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Abstract The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.

Abstract Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial–mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity. Graphical Abstract

Background Late 2022, an ICU nurse discovered that Seretide™ (salmeterol/Fluticasone) Evohaler, a commonly used inhaler, did not change its dose counter when used with the inhaler connector 22M-22F. This was identified as a medication safety issue. Knowledge gaps of inhaler use in mechanically ventilated patients were identified as well. Aims To effectively administer metered dose inhalers to ventilated patients and increase its accuracy and safety. Methods We instituted education programs for healthcare professional in the ICU and introduced a new inhaler connector RTC 24-V. This was compared with the existing 22M-22F connector in a comparative study. Results The dose counter of Seretide™ recorded prior to initiation and extubation showed an obvious drop in doses ranging from 15 to 63 in patients randomized to use RTC 24-V, compared to 0 to 2 drop in doses for patients using 22M-22F. A total of 51 pre study and 33 post study questionnaires were completed. Confidence that the accurate dose of medications was administered rose from 58.8% to 84.8% after using the RTC 24-V. Responses that there was no issue compromising patient safety rose from 0% to 51.5% and fewer staff expressed concern about disconnections causing infections, dropping from 51% to 9.1%. 93.9% of respondents chose the new RTC 24-V as the preferred inhaler connector. Conclusion The new inhaler connector RTC 24-V was assessed to have less medication errors. ICU healthcare professionals expressed greater confidence in its safety and accuracy. We will implement the use of this connector with continued medical education.

Abstract High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits even in TMB-H. In this study, we aimed to identify gene mutations associated with immunotherapy resistance and further informed mechanisms in NSCLC. A combined cohort of 350 immune checkpoint blockade-treated patients from Memorial Sloan Kettering Cancer Center (MSKCC) was used to identify genes whose mutations could negatively influence immunotherapy efficacy. An external NSCLC cohort for which profession-free survival (PFS) data were available was used for independent validation. CIBERSORT algorithms were used to characterize tumor immune infiltrating patterns. Immunogenomic features were analysed in the TCGA NSCLC cohort. We observed that PBRM1 mutations independently and negatively influence immunotherapy efficacy. Survival analysis showed that the overall survival (OS) and PFS of patients with PBRM1 mutations (MT) were significantly shorter than the wild type (WT). Moreover, compared with PBRM1-WT/TMB-H group, OS was worse in the PBRM1-MT/TMB-H group. Notably, in patients with TMB-H/PBRM1-MT, it was equal to that in the low-TMB group. The CIBERSORT algorithm further confirmed that the immune infiltration abundance of CD8+ T cells and activated CD4+ memory T was significantly lower in the MT group. Immunogenomic differences were observed in terms of immune signatures, T-cell receptor repertoire, and immune-related genes between WT and MT groups. Nevertheless, we noticed an inverse relationship, given that MT tumors had a higher TMB than the WT group in MSKCC and TCGA cohort. In conclusion, our study revealed that NSCLC with PBRM1 mutation might be an immunologically cold phenotype and exhibited immunotherapy resistance. NSCLC with PBRM1 mutation might be misclassified as immunoresponsive based on TMB.

Abstract The TBC (Tre-2/Bub2/Cdc16, TBC) structural domain is now considered as one of the factors potentially regulating tumor progression. However, to date, studies on the relationship between TBC structural domains and tumors are limited. In this study, we identified the role of TBC1 domain family member 8 (TBC1D8) as an oncogene in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and Cox regression analysis, showing that TBC1D8 may independently predict CRC outcome. Functional enrichment and single-cell analysis showed that TBC1D8 levels were associated with hypoxia. TBC1D8 levels were also positively correlated with M2 macrophage infiltration, which may have a complex association with hypoxia. Taken together, these results show that the TBC1D8 gene is involved in colorectal carcinogenesis, and the underlying molecular mechanisms may include hypoxia and immune cell infiltration.

Objective To explore the role and mechanism of angiopoietin-like protein 8 (ANGPTL8) on phenotypic transformation of rat aorta vascular smooth muscle cells (VSMCs). Methods ApoE-/- male mice (8 weeks of age) were fed with a western diet for 12 weeks to build the atherosclerosis mouse model. The expression and localization of ANGPTL8 in atherosclerotic plaques were detected by immunofluorescence staining. Stable transfections of the ANGPTL8 over-expression vector were performed. VSMCs were randomly divided into 5 groups: control group,LV-ANGPTL8 group,ox-LDL (50 mg/L)group,(ox-LDL+LV-ANGPTL8) group and (LV-ANGPTL8+PD98059 group. And cell migration was observed by wound-healing assay. The protein expressions of α-SMA, SM22α, OPN, PCNA and Ki67 in VSMCs was detected by Western blot. Results ANGPTL8 over-expression promoted the expression of OPN, PCNA and Ki67 in VSMCs (P＜0.05), decreased the expression of α-SMA and SM22α(P＜0.05) and enhanced migration ability of VSMCs(P＜0.05). After adding ERK pathway inhibitor PD98059, the expression of OPN, PCNA and Ki67 decreased (P＜0.05), α-SMA and SM22α expression increased(P＜0.05), and the migration capability of the VSMCs decreased (P＜0.05). Conclusions ANGPTL8 maybe promotes phenotypic transformation of VSMCs by activating ERK pathway.

Objective: To investigate the fertility quality of life (Ferti QoL) of female patients undergoing in vitro fertilization and embryo transfer (IVF-ET), and to explore the related influenced factors. Methods: The random sampling has been conducted to enroll subjects, and questionnaires (General Information, Fertility Quality of Life, Perceived Social Support Scale, Self-Rating Anxiety Scale and Self-rating Depression Scale) were performed in patients undergoing IVF-ET at Reproductive Medicine Center of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine during December 2018 to June 2019. Results: A total of 236 IVF-ET patients were recruited in the study, and the total score of Ferti QoL was (64.6±13.12). Multiple linear regression analysis indicated that longer years of infertility(β=-4.8769, P

Introduction Postmenopausal osteoporosis, caused by ageing and oestrogen deficiency, seriously threatens women’s physical and mental health. Postmenopausal osteopenia is the transition from healthy bone to osteoporosis, and it may be the key period for preventing bone loss. Moxibustion, a physical therapy of Traditional Chinese Medicine, has potential benefits for osteoporosis treatment and prevention, but it has not been adequately studied. This study aims to explore the clinical effects and safety of moxibustion in delaying bone loss in postmenopausal women.Methods and analysis In this parallel-design, randomised, patient-blind and assessor-blind, controlled clinical study, 150 women with osteopenia at low fracture risk will be randomly assigned to a moxibustion treatment (MT) group or a placebo-moxibustion control (PMC) group in a 1:1 ratio. In addition to the fundamental measures (vitamin D3 and calcium) as recommended by the guidelines, participants of the two groups will receive MT or PMC treatment for 42 sessions over 12 months. The primary outcome will be the bone mineral density (BMD) of the lumbar spine at the end of the 12-month treatment, and secondary outcomes will be the BMD of the femoral neck and total hip, T-scores, bone turnover markers, serum calcium levels, serum magnesium levels, serum phosphorus levels, serum parathyroid hormone levels and 25-hydroxyvitamin D levels, intensity of bone pain, quality of life, incidence of osteoporosis and fractures, usage of emergency drugs or surgery, participant self-evaluation of therapeutic effects and the rate of adverse events. All statistical analyses will be performed based on the intention-to-treat and per-protocol principle.Ethics and dissemination Ethics approval has been obtained from the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (permission number: 2021-1243). The results are expected to be published in peer-reviewed journals.Trial registration number ChiCTR2100053953.

Objectives Sleep disturbances increase the risk of dementia; however, there is insufficient information regarding this. We aimed to investigate public knowledge on the relationship between sleep disturbances and dementia, as well as attitudes towards improving sleep quality and obtaining knowledge on dementia.Design and setting A cross-sectional web-based questionnaire was administered between May and October 2019.Participants All participants provided informed consent and were able to respond to the survey.Primary outcomes Factors associated with the knowledge that sleep disturbances are risk factors for dementia and proportions of individuals with this knowledge; attitudes towards improving sleep quality and obtaining knowledge about dementia.Results Of the 3329 eligible samples, 72.57% correctly recognised that sleep disturbances increased the risk of dementia. In total, 92.97% of participants were willing to take at least one measure to improve sleep quality, and the percentages of those adopting these measures are as follows: 78.73% would lead a regular life, 67.88% would engage in strengthening exercise, 28.84% would undergo psychotherapy and 19.41% would take medication. The awareness regarding sleep disturbances increasing the risk of dementia was the only factor associated with the willingness to improve sleep quality in all four categories of measures. Almost all participants (95.25%) were willing to take at least one measure to acquire knowledge about dementia, with the following participants displaying higher willingness to obtain knowledge about dementia: female, had contact with dementia and considered sleep disturbances to increase the risk of dementia.Conclusions Our findings indicate an association between people’s knowledge and attitudes, suggesting the importance of disseminating knowledge about sleep disturbances and dementia to achieve dementia prevention in future.

Objective To explore the role of angiopoietin-like protein 3 (ANGPTL3) in the development of thoracic aortic aneurysm (TAA) and its possible mechanism. Methods The TAA patients who underwent open surgical repair in Beijing Anzhen Hospital were selected as the experimental group (n=6), and the aortic tissue in the control group was obtained from a heart transplant donor (n=6). Another 30 3-week-old male C57BL/6J mice were randomly divided into control (control) and β-aminopropionitrile (BAPN)-induced TAA model groups (n=15 per group). The aortic tissue was taken 4 weeks later. Immunohistochemical method was used to detect the expression of ANGPTL3 in human thoracic aortic aneurysm tissue, immunohistochemistry were used to detect the expression of ANGPTL3, IL-6, MMP2, and MMP9 in mouse aortic tissue, and TUNEL method was used to detect apoptosis. Immunofluorescence co-localization was used to detect the localization of ANGPTL3 in vascular tissues. Transfect human aortic smooth muscle cells with ANGPTL3 siRNA. Observe the effect of ANGPTL3 knockdown on AngⅡ-induced smooth muscle cell apoptosis and inflammatory response. Results In the aortic tissues of patients with thoracic aortic aneurysm and TAA mice, the expression of ANGPTL3 protein increased significantly (P＜0.05), vascular smooth muscle cell apoptosis, and the protein expressions of inflammatory factors IL-1β, MMP2, and MMP9 were all significantly increased(P＜0.05). In addition, ANGPTL3 knockdown can significantly reduce AngⅡ-induced smooth muscle cell apoptosis and inflammatory factor secretion (P＜0.05). Conclusions The ANGPTL3 protein level is increased in the development of thoracic aortic aneurysm. Inhibition of ANGPTL3 protein expression can reduce the cell apoptosis and inflammation of smooth muscle cells. It suggests that targeting ANGPTL3 may inhibit the development of thoracic aortic aneurysms by inhibiting cell apoptosis and inflammation in smooth muscle.

AbstractThis study aimed to validate the chronic obstructive pulmonary disease (COPD) Population Screener (COPD-PS) questionnaire as a screening tool in a cohort of Chinese subjects who underwent a health examination, and to summarise its overall performance through a meta-analysis. We enrolled 997 subjects aged ≥40 years who underwent a health examination, both lung function and COPD-PS data were collected. The screening performance of COPD-PS was evaluated with a receiver operating characteristic (ROC) curve analysis, using the area under the curve (AUC) to assess the screening accuracy. A standard diagnostic meta-analysis was used to summarise the screening performance of COPD-PS for COPD. Of the 997 subjects, 157 were identified as having COPD. The COPD-PS score was significantly higher in COPD patients than controls (5.03 ± 5.11 vs. 2.72 ± 1.80, p

Background Markers of idiopathic pulmonary fibrosis (IPF) severity are based on measurements of forced vital capacity (FVC), diffusing capacity (DLCO) and CT. The pulmonary vessel volume (PVV) is a novel quantitative and independent prognostic structural indicator derived from automated CT analysis. The current prospective cross-sectional study investigated whether respiratory oscillometry provides complementary data to pulmonary function tests (PFTs) and is correlated with PVV.Methods From September 2019 to March 2020, we enrolled 89 patients with IPF diagnosed according to international guidelines. We performed standard spectral (5–37 Hz) and novel intrabreath tracking (10 Hz) oscillometry followed by PFTs. Patients were characterised with the gender-age-physiology (GAP) score. CT images within 6 months of oscillometry were analysed in a subgroup (26 patients) using automated lung texture analysis. Correlations between PFTs, oscillometry and imaging variables were investigated using different regression models.Findings The cohort (29F/60M; age=71.7±7.8 years) had mild IPF (%FVC=70±17, %DLCO=62±17). Spectral oscillometry revealed normal respiratory resistance, low reactance, especially during inspiration at 5 Hz (X5in), elevated reactance area and resonance frequency. Intrabreath oscillometry identified markedly low reactance at end-inspiration (XeI). XeI and X5in strongly correlated with FVC (r2=0.499 and 0.435) while XeI was highly (p=0.004) and uniquely correlated with the GAP score. XeI and PVV exhibited the strongest structural-functional relationship (r2=0.690), which remained significant after adjusting for %FVC, %DLCO and GAP score.Interpretation XeI is an independent marker of IPF severity that offers additional information to standard PFTs. The data provide a cogent rationale for adding oscillometry in IPF assessment.

ObjectiveRepetitive Transcranial Magnetic Stimulation (rTMS) has been used in cognition impairment due to various neuropsychiatric disorders. However, its optimum parameters and the neuroimaging mechanism are still of uncertainty. In order to simulate a study setting as close to real world as possible, the present study introduces a new orthogonally-designed protocol, consisting of the rTMS intervention with four key parameters (stimulating site, frequency, intensity and pulse number) and three different levels in each one, and aims to investigate the optimum parameters and the brain activity and connectivity in default mode network (DMN), dorsal attention network (DAN), central executive network (CEN) following rTMS intervention to post-stroke cognition impairment (PSCI).MethodsA single-center, orthogonally-designed, triple-blind randomized controlled trial will be conducted and forty-five PSCI patients will be recruited and randomly assigned to one of nine active rTMS groups based on four rTMS paraments: stimulating site, frequency, intensity and pulse number. Neuropsychological, activities of daily living, quality of life and functional magnetic resonance imaging (fMRI) evaluations were be performed pre-, post- and 3 months after rTMS.DiscussionThis study evaluates the optimum parameters of rTMS for patients with post-stroke cognition impairment and explores the alteration of neural function in DMN, DAN, CEN brain network. These results would facilitate the standardized application of rTMS in cognition impairment rehabilitation.

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

Objective To develop a high performance liquid chromatography-tandem mass spectrometry （HPLC-MS/MS） method for the determination of the content of 4-fluoromethamphetamine （4-FMA） in rat plasma, and to provide a methodological basis for the study of the toxicokinetics of 4-FMA in rats. Methods Rat plasma samples were added into internal standard methamphetamine （MA）. Its proteins were precipitated with methanol and then separated with Poroshell 120 EC-C18 chromatographic column. A 0.1% formic acid aqueous solution and a 0.1% formic acid acetonitrile solution were used as the mobile phase at the flow rate of 0.4 mL/min. Electrospray ionization source was used for detection in the multiple reaction monitoring （MRM） mode. Results The linear relationship was good when the mass concentration of 4-FMA in plasma samples was in the range of 5-1 000 ng/mL （r>0.999）. The limit of detection （LOD） was 3 ng/mL and the limit of quantification （LOQ） was 5 ng/mL. The accuracy was expressed as relative error （RE）, and in the range of ±5%, the intra-day precision and inter-day precision （relative standard deviation, RSD） less than 9%, and the extraction recovery rate was more than 90%. The analysis and detection of plasma samples were completed within 2.5 min. Conclusion This study developed a HPLC-MS/MS method for the determination of 4-FMA in rat plasma samples. This method is accurate, rapid, simple and sensitive and can be applied to the study of toxicokinetics of 4-FMA.

Introduction Uterine serous carcinoma accounts for only about 10% of all endometrial cancers but this subtype is the most common amongst non-endometrioid endometrium cancers and contributes to more than half of recurrence and deaths attributed to endometrial cancers. A more extensive surgical staging and adjuvant therapies for uterine serous carcinoma are recommended by many guidelines. However, guidelines vary on recommendations for the methods that should be used for omentum assessment in uterine serous carcinoma and the previously reported incidence of omental metastasis in uterine serous carcinoma had a wide range because of the heterogeneity among these studies. As far as we know, there are no systematic review and meta-analysis available on this topic. The aim of our proposed study is to statistically synthesise the data examining the incidence of omental metastasis in uterine serous carcinoma.Methods and analysis Systematic searches of three databases (PubMed, Embase and Web of Science) will be performed using prespecified search strategies. We will include original studies that reported incidence of omental metastasis in uterine serous carcinoma and are published before 30 August 2020. Our different investigators will independently conduct the eligible study selection, assess the quality of included studies and extract the needed data. If appropriate, the relevant data will be pooled through a random-effect or fixed-effect meta-analysis based on the heterogeneity among included studies. We will evaluate the overall quality of evidence using appropriate methods.Ethics and dissemination This proposed study will be based on published data, and thus, there is no requirement for ethics approval. We aim to publish the results of this study in a peer-reviewed journal with good visibility for the fields of gynaecology and gynecologic oncology.PROSPERO registration number CRD42020200891.

While a number of tools have been developed for researchers to compute the lexical characteristics of words, extant resources are limited in their useability and functionality. Specifically, some tools require users to have some prior knowledge of some aspects of the applications, and not all tools allow users to specify their own corpora. Additionally, current tools are also limited in terms of the range of metrics that they can compute. To address these methodological gaps, this article introduces LexiCAL, a fast, simple, and intuitive calculator for lexical variables. Specifically, LexiCAL is a standalone executable that provides options for users to calculate a range of theoretically influential surface, orthographic, phonological, and phonographic metrics for any alphabetic language, using any user-specified input, corpus file, and phonetic system. LexiCAL also comes with a set of well-documented Python scripts for each metric, that can be reproduced and/or modified for other research purposes.

Background The oncological safety of diagnostic hysteroscopy in patients with stage Ⅰ endometrial cancer remains uncertain and conflicting. The aim of the proposed systematic review and meta-analysis is to summarise the available evidence examining the association between diagnostic hysteroscopy and the prognosis of stage Ⅰ endometrial cancer and to statistically synthesise the results of relevant studies.Methods and analysis Systematic searches of PubMed/MEDLINE, Embase, Cochrane Library and Web of Science will be undertaken using prespecified search strategies. Two authors will independently conduct eligible studies selection process, perform data extraction and appraise the quality of included studies. Original case–control studies, cohort studies and randomised controlled trails published in English will be considered for inclusion. The outcomes of interest will be 5-year recurrence-free survival, disease-specific survival and overall survival. Meta-analyses will be performed to calculate pooled estimates.Ethics and dissemination Our study will be based on published data, and thus there is no requirement for ethics approval. The results will be shared through publication in a peer-reviewed journal and presentations at academic conferences.PROSPERO registration number CRD42020193696.

Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1β) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p

Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.

To our knowledge, no studies have examined the role of IL-17 production by neutrophils in immune defense against Mycobacterium tuberculosis (MTB) infection and the pathogenesis of rheumatoid arthritis (RA) caused by MTB infection. Here, we determined that neutrophils express IL-17 in an autocrine IL-6- and IL-23-dependent manner during MTB infection. MTB H37Rv-induced IL-6 production was dependent on the NF-κB, p38, and JNK signaling pathways; however, IL-23 production was dependent on NF-κB and EKR in neutrophils. Furthermore, we found that Toll-like receptor 2 (TLR2) and TLR4 mediated the activation of the kinases NF-κB, p38, ERK, and JNK and the production of IL-6, IL-23, and IL-17 in neutrophils infected with MTB H37Rv. Autocrine IL-17 produced by neutrophils played a vital role in inhibiting MTB H37Rv growth by mediating reactive oxygen species production and the migration of neutrophils in the early stages of infection. However, IL-17 production by neutrophils contributed to collagen-induced arthritis development during MTB infection. Our findings identify a protective mechanism against mycobacteria and the pathogenic role of MTB in arthritis development.

Abstract Chronic administration of glucocorticoids has been shown to render individuals highly susceptible to mycobacterial infection and lead to reactivation of latent bacilli. However, the effect of glucocorticoids on innate anti-mycobacterial defense, especially in macrophages remains largely unknown. Here, we found that glucocorticoids inhibited the innate immune response, antimicrobial nitric oxide production and autophagy in mycobacteria-challenged macrophages. Meanwhile, maturation and acidification of mycobacterial phagosomes were attenuated in RAW264.7 cells after glucocorticoids treatment. Consequently, we observed a glucocorticoid-induced increase in the survival of intracellular mycobacteria in both primary macrophages and cell lines. Glucocorticoids treatment decreased the activation of TBK1 kinase, which promotes the maturation of autophagosomes. Inhibition of TBK1 also decreased the production of nitric oxide. Furthermore, several autophagy-related genes were down-regulated, while activation of the Akt/mTOR signaling pathway was increased after glucocorticoids treatment, which may account for autophagy inhibition during mycobacterial infection. Restoration of autophagy with the agonist rapamycin abolished glucocorticoid-mediated enhancement of mycobacterial survival, suggesting that glucocorticoids blocked anti-mycobacterial defense via autophagy inhibition. Collectively, this study demonstrates that glucocorticoids impair innate antimicrobial autophagy and promote mycobacterial survival in macrophages, which is a novel mechanism for glucocorticoid-mediated immunosuppression. Our findings may provide important clues for tuberculosis prevention.

Objective To assess clinical effect of replantation in avulsed immature permanent teeth.Methods 30 avulsed permanent teeth with immature apex treated following the International Association of Dental Traumatology treatment guidelines from July 2008 to June 2009 were analyzed in the retrospective study. The healing outcomes were classified into 4 categories：normal periodontal ligament healing, surface resorption, ankylosis and inflammatory resorption.Results The rate of normal periodontal ligament healing, surface resorption, ankylosis and inflammatory resorption were 23.3%, 3.3%, 43.3%, and 30.0％ respectively.Conclusion Traumatic injuries that result in ankylosis and inflammatory resorption of the permanent teeth in growing child leave the practitioners with many considerations to make the most appropriate treatment plan.

Rhein, an anthraquinone compound existing in many traditional herbal medicines, has anti-inflammatory, antioxidant, antitumor, antiviral, hepatoprotective, and nephroprotective activities, but its anti-influenza A virus (IAV) activity is ambiguous. In the present study, through plaque inhibition assay, time-of-addition assay, antioxidant assay, qRT-PCR, ELISA, and western blotting assays, we investigated the anti-IAV effect and mechanism of action of rhein in vitro and in vivo. The results showed that rhein could significantly inhibit IAV adsorption and replication, decrease IAV-induced oxidative stress, activations of TLR4, Akt, p38, JNK MAPK, and NF-κB pathways, and production of inflammatory cytokines and matrix metalloproteinases in vitro. Oxidant H2O2 and agonists of TLR4, Akt, p38/JNK and IKK/NF-κB could significantly antagonize the inhibitory effects of rhein on IAV-induced cytopathic effect (CPE) and IAV replication. Through an in vivo test in mice, we also found that rhein could significantly improve the survival rate, lung index, pulmonary cytokines, and pulmonary histopathological changes. Rhein also significantly decreased pulmonary viral load at a high dose. In conclusion, rhein can inhibit IAV adsorption and replication, and the mechanism of action to inhibit IAV replication may be due to its ability to suppress IAV-induced oxidative stress and activations of TLR4, Akt, p38, JNK MAPK, and NF-κB signal pathways.

Experience is well known to affect sensory-guided behaviors in many herbivorous insects. Here, we investigated the effects of natural feeding experiences of Helicoverpa armigera larvae on subsequent preferences of larval approaching and feeding, as well as the effect of host-contacting experiences of mated females on subsequent ovipositional preference. The results show that the extent of experience-induced preference, expressed by statistical analysis, depended on the plant species paired with the experienced host plant. Larval feeding preference was much easier to be induced by natural feeding experience than larval approaching preference. Naïve larvae, reared on artificial diet, exhibited clear host-ranking order as follows: tobacco ≥ cotton > tomato > hot pepper. Feeding experiences on hot pepper and tobacco could always induce positive feeding preference, while those on cotton often induced negative effect, suggesting that the direction of host plant experience-induced preference is not related to innate feeding preference. Inexperienced female adults ranked tobacco as the most preferred ovipositional host plant, and this innate preference could be masked or weakened but could not be reversed by host-contacting experience after emergence.

The aim of this study was to establish plasma cytokine/chemokine profiles in patients with 3 different presentations of active tuberculosis (TB), compared to the profiles observed in bacillus Calmette-Guérin (BCG)-vaccinated healthy individuals and patients with other pulmonary diseases (non-TB patients). To this end, plasma samples were collected from 151 TB patients including 68 pulmonary TB (PTB), 43 endobronchial TB, and 40 tuberculosis pleurisy (TP) patients, as well as 107 no-TB cases including 26 non-TB patients and 81 BCG-vaccinated healthy controls. A liquid array-based multiplexed immunoassay was used to screen plasma samples for 20 distinct cytokines and chemokines. Multinomial logistic regression was used to analyze associations between cytokines/chemokines and TB/non-TB patients. Compared to our findings with the no-TB donors, the median plasma levels of the proinflammatory cytokines/chemokines TNF-α, IL-6, IP-10, IFN-γ, and MIP-1β were significantly elevated in TB patients, suggesting their potential use as biomarkers for diagnosing TB patients. Further comparisons with healthy donors showed that only the median TNF-α plasma level was highly produced in the plasma of all 3 types of TB patients. Plasma IL-6 production was higher only in TP patients, while the plasma levels of IP-10, IFN-γ, and MIP-1β were markedly enhanced in both PTB and TP patients. Unexpectedly, among the above cytokines/chemokines, MIP-1β was also highly expressed in non-TB patients, compared with healthy donors. Our results suggested that TNF-α may be an ideal biomarker for diagnosing the 3 forms of TB presentation, while the other factors (IL-6, IP-10, MCP-1, and IFN-γ) can potentially facilitate differential diagnosis for the 3 TB presentation types. Further characterization of immune responses associated with different types of TB diseases will provide a basis for developing novel TB diagnostics.