Mesenchymal stem cells alleviate mouse liver fibrosis by inhibiting pathogenic function of intrahepatic B cells.

BACKGROUND AND AIMS: The immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them a promising therapeutic approach for liver fibrosis (LF). Here, we postulated that MSCs could potentially suppress the pro-fibrotic activity of intrahepatic B cells, thereby inhibiting LF progression. APPROACH AND RESULTS: Administration of MSCs significantly ameliorated LF as indicated by reduced myofibroblast activation, collagen deposition, and inflammation. The treatment efficacy of MSCs can be attributed to decreased infiltration, activation, and pro-inflammatory cytokine production of intrahepatic B cells. Single-cell RNA sequencing revealed a distinct intrahepatic B cell atlas, and a subtype of naive B cells (B-II) was identified, which were markedly abundant in fibrotic liver, displaying mature features with elevated expression of several proliferative and inflammatory genes. Transcriptional profiling of total B cells revealed that intrahepatic B cells displayed activation, proliferation, and pro-inflammatory gene profile during LF. Fibrosis was attenuated in mice ablated with B cells (µMT) or in vivo treatment with anti-CD20. Moreover, fibrosis was recapitulated in µMT after adoptive transfer of B cells, which in turn could be rescued by MSC injection, validating the pathogenic function of B cells and the efficacy of MSCs on B cell-promoted LF progression. Mechanistically, MSCs could inhibit the proliferation and cytokine production of intrahepatic B cells through exosomes, regulating the Mitogen-activated protein kinase and Nuclear factor kappa B signaling pathways. CONCLUSIONS: Intrahepatic B cells serve as a target of MSCs, play an important role in the process of MSC-induced amelioration of LF, and may provide new clues for revealing the novel mechanisms of MSC action.

MSCs alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of macrophages in mouse lung organoid-macrophage model.

Acute lung injury (ALI) is an inflammatory disease associated with alveolar injury, subsequent macrophage activation, inflammatory cell infiltration, and cytokine production. Mesenchymal stem cells (MSCs) are beneficial for application in the treatment of inflammatory diseases due to their immunomodulatory effects. However, the mechanisms of regulatory effects by MSCs on macrophages in ALI need more in-depth study. Lung tissues were collected from mice for mouse lung organoid construction. Alveolar macrophages (AMs) derived from bronchoalveolar lavage and interstitial macrophages (IMs) derived from lung tissue were co-cultured, with novel matrigel-spreading lung organoids to construct an in vitro model of lung organoids-immune cells. Mouse compact bone-derived MSCs were co-cultured with organoids-macrophages to confirm their therapeutic effect on acute lung injury. Changes in transcriptome expression profile were analyzed by RNA sequencing. Well-established lung organoids expressed various lung cell type-specific markers. Lung organoids grown on spreading matrigel had the property of functional cells growing outside the lumen. Lipopolysaccharide (LPS)-induced injury promoted macrophage chemotaxis toward lung organoids and enhanced the expression of inflammation-associated genes in inflammation-injured lung organoids-macrophages compared with controls. Treatment with MSCs inhibited the injury progress and reduced the levels of inflammatory components. Furthermore, through the nuclear factor-κB pathway, MSC treatment inhibited inflammatory and phenotypic transformation of AMs and modulated the antigen-presenting function of IMs, thereby affecting the inflammatory phenotype of lung organoids. Lung organoids grown by spreading matrigel facilitate the reception of external stimuli and the construction of in vitro models containing immune cells, which is a potential novel model for disease research. MSCs exert protective effects against lung injury by regulating different functions of AMs and IMs in the lung, indicating a potential mechanism for therapeutic intervention.

Stability of Plasmonic Mg-MgO Core-Shell Nanoparticles in Gas-Phase Oxidative Environments.

Magnesium is a recent addition to the plasmonic toolbox: nanomaterials that efficiently utilize photons' energy due to their ability to sustain localized surface plasmon resonances. Magnesium nanoparticles protected by a native oxide shell can efficiently absorb light across the solar spectrum, making them a promising photocatalytic material. However, their inherent reactivity toward oxidation may limit the number of reactions in which Mg-MgO can be used. Here, we investigate the stability of plasmonic Mg-MgO core-shell nanoplates under oxidative conditions. We demonstrate that the MgO shell stabilizes the metallic Mg core against oxidation in air at up to 400 °C. Furthermore, we show that the reactivity of Mg-MgO nanoplates with water vapor (3.5 vol % in N2) decreases with temperature, with no oxidation of the Mg core detected from 200 to 400 °C. This work unravels the potential of Mg-MgO nanoparticles for a broad range of catalytic transformations occurring in oxidative environments.

Association between body mass index and electrocardiogram indices: A Mendelian randomization study.

INTRODUCTION: Cardiovascular diseases (CVDs) remain a global health concern, and body mass index (BMI) is known to be associated with an increased risk of CVD, but the exact mechanisms underlying this relationship remain unclear. This study employs Mendelian randomization (MR) to investigate the causal association between BMI and electrocardiogram (ECG) indices, providing insights into potential pathways linking obesity to CVD. METHODS: We conducted a comprehensive MR study utilizing large-scale genetic and ECG data from diverse populations. Instrumental variables were selected from genome-wide association studies, ensuring their relevance to BMI. Causal relationships between BMI and ECG indices, including P wave duration, PR interval, QRS duration, and QT interval, were assessed using various MR methods, with inverse variance weighted (IVW) considered as the primary analysis. RESULTS: Our MR analysis revealed a significant positive causal association between higher BMI and P wave duration (ß = 8.078, 95% CI: 5.322 to 10.833, p < 0.001), suggesting a potential mechanism through which higher BMI may contribute to arrhythmogenic risks. However, no significant causal associations were observed between BMI and PR interval, QRS duration, or QT interval (all p > 0.005). In addition, our study also found that there is no horizontal pleiotropy between BMI and P wave duration, PR interval, QRS duration, and QT interval, suggesting that the conclusions of this study are robust. CONCLUSION: This study supports a causal relationship between elevated BMI and prolonged P wave duration, a marker of increased atrial arrhythmogenic risk. Further investigations are still needed to elucidate the underlying mechanisms.

Proportional feature pyramid network based on weight fusion for lane detection.

Lane detection under extreme conditions presents a highly challenging task that requires capturing each crucial pixel to predict the complex topology of lane lines and differentiate the various lane types. Existing methods predominantly rely on deep feature extraction networks with substantial parameters or the fusion of multiple prediction modules, resulting in large model sizes, embedding difficulties, and slow detection speeds. This article proposes a Proportional Feature Pyramid Network (P-FPN) through fusing the weights into the FPN for lane detection. For obtaining a more accurately detecting result, the cross refinement block is introduced in the P-FPN network. The cross refinement block takes the feature maps and anchors as inputs and gradually refines the anchors from high to low level feature maps. In our method, the high-level features are explored to predict lanes coarsely while local-detailed features are leveraged to improve localization accuracy. Extensive experiments on two widely used lane detection datasets, The Chinese Urban Scene Benchmark for Lane Detection (CULane) and the TuSimple Lane Detection Challenge (TuSimple) datasets, demonstrate that the proposed method achieves competitive results compared with several state-of-the-art approaches.

Serum EZH2 is a novel biomarker for bladder cancer diagnosis and prognosis.

Objective: The primary objective of this study was to examine the levels of serum EZH2 in patients diagnosed with bladder cancer, and subsequently evaluate its potential as a biomarker for both the diagnosis and prognosis of bladder cancer. Methods: Blood samples were obtained from 115 bladder cancer patients and 115 healthy persons. We measured the EZH2 concentrations in the serum of these subjects via enzyme-linked immunosorbent assay (ELISA). To assess the diagnostic performance of serum EZH2 in detecting bladder cancer, we plotted receiver operating characteristic (ROC) curves and calculated their corresponding area under the curve (AUC). We also used the Cox regression model and log-rank test to investigate the correlation between EZH2 levels and clinicopathological characteristics, and survival rates of bladder cancer patients. Results: Serum EZH2 levels were significantly higher in bladder cancer patients when compared to those in healthy persons. Serum EZH2 levels exhibited a significant correlation with TNM stage, lymph node metastasis, muscle invasion, and tumor size. At a cutoff value of 8.23 ng/mL, EZH2 was able to differentiate bladder cancer patients from healthy persons, with an AUC of 0.87, a sensitivity of 81.31%, and a specificity of 78.42%. High EZH2 levels correlated with poor overall survival rates and progression-free survival rates of bladder cancer patients. Conclusions: Serum EZH2 levels were elevated in bladder cancer patients, and patients with higher serum EZH2 levels exhibited a poorer prognosis. This indicates that serum EZH2 could be a novel biomarker for bladder cancer diagnosis and prognosis. Such findings could improve the prognosis of bladder cancer patients by facilitating early detection and continuous monitoring.

Prognostic stratification of sepsis through DNA damage response based RiskScore system: insights from single-cell RNA-sequencing and transcriptomic profiling.

Background: A novel risk scoring system, predicated on DNA damage response (DDR), was developed to enhance prognostic predictions and potentially inform the creation of more effective therapeutic protocols for sepsis. Methods: To thoroughly delineate the expression profiles of DDR markers within the context of sepsis, an analytical approach utilizing single-cell RNA-sequencing (scRNA-seq) was implemented. Our study utilized single-cell analysis techniques alongside weighted gene co-expression network analysis (WGCNA) to pinpoint the genes that exhibit the most substantial associations with DNA damage response (DDR). Through Cox proportional hazards LASSO regression, we distinguished DDR-associated genes and established a risk model, enabling the stratification of patients into high- and low-risk groups. Subsequently, we carried out an analysis to determine our model's predictive accuracy regarding patient survival. Moreover, we examined the distinct biological characteristics, various signal transduction routes, and immune system responses in sepsis patients, considering different risk categories and outcomes related to survival. Lastly, we conducted experimental validation of the identified genes through in vivo and in vitro assays, employing RT-PCR, ELISA, and flow cytometry. Results: Both single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic analyses have demonstrated a strong correlation between DNA damage response (DDR) levels and sepsis prognosis. Specific cell subtypes, including monocytes, megakaryocytes, CD4+ T cells, and neutrophils, have shown elevated DDR activity. Cells with increased DDR scores exhibited more robust and numerous interactions with other cell populations. The weighted gene co-expression network analysis (WGCNA) and single-cell analyses revealed 71 DDR-associated genes. We developed a four-gene risk scoring system using ARL4C, CD247, RPL7, and RPL31, identified through univariate COX, LASSO COX regression, and log-rank (Mantel-Cox) tests. Nomograms, calibration plots, and decision curve analyses (DCA) regarding these specific genes have provided significant clinical benefits for individuals diagnosed with sepsis. The study suggested that individuals categorized as lower-risk demonstrated enhanced infiltration of immune cells, upregulated expression of immune regulators, and a more prolific presence of immune-associated functionalities and pathways. RT-qPCR analyses on a sepsis rat model revealed differential gene expression predominantly in the four targeted genes. Furthermore, ARL4C knockdown in sepsis model in vivo and vitro caused increased inflammatory response and a worse prognosis. Conclusion: The delineated DDR expression landscape offers insights into sepsis pathogenesis, whilst our riskScore model, based on a robust four-gene signature, could underpin personalized sepsis treatment strategies.

Mediating effect of sleep quality on the association between job stress and health-related productivity loss among workers in R&D enterprises in Shanghai.

Background: Past research indicates that occupational stress negatively predicts health-related productivity. Simultaneously, sleep problem among workers may stem from job stress, subsequently leading to a decline in sleep quality and resulting in reduced health productivity. Therefore, this study aims to idenitify whether the sleep quality of employees functions as a mediator in the process through which job stress impacts health productivity. Objectives: This study aimed to assess the status and analyze differences in quality of sleep, job stress, and health-related productivity loss (HRPL) among workers in research and development (R&D) enterprises in Minhang District, Shanghai. We also assessed the mediating effect of sleep quality on the relationship between job stress and HRPL. Methods: A total of 3,216 workers in R&D firms aged between 18 and 60 years participated in this study (mean age 35.15 years; standard deviation 8.44; male-to-female ratio≈2:1). The Nakata Insomnia Questionnaire, the Chinese version of the Brief Job Stress Questionnaire revised edition, and the Chinese version of the Work Productivity and Activity Impairment Questionnaire were used in this study. And the Kruskal-Wallis test, Hierarchical Multiple Regression Analysis, and Path Analysis were utilized for data analysis in this study. Results: There were significant differences in the positive detection rate of insomnia among participants according to age, educational level, marital status, position, length of service, and level of financial difficulties (all P < 0.05). We also found significant differences in the positive detection rate of HRPL among participants according to age, marital status, length of service, and level of financial difficulties (all P < 0.05); participants with insomnia scored higher for HRPL than those without insomnia (6.00 vs. 4.20, P < 0.001). Additionally, participants with job stress problems had higher HRPL than those without these issues (7.00 vs. 4.20, P < 0.001). Our findings suggest that sleep quality plays a mediating role between job stress and HRPL (all P < 0.05). Conclusions: Occupational health professionals must pay particular attention to job stress, sleep quality, and their influencing factors to positively influence the wellbeing of workers while improving productivity.

Intestinal nontuberculous mycobacteria infection: A case report.

BACKGROUND: Intestinal nontuberculous mycobacteriosis due to nontuberculous mycobacteria infection has clinical manifestations similar to intestinal tuberculosis and inflammatory bowel disease, causing difficulties in clinical diagnosis. CASE PRESENTATION: A 42-year-old male patient was admitted to the Sino-Japanese Friendship Hospital of Jilin University in June 2021 for diarrhea and intermittent hematochezia since April 2021. He was diagnosed with inflammatory intestinal disease by colonoscopy and midtransverse colon biopsy. However, the symptoms did not relieve after 2 months of mesalazine treatment. In August 2021, the patient was admitted to the outpatient department for suspected "intestinal tuberculosis." A diagnosis of intestinal nontuberculous mycobacteriosis was confirmed based on pathology and nucleotide-based matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). After 2 weeks of antimycobacterial therapy, the patient's diarrhea was relieved, and hematochezia no longer appeared. In November 2021, recolonoscopy revealed scattered erosions and ulcers in ileocecal valve and ascending colon, while both nucleotide-based MALDI-TOF MS and next-generation sequencing could still detect Mycobacterium intracellulare. CONCLUSION: This study reported a patient with an intestinal nontuberculous mycobacteriosis diagnosed by colonoscopy biopsy and nucleotide-based MALDI-TOF MS, and symptoms were relieved after antimycobacterial treatment.

Fluorescence Characteristics and Main Fluorescence Component in Burmese 'chameleon' Amber.

One special variety of Burmese amber is "chameleon" amber, named for the bluish-green colour that appears to float on its surface. This material is found in the famous Tengchong market in Yunnan Province, China's largest Burmese amber market. Its bodycolour ranges from golden brown to brownish-red or even red. When exposed to sunlight or strong white light against a black background, its surface shows a uniform green colour. This research presents the gemological properties, spectral characteristics and organic components of Burmese 'chameleon' amber. Three-dimensional (3D) fluorescence spectra showed that Burmese 'chameleon' amber had fluorescence centres near 433, 465 and 470 nm, and the excitation wavelengths of the fluorescence centres of Burmese 'chameleon' amber were shifted from the ultraviolet region (380 ± 10 nm) to the visible region (410 ± 10 nm), with the emission wavelengths concentrated at the bluish-green region. Through the colour simulation and superimposition, the phenomenon of floating bluish-green fluorescence colour of Burmese 'chameleon' amber is not only derived from bluish-green fluorescence centres, but also enhanced by the mixture of surface fluorescence and its bodycolour. Headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) analysis demonstrated the variety of aromatic compounds in Burmese 'chameleon' amber was related to geological process and the presence of fluorescence components. The high-performance liquid chromatography-fluorescence detector obtained some fluorescent aromatics, particularly benzo[a]anthracene with yellowish-green fluorescence, which is responsible for the fluorescence characteristics of Burmese 'chameleon' amber.

Learning From Human Educational Wisdom: A Student-Centered Knowledge Distillation Method.

Existing studies on knowledge distillation typically focus on teacher-centered methods, in which the teacher network is trained according to its own standards before transferring the learned knowledge to a student one. However, due to differences in network structure between the teacher and the student, the knowledge learned by the former may not be desired by the latter. Inspired by human educational wisdom, this paper proposes a Student-Centered Distillation (SCD) method that enables the teacher network to adjust its knowledge transfer according to the student network's needs. We implemented SCD based on various human educational wisdom, e.g., the teacher network identified and learned the knowledge desired by the student network on the validation set, and then transferred it to the latter through the training set. To address the problems of current deficiency knowledge, hard sample learning and knowledge forgetting faced by a student network in the learning process, we introduce and improve Proportional-Integral-Derivative (PID) algorithms from automation fields to make them effective in identifying the current knowledge required by the student network. Furthermore, we propose a curriculum learning-based fuzzy strategy and apply it to the proposed PID control algorithm, such that the student network in SCD can actively pay attention to the learning of challenging samples after with certain knowledge. The overall performance of SCD is verified in multiple tasks by comparing it with state-of-the-art ones. Experimental results show that our student-centered distillation method outperforms existing teacher-centered ones.

[Effect of different durations of prone ventilation on the efficacy of patients with acute respiratory distress syndrome: a small Meta-analysis].

OBJECTIVE: To systematically evaluate the effect of different durations of prone ventilation on the efficacy of patients with acute respiratory distress syndrome (ARDS). METHODS: A computer search was conducted in databases including PubMed, Cochrane Library, Embase, CNKI, Wanfang Database, VIP Database, and China Biomedical Literature Database for studies on prone ventilation for the treatment of adult patients with ARDS published from the establishment of the database to September 2023. Studies were categorized into ≤ 24 hours group and > 24 hours group based on the duration of prone ventilation. Outcome indicators included mortality, the length of intensive care unit (ICU) stay, incidence of pressure ulcers, and operation of tracheotomy. Two researchers independently screened the literature, extracted information, and evaluated the risk of bias of the included literature. The quality of the included literature was assessed using the NOS scale, and the effect of different durations of prone ventilation on the efficacy of ARDS was analyzed by Meta-analysis. RESULTS: A total of 517 patients from 4 papers were finally included, including 249 patients with prone ventilation duration ≤ 24 hours and 268 patients with prone ventilation duration > 24 hours. All 4 studies were cohort studies, and the overall inclusion of literature assessed for methodological quality indicated high study quality and low risk of bias. Meta-analysis showed that there were no significantly differences in mortality [relative risk (RR) = 1.02, 95% confidence interval (95%CI) was 0.79 to 1.31, P = 0.88], the length of ICU stay [mean difference (MD) = -2.68, 95%CI was -5.30 to - 0.05, P = 0.05] between the prone ventilation duration ≤ 24 hours group and prone ventilation duration > 24 hours group. Compared with the prone ventilation duration ≤24 hours group, the incidence of pressure ulcers (RR = 0.76, 95%CI was 0.59 to 0.98, P = 0.04) and the operation of tracheotomy (RR = 0.71, 95%CI was 0.53 to 0.94, P = 0.02) were significantly increased in the prone ventilation duration > 24 hours group. CONCLUSIONS: The duration of prone ventilation had no significant effect on the mortality and the length of ICU stay in ARDS patients, but prone ventilation for > 24 hours increased the incidence of pressure ulcers and the operation of tracheotomy, which still needs to be further verified by a large number of studies due to the small number of included studies.

Deciphering the immune-metabolic nexus in sepsis: a single-cell sequencing analysis of neutrophil heterogeneity and risk stratification.

Background: Metabolic dysregulation following sepsis can significantly compromise patient prognosis by altering immune-inflammatory responses. Despite its clinical relevance, the exact mechanisms of this perturbation are not yet fully understood. Methods: Single-cell RNA sequencing (scRNA-seq) was utilized to map the immune cell landscape and its association with metabolic pathways during sepsis. This study employed cell-cell interaction and phenotype profiling from scRNA-seq data, along with pseudotime trajectory analysis, to investigate neutrophil differentiation and heterogeneity. By integrating scRNA-seq with Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning techniques, key genes were identified. These genes were used to develop and validate a risk score model and nomogram, with their efficacy confirmed through Receiver Operating Characteristic (ROC) curve analysis. The model's practicality was further reinforced through enrichment and immune characteristic studies based on the risk score and in vivo validation of a critical gene associated with sepsis. Results: The complex immune landscape and neutrophil roles in metabolic disturbances during sepsis were elucidated by our in-depth scRNA-seq analysis. Pronounced neutrophil interactions with diverse cell types were revealed in the analysis of intercellular communication, highlighting pathways that differentiate between proximal and core regions within atherosclerotic plaques. Insight into the evolution of neutrophil subpopulations and their differentiation within the plaque milieu was provided by pseudotime trajectory mappings. Diagnostic markers were identified with the assistance of machine learning, resulting in the discovery of PIM1, HIST1H1C, and IGSF6. The identification of these markers culminated in the development of the risk score model, which demonstrated remarkable precision in sepsis prognosis. The model's capability to categorize patient profiles based on immune characteristics was confirmed, particularly in identifying individuals at high risk with suppressed immune cell activity and inflammatory responses. The role of PIM1 in modulating the immune-inflammatory response during sepsis was further confirmed through experimental validation, suggesting its potential as a therapeutic target. Conclusion: The understanding of sepsis immunopathology is improved by this research, and new avenues are opened for novel prognostic and therapeutic approaches.

Formation of a planar biomimetic membrane with a novel zwitterionic polymer for nanopore sequencing.

Biological membranes containing transmembrane channels play a crucial role in numerous cellular processes, and mimicking of cell membranes has garnered significant interest in various biomedical applications, particularly nanopore sequencing technology, where remarkable progress has been made with nanopore membranes. Considering the fragility of biomimetic membranes formed by artificial lipids and the limited mimicry of those formed by common block copolymers, this study developed a novel amphiphilic polymer by covalently linking hydrophilic heads of phospholipids to the ends of hydrophobic poly(dimethyl siloxane) (PDMS) chains. The absence of hydrophilic blocks allowed for good control over the polydispersity of this polymer within a narrow range. The high flexibility of PDMS chains, combined with relatively uniform molecular weights, would confer enhanced stability and robustness to polymeric membranes. Dynamic light scattering measurements and microdroplet formation tests demonstrated good amphipathic properties of these novel polymers when maintaining an appropriate hydrophilic-hydrophobic ratio. Moreover, the high similarity between the hydrophilic heads and natural phospholipids makes this polymer more compatible with biomolecules. A successful protein insertion experiment confirmed both the stability of this polymeric membrane and its compatibility with membrane proteins. As a result, this novel amphiphilic polymer exhibits great potential for biomembrane mimicking and paves a new path for material design in biomedical applications.

Enhancing Soybean and Maize Yields through Improved Nitrogen and Soil Water Use Efficiencies: A 40-Year Study on the Impact of Farmyard Manure Amendment in Northeast China.

The combined application of manure and chemical fertilizers has been recognized as a critical factor driving significant changes in crop yield and nutrient use efficiency, holding the potential to optimize agricultural management to achieve high yields. In this 40-year study, we investigated the effect of manure amendment on soybean and maize yields, water and nitrogen use efficiencies (WUE and NUE), and water and mineral N storage at 0-100 cm soil depths from 2017 to 2018 to explore the optimization of fertilization management strategies for soybean and maize production in Northeast China. To elucidate the impact of chemical fertilizers and manure, twelve treatments-control (CK); single N fertilizer at a low rate (N1) and that at a high rate (N2); N1, phosphorus (P), and potassium (K) fertilizer (N1PK); manure alone at 13.5 and 27 t ha-1 (M1 and M2); and those combined with N, P, or K fertilizer (M1N1, M1N2, and M1N1PK and M2N1, M2N2, and M2N1PK)-were selected and studied. The results showed that long-term amendment with manure significantly increased crop biomass and yield in the soybean-maize-maize rotation system. Combining with manure increased the WUE, the partial factor productivity of N fertilizer (PFPN), and N physiological efficiency (PEN) in both the soybean and maize seasons; conserved soil water (mainly at 40-60 cm); and increased soil N retention (in the upper 60 cm layer), which reduced the risk of N leaching, with a better effect being observed after the application of 13.5 t ha-1 manure. These results provide insight into the potential of using fertilization management strategies that include amendment with 13.5 t ha-1 manure in combination with N, P, and K fertilizer in the maize season and only chemical fertilizer in the soybean season, as these results indicate that such strategies can achieve high yields and be used to implement agricultural sustainable development in brown soil regions in Northeast China.

Role of Ubiquitin-specific Proteases in Hepatocellular Carcinoma Pathogenesis.

Signaling pathways in hepatocellular carcinoma are primarily mediated by the phosphorylation and ubiquitination of post-translational proteins. In mammalian cells, ubiquitin-specific proteases (USPs) account for the majority of protein deubiquitination activities. In addition to transcriptional and post-translational regulation, ubiquitination plays an important role in the regulation of key proteins. There is a possibility that altered biological processes may lead to serious human diseases, including cancer. Recent studies have revealed the role of USPs in hepatocellular carcinoma tumorigenesis. The purpose of this review is to summarize the involvement of this class of enzymes in the regulation of cell signaling in hepatocellular carcinoma and the therapeutic development of inhibitors that target USPs, which may lead to novel therapies to treat hepatocellular carcinoma.

ROS-responsive nanoparticle delivery of obeticholic acid mitigate primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC.

MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation.

Primary sclerosing cholangitis (PSC) is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis, with no curative treatment available, and liver transplantation is inevitable for end-stage patients. Human placental mesenchymal stem cell (hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis, inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease. Here, we prepared hpMSC-derived exosomes (ExoMSC) and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2-/- mice and multicellular organoids established from PSC patients. The results showed that ExoMSC ameliorated liver fibrosis in Mdr2-/- mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis, and the percentage of CD4+IL-17A+T cells was reduced both in ExoMSC-treated Mdr2-/- mice (Mdr2-/--Exo) in vivo and ExoMSC-treated Th17 differentiation progressed in vitro. Furthermore, ExoMSC improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids. Thus, our data demonstrate the anti-fibrosis effect of ExoMSC in PSC disease by inhibiting Th17 differentiation, and ameliorating the Th17-induced microenvironment, indicating the promising potential therapeutic role of ExoMSC in liver fibrosis of PSC or Th17-related diseases.

An improved memetic algorithm to solve the energy-efficient distributed flexible job shop scheduling problem with transportation and start-stop constraints.

In the current global cooperative production environment, modern industries are confronted with intricate production plans, demanding the adoption of contemporary production scheduling strategies. Within this context, distributed manufacturing has emerged as a prominent trend. Manufacturing enterprises, especially those engaged in activities like automotive mold production and welding, are facing a significant challenge in managing a significant amount of small-scale tasks characterized by short processing times. In this situation, it becomes imperative to consider the transportation time of jobs between machines. This paper simultaneously considers the transportation time of jobs between machines and the start-stop operation of the machines, which is the first time to our knowledge. An improved memetic algorithm (IMA) is proposed to solve the multi-objective distributed flexible job shop scheduling problem (MODFJSP) with the goal of minimizing maximum completion time and energy consumption. Then, a new multi-start simulated annealing algorithm is proposed and integrated into the IMA to improve the exploration ability and diversity of the algorithm. Furthermore, a new multiple-initialization rule is designed to enhance the quality of the initial population. Additionally, four improved variable neighborhood search strategies and two energy-saving strategies are designed to enhance the search ability and reduce energy consumption. To verify the effectiveness of the IMA, we conducted extensive testing and comprehensive evaluation on 20 instances. The results indicate that, when faced with the MODFJSP, the IMA can achieve better solutions in almost all instances, which is of great significance for the improvement of production scheduling in intelligent manufacturing.