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BackgroundElectroencephalogram (EEG) is widely used in emotion recognition due to its precision and reliability. However, the nonstationarity of EEG signals causes significant differences between individuals or sessions, making it challenging to construct a robust model. Recently, domain adaptation (DA) methods have shown excellent results in cross-subject EEG emotion recognition by aligning marginal distributions. Nevertheless, these methods do not consider emotion category labels, which can lead to label confusion during alignment. Our study aims to alleviate this problem by promoting conditional distribution alignment during domain adaptation to improve cross-subject and cross-session emotion recognition performance.MethodThis study introduces a multi-source domain adaptation common-branch network for EEG emotion recognition and proposes a novel sample hybridization method. This method enables the introduction of target domain data information by directionally hybridizing source and target domain samples without increasing the overall sample size, thereby enhancing the effectiveness of conditional distribution alignment in domain adaptation. Cross-subject and cross-session experiments were conducted on two publicly available datasets, SEED and SEED-IV, to validate the proposed model.ResultIn cross-subject emotion recognition, our method achieved an average accuracy of 90.27% on the SEED dataset, with eight out of 15 subjects attaining a recognition accuracy higher than 90%. For the SEED-IV dataset, the recognition accuracy also reached 73.21%. Additionally, in the cross-session experiment, we sequentially used two out of the three session data as source domains and the remaining session as the target domain for emotion recognition. The proposed model yielded average accuracies of 94.16 and 75.05% on the two datasets, respectively.ConclusionOur proposed method aims to alleviate the difficulties of emotion recognition from the limited generalization ability of EEG features across subjects and sessions. Though adapting the multi-source domain adaptation and the sample hybridization method, the proposed method can effectively transfer the emotion-related knowledge of known subjects and achieve accurate emotion recognition on unlabeled subjects.

BackgroundErectile dysfunction (ED) is a very common condition among adult men and its prevalence increases with age. The ankle-brachial blood pressure index (ABPI) is a noninvasive tool used to assess peripheral vascular disease (PAD) and vascular stiffness. However, the association between ABPI and ED is unclear. We aimed to explore the association between ABPI and ED in the US population.MethodsOur study used data from two separate National Health and Nutrition Examination Survey (NHANES) datasets (2001-2002 and 2003-2004). Survey-weighted logistic regression models were used to explore the association between ABPI as a continuous variable and quartiles with ED. We further assessed the association between ABPI and ED using restricted cubic regression while selecting ABPI thresholds using two-piecewise Cox regression models. In addition, we performed subgroup analyses stratified by BMI, race, marital status, diabetes, and hypertension.Main outcome measureABPI was calculated by dividing the mean systolic blood pressure at the ankle by the mean systolic blood pressure at the arm.ResultsFinally, 2089 participants were enrolled in this study, including 750 (35.90%) ED patients and 1339 (64.10%) participants without ED. After adjusting for all confounding covariates, logistic regression analyses showed a significant association between ABPI and ED (OR=0.19; 95% CI, 0.06-0.56, P=0.01); with ABPI as a categorical variable, compared with the lowest quartile, the OR and 95% CI for the second quartile were 0.58 (0.34-0.97; P = 0.04).Besides, splines indicated that there was an L-shaped relationship between ABPI levels and the risk of ED. Piecewise Cox regression demonstrated the inflection point at 1.14, below which the OR for ED was 0.06 (0.02-0.20; P < 0.001), and above which the OR was 2.79 (0.17-4.53; P = 0.469).ConclusionIn our study, lower ABPI was independently associated with ED risk. In addition, the lowest ABPI level associated with ED risk was 1.14, below this level, lower ABPI was associated with higher ED risk.

Oncolytic viruses (OVs) have emerged as a potential strategy for tumor treatment due to their ability to selectively replicate in tumor cells, induce apoptosis, and stimulate immune responses. However, the therapeutic efficacy of single OVs is limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). To overcome these challenges, engineering OVs has become an important research direction. This review focuses on engineering methods and multi-modal combination therapies for OVs aimed at addressing delivery barriers, viral phagocytosis, and antiviral immunity in tumor therapy. The engineering approaches discussed include enhancing in vivo immune response, improving replication efficiency within the tumor cells, enhancing safety profiles, and improving targeting capabilities. In addition, this review describes the potential mechanisms of OVs combined with radiotherapy, chemotherapy, cell therapy and immune checkpoint inhibitors (ICIs), and summarizes the data of ongoing clinical trials. By continuously optimizing engineering strategies and combination therapy programs, we can achieve improved treatment outcomes and quality of life for cancer patients.

IntroductionLiuweizhiji Gegen-Sangshen beverage (LGS) is popular in China, which has been used for alleviating alcohol-mediated discomfort and preventing alcoholic liver disease (ALD). This beverage is consisted of six herbal components that are known as functional foods and fruits. LGS is rich in polysaccharides, however, the activity and quality evaluation of LGS-derived polysaccharides remain unexplored. The purpose of this study is thus to establish a comprehensive quality control methodology for the assessment of LGS polysaccharides (LGSP) and to further explore the anti-oxidant, anti-inflammatory as well as prebiotic effect of LGSP.MethodsLGSP was extracted, followed by analysis of molecular weight distribution, monosaccharide content and structural characterization via integrating the application of high-performance size exclusion chromatography (HPSEC), 1-phenyl-3-methyl-5-pyrazolone-HPLC (PMP-HPLC), fourier transform infrared spectroscopy (FT-IR) as well as nuclear magnetic resonance spectroscopy (NMR) techniques. The anti-oxidation activity of LGSP was determined by DPPH, ABTS, hydroxyl radical scavenging capacity and total antioxidant capacity. The anti-inflammation of LGSP were assessed on the RAW 264.7 cells. The effect of LGSP on growth of Lactobacillus, Bifidobacterium bifidum and Bifidobacterium adolescentis was evaluated.ResultsThe results demonstrated that LGSP had two molecular weight distribution peaks, with the average molecular weights of (6.569 ± 0.12) × 104 Da and (4.641 ± 0.30) × 104 Da. LGSP was composed of 8 monosaccharides, with galacturonic acid, glucose rhamnose and galactose representing the highest molar ratios. Homogalacturonic acid (HG) type and rhamnosegalacturonic acid glycans I (RG-I) type and α-1,4-glucan were present in LGSP. LGSP concentration in LGS was 17.94 ± 0.28 mg/mL. Furthermore, fingerprint analysis combined with composition quantification of 10 batches of LGSP demonstrated that there was a high similarity among batches. Notably, LGSP exhibited anti-oxidant effect and inhibited expressions of pro-inflammatory factors (TNF-α and IL-6) in LPS-stimulated RAW 264.7 cells. In addition, LGSP remarkably promoted the proliferation of probiotics Lactobacillus, Bifidobacterium bifidum and Bifidobacterium adolescentis, showing good prebiotic activity.DiscussionThe results of present study would be of help to gain the understanding of structure–activity relationship of LGSP, provide a reference for quality evaluation of bioactive LGSP, and facilitate development of unique health and functional products in the future.

The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with limited therapeutic options. Recent studies have demonstrated that chemokines play a vital role in IPF pathogenesis. In the present study, we explored whether the gene signature associated with chemokines could be used as a reliable biological marker for patients with IPF.MethodsChemokine-related differentially expressed genes (CR-DEGs) in IPF and control lung tissue samples were identified using data from the Gene Expression Omnibus database. A chemokine-related signature of the diagnostic model was established using the LASSO-Cox regression. In addition, unsupervised cluster analysis was conducted using consensus-clustering algorithms. The CIBERSORT algorithm was used to calculate immune cell infiltration across patient subgroups. Finally, we established a mouse model of bleomycin-induced pulmonary fibrosis and a model of fibroblasts treated with TGFβ1. Expression levels of chemokine-related signature genes were determined using real-time quantitative polymerase chain reaction (RT-qPCR).ResultsWe established a chemokine-related eleven-gene signature of a diagnostic model consisting of CXCL2, CCRL2, ARRB1, XCL1, GRK5, PPBP, CCL19, CCL13, CCL11, CXCL6, and CXCL13, which could easily distinguish between IPF patients and controls. Additionally, we identified two subtypes of IPF samples based on chemokine-related gene expression. Pulmonary function parameters and stromal scores were significantly higher in subtype 1 than in subtype 2. Several immune cell types, especially plasma cells and macrophages, differ significantly between the two subtypes. RT-qPCR results showed that the expression levels of Cxcl2 and Ccl2 increased considerably in bleomycin-induced mice. Meanwhile, Arrb1, Ccrl2, Grk5, and Ppbp expression was significantly reduced. Furthermore, multiple chemokine-related genes were altered in TGFβ1 or TNFα-induced fibroblast cells.ConclusionsA novel chemokine-related eleven-signature of diagnostic model was developed. These genes are potential biomarkers of IPF and may play essential roles in its pathogenesis.

Epicenter locations are generally adjacent to active faults and past seismicity regions. Past earthquake catalogs and the geometry of the active faults can provide key prior knowledge concerning earthquake forecasts. In this study, we first introduce two straightforward dedicated models, the proximity-to-past-earthquakes (PPE) and proximity-to-mapped-faults (PMF) models, to fit the seismicity in the Sichuan-Yunnan region, China. The hybrid proximity-to-known-sources (PKS) model with the optimized model parameters is then used to estimate the probability of earthquake occurrence. Second, to compare the PKS forecast efficiency to those of different models, retrospective tests are applied to a dataset located in the Sichuan-Yunnan region. The results show that the probability maps derived from PPE, PMF, and PKS have non-uniform Poisson distribution features and that there is forecasting significance for past cases of moderate earthquakes in the test region. Finally, using Molchan error diagram tests, we find that the hybrid PKS model performs better than the other models in the testing region. The unsatisfactory performance of the PMF model for earthquake forecasting may lie both in the incompleteness of the fault database and the lack of consideration of co-seismic ruptures. Therefore, one of the three models can be used as a base model for comparing and evaluating earthquake forecast strategies.

Hypoxia-inducible factors (HIFs), central regulators for cells to adapt to low cellular oxygen levels, are often overexpressed and activated in breast cancer. HIFs modulate the primary transcriptional response of downstream pathways and target genes in response to hypoxia, including glycolysis, angiogenesis and metastasis. They can promote the development of breast cancer and are associated with poor prognosis of breast cancer patients by regulating cancer processes closely related to tumor invasion, metastasis and drug resistance. Thus, specific targeting of HIFs may improve the efficiency of cancer therapy. In this review, we summarize the advances in HIF-related molecular mechanisms and clinical and preclinical studies of drugs targeting HIFs in breast cancer. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for HIF targeting are increasingly being developed. Therefore, we highlight the HIF related DDS, including liposomes, polymers, metal-based or carbon-based nanoparticles.

ObjectivesTo investigate the role of immune escape encoding genes on the prognosis of BC, and to predict the novel targeting agents.MethodsHuman immune genes and immune escape encoding genes were obtained from the IMMPORT database and the previous study. Sample information and clinical data on BC were obtained from the TCGA and GTEX databases. Obtaining differentially expressed protein data from cBioportal database. To construct a risk score model by lasso analysis, and nomogram was used to predict score core. GSCA, TIMER and CELLMINER databases were used for immune and drug susceptibility correlation analyses. Cell experiments were verified by MTT, Western blotting, and RT-qPCR.ResultsWe found prognostic models consisting of eleven immune escape related protein-coding genes with ROC curves that performed well in the ontology data (AUC for TCGA is 0.672) and the external data (AUC for GSE20685 is 0.663 and for GES42568 is 0.706). Five core prognostic models are related to survival (EIF4EBP1, BCL2A1, NDRG1, ERRFI1 and BRD4) were summarized, and a nomogram was constructed to validate a C-index of 0.695, which was superior to other prognostic models. Relevant drugs targeting core genes were identified based on drug sensitivity analysis, and found that Vemurafenib downregulates the PI3K-AKT pathway and BCL2A1 protein in BC, as confirmed by external data and cellular assays.ConclusionsBriefly, our work establishes and validates an 11-immune escape risk model, and five core prognostic factors that are mined deeply from this model, and elucidates in detail that Vemurafenib suppresses breast cancer by targeting the PI3K/AKT signaling pathway to inhibit the immune escape biomarker BCL2A1, confirms the validity of the prognostic model, and provides corresponding targeted agents to guide individualized treatment of BC patients.

The tumor microenvironment is complicated and continuously evolving. This study was devoted to the identification of potential prognostic biomarkers based on the tumor microenvironment associated with immunotherapy for melanoma. This study integrates a couple of melanoma single cell and transcriptome sequencing datasets and performs a series of silico analyses as nicely as validation of molecular biology techniques. A core set of immune escape related genes was identified through Lawson et al. and the ImmPort portal. The differential proteins were identified through the cBioPortal database. Regression analysis was used to profile independent prognostic factors. Correlation with the level of immune cell infiltration was evaluated by multiple algorithms. The capacity of LCK to predict response was assessed in two independent immunotherapy cohorts. High LCK expression is associated with better prognosis, high levels of TILs and better clinical staging. Pathway analysis showed that high expression of LCK was significantly associated with activation of multiple tumor pathways as well as immune-related pathways. LCK expression tends to be higher in immunotherapy-responsive patients and those with lower IC50s treated with chemotherapeutic agents. RT-qPCR detected that LCK expression was significantly upregulated in melanoma cell lines. Single-cell transcriptome analysis showed that LCK was specifically highly expressed on T cells. CellChat analysis confirmed that LCK in C2 subpopulations and T cell subpopulations exerted immune promotion between cells by binding to CD8 receptors. In conclusion, LCK is a reliable biomarker for melanoma and will contribute to its immunotherapy.

BackgroundUveal melanoma (UVM) is the most common primary intraocular malignancy in adults with a poor prognosis. B7 family is an important modulator of the immune response. However, its dysregulation and underlying molecular mechanism in UVM still remains unclear.MethodsData were derived from TCGA and GEO databases. The prognosis was analyzed by Kaplan-Meier curve. The ESTIMATE algorithm, CIBERSORT algorithm, and TIMER database were used to demonstrate the correlation between B7 family and tumor immune microenvironment in UVM. Single-cell RNA sequencing was used to detect the expression levels of the B7 family in different cell types of UVM. UVM was classified into different types by consistent clustering. Enrichment analysis revealed downstream signaling pathways of the B7 family. The interaction between different cell types was visualized by cell chat.ResultsThe expression level of B7 family in UVM was significantly dysregulated and negatively correlated with methylation level. The expression of B7 family was associated with prognosis and immune infiltration, and B7 family plays an important role in the tumor microenvironment (TME). B7 family members were highly expressed in monocytes/macrophages of UVM compared with other cell types. Immune response and visual perception were the main functions affected by B7 family. The result of cell chat showed that the interaction between photoreceptor cells and immune-related cells was mainly generated by HLA-C-CD8A. CABP4, KCNJ10 and RORB had the strongest correlation with HLA-C-CD8A, and their high expression was significantly correlated with poor prognosis. CABP4 and RORB were specifically expressed in photoreceptor cells.ConclusionsDysregulation of the B7 family in UVM is associated with poor prognosis and affects the tumor immune microenvironment. CABP4 and RORB can serve as potential therapeutic targets for UVM, which can be regulated by the B7 family to affect the visual perception and immune response function of the eye, thus influencing the prognosis of UVM.

Acute respiratory distress syndrome (ARDS) is a common critical illness in respiratory care units with a huge public health burden. Despite tremendous advances in the prevention and treatment of ARDS, it remains the main cause of intensive care unit (ICU) management, and the mortality rate of ARDS remains unacceptably high. The poor performance of ARDS is closely related to its heterogeneous clinical syndrome caused by complicated pathophysiology. Based on the different pathophysiology phases, drugs, protective mechanical ventilation, conservative fluid therapy, and other treatment have been developed to serve as the ARDS therapeutic methods. In recent years, there has been a rapid development in nanomedicine, in which nanoparticles as drug delivery vehicles have been extensively studied in the treatment of ARDS. This study provides an overview of pharmacologic therapies for ARDS, including conventional drugs, natural medicine therapy, and nanomedicine. Particularly, we discuss the unique mechanism and strength of nanomedicine which may provide great promises in treating ARDS in the future.

Since the end of 2019, COVID-19 caused by SARS-CoV-2 has spread worldwide, and the understanding of the new coronavirus is in a preliminary stage. Currently, immunotherapy, cell therapy, antiviral therapy, and Chinese herbal medicine have been applied in the clinical treatment of the new coronavirus; however, more efficient and safe drugs to control the progress of the new coronavirus are needed. Long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) may provide new therapeutic targets for novel coronavirus treatments. The first aim of this paper is to review research progress on COVID-19 in the respiratory, immune, digestive, circulatory, urinary, reproductive, and nervous systems. The second aim is to review the body systems and potential therapeutic targets of lncRNAs, miRNAs, and circRNAs in patients with COVID-19. The current research on competing endogenous RNA (ceRNA) (lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA) in SARS-CoV-2 is summarized. Finally, we predict the possible therapeutic targets of four lncRNAs, MALAT1, NEAT1, TUG1, and GAS5, in COVID-19. Importantly, the role of PTEN gene in the ceRNA network predicted by lncRNA MALAT1 and lncRNA TUG1 may help in the discovery and clinical treatment of effective drugs for COVID-19.

To solve a series of pension problems caused by aging, based on the emotional recognition of the Internet of Things, the control method and system research of smart homes are proposed. This article makes a detailed analysis and research on the necessity, feasibility, and how to realize speech emotion recognition technology in smart families, introduces the definition and classification of emotion, and puts forward five main emotions to be recognized in speech emotion recognition based on smart family environment. Then, based on this, it analyses the acquisition methods of emotional speech data. On this premise, this article discusses and analyses the related problems of voice data acquisition in smart homes, such as the voice characteristics and acquisition methods, puts forward three rules for voice text design, and determines the relatively suitable hybrid recording acquisition method applied in a smart home environment. At the same time, the design and establishment process of intelligent family emotional speech database is described in detail. The related problems of feature extraction in speech emotion recognition are studied. Starting from the definition of feature extraction, this article expounds on the necessity of feature extraction in the process of recognition and analyses the characteristics of the speech signals. For the specific environment of the smart family, the speech signal required to be processed needs to be close to the auditory characteristics of the human ears, and the speech signal contains enough information. Finally, the Mel frequency cepstrum coefficient (MFCC) is selected as the feature parameter applied in this article, and the extraction process of MFCC is introduced in detail.

The rapid development of computer technology and artificial intelligence is affecting people’s daily lives, where language is the most common way of communication in people’s daily life. To apply the emotion information contained in voice signals to artificial intelligence products after analysis, this article proposes a design based on voice emotion recognition for aging intelligent home products with RBF. The authors first aimed at a smart home design, and based on the problem of weak adaptability and learning ability of the aging population, a speech emotion recognition method based on a hybrid model of Hidden Markov/Radial Basis Function Neural Network (HMM/RBF) is proposed. This method combines the strong dynamic timing modeling capabilities of the HMM model and the strong classification decision-making ability of the RBF model, and by combining the two models, the speech emotion recognition rate is greatly improved. Furthermore, by introducing the concept of the dynamic optimal learning rate, the convergence speed of the network is reduced to 40.25s and the operation efficiency is optimized. Matlab’s simulation tests show that the recognition speed of the HMM/RBF hybrid model is 9.82–12.28% higher than that of the HMM model and the RBF model alone, confirming the accuracy and superiority of the algorithm and model.

BackgroundImmune dysfunction is the main characteristic of severe acute pancreatitis (SAP), and the timing of immune regulation has become a major challenge for SAP treatment. Previous reports about the time point at which the immune status of SAP changed from excessive inflammatory response to immunosuppression (hypo-inflammatory response) are conflicting.PurposesThe aims of this study are to explore the immunological dynamic changes in SAP rats from the perspective of intestinal mucosal immune function, and to determine the immunoswitching point from excessive inflammatory response to immunosuppression.MethodsRetrograde injection of sodium taurocholate into the pancreaticobiliary duct was applied to establish a SAP model in rats. The survival rate and the activities of serum amylase and pancreatic lipase in SAP rats were measured at different time points after model construction. The pathological changes in the pancreas and small intestines were analyzed, and the levels of intestinal pro- and anti-inflammatory cytokines and the numbers of intestinal macrophages, dendritic cells, Th1, Th2, and T regulatory cells were assessed. Meanwhile, the SAP rats were challenged with Pseudomonas aeruginosa (PA) strains to simulate a second hit, and the levels of intestinal inflammatory cytokines and the numbers of immune cells were analyzed to confirm the immunoswitching point.ResultsThe time periods of 12–24 h and 48–72 h were the two death peaks in SAP rats. The pancreas of SAP rats showed self-limiting pathological changes, and the switching period of intestinal cytokines, and innate and adaptive immunity indexes occurred at 24–48 h. It was further confirmed that 48 h after SAP model construction was the immunoswitching point from excessive inflammatory response to immunosuppression.ConclusionThe SAP rats showed characteristics of intestinal mucosal immune dysfunction after model construction, and the 48th h was identified as the immunoswitching point from excessive inflammatory response to immunosuppression. The results are of great significance for optimizing the timing of SAP immune regulation.

Gastric cancer has developed as a very common gastrointestinal tumors, with recent effective advancements in the diagnosis and treatment of early gastric cancer. However, the prognosis for gastric cancer remains poor. As a result, there is in sore need of better understanding the mechanisms of gastric cancer development and progression to improve existing diagnostic and treatment options. In recent years, epigenetics has been recognized as an important contributor on tumor progression. Epigenetic changes in cancer include chromatin remodeling, DNA methylation and histone modifications. An increasing number of studies demonstrated that noncoding RNAs (ncRNAs) are associated with epigenetic changes in gastric cancer. Herein, we describe the molecular interactions of histone modifications and ncRNAs in epigenetics. We focus on ncRNA-mediated histone modifications of gene expression associated with tumorigenesis and progression in gastric cancer. This molecular mechanism will contribute to our deeper understanding of gastric carcinogenesis and progression, thus providing innovations in gastric cancer diagnosis and treatment strategies.

Gut microbiota is a complex aggregation of microbial organisms, which offers diverse protective benefits to the host. Dysbiosis of intestinal microbiota is frequently associated with many diseases. Vitamin D3 (VD), which was originally associated with bone health, also possesses antimicrobial activities and can act through antimicrobial peptide. Cathelicidin is a type of antimicrobial peptide in host to maintain the balance of gut microbiome. Our current study sought to evaluate the protective effect of VD and cathelicidin in mice intestines by administration of VD or mCRAMP-encoding L. lactis. We herein provided a comprehensive profile of the impact of VD and mCRAMP on gut microbiota using 16S rRNA sequencing, followed by bioinformatics and statistical analysis. Our results revealed an increased richness of bacterial community in mice intestines due to VD administration. Moreover, we showed a beneficial effect of VD and mCRAMP by enhancing the colonization of bacterial taxa that are associated with protective effects to the host but repressing the propagation of bacterial taxa that are associated with harmful effects to the host. Various metabolic pathways related to amino acid and lipid metabolism were affected in this process. We further established a bacterial panel as a reliable biomarker to evaluate the efficacy of remodeling the mice gut microbiota by VD and mCRAMP administration. The uncovered effects will deepen the comprehension about the antibacterial mechanisms of VD and mCRAMP and provide new insights for therapeutic implication of them.

Gastrointestinal cancer is by far the most common malignancy and the most common cause of cancer-related deaths worldwide. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the epigenetic regulation of cancer cells and regulate tumor progression by affecting chromatin modifications, gene transcription, translation, and sponge to miRNAs. In particular, lncRNA has recently been found to possess open reading frame (ORF), which can encode functional small peptides or proteins. These peptides interact with its targets to regulate transcription or the signal axis, thus promoting or inhibiting the occurrence and development of tumors. In this review, we summarize the involvement of lncRNAs and the function of lncRNAs encoded small peptides in gastrointestinal cancer.

As an important physiological and reproductive organ, the silique is a determining factor of seed yield and a breeding target trait in rapeseed (Brassica napus L.). Genetic studies of silique-related traits are helpful for rapeseed marker-assisted high-yield breeding. In this study, a recombinant inbred population containing 189 lines was used to perform a quantitative trait loci (QTLs) analysis for five silique-related traits in seven different environments. As a result, 120 consensus QTLs related to five silique-related traits were identified, including 23 for silique length, 25 for silique breadth, 29 for silique thickness, 22 for seed number per silique and 21 for silique volume, which covered all the chromosomes, except C5. Among them, 13 consensus QTLs, one, five, two, four and one for silique length, silique breadth, silique thickness, seed number per silique and silique volume, respectively, were repeatedly detected in multiple environments and explained 4.38–13.0% of the phenotypic variation. On the basis of the functional annotations of Arabidopsis homologous genes and previously reported silique-related genes, 12 potential candidate genes underlying these 13 QTLs were screened and found to be stable in multiple environments by analyzing the re-sequencing results of the two parental lines. These findings provide new insights into the gene networks affecting silique-related traits at the QTL level in rapeseed.

Oxidative stress caused by an imbalance between the production and elimination of reactive metabolites and free radicals can lead to the development of a variety of diseases. Over the past years, with the development of science and technology, circular RNA (circRNA) has been found to be closely associated with oxidative stress, which plays an important role in the process of oxidative stress. Currently, the understanding of circRNAs in the mechanism of oxidative stress is limited. In this review, we described the relationship between oxidative stress and circRNAs, the circRNAs related to oxidative stress, and the role of circRNAs in promoting or inhibiting the occurrence and development of diseases associated with the oxidative stress system.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The efficacy of immunotherapy usually depends on the interaction of immunomodulation in the tumor microenvironment (TME). This study aimed to explore the potential stromal-immune score-based prognostic genes related to immunotherapy in HCC through bioinformatics analysis.Methods: ESTIMATE algorithm was applied to calculate the immune/stromal/Estimate scores and tumor purity of HCC using the Cancer Genome Atlas (TCGA) transcriptome data. Functional enrichment analysis of differentially expressed genes (DEGs) was analyzed by the Database for Annotation, Visualization, and Integrated Discovery database (DAVID). Univariate and multivariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were performed for prognostic gene screening. The expression and prognostic value of these genes were further verified by KM-plotter database and the Human Protein Atlas (HPA) database. The correlation of the selected genes and the immune cell infiltration were analyzed by single sample gene set enrichment analysis (ssGSEA) algorithm and Tumor Immune Estimation Resource (TIMER).Results: Data analysis revealed that higher immune/stromal/Estimate scores were significantly associated with better survival benefits in HCC within 7 years, while the tumor purity showed a reverse trend. DEGs based on both immune and stromal scores primarily affected the cytokine–cytokine receptor interaction signaling pathway. Among the DEGs, three genes (CASKIN1, EMR3, and GBP5) were found most significantly associated with survival. Moreover, the expression levels of CASKIN1, EMR3, and GBP5 genes were significantly correlated with immune/stromal/Estimate scores or tumor purity and multiple immune cell infiltration. Among them, GBP5 genes were highly related to immune infiltration.Conclusion: This study identified three key genes which were related to the TME and had prognostic significance in HCC, which may be promising markers for predicting immunotherapy outcomes.

Purpose: We developed a nomogram to predict the possibility of lymph node metastasis in patients with squamous cell carcinoma of the penis.Methods: Identifying patients with squamous cell carcinoma of the penis diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses were carried out by logistic regression to assess significant predictors associated with lymph node metastasis. A nomogram was established and validated by a calibration plot and receptor operating characteristic curve (ROC) analysis.Results: A total of 1,016 patients with penile squamous cell carcinoma (SCCP) were enrolled in this study. One hundred and ninety-five patients (19%) had lymph node involvement (N1-3). Multivariate analysis showed that age, primary tumor site, grade, tumor size, and T stage were identified as being significantly (p < 0.05) associated with lymph node involvement. All the above factors that showed a statistically significant predictive capability were selected for building the nomogram. This model had a calibration slope of 0.9 and a c-index of 0.776, indicating the good discrimination and effectiveness of the nomogram in predicting lymph node status.Conclusion: Although the prediction model has some limitations, the nomogram revealed the relationship between the clinicopathological characteristics of SCCP patients and the risk of lymph node metastasis. This tool will assist patients in counseling and guide treatment decisions for SCCP patients.

Background: Longan is the fruit of Dimocarpus longan Lour. and the longan arillus has long been used in traditional Chinese medicine possessing various health benefits. However, the excessive intake of longan is found in daily life to cause “shanghuo” syndrome. “Shanghuo” has been linked to increased disease susceptibility. The present study thus aimed to investigate the toxicological outcomes after excessive longan treatment.Methods: Longan extract at a normal dosage of 4 g/kg and two excess dosages of 8 and 16 g/kg was orally administered to normal C57BL/6J mice for two weeks or to C57BL/6J mice with DSS-induced colitis. Mouse gut microbiome were analyzed by 16S rRNA sequencing. Short chain fatty acid (SCFA) contents in colonic contents were measured by GC-MS. Colon tissue was used for histopathological observation after H and E staining, detection of protein expression by western blot, analysis of gene expression by qPCR, and detection of apoptotic cells by TUNEL assay. ELISA was used for biochemical analysis in serum.Results: In normal mice, repeated longan intake at excess doses, but not the normal dose, increased infiltration of inflammatory cells, elevated serum levels of TNF-α and IL-6 and reduced production of SCFAs. In DSS-induced colitic mice, longan intake at 4 g/kg did not promote colitis in mice, while excessive longan (8 or 16 g/kg) aggravated colitis in mice, showing increased inflammation, more serious histological abnormalities, increased gut permeability, and increased epithelia injury when compared to DSS alone. Excessive longan induced a significant reduction of microbial diversity in colitic mice, accompanied with aggravated alterations of DSS-associated bacteria including the increase of Proteobacteria phylum and genera of Bacteroides, Akkermansia, Turicibacter and Escherchia-Shigella, and the decrease of norank_f__Muribaculaceae. The changed microbial compositions were accompanied with decreased SCFAs when longan was supplemented with DSS. The aggravated colon injury by excessive intake of longan in colitic mice was tightly correlated with the altered microbial communities and decreased SCFAs production.Conclusion: Excessive longan intake disturbs gut homeostasis and aggravates colitis via promoting inflammation and altering gut microbe compositions and associated metabolism in mice. Our findings warrant rational longan arillus consumption as a dietary supplement or herbal medicine.

This review provides insight into the role of engineered T-cell receptors (TCRs) in immunotherapy. Novel approaches have been developed to boost anticancer immune system, including targeting new antigens, manufacturing new engineered or modified TCRs, and creating a safety switch for endo-suicide genes. In order to re-activate T cells against tumors, immune-mobilizing monoclonal TCRs against cancer (ImmTAC) have been developed as a novel class of manufactured molecules which are bispecific and recognize both cancer and T cells. The TCRs target special antigens such as NY-ESO-1, AHNAKS2580F or ERBB2H473Y to boost the efficacy of anticancer immunotherapy. The safety of genetically modified T cells is very important. Therefore, this review discusses pros and cons of different approaches, such as ImmTAC, Herpes simplex virus thymidine kinase (HSV-TK), and inducible caspase-9 in cancer immunotherapy. Clinical trials related to TCR-T cell therapy and monoclonal antibodies designed for overcoming immunosuppression, and recent advances made in understanding how TCRs are additionally examined. New approaches that can better detect antigens and drive an effective T cell response are discussed as well.

Airway barrier damage and excessive inflammation induced by influenza A virus (IAV) are associated with disease progression and prognosis. ResolvinD1 (RvD1) is a promising lipid mediator with critical protection against infection in the lung. However, whether RvD1 protects against IAV-induced injury and the underlying mechanisms remain elusive. In this study, primary normal human bronchial epithelial (pNHBE) cells were isolated and co-cultured with IAV and/or RvD1. Then, the expressions of E-cadherin, Zonula occludins-1, inflammatory mediators and proteins in Nrf2-dependent pathway were detected. To further explore the mechanisms, Nrf2 short hairpin RNA (Nrf2 shRNA) was applied in pNHBE cells. Furthermore, mice were infected with IAV, and were subsequently treated with RvD1. We found that IAV downregulated expressions of E-cadherin, Zonula occludins-1, Nrf2 and HO-1, upregulated the phosphorylation of NF κ B p65 and IKBα, levels of IL-8 and TNF-α, as well as ROS production. RvD1 reversed these damaging effects induced by IAV. However, when Nrf2 expression was suppressed with shRNA in pNHBE cells, the protective effects of RvD1 on IAV-induced injury were inhibited. In vivo studies further demonstrated that RvD1 could alleviate barrier protein breakdown and reduce airway inflammatory reactions. Collectively, the study demonstrated that RvD1 could play dual beneficial roles in protecting airway epithelium barrier function and reducing inflammation via the Nrf2 pathway, which may provide a better treatment option for influenza A virus infection.

Obstructive sleep apnea (OSA) associated neurocognitive impairment is mainly caused by chronic intermittent hypoxia (CIH)-triggered neuroinflammation and oxidative stress. Previous study has demonstrated that mitochondrial reactive oxygen species (mtROS) was pivotal for hypoxia-related tissue injury. As a cytosolic multiprotein complex that participates in various inflammatory and neurodegenerative diseases, NLRP3 inflammasome could be activated by mtROS and thereby affected by the mitochondria-selective autophagy. However, the role of NLRP3 and possible mitophagy mechanism in CIH-elicited neuroinflammation remain to be elucidated. Compared with wild‐type mice, NLRP3 deficiency protected them from CIH-induced neuronal damage, as indicated by the restoration of fear-conditioning test results and amelioration of neuron apoptosis. In addition, NLRP3 knockout mice displayed the mitigated microglia activation that elicited by CIH, concomitantly with elimination of damaged mitochondria and reduction of oxidative stress levels (malondialdehyde and superoxide dismutase). Elevated LC3 and beclin1 expressions were remarkably observed in CIH group. In vitro experiments, intermittent hypoxia (IH) significantly facilitated mitophagy induction and NLRP3 inflammasome activation in microglial (BV2) cells. Moreover, IH enhanced the accumulation of damaged mitochondria, increased mitochondrial depolarization and augmented mtROS release. Consistently, NLRP3 deletion elicited a protective phenotype against IH through enhancement of Parkin-mediated mitophagy. Furthermore, Parkin deletion or pretreated with 3MA (autophagy inhibitor) exacerbated these detrimental actions of IH, which was accompanied with NLRP3 inflammasome activation. These results revealed NLRP3 deficiency acted as a protective promotor through enhancing Parkin-depended mitophagy in CIH-induced neuroinflammation. Thus, NLRP3 gene knockout or pharmacological blockage could be as a potential therapeutic strategy for OSA-associated neurocognitive impairment.

ObjectivesSeveral reports suggesting that the intestinal microbiome plays a key role in the development of inflammatory bowel disease (IBD) or colorectal cancer (CRC), but the changes of intestinal bacteria in healthy people, patients with IBD and CRC are not fully explained. The study aimed to investigate changes of intestinal bacteria in healthy subjects, patients with IBD, and patients with CRC.MaterialsWe collected data from the European Nucleotide Archive on healthy people and patients with colorectal cancer with the study accession number PRJEB6070, PRJEB7774, PRJEB27928, PRJEB12449, and PRJEB10878, collected IBD patient data from the Integrated Human Microbiome Project from the Human Microbiome Project Data Portal. We performed metagenome-wide association studies on the fecal samples from 290 healthy subjects, 512 IBD patients, and 285 CRC patients. We used the metagenomics dataset to study bacterial community structure, relative abundance, functional prediction, differentially abundant bacteria, and co-occurrence networks.ResultsThe bacterial community structure in both IBD and CRC was significantly different from healthy subjects. Our results showed that IBD patients had low intestinal bacterial diversity and CRC patients had high intestinal bacterial diversity compared to healthy subjects. At the phylum level, the relative abundance of Firmicutes in IBD decreased significantly, while the relative abundance of Bacteroidetes increased significantly. At the genus level, the relative abundance of Bacteroides in IBD was higher than in healthy people and CRC. Compared with healthy people and CRC, the main difference of intestinal bacteria in IBD patients was Bacteroidetes, and compared with healthy people and IBD, the main difference of intestinal bacteria in CRC patients was in Fusobacteria, Verrucomicrobia, and Proteobacteria. The main differences in the functional composition of intestinal bacteria in healthy people, IBD and CRC patients were L-homoserine and L-methionine biosynthesis, 5-aminoimidazole ribonucleotide biosynthesis II, L-methionine biosynthesis I, and superpathway of L-lysine, L-threonine, and L-methionine biosynthesis I. The results of stratified showed that the abundance of Firmicutes, Bacteroidetes, and Actinobacteria involved in metabolic pathways has significantly changed. Besides, the association network of intestinal bacteria in healthy people, IBD, and CRC patients has also changed.ConclusionsIn conclusion, compared with healthy people, the taxonomic and functional composition of intestinal bacteria in IBD and CRC patients was significantly changed.

5-Methylcytosine (m5C) is a kind of methylation modification that occurs in both DNA and RNA and is present in the highly abundant tRNA and rRNA. It has an important impact on various human diseases including cancer. The function of m5C is modulated by regulatory proteins, including methyltransferases (writers) and special binding proteins (readers). This study aims at comprehensive study of the m5C RNA methylation-related genes and the main pathways under m5C RNA methylation in gastrointestinal (GI) cancer. Our result showed that the expression of m5C writers and reader was mostly up-regulated in GI cancer. The NSUN2 gene has the highest proportion of mutations found in GI cancer. Importantly, in liver cancer, higher expression of almost all m5C regulators was significantly associated with lower patient survival rate. In addition, the expression level of m5C-related genes is significantly different at various pathological stages. Finally, we have found through bioinformatics analysis that m5C regulatory proteins are closely related to the ErbB/PI3K–Akt signaling pathway and GSK3B was an important target for m5C regulators. Besides, the compound termed streptozotocin may be a key candidate drug targeting on GSK3B for molecular targeted therapy in GI cancer.

Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.

The monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 are essential components of the astrocyte-neuron lactate shuttle (ANLS), which is a fundamental element of brain energetics. Decreased expression of MCTs can induce cognitive dysfunction of the brain. In the present study, we established a mouse model of long-term ketamine administration by subjecting mice to a 6-month course of a daily intraperitoneal injection of ketamine. These mice demonstrated learning and memory deficits and a significant decline in MCT1 and MCT4 proteins in the hippocampal membrane fraction, while cytoplasmic MCT1 and MCT4 protein levels were significantly increased. In contrast, the levels of global MCT2 protein were significantly increased. Analysis of mRNA levels found no changes in MCT1/4 transcripts, although the expression of MCT2 mRNA was significantly increased. We suggest that redistribution of hippocampal MCT1 and MCT4, but not MCT2 up-regulation, may be related to learning and memory deficits induced by long-term ketamine administration.

Background: We previously demonstrated that a Danshensu-Tetramethylpyrazine conjugate DT-010 enhanced anticancer effect of doxorubicin (Dox) in Dox-sensitive human breast cancer cells, and protected against Dox-induced cardiotoxicity. This work was designed to see whether DT-010 overcomes Dox resistance in resistant human breast cancer cells.Methods: The effects of DT-010, Dox or their combination on cell viability of Dox-resistant human breast cancer MCF-7/ADR cells were conducted using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry after Annexin V-FITC/PI co-staining. Dox accumulation in MCF-7/ADR cells was detected by flow cytometry and fluorescence microscopy. A fluorometric multidrug resistance (MDR) assay kit was used to evaluate the effect of DT-010 on MDR transporter activity. P-glycoprotein (P-gp) expression and activity were analyzed by Western blot and rhodamine 123 (Rh123) efflux assay, respectively. The effects of DT-010 on glycolysis and mitochondrial stress were detected using an Extracellular Flux Analyzer. A Succinate Dehydrogenase Activity Assay kit was used to measure mitochondrial complex II activity.Results: At non-cytotoxic concentrations, DT-010 in combination with Dox led to a significant growth inhibition of MCF-7/ADR cells, suggesting a synergy between DT-010 and Dox to reverse Dox resistance. DT-010 restored Dox-mediated apoptosis and p53 induction in MCF-7/ADR cells. DT-010 increased Dox accumulation in MCF-7/ADR cells via inhibiting P-gp activity, but without changing P-gp expression. Further studies showed that DT-010 significantly inhibited glycolysis and mitochondrial function of MCF-7/ADR cells. Mitochondrial complex II activity was inhibited by DT-010 or DT-010/Dox combination, but not by Dox. The DT-010-mediated suppression of metabolic process may render cells more vulnerable to Dox treatment and thus result in enhanced efficacy.Conclusions: The results indicate that DT-010 overcomes Dox resistance in human breast cancer cells through a dual action via simultaneously inhibiting P-gp-mediated drug efflux and influencing metabolic process.

Tau protein is known to play an important role in maintaining microtubule assembly and stabilization, and maintaining the normal morphology of neurons, but several studies have found that chronic stress leads to Tau hyperphosphorylation. A large number of clinical trials have found that ketamine, which is an N-methyl-D-aspartate receptor antagonist, produces a rapid, long-lasting, and potent antidepressant effect in patients suffering from major depression. This rapid antidepressant effect of ketamine, which involves many mechanisms, has attracted wide attention. However, the relationship between ketamine’s antidepressant effects and Tau protein has rarely been examined. We used C57BL/6 and Tau KO mice exposed to 42 days of chronic unpredictable mild stress (the CUMS model) to investigate the effect of ketamine on behavioral changes and synaptic functioning of the hippocampus. The results showed that a single treatment of ketamine rapidly relieved the CUMS-induced anhedonia, depression-like, and anxious behaviors of the C57BL/6 mice. The abnormal behaviors were accompanied by increased levels of specific alterations of hyperphosphorylated Tau protein in cytoplasm and synapse in the hippocampus of the C57BL/6 mice, but ketamine reduced the aggregation of hyperphosphorylated Tau protein only in the synapse. We also found that CUMS exposure reduced the levels of GluA1 and PSD95 in the hippocampus of the C57BL/6 mice and that these deficits were reversed by ketamine. However, the Tau KO mice did not develop any stress-induced depressive behaviors or deficits of hippocampal function. The antidepressant effect of ketamine may decrease the levels of hyperphosphorylated Tau protein in synapse of C57BL/6 mice.

The introduction of targeted therapy is the biggest success in the treatment of cancer in the past few decades. However, heterogeneous cancer is characterized by diverse molecular alterations as well as multiple clinical profiles. Specific genetic mutations in cancer therapy targets may increase drug sensitivity, or more frequently result in therapeutic resistance. In the past 3 years, several novel targeted therapies have been approved for cancer treatment, including drugs with new targets (i.e., anti-PD1/PDL1 therapies and CDK4/6 inhibitors), mutation targeting drugs (i.e., the EGFR T790M targeting osimertinib), drugs with multiple targets (i.e., the EGFR/HER2 dual inhibitor neratinib) and drug combinations (i.e., encorafenib/binimetinib and dabrafenib/trametinib). In this perspective, we focus on the most up-to-date knowledge of targeted therapy and describe how genetic mutations influence the sensitivity of targeted therapy, highlighting the challenges faced within this era of precision medicine. Moreover, the strategies that deal with mutation-driven resistance are further discussed. Advances in these areas would allow for more targeted and effective therapeutic options for cancer patients.

Background: Erectile dysfunction (ED) is a very common condition among adult men and its prevalence increases with age. The ankle-brachial blood pressure index (ABPI) is a noninvasive tool used to assess peripheral vascular disease (PAD) and vascular stiffness. However, the association between ABPI and ED is unclear. We aimed to explore the association between ABPI and ED in the US population. Methods: Our study used data from two separate National Health and Nutrition Examination Survey (NHANES) datasets (2001-2002 and 2003-2004). Surveyweighted logistic regression models were used to explore the association between ABPI as a continuous variable and quartiles with ED. We further assessed the association between ABPI and ED using restricted cubic regression while selecting ABPI thresholds using two-piecewise Cox regression models. In addition, we performed subgroup analyses stratified by BMI, race, marital status, diabetes, and hypertension. Main outcome measure: ABPI was calculated by dividing the mean systolic blood pressure at the ankle by the mean systolic blood pressure at the arm. Results: Finally, 2089 participants were enrolled in this study, including 750 (35.90%) ED patients and 1339 (64.10%) participants without ED. After adjusting for all confounding covariates, logistic regression analyses showed a significant association between ABPI and ED (OR=0.19; 95% CI, 0.06-0.56, P=0.01); with ABPI as a categorical variable, compared with the lowest quartile, the OR and 95% CI for the second quartile were 0.58 (0.34-0.97; P = 0.04). Besides, splines indicated that there was an L-shaped relationship between ABPI levels and the risk of ED. Piecewise Cox regression demonstrated the inflection point at 1.14, below which the OR for ED was 0.06 (0.02-0.20; P < 0.001), and above which the OR was 2.79 (0.17-4.53; P = 0.469). Conclusion: In our study, lower ABPI was independently associated with ED risk. In addition, the lowest ABPI level associated with ED risk was 1.14, below this level, lower ABPI was associated with higher ED risk. [ABSTRACT FROM AUTHOR]

Accurate wind power forecasting is essential for both optimal grid scheduling and the massive absorption of wind power into the grid. However, the continuous changes in the contribution of various meteorological features to the forecasting of wind power output under different time or weather conditions, and the overlapping of wind power sequence cycles, make forecasting challenging. To address these problems, a short-term wind power forecasting model is established that integrates a gated recurrent unit (GRU) network with a dual attention mechanism (DAM). To compute the contributions of different features in real time, historical wind power data and meteorological information are first extracted using a feature attention mechanism (FAM). The feature sequences collected by the FAM are then used by the GRU network for preliminary forecasting. Subsequently, one-dimensional convolution employing several distinct convolution kernels is used to filter the GRU outputs. In addition, a multi-head time attention mechanism (MHTAM) is proposed and a Gaussian bias is introduced to assign different weights to different time steps of each modality. The final forecast results are produced by combining the outputs of the MHTAM. The results of the simulation experiment show that for 5-h, 10-h, and 20-h short-term wind power forecasting, the establishedÁ DAM-GRU model performs better than comparative models on the basis of Root Mean Square Error (RMSE), Mean Absolute Error (MAE), R-squared (R2), Square sum error (SSE), Mean absolute percentile error (MAPE), and Relative root mean square error (RRMSE) index. [ABSTRACT FROM AUTHOR]

The honey locusts (genus Gleditsia) are a genus of high-value trees in Asia. Seed beetle, Megabruchidius dorsalis (Fåhraeus) (Col.: Chrysomelidae: Bruchinae), is a Gleditsia oligophagous pest that causes severe yield reduction. To understand the cold tolerance of M. dorsalis adults, this study investigated its cold tolerance strategy and the influence of low temperatures on its physiology and biochemistry. The lowtemperature treatments were divided into three groups: long-term temperature acclimation (Group 1; 15°C, or 20°C, or 25°C, or 28°C [control check, CK] for 10 days), short-term low-temperature exposure (Group 2; 0°C or 4°C for 2 h), and long-term low-temperature induction (Group 3; 0°C or 4°C for 1, 3, or 5 d). The supercooling point (SCP; temperature at which spontaneous nucleation and ice lattice growth begin), freezing point (FP; temperature at which insect fluids freeze), low lethal temperature (LLT; temperature at which all individuals are killed), water, lipid, glycerol, and total sugars contents were measured under different temperature stresses. The results showed that M. dorsalis adults were a freeze-avoidant species. The SCP and LLT at 28°C were -10.62°C and -19.48°C, respectively. The SCP and FP of long-term temperature acclimation (15°C, or 20°C, or 25°C) were significantly lower than that of the control group (28°C). The water content of the long-term low temperature induction (0°C) group was significantly lower than that of the control group. The lipid and glycerol content in the acclimated group at 20°C and 25°C were significantly higher than in the control group. M. dorsalis adults may maintain their biofluids in a supercooled state via cryoprotectant accumulation and cryoprotective dehydration to prevent ice nucleation. This study provides a theoretical basis for future research on overwintering and potential distribution and related prediction of M. dorsalis adults. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is complicated and continuously evolving. This study was devoted to the identification of potential prognostic biomarkers based on the tumor microenvironment associated with immunotherapy for melanoma. This study integrates a couple of melanoma single cell and transcriptome sequencing datasets and performs a series of silico analyses as nicely as validation of molecular biology techniques. A core set of immune escape related genes was identified through Lawson et al. and the ImmPort portal. The differential proteins were identified through the cBioPortal database. Regression analysis was used to profile independent prognostic factors. Correlation with the level of immune cell infiltration was evaluated by multiple algorithms. The capacity of LCK to predict response was assessed in two independent immunotherapy cohorts. High LCK expression is associated with better prognosis, high levels of TILs and better clinical staging. Pathway analysis showed that high expression of LCK was significantly associated with activation of multiple tumor pathways as well as immune-related pathways. LCK expression tends to be higher in immunotherapy-responsive patients and those with lower IC50s treated with chemotherapeutic agents. RT-qPCR detected that LCK expression was significantly upregulated in melanoma cell lines. Single-cell transcriptome analysis showed that LCK was specifically highly expressed on T cells. CellChat analysis confirmed that LCK in C2 subpopulations and T cell subpopulations exerted immune promotion between cells by binding to CD8 receptors. In conclusion, LCK is a reliable biomarker for melanoma and will contribute to its immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Intracerebral hemorrhage (ICH) is associated with high mortality and disability rates. This study aimed to investigate the relationship between sex, age, study year, risk factors, bleeding site, median year of study, and the incidence of ICH. Method: Literature on the incidence of ICH published on 1 January 1980 and 1 January 2020, was systematically retrieved from PubMed and Embase databases. The random-eects model and subgroup analysis were used to explore the relationship between the incidence of ICH and dierent ages, sex, bleeding sites, and risk factors. Results: We summarized the epidemiological changes in ICH in the past 40 years according to 52 studies and found that the total incidence of ICH is 29.9 per 100,000 person-years (95% CI: 26.5–33.3), which has not decreased worldwide. The incidence of ICH in the Asian population is much higher than in other continents. In addition, the incidence of ICH increases with age and diers at the 85-year-old boundary. Men are more likely to develop ICH than women, and the basal ganglia region is the most common area for ICH. Of the 10 risk factors examined in this study, those with hypertension had the highest incidence of ICH, followed by those with excessive alcohol consumption and heart disease. Conclusion: The prevention and treatment of ICH still need to be improved continuously according to age, sex, risk factors, and other factors, and targeted and normative strategies should be gradually developed in the future. [ABSTRACT FROM AUTHOR]

Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile, ketamine has been shown to modulate the levels of inflammatory cytokines. We hypothesized that the effects of ketamine on the central nervous system are associated with inflammatory cytokines. Therefore, we set out to establish acute and chronic ketamine administration models in C57BL/6 mice, to evaluate spatial recognition memory and emotional response, to analyze the changes in the levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the mouse hippocampus, employing behavioral tests, Western blot, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Our results showed that ketamine at the dose of 60 mg/kg induced spatial recognition memory deficit and reduced anxietylike behaviors in mice after chronic administration. Moreover, we found that ketamine increased the hippocampal levels of IL-6 and IL-1β after single, multiple and long-term administration in a dose-dependent manner. However, the expression level of TNF-α differed in the mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α, whereas multiple and long-term administration decreased it significantly. We considered that TNF-α expression could be controlled by a bi-directional regulatory pathway, which was associated with the dose and duration of ketamine administration. Our results suggest that the alterations in the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α may be involved in the neurotoxicity of ketamine. [ABSTRACT FROM AUTHOR]

Progressive myoclonic epilepsy (PME) is a rare neurodegenerative disease, characterized by myoclonic seizures and tonic clonic seizures, with genetical and phenotypical heterogeneity. The semaphorin 6B (SEMA6B) gene has been recently reported a causal gene of PME. Independent studies are warranted to further support these findings. Here we report that one nonsense variant in NM_032108.3 exon17 c.2056C > T (p.Gln686∗) and one missense variant in exon14 c.1483G > T (p.Gly495Trp) of SEMA6B, both occurring de novo, underlie early-onset epilepsy with variable severity and different response to treatment in two patients. In vitro analyses have demonstrated that the nonsense variant, p.Gln686∗, results in a truncated protein with remarkably increased expression compared to that of the wild type. The truncated protein presented more homogeneous and failed to locate in the plasma membrane. The missense variant p.Gly495Trp affects evolutionarily conserved amino acid and is located in the sema domain, a key functional domain of SEMA6B. It was predicted to perturb the SEMA6B function by altering the tertiary structure of mutant protein, although neither change of protein length and expression nor difference of cellular distribution was observed. Co-immunoprecipitation studies have demonstrated that both variants influence protein binding of SEMA6B and PlxnA2 with varying degrees. Our results provide further evidence to support the initial findings of SEMA6B being causal to epilepsy and indicate that mediating Semaphorin/Plexin signaling is the potential mechanism of the SEMA6B-related disease.

Commonly used anesthetic isoflurane has been reported to promote Alzheimer's disease (AD) neuropathogenesis by inducing caspase-3 activation. However, the up-stream mechanisms of isoflurane's effects remain largely to be determined. Specifically, there is a lack of a good model/system to elucidate the underlying mechanism of the isoflurane-induced caspase-3 activation. We therefore set out to assess and compare the effects of isoflurane on caspase-3 activation in neural progenitor cells (NPCs) and in primary neurons from wild-type (WT) and AD transgenic (Tg) mice. The NPCs and neurons were obtained, cultured and then treated with either 2% isoflurane or under control condition for 6 h. The NPCs or neurons were harvested at the end of the treatment and were subjected to Western blot analysis. Here we showed for the first time that the isoflurane treatment induced caspase-3 activation in neurons, but not in NPCs, from either WT or AD Tg mice. Consistently, the isoflurane treatment increased cytosol levels of cytochrome c, a potential up-stream mechanism of isoflurane-induced caspase-3 activation in the mice neurons, but not NPCs. Finally, the isoflurane treatment induced a greater casapse-3 activation in the neurons, but not the NPCs, from AD Tg mice as compared to the WT mice. These data demonstrated that investigation and comparison of isoflurane's effects between mice NPCs and neurons would serve as a model/system to determine the underlying mechanism by which isoflurane induces caspase-3 activation. These findings would promote more research to investigate the effects of anesthetics on AD neuropathogenesis and the underlying mechanisms. [ABSTRACT FROM AUTHOR]

We have synthesized Rhopaladins’ analog (2E,4E)-4-chlorobenzylidene-2-(4-chlorostyryl)-N-cyclohexyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (RPDPRH) via a highly facile, inexpensive and green approach and verified the structural superiority of compound RPDPRH through molecular docking. Moreover, we further detected the anti-proliferation, apoptosis and HPV E6/E7 effects of RPDPRH on CaSki cells. Finally, we confirmed that compared with the previous compound (E)-N-(tert-butyl)-2-(4-chlorobenzoyl)-4-(4-fluorobenzylidene)-1-isopropyl-5-oxopyrrolidine-2-carboxamide (RPDPB), RPDPRH could better inhibit proliferation, induce apoptosis, and down-regulate HPV E6/E7 mRNA expression on Caski cells. And preliminary RT-PCR experiments have demonstrated that RPDPRH also could affect the expression of Bcl-2, Bax and Caspase-3 mRNA in Caski cells. In summary, RPDPRH has potential as an effective agent against cervical cancer and will play an important role in our subsequent research.

Toll-like receptors (TLRs) are major molecular pattern recognition receptors, which are essential for triggering a series of innate immune responses against invading pathogens by recognizing their evolutionary conserved molecular patterns. The mudskipper, Boleophthalmus pectinirostris is exceptional among fishes due to its amphibious lifestyle and adaptation to living on mudflats. The whole-genome sequencing of B. pectinirostris has revealed that this species possesses an expansion of Tlr11 family [12 Tlr11 family genes (one tlr21, 4 tlr22, and 7 tlr23)] that we focused on in the present study. The full-length cDNA sequences of the 12 tlrs in B. pectinirostris were cloned and their deduced amino acid sequences possessed a typical TLR domain arrangement. Likelihood tests of selection revealed that these 12 Tlr11 family genes are under diversifying selection. A total of 13 sites were found to be positively selected by more than one evolution model, of which 11 were located in the ligand-binding ectodomain. The observed non-synonymous substitutions may have functional implications in antigen and pathogen recognition specificity. These 12 tlrs were highly expressed in immune-related tissues, i.e. spleen and kidney. Tlr21 and tlr22b transcripts were significantly up-regulated by LPS, whereas tlr22a, tlr22d, tlr23b, tlr23e, tlr23g were significantly up-regulated by poly(I:C) in the spleen or/and kidney, which implies that the expanded Tlr11 family genes may play roles in protecting the fish from the invasion of gram-negative bacteria and double-stranded RNA viruses. The results from the present study suggested that the expansion of Tlr11 family genes in B. pectinirostris may recognize ligands from various pathogens found in the intertidal zone.