ultimately lead to conflict adaptation (i.e., reduced interference effect after conflict trials compared to nonconflict trials). However, this theory does not explicitly assume whether the involvement of response execution is necessary in the process of conflict occurrence. Research on the negative emotion theory suggests that even in the absence of response execution, incompatible response representations can induce conflict. Our present study aimed to provide direct behavioural evidence regarding whether conflict activated without response execution is sufficient to trigger conflict adaptation. In a word-colour Stroop task, this study employed the LOOK-to-DO transition design, in which participants refrained from responding in half of the trials (LOOK trials) and responded with key presses in the other half (DO trials). Across three experiments, we controlled for feature integration and contingency learning and manipulated the stimulus presentation duration in the previous trial. The results indicated a significant conflict adaptation effect in reaction time when the stimulus presentation duration was shorter in the previous trial. This finding suggested that in a confounding-minimal design with no response execution in the previous trial, conflict triggers control adjustments and leads to conflict adaptation. This finding aligns with and further elaborates on the original conflict monitoring theory by demonstrating that response execution is not a necessary condition for the generation of response conflict. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Quantitative response of the spatial distribution of diesel oil to freezing and thawing temperatures in groundwater.

The mobilization and redistribution of organic contaminants in groundwater is the basis and key to explore its dynamic evolution and appropriate remediation. The naturally occurring diametrical temperature gradient during freezing and thawing cycle leads to distinct behaviors of organic contaminants in groundwater. In this study, the pore-scale distribution of diesel oil in the porous media was quantitatively divided into capillary fluid state (CFS) and free fluid state (FFS) based on multiphase flow dynamics, employing low-field nuclear magnetic resonance (LF-NMR) technology. The pore-scale distribution of diesel oil depends not only on the freezing and thawing cycle but also on the temperature gradient according to LF-NMR results. The content of diesel oil in the CFS generally increases with a positive temperature gradient (e.g. freezing) compared to a negative temperature gradient (e.g. thawing), while the content of diesel oil in the FFS generally decreases. This dependence of the temperature gradient on pore-scale distribution of the diesel oil is positively correlated with the particle size of the porous medium. Furthermore, the pore-scale distribution of the diesel oil during the freezing and thawing cycle is influenced by the kinematic viscosity of the diesel oil. There is an exponential relationship between the diesel oil content and the kinematic viscosity, independent of the freezing or thawing process. During the freezing process, the diesel oil migrates from FFS to CFS, while this migration is reversed during the thawing process. The reverse migration of the diesel oil between the freezing and thawing processes leads to a spatial redistribution of the diesel oil, which is controlled by both the fluid energy and the capillary force. The present work provide meaningful guidance for the remediation of groundwater contamination in cold regions.

Decoding the task specificity of post-error adjustments: Features and determinants.

Errors typically trigger post-error adjustments aimed at improving subsequent reactions within a single task, but little work has focused on whether these adjustments are task-general or task-specific across different tasks. We collected behavioral and electrophysiological (EEG) data when participants performed a psychological refractory period paradigm. This paradigm required them to complete Task 1 and Task 2 separated by a variable stimulus onset asynchrony (SOA). Behaviorally, post-error slowing and post-error accuracy exhibited task-general features at short SOAs but some task-specific features at long SOAs. EEG results manifest that task-general adjustments had a short-lived effect, whereas task-specific adjustments were long-lasting. Moreover, error awareness specifically conduced to the improvement of subsequent sensory processing and behavior performance in Task 1 (the task where errors occurred). These findings demonstrate that post-error adjustments rely on both transient, task-general interference and longer-lasting, task-specific control mechanisms simultaneously, with error awareness playing a crucial role in determining these mechanisms. We further discuss the contribution of central resources to the task specificity of post-error adjustments.

Knockdown of microRNA390 Enhances Maize Brace Root Growth.

Brace root architecture is a critical determinant of maize's stalk anchorage and nutrition uptake, influencing root lodging resistance, stress tolerance, and plant growth. To identify the key microRNAs (miRNAs) in control of maize brace root growth, we performed small RNA sequencing using brace root samples at emergence and growth stages. We focused on the genetic modulation of brace root development in maize through manipulation of miR390 and its downstream regulated auxin response factors (ARFs). In the present study, miR167, miR166, miR172, and miR390 were identified to be involved in maize brace root growth in inbred line B73. Utilizing short tandem target mimic (STTM) technology, we further developed maize lines with reduced miR390 expression and analyzed their root architecture compared to wild-type controls. Our findings show that STTM390 maize lines exhibit enhanced brace root length and increased whorl numbers. Gene expression analyses revealed that the suppression of miR390 leads to upregulation of its downstream regulated ARF genes, specifically ZmARF11 and ZmARF26, which may significantly alter root architecture. Additionally, loss-of-function mutants for ZmARF11 and ZmARF26 were characterized to further confirm the role of these genes in brace root growth. These results demonstrate that miR390, ZmARF11, and ZmARF26 play crucial roles in regulating maize brace root growth; the involved complicated molecular mechanisms need to be further explored. This study provides a genetic basis for breeding maize varieties with improved lodging resistance and adaptability to diverse agricultural environments.

Comprehensive Urinary Proteome Profiling Analysis Identifies Diagnosis and Relapse Surveillance Biomarkers for Bladder Cancer.

Bladder cancer (BCa) is the predominant malignancy of the urinary system. Herein, a comprehensive urine proteomic feature was initially established for the noninvasive diagnosis and recurrence monitoring of bladder cancer. 279 cases (63 primary BCa, 87 nontumor controls (NT), 73 relapsed BCa (BCR), and 56 nonrelapsed BCa (BCNR)) were collected to screen urinary protein biomarkers. 4761 and 3668 proteins were qualified and quantified by DDA and sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis in two discovery sets, respectively. Upregulated proteins were validated by multiple reaction monitoring (MRM) in two independent combined sets. Using the multi-support vector machine-recursive feature elimination (mSVM-RFE) algorithm, a model comprising 13 proteins exhibited good performance between BCa and NT with an AUC of 0.821 (95% CI: 0.675-0.967), 90.9% sensitivity (95% CI: 72.7-100%), and 73.3% specificity (95% CI: 53.3-93.3%) in the diagnosis test set. Meanwhile, an 11-marker classifier significantly distinguished BCR from BCNR with 75.0% sensitivity (95% CI: 50.0-100%), 81.8% specificity (95% CI: 54.5-100%), and an AUC of 0.784 (95% CI: 0.609-0.959) in the test cohort for relapse surveillance. Notably, six proteins (SPR, AK1, CD2AP, ADGRF1, GMPS, and C8A) of 24 markers were newly reported. This paper reveals novel urinary protein biomarkers for BCa and offers new theoretical insights into the pathogenesis of bladder cancer (data identifier PXD044896).

Low-dose metformin suppresses hepatocellular carcinoma metastasis via the AMPK/JNK/IL-8 pathway.

BACKGROUND AND OBJECTIVES: Metformin, an oral hypoglycemic drug, has been suggested to possess antitumour activity in several types of cancers. Additionally, interleukin-8 (IL-8) has been reported to be involved in the development and metastasis of many cancers. However, the effect of metformin on IL-8 expression in hepatocellular carcinoma (HCC) remains unclear. Therefore, this study aimed to investigate whether metformin could inhibit IL-8 expression to exert an inhibitory effect on HCC progression. MATERIALS AND METHODS: The IL-8 levels were measured in the plasma of 159 HCC patients (86 men, 73 women; average age 56 years) and in the culture supernatant of HCC cells (Hep3B and HuH7) using flow cytometry. In addition, the protein expression levels of IL-8 were also validated by the Human Protein Atlas (HPA) database. The prognostic value of IL-8 was evaluated using the Kaplan-Meier Plotter database. The association between IL-8 expression and immune checkpoints was estimated using the TIMER and The Cancer Genome Atlas (TCGA) databases. What's more, bioinformatics analysis, western blotting, and transwell assays were conducted to illustrate the molecular mechanism of metformin (≤1 mM) on IL-8 in HCC. RESULTS: IL-8 expression was found to be increased in the plasma of HCC patients, which is consistent with the expression of IL-8 in HCC cells and tissues. High expression of IL-8 was significantly related to poor prognosis. In addition, IL-8 was positively correlated with immune checkpoints in HCC. Notably, we found that low-dose metformin could inhibit the secretion of IL-8 by HCC cells and the migration of HCC cells. Mechanistically, low-dose metformin significantly suppresses HCC metastasis mainly through the AMPK/JNK/IL-8/MMP9 pathway. CONCLUSION: The results indicate that low-dose metformin can inhibit HCC metastasis by suppressing IL-8 expression. Targeting the AMPK/JNK/IL-8 axis may be a promising treatment strategy for patients with HCC metastasis.

Solving the non-submodular network collapse problems via Decision Transformer.

Given a graph G, the network collapse problem (NCP) selects a vertex subset S of minimum cardinality from G such that the difference in the values of a given measure function f(G)-f(G∖S) is greater than a predefined collapse threshold. Many graph analytic applications can be formulated as NCPs with different measure functions, which often pose a significant challenge due to their NP-hard nature. As a result, traditional greedy algorithms, which select the vertex with the highest reward at each step, may not effectively find the optimal solution. In addition, existing learning-based algorithms do not have the ability to model the sequence of actions taken during the decision-making process, making it difficult to capture the combinatorial effect of selected vertices on the final solution. This limits the performance of learning-based approaches in non-submodular NCPs. To address these limitations, we propose a unified framework called DT-NC, which adapts the Decision Transformer to the Network Collapse problems. DT-NC takes into account the historical actions taken during the decision-making process and effectively captures the combinatorial effect of selected vertices. The ability of DT-NC to model the dependency among selected vertices allows it to address the difficulties caused by the non-submodular property of measure functions in some NCPs effectively. Through extensive experiments on various NCPs and graphs of different sizes, we demonstrate that DT-NC outperforms the state-of-the-art methods and exhibits excellent transferability and generalizability.

A challenging surgical technique: single-port endoscopic-assisted radical mastectomy in retrograde way and immediate reconstruction using prosthesis implantation.

Background: Endoscopic surgery for malignant breast tumors is becoming more and more popular and has been applied in the clinical setting. Single-port endoscopic-assisted radical mastectomy in retrograde way and immediate reconstruction using prosthesis implantation are rare. Therefore, this study described a new endoscopic technique for breast surgery. Methods: This is a cross-sectional study. A total of 12 patients with breast cancer diagnosed in the Department of Thyroid Breast Surgery of The Second Affiliated Hospital of Fujian Medical University from January 2019 to June 2022 were retrospectively selected and underwent axillary single-port endoscopic-assisted radical mastectomy in retrograde way and immediate reconstruction using prosthesis implantation. Results: The average operation time was 190.25±25.40 min, the average blood loss was 86.25±33.11 mL, the average drainage volume was 207.92±65.90 mL 3 days after surgery, and the average hospital stay was 9.67±2.57 days. The follow-up period ranged from 11 to 21 months, with an average of 16.75 months. Medial paresthesia was present in only one patient, which decreased or disappeared after 3 months. No complications such as wound infection or limb dysfunction occurred in the remaining patients. Postoperative follow-up showed that 10 patients were very satisfied, one patient was relatively satisfied, and one patient was not satisfied. Conclusions: Preliminary data attested the feasibility and the safety of this approach. It can improve patient satisfaction compared with traditional modified radical mastectomy for suitable candidates. However, long-term data are needed to confirm the oncological safety and the esthetic stability of the result.

The neural dynamics of conflict adaptation induced by conflict observation: Evidence from univariate and multivariate analysis.

Conflict adaptation can be expressed as greater performance (shorter response time and lower error rate) after incongruent trials when compared to congruent trials. It has been observed in designs that minimize confounding factors, i.e., feature integration, contingency learning, and temporal learning. Our current study aimed to further elucidate the temporal evolution mechanisms of conflict adaptation. To address this issue, the current study employed a combination of behavioral, univariate, and multivariate analysis (MVPA) methods in a modified color-word Stroop task, where half of the trials required button presses (DO trials), and the other half only required observation (LOOK trials). Both behavioral and the ERP results (N450 and SP) in the LOOK-DO transition trials revealed significant conflict adaptation without feature integration, contingency learning, and temporal learning, providing support for the conflict monitoring theory. Furthermore, during the LOOK trials, significant Stroop effect in the N450 and SP components were observed, indicating that conflict monitoring occurred at the stimulus level and triggered reactive control adjustments. The MVPA results decoded the congruent-incongruent and incongruent-incongruent conditions during the conflict adjustment phase but not during the conflict monitoring phase, emphasizing the unique contribution of conflict adjustment to conflict adaptation. The current research findings provided more compelling supporting evidence for the conflict monitoring theory, while also indicating that future studies should employ the present design to elucidate the specific processes of conflict adaptation.

Interferon-α induces differentiation of cancer stem cells and immunosuppression in hepatocellular carcinoma by upregulating CXCL8 secretion.

Interferon-alpha (IFN-α) is widely used in the clinical treatment of patients with chronic hepatitis B and hepatocellular carcinoma (HCC). However, high levels of CXCL8 are associated with resistance to IFN-α therapy and poorer prognosis in advanced cancers. In this study, we investigated whether IFN-α could directly induce the production of CXCL8 in HCC cells and whether CXCL8 could antagonize the antitumor activity of IFN-α. We found that IFN-α not only upregulated the expression of the inducible genes CXCL9, CXCL10, CXCL11 and PD-L1, but also significantly stimulated CXCL8 secretion in HCC cells. Mechanically, IFN-α induces CXCL8 expression by activating the AKT and JNK pathways. In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic. Besides, our study reveals that the cytokine CXCL8 secreted by IFN-α-induced HCC cells inhibits T-cell function. Conversely, inhibition of CXCL8 promotes TNF-α and IFN-γ secretion by T cells. Finally, liver cancer patients who received anti-PD-1/PD-L1 immunotherapy with high CXCL8 expression had a lower immunotherapy efficacy. Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.

The Role of the Notch Signaling Pathway in the Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells.

Human umbilical cord mesenchymal stem cells (hUCMSCs) exhibit potent self-renewal and multilineage differentiation characteristics. They have garnered substantial attention within the domain of regenerative medicine owing to their therapeutic potential, such as in tissue repair, regeneration, immunomodulation, anti-inflammation, angiogenesis, wound healing, neuroprotection, and neuroregeneration. The process of fate determination is initiated by multiple signaling molecules. During development and tissue homeostasis, the Notch signaling pathway assumes a pivotal function in cell differentiation and the renewal of stem cells. A growing body of research has revealed that the Notch signaling pathwayplays a pivotal role in hUCMSC proliferation and differentiation. The latest progress concerning the crucial functions of the Notch signaling pathway in maintaining homeostasis and determining the cell fate of hUCMSCs is summarized. Furthermore, the authors also summarized the mediators related to the Notch signaling pathway in hUCMSC differentiation, as well as the pathway alterations and mechanisms involved in hUCMSC therapy.

Tumor cell-derived LC3B+extracellular vesicles mediate the crosstalk between tumor microenvironment and immunotherapy efficacy in hepatocellular carcinoma via the HSP90α-IL-6/IL-8 signaling axis.

BACKGROUND: Inflammatory factors are being recognized as critical modulators of host antitumor immunity in liver cancer. We have previously shown that tumor cell-released LC3B positive extracellular vesicles (LC3B+ EVs) are responsible for malignant progression by dampening antitumor immunity. However, the relationship between LC3B+ EVs and inflammatory factors in the regulation of the liver cancer microenvironment remains unclear. METHODS: Flow cytometry analyses were performed to examine the panel of 12 cytokines, the main source of positive cytokines, and plasma LC3B+ EVs carrying HSP90α in peripheral blood of liver cancer patients. We correlated the levels of plasma IL-6, IL-8 with LC3B+ EVs carrying HSP90α and with prognosis. In vitro culture of healthy donor leukocytes with liver cancer-derived LC3B+ EVs was performed to evaluate the potential effect of blocking HSP90α, IL-6 or IL-8 alone or in combination with PD-1 inhibitor on CD8+ T cell function. We also investigated the potential associations of MAP1LC3B, HSP90AA1, IL6 or IL8 with immunotherapy efficacy using the TCGA databases. RESULTS: In liver cancer patients, plasma IL-6 and IL-8 levels were significantly higher than in healthy controls and associated with poor clinical outcome. In peripheral blood, levels of plasma LC3B+ EVs carrying HSP90α were significantly elevated in HCC patients and positively associated with IL-6 and IL-8 levels, which are predominantly secreted by monocytes and neutrophils. Moreover, LC3B+ EVs from human liver cancer cells promoted the secretion of IL-6 and IL-8 by leukocytes through HSP90α. Besides, we show that the cytokines IL-6 and IL-8 secreted by LC3B+ EVs-induced leukocytes were involved in the inhibition of CD8+ T-cell function, while blockade of the HSP90α on the LC3B+ EVs, IL-6, or IL-8 could enhance anti-PD-1-induced T cell reinvigoration. Finally, patients who received anti-PD-1/PD-L1 immunotherapy with high MAP1LC3B, HSP90AA1, IL6, or IL8 expression had a lower immunotherapy efficacy. CONCLUSIONS: Our data suggest that liver cancer-derived LC3B+ EVs promote a pro-oncogenic inflammatory microenvironment by carrying membrane-bound HSP90α. Targeting HSP90α on the LC3B+ EVs, IL-6, or IL-8 may synergize with anti-PD-1 treatment to enhance the CD8+ T-cell functions, which may provide novel combination strategies in the clinic for the treatment of liver cancer.