Antibacterial Activity and Mechanism of Action of Osthole against Listeria monocytogenes.

The purpose of this study was to investigate the antibacterial activity and mechanism of action of osthole against Listeria monocytogenes. The antibacterial activity of osthole was evaluated by determining the minimum inhibitory concentration (MIC) and growth curve. Cell morphology, membrane permeability, membrane integrity, bacterial physiology, and metabolism were explored using different methods to elucidate the mechanism of action of osthole. It was shown that the MIC of osthole against L. monocytogenes was 62.5 µg/mL and it inhibited the growth of L. monocytogenes effectively in a concentration-dependent manner. Scanning electron microscopy (SEM) images demonstrated morphology changes of L. monocytogenes, including rough surface, cell shrinkage, and rupture. It was found that extracellular conductivity and macromolecule content were increased significantly in the presence of osthole, indicating the disruption of cell membrane integrity and permeability. Laser confocal microscopy results supported the conclusion that osthole caused severe damage to the cell membrane. It was also noticed that osthole depleted intracellular adenosine triphosphate (ATP), inhibited Na+-K+-ATPase and Ca2+-Mg2+-ATPase activity, and promoted the accumulation of intracellular reactive oxygen species (ROS), leading to cell death. This study suggests that osthole is a promising antibacterial agent candidate against L. monocytogenes, and it shows potential in the prevention and control of foodborne pathogens.

Identification of fibronectin type III domain containing 3B as a potential prognostic and therapeutic target for pancreatic cancer: a preliminary analysis.

BACKGROUND: Fibronectin type III domain containing 3B (FNDC3B), a member of the fibronectin type III domain-containing protein family, has been indicated in various malignancies. However, the precise role of FNDC3B in the progression of pancreatic cancer (PC) still remains to be elucidated. METHODS: In this study, we integrated data from the National Center for Biotechnology Information, the Cancer Genome Atlas, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets to analyze FNDC3B expression and its association with various clinicopathological parameters. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, along with Gene Set Enrichment Analysis (GSEA), single sample Gene Set Enrichment Analysis (ssGSEA) and estimate analysis were recruited to delve into the biological function and immune infiltration based on FNDC3B expression. Additionally, the prognostic estimation was conducted using Cox analysis and Kaplan-Meier analysis. Subsequently, a nomogram was constructed according to the result of Cox analysis to enhance the prognostic ability of FNDC3B. Finally, the preliminary biological function of FNDC3B in PC cells was explored. RESULTS: The study demonstrated a significantly higher expression of FNDC3B in tumor tissues compared to normal pancreatic tissues, and this expression was significantly associated with various clinicopathological parameters. GSEA revealed the involvement of FNDC3B in biological processes and signaling pathways related to integrin signaling pathway and cell adhesion. Additionally, ssGSEA analysis indicated a positive correlation between FNDC3B expression and infiltration of Th2 cells and neutrophils, while showing a negative correlation with plasmacytoid dendritic cells and Th17 cells infiltration. Kaplan-Meier analysis further supported that high FNDC3B expression in PC patients was linked to shorter overall survival, disease-specific survival, and progression-free interval. However, although univariate analysis demonstrated a significant correlation between FNDC3B expression and prognosis in PC patients, this association did not hold true in multivariate analysis. Finally, our findings highlight the crucial role of FNDC3B expression in regulating proliferation, migration, and invasion abilities of PC cells. CONCLUSION: Despite limitations, the findings of this study underscored the potential of FNDC3B as a prognostic biomarker and its pivotal role in driving the progression of PC, particularly in orchestrating immune responses.

Optimizing the intermediates adsorbability and revealing the dynamic reconstruction of Co6Fe3S8 solid solution for bifunctional water splitting.

Co9S8 has been extensively studied as a promising catalyst for water electrolysis. Doping Co9S8 with Fe improves its oxygen evolution reaction (OER) performance by regulating the catalyst self-reconfigurability and enhancing the absorption capacity of OER intermediates. However, the poor alkaline hydrogen evolution reaction (HER) properties of Co9S8 limit its application in bifunctional water splitting. Herein, we combined Fe doping and sulfur vacancy engineering to synergistically enhance the bifunctional water-splitting performance of Co9S8. The as-synthesized Co6Fe3S8 catalyst exhibited excellent OER and HER characteristics with low overpotentials of 250 and 84 mV, respectively. It also resulted in the low Tafel slopes of 135 mV dec-1 for the OER and 114 mV dec-1 for the HER. A two-electrode electrolytic cell with Co6Fe3S8 used as both the cathode and anode produced a current density of 10 mA cm-2 at a low voltage of only 1.48 V, maintaining high stability for 100 h. The results of in/ex-situ experiments indicated that the OER process induced electrochemical reconfiguration, forming CoOOH/FeOOH active species on the catalyst surface to enhance its OER performance. Density functional theory (DFT) simulations revealed that Fe doping and the presence of unsaturated coordination metal sites in Co6Fe3S8 promoted H2O and H* adsorption for the HER. The findings of this study can help develop a strategy for designing highly efficient bifunctional water splitting electrocatalysts.

Survival benefit of adjuvant chemotherapy in patients with resected gallbladder adenocarcinoma: An updated retrospective cohort analysis.

BACKGROUND: The rarity yet high malignancy of gallbladder adenocarcinoma (GBA) endows it with a distinctive nature. Radical resection remains the foremost therapeutic approach for GBA, while the impact of early recurrence and metastasis on patient prognosis necessitates the utilization of adjuvant chemotherapy (AC). Despite numerous previous studies on this topic, a consensus regarding the authentic efficacy of AC has yet to be reached. METHODS: We conducted an updated retrospective cohort analysis utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2010 to 2020 to explore the association between AC and survival outcomes in patients with resected GBA. RESULTS: Our study included 2782 patients from the SEER database, with further evaluation of 843 patients in each cohort following meticulous execution of a 1:1 propensity score matching. Remarkably, the AC cohort exhibited a significant survival advantage when juxtaposed against the non-AC cohort. Multivariable Cox regression analysis identified age at diagnosis, year at diagnosis, grade, AJCC T stage, AJCC N stage as well as AC as independent prognostic factors. Furthermore, our findings unveiled that poor/undifferentiated tumor histology, pathological T2 or higher category and pathological N1 category were significantly associated with improved survival when treated with AC while simultaneously observing improved survival across all age categories. CONCLUSION: These results provide additional evidence supporting the survival benefits of AC and offer guidance for personalized therapy in patients with resected GBA.

Causal association between adiponectin and risk of trigeminal neuralgia: A Mendelian randomization study.

OBJECTIVE: To determine whether adiponectin levels and the risk of trigeminal neuralgia (TN) were causally related, a two-sample Mendelian Randomization (MR) study design was used. METHODS: We obtained data regarding adiponectin from the UK Biobank genome wide association studies (GWAS) (n = 39,883) as the exposure and TN, using GWAS summary statistics generated from FinnGen, (total n = 195 847 159; case = 800, control = 195 047) as the outcome. We conducted a two-sample Mendelian randomization analysis employing inverse variance-weighted (IVW), MR-Egger regression, weighted median, and weighted mode analyses. RESULTS: We selected 14 single nucleotide polymorphisms (SNPs) with genome-wide significance from the GWAS on adiponectin as instrumental variables. Based on the IVW method, a causal association between adiponectin levels and TN was evidenced (OR= 0.577, 95 %CI: 0.393-0.847). MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = -0.01; P = 0.663), but it showed no causal association between adiponectin and TN (OR=0.627, 95 %CI: 0.369-1.067). However, the weighted median (OR=0.569, 95 %CI: 0.353-0.917) and Weighted mode (OR= 0.586, 95 %CI: 0.376-0.916) approach yielded evidence of a causal association between adiponectin and TN. Cochran's Q-statistics and funnel plots indicated no evidence of heterogeneity or asymmetry, indicating no directional pleiotropy. CONCLUSION: The results of the MR analysis suggested that adiponectin may be causally associated with an increased TN risk.

Research on collaborative development mechanism of multiple stakeholders in medical institutions based on rough set.

Reducing doctor-patient conflict is an important part of coordinating doctor-patient disputes and easing doctor-patient relationship, which is conducive to building a harmonious medical environment and promoting the healthy development of medical undertakings. This paper constructs a multi-decision-maker mixed conflict model based on rough set theory, puts forward the matrix operation expression of the conflict degree theory in the Pawlak model, and gives a more objective and scientific evaluation function. Combined with hot issues of doctor-patient conflict, the proposed multi-decision-maker mixed conflict model is applied to doctor-patient conflict, examines the doctor-patient relationship in the medical institution system from multiple internal perspectives, and calculates feasible solutions in the conflict system. The results show that high medical quality, high standardize medication, high institutional efficiency, high staff efficiency, high hospital benefits, high hospital revenue, medium employee development, medium equipment development, or high medical quality, high standardize medication, high institutional efficiency, medium staff efficiency, medium hospital benefits, high hospital revenue, high employee development, and high equipment development are important conditions for building a harmonious medical environment and reducing doctor-patient conflicts.

Dynamic Changes and Effects of H2S, IGF-1, and GH in the Traumatic Brain Injury.

The aim of this study was to examine the expression changes of H2S, IGF-1, and GH in traumatic brain injury (TBI) patients and to detect their neuroprotective functions after TBI. In this study, we first collected cerebrospinal fluid (CSF) and plasma from TBI patients at different times after injury and evaluated the concentrations of H2S, IGF-1, and GH. In vitro studies were using the scratch-induced injury model and cell-cell interaction model (HT22 hippocampal neurons co-cultured with LPS-induced BV2 microglia cells). In vivo studies were using the controlled cortical impact (CCI) model in mice. Cell viability was assessed by CCK-8 assay. Pro-inflammatory cytokines expression was determined by qRT-PCR, ELISA, and nitric oxide production. Western blot was performed to assess the expression of CBS, CSE, IGF-1, and GHRH. Moreover, the recovery of TBI mice was evaluated for behavioral function by applying the modified Neurological Severity Score (mNSS), the Rotarod test, and the Morris water maze. We discovered that serum H2S, CSF H2S, and serum IGF-1 concentrations were all adversely associated with the severity of the TBI, while the concentrations of IGF-1 and GH in CSF and GH in the serum were all positively related to TBI severity. Experiments in vitro and in vivo indicated that treatment with NaHS (H2S donor), IGF-1, and MR-409 (GHRH agonist) showed protective effects after TBI. This study gives novel information on the functions of H2S, IGF-1, and GH in TBI.

Targeting POLRMT by a first-in-class inhibitor IMT1 inhibits osteosarcoma cell growth in vitro and in vivo.

Osteosarcoma (OS) is a highly aggressive form of bone cancer that predominantly affects adolescents and young adults. In this study, we have undertaken an investigation into the potential anti-OS cell activity of IMT1 (inhibitor of mitochondrial transcription 1), a first-in-class inhibitor of RNA polymerase mitochondrial (POLRMT). IMT1 exhibited a profound inhibitory effect on cell survival, proliferation, cell cycle progression, and migration in primary and immortalized OS cells. Furthermore, this POLRMT inhibitor elicited apoptosis in the OS cells, without, however, inducing cytotoxicity in human osteoblasts or osteoblastic cells. IMT1 disrupted mitochondrial functions in OS cells, resulting in mitochondrial depolarization, oxidative injury, lipid peroxidation, and ATP reduction in OS cells. Silencing POLRMT using targeted shRNA closely mimicked the actions of IMT1 and exerted potent anti-OS cell activity. Importantly, IMT1's effectiveness was diminished in POLRMT-silenced OS cells. Subsequent investigations revealed that IMT1 suppressed the activation of the Akt-mammalian target of rapamycin (mTOR) cascade in OS cells. IMT1 treatment or POLRMT silencing in primary OS cells led to a significant reduction in Akt1-S6K-S6 phosphorylation. Conversely, it was enhanced upon POLRMT overexpression. The restoration of Akt-mTOR activation through the introduction of a constitutively active S473D mutant Akt1 (caAkt1) mitigated IMT1-induced cytotoxicity in OS cells. In vivo, oral administration of IMT1 robustly curtailed the growth of OS xenografts in nude mice. Furthermore, IMT1 suppressed POLRMT activity, impaired mitochondrial function, repressed Akt-mTOR activation, and induced apoptosis within xenograft tissues. Collectively, these findings underscore the potent growth-inhibitory effects attributed to IMT1 via targeted POLRMT inhibition. The utilization of this POLRMT inhibitor carries substantial therapeutic promise in the context of OS treatment.

Par3L, a polarity protein, promotes M1 macrophage polarization and aggravates atherosclerosis in mice via p65 and ERK activation.

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.

Spatiotemporal control of genome engineering in cone photoreceptors.

BACKGROUND: Cones are essential for color recognition, high resolution, and central vision; therefore cone death causes blindness. Understanding the pathophysiology of each cell type in the retina is key to developing therapies for retinal diseases. However, studying the biology of cone cells in the rod-dominant mammalian retina is particularly challenging. In this study, we used a bacterial artificial chromosome (BAC) recombineering method to knock in the "CreERT2" sequence into the Gnat2 and Arr3 genes, respectively and generated three novel inducible CreERT2 mice with different cone cell specificities. RESULTS: These models (Gnat2CreERT2, Arr3T2ACreERT2, and Arr3P2ACreERT2) express temporally controllable Cre recombinase that achieves conditional alleles in cone photoreceptors. Cre-LoxP recombination can be induced as early as postnatal day (PD) two upon tamoxifen injection at varying efficiencies, ranging from 10 to 15% in Gnat2CreERT2, 40% in Arr3T2ACreERT2, and 100% in Arr3P2ACreERT2. Notably, knocking in the P2A-CreERT2 cassette does not affect cone cell morphology and functionality. Most cone-phototransduction enzymes, including Opsins, CNGA3, etc. are not altered except for a reduction in the Arr3 transcript. CONCLUSIONS: The Arr3P2ACreERT2 mouse, an inducible cone-specific Cre driver, is a valuable line in studying cone cell biology, function, as well as its relationship with rod and other retinal cells. Moreover, the Cre activity can be induced by delivering tamoxifen intragastrically as early as PD2, which will be useful for studying retinal development or in rapid degenerative mouse models.

[Latest Findings on the Role of CD47 in Tumor Immune Evasion and Related Targeted Therapies].

CD47 is an immunoglobulin that is overexpressed on the surface of a variety of cancer cells. CD47 forms a signaling complex with signal regulatory protein alpha (SIRPα), prompting the escape of cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed in many types of solid tumors and is associated with poor prognosis in patients. More and more studies have shown that inhibition of the CD47-SIRPα signaling pathway can promote adaptive immune responses and enhance the phagocytosis of tumor cells by macrophages. Humanized anti-CD47 IgG4 monoclonal antibody has been studied in clinical trials for the treatment of a variety of advanced solid tumors and lymphomas, demonstrating a sound safety profile and achieving partial remission in some patients. In this review we discuss the structure and function of CD47 and the mechanism of CD47 regulation in tumors, summarize the research progress in therapeutic antibody drugs targeting CD47 and a bottleneck in research that targeted drugs are more prone to result in serious adverse effects, and evaluated the potential of the applying CD47-SIRPα signaling pathway in anti-cancer therapy.

CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with ARMS2/HTRA1-related AMD.

Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (ARMS2) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (HTRA1) promoter. The fourth variant is Y402H complement factor H (CFH), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.

Preliminary identification of soil fungi for the degradation of polyurethane film.

Polyurethane (PU) is a versatile plastic that boasts high environmental resistance. The biodegradation of PU has become a hot topic of research aimed at finding ways to potentially solve PU pollutants. Identifying microorganisms capable of efficiently degrading PU plastics is pivotal for the development of a green recycling process for PU. This study aimed to isolate and characterize PU-degrading fungi from the soil of a waste transfer station in Luoyang, China. We isolated four different fungal strains from the soil. Among the isolates, the P2072 and P2073 strains were identified as Rhizopus oryzae (internal transcribed spacer identity, 99.66%) and Alternaria alternata (internal transcribed spacer identity, 99.81%), respectively, through microscopic, morphologic, as well as 18S rRNA sequencing. The degradation ability of strains P2072 and P2073 was analyzed through measurement of weight loss, and they exhibited a degradation rate of 2.7% and 3.3%, respectively, for the PU films after 2 months' growth in mineral salt medium (MSM) with PU films as the sole carbon source. In addition, the P2073 strain exhibited protease activity in the presence of PU. To our knowledge, R. oryzae has never been reported as a PU-degrading fungus. This study provides a new perspective on the biodegradation of PU.

TRAP1 Is Expressed in Human Retinal Pigment Epithelial Cells and Is Required to Maintain their Energetic Status.

Age-related macular degeneration (AMD) is the leading cause of severe vision loss and blindness in elderly people worldwide. The damage to the retinal pigment epithelium (RPE) triggered by oxidative stress plays a central role in the onset and progression of AMD and results from the excessive accumulation of reactive oxygen species (ROS) produced mainly by mitochondria. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecular chaperone that contributes to the maintenance of mitochondrial integrity by decreasing the production and accumulation of ROS. The present study aimed to evaluate the presence and the role of TRAP1 in the RPE. Here, we report that TRAP1 is expressed in human adult retinal pigment epithelial cells and is located mainly in the mitochondria. Exposure of RPE cells to hydrogen peroxide decreases the levels of TRAP1. Furthermore, TRAP1 silencing increases intracellular ROS production and decreases mitochondrial respiratory capacity without affecting cell proliferation. Together, these findings offer novel insights into TRAP1 functions in RPE cells, opening possibilities to develop new treatment options for AMD.

HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.

Development of multidimensional water poverty in the Yangtze River Economic Belt, China.

As a basic natural and strategic resource, water is of great significance to the sustainable development of economies and societies. Owing to population growth, industrialization, the acceleration of urbanization, and global warming, water poverty is gradually increasing in some parts of the world. Effectively assessing water poverty from different dimensions is still a serious challenge for global water resources planning. This paper establishes a framework of multidimensional water poverty (MWP) from six dimensions: water management, water technology, water assets, water welfare, water resources, and water environment. The measurement model of MWP is built based on the Back Propagation Neural Network (BPNN), and the Spatial Correlation Analysis tool is used to visualize the spatial effects of MWP. The Yangtze River Economic Belt (YREB) was used as a case study and the main factors affecting the MWP of the YREB were determined by the Geodetector. When analyzing the results the following observations were made: (1) In terms of time distribution, the level of MWP in the YREB has gradually increased, and the poverty gap between the upper reaches, as well as the middle and lower reaches, shows an increasing trend. (2) With respect to spatial distribution, there is a continuously increasing agglomeration effect that shows a gradient-increasing distribution pattern of "West-Central-East." (3) The MWP in the YREB is mainly affected by these indicators in the three dimensions consisting of water resources, water technology, and water management. Specifically, R&D expenditure as a percentage of GDP, the proportion of water-saving irrigation area in the cultivable land area, the urban daily wastewater treatment capacity, the land surface water resources per capita, and the groundwater resources per capita play an important role in the MWP. Based on the above findings, targeted policy recommendations are proposed to alleviate the MWP in the YREB.

Supersaturation and phase behavior during dissolution of amorphous solid dispersions.

Amorphous solid dispersion (ASD) is a promising strategy to enhance solubility and bioavailability of poorly water-soluble drugs. Due to higher free energy of ASD, supersaturated drug solution could be generated during dissolution. When amorphous solubility of a drug is exceeded, drug-rich nanodroplets could form and act as a reservoir to maintain the maximum free drug concentration in solution, facilitating the absorption of the drug in vivo. Dissolution behavior of ASD has received increasing interests. This review will focus on the recent advances in ASD dissolution, including the generation and maintenance of supersaturated drug solution in absence or presence of liquid-liquid phase separation. Mechanism of drug release from ASD including polymer-controlled dissolution and drug-controlled dissolution will be introduced. Formation of amorphous drug-rich nanodroplets during dissolution and the underlying mechanism will be discussed. Phase separation morphology of hydrated ASD plays a critical role in dissolution behavior of ASD, which will be highlighted. Supersaturated drug solution shows poor physical stability and tends to crystallize. The effect of polymer and surfactant on supersaturated drug solution will be demonstrated and some unexpected results will be shown. Physicochemical properties of drug and polymer could impact ASD dissolution and some of them even show opposite effect on dissolution and physical stability of ASD in solid state, respectively. This review will contribute to a better understanding of ASD dissolution and facilitate a rational design of ASD formulation.

m6A regulator-mediated methylation modification highlights immune infiltration patterns for predicting risk in hepatocellular carcinoma.

BACKGROUND: Increasing studies have demonstrated the biological function of RNA N6-methyladenosine (m6A) modifications in tumorigenesis. However, the potential role of m6A modifications in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) remains unclear. METHODS: Herein, 23 m6A regulators were fetched and introduced into consensus clustering to identify distinct m6A modification patterns and develop m6A-based molecular signatures. Then, a principal component analysis algorithm was employed to construct an m6A-based scoring system to further quantify m6A modification patterns in individual tumors. Immunophenoscore (IPS) was used to estimate the immunotherapeutic response of patients. RESULTS: Three different m6A modification patterns with distinct prognoses and biological signatures were identified among 611 HCC samples. The TIME characteristics of these three patterns were consistent with three known immune profiles: immune-oasis, immune-excluded, and immune-inflamed phenotypes. Identifying m6A modification patterns within individual tumors based on the m6Ascore, developed under the m6A-related signature genes, contributed to elaborating biological processes, clinical outcomes, immune cell infiltration, immunotherapeutic effects, and genetic variations. The low-m6Ascore subtype, characterized by immunosuppression, suggested an immune-suppressed phenotype and a low probability of benefiting from immunotherapy. Finally, the potential function of PRDM4 in HCC was explored. CONCLUSION: This study comprehensively elucidated the indispensable role of m6A modification patterns in the complexity of TIME. The quantitative identification of m6A modification patterns in individual tumors will contribute to optimizing precision immunotherapy.

USPs in Pancreatic Ductal Adenocarcinoma: A Comprehensive Bioinformatic Analysis of Expression, Prognostic Significance, and Immune Infiltration.

Pancreatic ductal adenocarcinoma (PDAC), as an intractable malignancy, still causes an extremely high mortality worldwide. The ubiquitin-specific protease (USP) family constitutes the major part of deubiquitinating enzymes (DUBs) which has been reported to be involved in initiation and progression of various malignancies via the function of deubiquitination. However, the biological function and clinical values of USPs in PDAC have not been comprehensively elucidated. In this study, Gene Expression Profiling Interactive Analysis (GEPIA), Gene Expression Omnibus (GEO) datasets, UALCAN database, and the Human Protein Atlas (HPA) online tool were used to analyze the expression level and the relationship between USP expression and clinicopathological features in PDAC. Survival module of HPA and Kaplan-Meier plotter (KMP) databases was recruited to explore the prognostic value of USPs. Tumor Immune Estimation Resource (TIMER) online tool and KMP databases were utilized to elucidate tumor immune infiltration and immune-related survival of USPs. CBioPortal online tool was used to identify the gene mutation level of USPs in PDAC. Both cBioPortal and LinkedOmics were used to confirm the potential biological functions of USPs in PDAC. Our study showed that USP10, USP14, USP18, USP32, USP33, and USP39 (termed as six-USPs) expressions were significantly elevated in tumor tissues. The high expression of the four USPs (USP10, USP14, USP18, and USP39) indicated a poor prognosis. A significant relationship was indicated between the expression of six-USPs and clinicopathological features. Also, the expression of six-USPs was related to promoter methylation level. Moreover, more than 40% genetic alterations and mutations were discovered in six-USPs. Furthermore, the six-USP expression was correlated with immune infiltration and immune-related prognosis. The functional analysis found that the six-USPs were involved in various biological processes and signaling pathways, such as nucleocytoplasmic transport, choline metabolism in cancer, cell cycle, ErbB signaling pathway, RIG-I-like receptor signaling pathway, TGF-ß signaling pathway, and TNF signaling pathway. In conclusion, the results showed that six-USPs are potential prognostic biomarkers and can be recruited as possible therapeutic targets of PDAC.

The influence of internet use frequency, family atmosphere, and academic performance on adolescent depression: Based on the chain mediating effect of self-adjustment and campus deviant behavior.

Introduction: Depression has become a prominent psychological problem among young people. The purpose of this study was to investigate the potential relationship between the frequency of Internet use, family atmosphere, academic performance, self-adjustment, campus deviant behavior, and depressive symptoms among adolescents. Methods: Based on the survey data of the fifth wave (2017~2018) and the sixth wave (2019~2020) of the China Family Panel Studies (CFPS), this study used LISREL8.8 software to analyze 1,577 10~15 data on adolescents. Results: In this study, the mean score of self-adjustment was 42.40 (SD = 6.79), the mean score of campus deviant behavior was 12.59 (SD = 4.00), the mean score of depressive symptoms in 2018 was 11.88 (SD = 3.04), and the mean score of depressive symptoms in 2020 was 7.64 (SD = 2.20). Secondly, the frequency of Internet use had no direct effect on the depressive symptoms of adolescents, family atmosphere was negatively correlated with depressive symptoms (p < 0.005), and academic performance was positively correlated with depressive symptoms (p < 0.005). Depressive symptoms in 2020 had a direct effect (ß = 0.37, p < 0.001), and also had a negative effect on depressive symptoms in 2020, with a total effect of-0.07 (p < 0.001); self-adjustment had no direct effect on depressive symptoms in adolescents in 2018, However, the total effect was -0.14 (p < 0.001), which had a significant positive effect on 2020 depressive symptoms, and the total effect was 0.18 (p < 0.001), and self-adjustment had a significant negative effect on adolescent campus deviant behavior (ß = -0.38, p < 0.001); in addition, the frequency of Internet use, family atmosphere, and academic performance all had indirect effects on adolescents' 2020 depressive symptoms, with total effects of -0.60, 0.01, and 0.02 (p < 0.001), respectively. This study also found depressive symptoms in adolescents have a certain persistence in time. Discussion: Based on this study, it is necessary to pay more attention to the depression of adolescents, strengthen the training of self-adjustment, improve the anti-frustration ability and psychological resilience, and reduce the campus deviant behavior of adolescents. It is recommended to try to start from emotional self-adjustment to promote the personality health of adolescents.