Apple SUMO E3 ligase MdSIZ1 regulates cuticular wax biosynthesis by SUMOylating transcription factor MdMYB30.

A key function of SUMOylation is the coordinated modification of numerous proteins to optimize plant growth and resistance to environmental stress. Plant cuticular wax is deposited on the surface of primary plant organs to form a barrier that provides protection against changes in terrestrial environments. Many recent studies have examined cuticular wax biosynthetic pathways and regulation. However, whether SUMOylation is involved in the regulation of cuticle wax deposition at the posttranslational level remains unclear. Here, we demonstrate that a small ubiquitin-like modifier (SUMO) E3 ligase, SAP AND MIZ1 DOMAIN CONTAINING LIGASE1 (MdSIZ1), regulates wax accumulation and cuticle permeability in apple (Malus domestica Borkh), SUMO E2 CONJUGATING ENZYME 1(MdSCE1) physically interacts with MdMYB30, a transcription factor involved in the regulation of cuticle wax accumulation. MdSIZ1 mediates the SUMOylation and accumulation of MdMYB30 by inhibiting its degradation through the 26S proteasome pathway. Furthermore, MdMYB30 directly binds to the ß-KETOACYL-COA SYNTHASE 1 (MdKCS1) promoter to activate its expression and promote wax biosynthesis. These findings indicate that the MdSIZ1-MdMYB30-MdKCS1 module positively regulates cuticular wax biosynthesis in apples. Overall, the findings of our study provide insights into the regulation pathways involved in cuticular wax biosynthesis.

Inhibitory effect and mechanism of oregano essential oil on Listeria monocytogenes cells, toxins and biofilms.

Listeria monocytogenes (L. monocytogenes) is a prevalent foodborne pathogen with a remarkable capacity to form biofilms on utensil surfaces. The Listeriolysin O (LLO) exhibits hemolytic activity, which is responsible for causing human infections. In this study, we investigated the inhibitory effect and mechanism of oregano essential oil (OEO) on L. monocytogenes, evaluated the effects on its biofilm removal and hemolytic activity. The minimum inhibitory concentration (MIC) of OEO against L. monocytogenes was 0.03% (v/v). L. monocytogenes was treated with OEO at 3/2 MIC for 30 min the bacteria was decreased below the detection limit (10 CFU/mL) in PBS and TSB (the initial bacterial load was about 6.5 log CFU/mL). The level of L. monocytogenes in minced pork co-cultured with OEO (15 MIC) about 2.5 log CFU/g lower than that in the untreated group. The inhibitory mechanisms of OEO against planktonic L. monocytogenes encompassed perturbation of cellular morphology, elevation in reactive oxygen species levels, augmentation of lipid oxidation extent, hyperpolarization of membrane potential, and reduction in intracellular ATP concentration. In addition, OEO reduced biofilm coverage on the surface of glass slides by 62.03% compared with the untreated group. Meanwhile, OEO (1/8 MIC) treatment reduced the hemolytic activity of L. monocytogenes to 24.6% compared with the positive control. Molecular docking suggested carvacrol and thymol might reduce the hemolytic activity of L. monocytogenes. The results of this study demonstrate that OEO exhibits inhibitory effects against L. monocytogenes, biofilms and LLO, which had potential as natural antimicrobial for the inhibition of L. monocytogenes.

Cognition of diet quality and dietary management in elderly patients with coronary and other atherosclerotic vascular disease in western China, a qualitative research study.

BACKGROUND: Healthy eating is one of the most important nonpharmacologic treatments for patients with atherosclerosis(AS). However, it is unclear how elderly AS patients in western China perceive their dietary status and which type of nutritional assistance they would be willing to receive. Therefore, the primary purpose of this study was to understand the level of knowledge about current dietary habits and healthy eating habits among elderly AS patients in western China, and the secondary purpose was to identify acceptable nutritional assistance measures or pathways for those patients to help them manage disease progression. METHODS: An implementation study approach was used to recruit elderly patients with AS-related diseases in western China for semistructured interviews. RESULTS: 14 participants were included in the study, and the following three themes were identified from the interviews:(1) the diet with regional characteristics; (2) low nutrition-related health literacy; (3) complex attitudes towards nutritional assistance. Most participants had misconceptions about healthy eating, and the sources of their knowledge might not be trustworthy. Participants expressed a preference for personalized nutritional assistance, especially that provided by medical-nursing combined institutions. CONCLUSION: Patients in western China need nutritional assistance for their regional dietary habits; therefore, healthy dietary patterns consistent with the regional culture are proposed to improve the prevailing lack of knowledge about healthy diets, improve the dietary structure of patients, and control the development of the disease.

Analyze the Influence of Cement Infusion for Bones in Different Mix States on PKP Surgery for Osteoporotic Vertebral Fractures.

Aim: To determine how bone cement is infused into the vertebral body at different periods during kyphoplasty and its effect on vertebral strength, stiffness, and height. Method: In this study, 40 L1-5 vertebrae were obtained from eight healthy adult sheep randomly divided into reference, thin, sticky, and coagulation groups based on the digital expression from 1 November 2022 to 31 December 2022. Each group had 10 vertebrae. The vertebral bodies of each group were immersed in hydrochloric acid and infused with a bilateral pedicle micro-pump to construct the osteoporotic vertebral body model. On this basis, the vertebral body model of compression fracture was established by using a biomechanical machine to compress the vertebral body height, and a bone cement perfusion channel was made. The bone cement infusion scheme was implemented after the reduction of the fractured vertebra. Following mixing of the bone cement, the thin, sticky, and coagulation groups, respectively, received bone cement at 2 minutes, 4 minutes, and 6 minutes after mixing. 24 hours before and after the procedure, each vertebra's strength, stiffness, and leading-edge height were measured, and a comparative analysis was performed. Result: (1) Bone mineral density after decalcification was significantly lower than that before and there was a statistical difference (P < .001). (2) Compared with pre-operation, the vertebral strength and stiffness of the reference group decreased significantly after surgery, while the strength and stiffness of the thin group, the sticky group, and the coagulation group changed significantly. The vertebral strength and stiffness of the thin group (P < .001) and the sticky group (P < .001) were higher than those of the coagulation group and higher than those of the reference group. (3) Compared with the original height of the anterior edge of the vertebral body, the height of the anterior edge of each group decreased significantly after fracture and surgery, and the height of the anterior edge of each group was higher than that after fracture. Compared with the reference group, the height of the anterior edge of the thin group, the sticky group, and the coagulation group decreased significantly (P < .001). Conclusion: Percutaneous kyphoplasty application to L1-5 vertebrae of OVCF sheep infused with bone cement in different states enhanced vertebral body strength, but not vertebral body stiffness. There was a significant increase in vertebral body stiffness and strength after the infusion of thin and thick bone cement for 2 minutes.

Emodin Blocks mPTP Opening and Improves LPS-Induced HMEC-1 Cell Injury by Upregulation of ATP5A1.

BACKGROUND: Emodin has been shown to exert anti-inflammatory and cytoprotective effects. Our study aimed to identify a novel anti-inflammatory mechanism of emodin. METHODS: An LPS-induced model of microvascular endothelial cell (HMEC-1) injury was constructed. Cell proliferation was examined using a CCK-8 assay. The effects of emodin on reactive oxygen species (ROS), cell migration, the mitochondrial membrane potential (MMP), and the opening of the mitochondrial permeability transition pore (mPTP) were evaluated. Actin-Tracker Green was used to examine the relationship between cell microfilament reconstruction and ATP5A1 expression. The effects of emodin on the expression of ATP5A1, NALP3, and TNF-α were determined. After treatment with emodin, ATP5A1 and inflammatory factors (TNF-α, IL-1, IL-6, IL-13 and IL-18) were examined by Western blotting. RESULTS: Emodin significantly increased HMEC-1 cell proliferation and migration, inhibited the production of ROS, increased the mitochondrial membrane potential, and blocked the opening of the mPTP. Moreover, emodin could increase ATP5A1 expression, ameliorate cell microfilament remodeling, and decrease the expression of inflammatory factors. In addition, when ATP5A1 was overexpressed, the regulatory effect of emodin on inflammatory factors was not significant. CONCLUSION: Our findings suggest that emodin can protect HMEC-1 cells against inflammatory injury. This process is modulated by the expression of ATP5A1.

Energy-Efficient Electrosynthesis of High Value-Added Active Chlorine Coupled with H2 Generation from Direct Seawater Electrolysis through Decoupling Electrolytes.

Direct saline (seawater) electrolysis is a well-recognized system to generate active chlorine species for the chloride-mediated electrosynthesis, environmental remediation and sterilization over the past few decades. However, the large energy consumption originated from the high cell voltage of traditional direct saline electrolysis system, greatly restricts its practical application. Here, we report an acid-saline hybrid electrolysis system for energy-saving co-electrosynthesis of active chlorine and H2. We demonstrate that this system just requires a low cell voltage of 1.59 V to attain 10 mA cm-2 with a large energy consumption decrease of 27.7 % compared to direct saline electrolysis system (2.20 V). We further demonstrate that such acid-saline hybrid electrolysis system could be extended to realize energy-saving and sustainable seawater electrolysis. The acidified seawater in this system can absolutely avoid the formation of Ca/Mg-based sediments that always form in the seawater electrolysis system. We also prove that this system in the half-flow mode can realize real-time preparation of active chlorine used for sterilization and pea sprout production.

Apple SINA E3 ligase MdSINA3 negatively mediates JA-triggered leaf senescence by ubiquitinating and degrading the MdBBX37 protein.

Jasmonic acid (JA) induces chlorophyll degradation and leaf senescence. B-box (BBX) proteins play important roles in the modulation of leaf senescence, but the molecular mechanism of BBX protein-mediated leaf senescence remains to be further studied. Here, we identified the BBX protein MdBBX37 as a positive regulator of JA-induced leaf senescence in Malus domestica (apple). Further studies showed that MdBBX37 interacted with the senescence regulatory protein MdbHLH93 to enhance its transcriptional activation on the senescence-associated gene MdSAG18, thereby promoting leaf senescence. Moreover, the JA signaling repressor MdJAZ2 interacted with MdBBX37 and interfered with the interaction between MdBBX37 and MdbHLH93, thereby negatively mediating MdBBX37-promoted leaf senescence. In addition, the E3 ubiquitin ligase MdSINA3 delayed MdBBX37-promoted leaf senescence through targeting MdBBX37 for degradation. The MdJAZ2-MdBBX37-MdbHLH93-MdSAG18 and MdSINA3-MdBBX37 modules realized the precise modulation of JA on leaf senescence. In parallel, our data demonstrate that MdBBX37 was involved in abscisic acid (ABA)- and ethylene-mediated leaf senescence through interacting with the ABA signaling regulatory protein MdABI5 and ethylene signaling regulatory protein MdEIL1, respectively. Taken together, our results not only reveal the role of MdBBX37 as an integration node in JA-, ABA- and ethylene-mediated leaf senescence, but also provide new insights into the post-translational modification of BBX proteins.

PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-ß1 overcomes radiotherapy resistance in breast cancer.

BACKGROUND: Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-ß1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-ß1 is secreted in an extracellular vesicles-associated form (TGF-ß1EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-ß1EV will pave a way for overcoming the radiotherapy resistance in cancer treatment. METHODS: The superoxide-Zinc-PKC-ζ-TGF-ß1EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups. RESULTS: The radiotherapy resulted in an increased expression of the intratumoral TGF-ß1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-ß1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-ß1EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-ß1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-ß1EV pathway. CONCLUSIONS: The superoxide-zinc-PKC-ζ-TGF-ß1EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-ß1EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers. TRIAL REGISTRATION: The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).

Primary adrenal diffuse large B cell Lymphoma with Tumor thrombus in central adrenal vein: a case report and literature review.

BACKGROUND: Primary adrenal lymphoma (PAL) is a rare disease confined wholly or chiefly to extramural involvement. Tumor thrombus in the central adrenal vein, renal vein, and inferior vena cava has been reported in adrenal pheochromocytoma, adrenocortical carcinoma, adrenal metastasis carcinoma, and adrenal leiomyosarcoma. Primary adrenal diffuse large B cell lymphoma with tumor thrombus in the central adrenal vein has rarely been reported in the current study. ( We searched in PubMed, Web of Science databases, Embase, and Medline in the English language from 1970 to December 2022. The keywords used were "Primary adrenal lymphoma " and " tumor thrombus".) CASE PRESENTATION: In this report, we discuss the case of a 57-year-old woman who complained of abdominal discomfort following cold stimulation, low back pain, anorexia, fatigue, and weight loss for 1 year. Contrast-enhanced spiral computed tomography (CT) showed mild-to-moderate enhancement of the bilateral masses and central adrenal vein tumor thrombus. After an exhaustive study, the patient was diagnosed with primary adrenal diffuse large B-cell lymphoma. In the diagnosis of PAL, the possibility of a tumor embolism in the central adrenal vein, renal vein, or inferior vena cava should be considered, although this is rare.

Multi-classification model incorporating radiomics and clinic-radiological features for predicting invasiveness and differentiation of pulmonary adenocarcinoma nodules.

PURPOSE: To develop a comprehensive multi-classification model that combines radiomics and clinic-radiological features to accurately predict the invasiveness and differentiation of pulmonary adenocarcinoma nodules. METHODS: A retrospective analysis was conducted on a cohort comprising 500 patients diagnosed with lung adenocarcinoma between January 2020 and December 2022. The dataset included preoperative CT images and histological reports of adenocarcinoma in situ (AIS, n = 97), minimally invasive adenocarcinoma (MIA, n = 139), and invasive adenocarcinoma (IAC, n = 264) with well-differentiated (WIAC, n = 99), moderately differentiated (MIAC, n = 84), and poorly differentiated IAC (PIAC, n = 81). The patients were classified into two groups (IAC and non-IAC) for binary classification and further divided into three and five groups for multi-classification. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO) algorithm to identify the most informative radiomics and clinic-radiological features. Eight machine learning (ML) models were developed using these features, and their performance was evaluated using accuracy (ACC) and the area under the receiver-operating characteristic curve (AUC). RESULTS: The combined model, utilizing the support vector machine (SVM) algorithm, demonstrated improved performance in the testing cohort, achieving an AUC of 0.942 and an ACC of 0.894 for the two-classification task. For the three- and five-classification tasks, the combined model employing the one versus one strategy of SVM (SVM-OVO) outperformed other models, with ACC values of 0.767 and 0.607, respectively. The AUC values for histological subtypes ranged from 0.787 to 0.929 in the testing cohort, while the Macro-AUC and Micro-AUC of the multi-classification models ranged from 0.858 to 0.896. CONCLUSIONS: A multi-classification radiomics model combined with clinic-radiological features, using the SVM-OVO algorithm, holds promise for accurately predicting the histological characteristics of pulmonary adenocarcinoma nodules, which contributes to personalized treatment strategies for patients with lung adenocarcinoma.

Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors.

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.

Steroid-Resistant Nephrotic Syndrome-Associated MYO1E Mutations Have Differential Effects on Myosin 1e Localization, Dynamics, and Activity.

BACKGROUND: Myo1e is a nonmuscle motor protein enriched in podocytes. Mutations in MYO1E are associated with steroid-resistant nephrotic syndrome (SRNS). Most of the MYO1E variants identified by genomic sequencing have not been functionally characterized. Here, we set out to analyze two mutations in the Myo1e motor domain, T119I and D388H, which were selected on the basis of protein sequence conservation. METHODS: EGFP-tagged human Myo1e constructs were delivered into the Myo1e-KO mouse podocyte-derived cells via adenoviral infection to analyze Myo1e protein stability, Myo1e localization, and clathrin-dependent endocytosis, which is known to involve Myo1e activity. Furthermore, truncated Myo1e constructs were expressed using the baculovirus expression system and used to measure Myo1e ATPase and motor activity in vitro. RESULTS: Both mutants were expressed as full-length proteins in the Myo1e-KO cells. However, unlike wild-type (WT) Myo1e, the T119I variant was not enriched at the cell junctions or clathrin-coated vesicles (CCVs). In contrast, D388H variant localization was similar to that of WT. The rate of dissociation of the D388H variant from cell-cell junctions and CCVs was decreased, suggesting this mutation affects Myo1e interactions with binding partners. ATPase activity and ability to translocate actin filaments were drastically reduced for the D388H mutant, supporting findings from cell-based experiments. CONCLUSIONS: T119I and D388H mutations are deleterious to Myo1e functions. The experimental approaches used in this study can be applied to future characterization of novel MYO1E variants associated with SRNS.

Inactivation of two SARS-CoV-2 virus surrogates by electron beam irradiation on large yellow croaker slices and their packaging surfaces.

The detection of infectious SARS-CoV-2 in food and food packaging associated with the cold chain has raised concerns about the possible transmission pathway of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in foods transported through cold-chain logistics and the need for novel decontamination strategies. In this study, the effect of electron beam (E-beam) irradiation on the inactivation of two SARS-CoV-2surrogate, viruses porcine epidemic diarrhea virus (PEDV) and porcine transmissible gastroenteritis virus (TGEV), in culture medium and food substrate, and on food substrate were investigated. The causes of virus inactivation were also investigated by transmission electron microscopy (TEM) and Quantitative Real-time PCR (QRT-PCR). Samples packed inside and outside, including virus-inoculated large yellow croaker and virus suspensions, were irradiated with E-beam irradiation (2, 4, 6, 8, 10 kGy) under refrigerated (0 °C)and frozen (-18 °C) conditions. The titers of both viruses in suspension and fish decreased significantly (P < 0.05) with increasing doses of E-beam irradiation. The maximum D10 value of both viruses in suspension and fish was 1.24 kGy. E-beam irradiation at doses below 10 kGy was found to destroy the spike proteins of both SARS-CoV-2 surrogate viruses by transmission electron microscopy (TEM) and negative staining of thin-sectioned specimens, rendering them uninfectious. E-beam irradiation at doses greater than 10 kGy was also found to degrade viral genomic RNA by qRT-PCR. There were no significant differences in color, pH, TVB-N, TBARS, and sensory properties of irradiated fish samples at doses below 10 kGy. These findings suggested that E-beam irradiation has the potential to be developed as an efficient non-thermal treatment to reduce SARS-CoV-2 contamination in foods transported through cold chain foods to reduce the risk of SARS-CoV-2 infection in humans through the cold chain.

Spectrum-Effect Relationships as an Effective Approach for Quality Control of Natural Products: A Review.

As natural products with biological activity, the quality of traditional Chinese medicines (TCM) is the key to their clinical application. Fingerprints based on the types and contents of chemical components in TCM are an internationally recognized quality evaluation method but ignore the correlation between chemical components and efficacy. Through chemometric methods, the fingerprints represented by the chemical components of TCM were correlated with its pharmacodynamic activity results to obtain the spectrum-effect relationships of TCM, which can reveal the pharmacodynamic components information related to the pharmacodynamic activity and solve the limitations of segmentation of chemical components and pharmacodynamic research in TCM. In the 20th anniversary of the proposed spectrum-effect relationships, this paper reviews its research progress in the field of TCM, including the establishment of fingerprints, pharmacodynamic evaluation methods, chemometric methods and their practical applications in the field of TCM. Furthermore, the new strategy of spectrum-effect relationships research in recent years was also discussed, and the application prospects of this technology were discussed.

Twenty years of ocean observations with China Argo.

The international Argo program, a global observational array of nearly 4 000 autonomous profiling floats initiated in the late 1990s, which measures the water temperature and salinity of the upper 2 000 m of the global ocean, has revolutionized oceanography. It has been recognized one of the most successful ocean observation systems in the world. Today, the proposed decade action "OneArgo" for building an integrated global, full-depth, and multidisciplinary ocean observing array for beyond 2020 has been endorsed. In the past two decades since 2002, with more than 500 Argo deployments and 80 operational floats currently, China has become an important partner of the Argo program. Two DACs have been established to process the data reported from all Chinese floats and deliver these data to the GDACs in real time, adhering to the unified quality control procedures proposed by the Argo Data Management Team. Several Argo products have been developed and released, allowing accurate estimations of global ocean warming, sea level change and the hydrological cycle, at interannual to decadal scales. In addition, Deep and BGC-Argo floats have been deployed, and time series observations from these floats have proven to be extremely useful, particularly in the analysis of synoptic-scale to decadal-scale dynamics. The future aim of China Argo is to build and maintain a regional Argo fleet comprising approximately 400 floats in the northwestern Pacific, South China Sea, and Indian Ocean, accounting for 9% of the global fleet, in addition to maintaining 300 Deep Argo floats in the global ocean (25% of the global Deep Argo fleet). A regional BGC-Argo array in the western Pacific also needs to be established and maintained.

Robust quantum state transfer by optimal invariant-based reverse engineering.

Shortening the operation time of implementing scheme and reducing the influence of harmful factors have always been the research objectives pursued by people. Based on invariant-based reverse engineering, we present a general scheme for implementing robust population transfer in a three-level system via optimal shortcut to adiabatic passage. The systematic error sensitivity is introduced to measure the robustness of the process. The smooth Rabi frequencies are expressed with some coefficients, which are also related to the systematic error sensitivity and the population of intermediate state. When the amplitude of control field is given, the transfer can be optimized within as small systematic error sensitivity as possible, i.e., the robustness against systematic errors is further improved by choosing suitable correlation coefficient. Additionally, we apply the technique to achieve robust excitation fluctuation transfer between two membranes in an optomechanical system. The relation between the fidelity of excitation fluctuation transfer and variation of effective optomechanical coupling strengths is analysed. Numerical result shows that the fidelity keeps over 0.95 even if the coupling strengths deviates from 20% of the theoretical value. Moreover, comparison with existing literature [Opt. Express29, 7998 (2021)10.1364/OE.417343], the proposed scheme possesses stronger robustness against variations of effective optomechanical coupling strengths and lower population of unwanted states. The idea may provide a promising approach for quantum information processing.

Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders.

Many psychiatric disorders are characterized by a strong sex difference, but the mechanisms behind sex-bias are not fully understood. DNA methylation plays important roles in regulating gene expression, ultimately impacting sexually different characteristics of the human brain. Most previous literature focused on DNA methylation alone without considering the regulatory network and its contribution to sex-bias of psychiatric disorders. Since DNA methylation acts in a complex regulatory network to connect genetic and environmental factors with high-order brain functions, we investigated the regulatory networks associated with different DNA methylation and assessed their contribution to the risks of psychiatric disorders. We compiled data from 1408 postmortem brain samples in 3 collections to identify sex-differentially methylated positions (DMPs) and regions (DMRs). We identified and replicated thousands of DMPs and DMRs. The DMR genes were enriched in neuronal related pathways. We extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data. We observed significant enrichment of sex-associated genes in psychiatric disorder-associated gene sets. We prioritized 2080 genes that were sex-biased and associated with psychiatric disorders, such as NRXN1, NRXN2, NRXN3, FDE4A, and SHANK2. These genes are enriched in synapse-related pathways and signaling pathways, suggesting that sex-differential genes of these neuronal pathways may cause the sex-bias of psychiatric disorders.

Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that POU3F2 regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2-binding efficiency at the promoter region of TRIM8. We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.

Naringenin Enhances the Antitumor Effect of Therapeutic Vaccines by Promoting Antigen Cross-Presentation.

Dendritic cells (DCs) can internalize and cross-present exogenous Ags to CD8+ T cells for pathogen or tumor cell elimination. Recently, growing evidences suggest the possible immunoregulatory role of flavonoids through modulating the Ag presentation of DCs. In this study, we report that naringenin, a grapefruit-derived flavonoid, possesses the ability to increase the Ag cross-presentation in both murine DC line DC2.4 as well as bone marrow-derived DCs, and naringenin-induced moderate intracellular oxidative stress that contributed to the disruption of lysosomal membrane enhanced Ag leakage to cytosol and cross-presentation. Moreover, in a murine colon adenocarcinoma model, naringenin induced more CD103+ DCs infiltration into tumor and facilitated the activation of CD8+ T cells and strengthened the performance of therapeutic E7 vaccine against TC-1 murine lung cancer. Our investigations may inspire novel thoughts for vaccine design and open a new field of potential applications of flavonoids as immunomodulators to improve host protection against infection and tumor.

Differential expression of Chitinase 3-Like 1 protein in appendicitis and appendix carcinomas.

BACKGROUND: Chitinase 3-Like 1 (CHI3L1) has been used as an inflammatory biomarker for a variety of diseases, but its expression in acute appendicitis and appendix carcinomas remains unclear. METHODS: Sixty cases of patients were studied, including 46 acute appendicitis and 14 appendix carcinomas. We divided the acute appendicitis group into acute uncomplicated appendicitis (AUA), suppurative appendicitis (SA), and gangrenous appendicitis (GA). The appendix carcinoma group was divided into appendiceal neuroendocrine neoplasms (ANENs) and appendiceal mucinous neoplasms (AMN). Controls were 32 healthy donors. Blood neutrophil to lymphocyte ratio (NLR), CHI3L1, C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) were measured in the patients. Meanwhile, immunohistochemistry and immunofluorescence were used to identify the expression level and location of CHI3L1 in different cell types in appendix tissues. RESULTS: Compared with the controls, CHI3L1 serum levels were up-regulated in SA, GA, and AMN groups, while no significant difference was observed in the AUA and ANEN groups. Immunofluorescence revealed that CHI3L1 expression was high in macrophages and adenocarcinoma cells of appendix tissues but not in the neuroendocrine carcinoma tissues. Moreover, levels of NLR and CRP in the SA and GA groups were considerably higher than in the control group. IL-6 and SAA in SA, GA, ANENs, and AMN groups were also increased compared with the control group. In addition, CHI3L1 displayed good performance in predicting appendicitis, with an AUC of 0.862. CONCLUSION: CHI3L1 was highly expressed in acute appendicitis and appendiceal mucinous neoplasms, which can be used as a novel biomarker predicting appendicitis.