Molecular simulations guide immobilization of lipase on nest-like ZIFs with regulatable hydrophilic/hydrophobic surface.

The catalytic performance of immobilized lipase is greatly influenced by functional support, which attracts growing interest for designing supports to achieve their promotive catalytic activity. Many lipases bind strongly to hydrophobic surfaces where they undergo interfacial activation. Herein, the behavioral differences of lipases with distinct lid structures on interfaces of varying hydrophobicity levels were firstly investigated by molecular simulations. It was found that a reasonable hydrophilic/hydrophobic surface could facilitate the lipase to undergo interfacial activation. Building on these findings, a novel "nest"-like superhydrophobic ZIFs (ZIFN) composed of hydrophobic ligands was prepared for the first time and used to immobilize lipase from Aspergillus oryzae (AOL@ZIFN). The AOL@ZIFN exhibited 2.0-folds higher activity than free lipase in the hydrolysis of p-Nitrophenyl palmitate (p-NPP). Especially, the modification of superhydrophobic ZIFN with an appropriate amount of hydrophilic tannic acid can significantly improve the activity of the immobilized lipase (AOL@ZIFN-TA). The AOL@ZIFN-TA exhibited 30-folds higher activity than free lipase, and still maintained 82% of its initial activity after 5 consecutive cycles, indicating good reusability. These results demonstrated that nanomaterials with rational arrangement of the hydrophilic/hydrophobic surface could facilitate the lipase to undergo interfacial activation and improve its activity, displaying the potential of the extensive application.

Endocytic activation and exosomal secretion of matriptase stimulate the second wave of EGF signaling to promote skin and breast cancer invasion.

The dysfunction of matriptase, a membrane-anchored protease, is highly related to the progression of skin and breast cancers. Epidermal growth factor (EGF)-induced matriptase activation and cancer invasion are known but with obscure mechanisms. Here, we demonstrate a vesicular-trafficking-mediated interplay between matriptase and EGF signaling in cancer promotion. We found that EGF induces matriptase to undergo endocytosis together with the EGF receptor, followed by acid-induced activation in endosomes. Activated matriptase is then secreted extracellularly on exosomes to catalyze hepatocyte growth factor precursor (pro-HGF) cleavage, resulting in autocrine HGF/c-Met signaling. Matriptase-induced HGF/c-Met signaling represents the second signal wave of EGF, which promotes cancer cell scattering, migration, and invasion. These findings demonstrate a role of vesicular trafficking in efficient activation and secretion of membrane matriptase and a reciprocal regulation of matriptase and EGF signaling in cancer promotion, providing insights into the physiological functions of vesicular trafficking and the molecular pathological mechanisms of skin and breast cancers.

Incidence, clearance, and factors associated with anal human papilloma virus infection among men with HIV.

OBJECTIVES: This study aims to estimate the incidence and persistence/clearance of anal human papilloma virus (HPV) infection and related factors among men with HIV in Taizhou, China. DESIGN: A prospective cohort study. METHODS: Men with HIV were recruited and followed up from 2016 to 2021. Questionnaire surveys were used to collect social-demographic and behavioral characteristics, and anal swabs were collected for HPV Genotyping. RESULTS: A total of 675 men with HIV were recruited and followed up. After an average follow-up time of 1.75 years, HPV39 (3.8/100 person-years), HPV52 (3.6/100 person-years), HPV51 (3.1/100 person-years), HPV58 (2.5/100 person-years) and HPV16 (2.4 cases/100 person-years) in the high-risk types showed the highest incidence rate. In marriage with woman [adjusted hazard ratio (aHR) = 0.44, 95% confidence interval (CI) 0.20-0.99] showed an inverse association with HPV incidence, while bisexuality or undetermined sexual orientation (aHR = 2.62, 95% CI 1.08-6.36) showed a positive association. For those infected at baseline, the top three high-risk HPV with the lowest clearance density were HPV52 (32.2/100 person-years), HPV58 (38.1/100 person-years), and HPV16 (43.5/100 person-years). Daily consumption of 1-28 g alcohol (aHR = 0.62, 95% CI 0.41-0.95) showed an inverse association with HPV clearance, while illicit drug use (aHR = 3.24, 95% CI 1.59-6.59) showed a positive association. CONCLUSION: Anal HPV infection and clearance were both active in men with HIV in China. Marriage status and sexuality were associated with the incidence of HPV infection, while substance use including alcohol and illicit drug were associated with HPV clearance. More studies are needed to explore the risk factors of HPV persistence.

Nuclear receptor RXRα binds the precursor of miR-103 to inhibit its maturation.

BACKGROUND: The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute -mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known. RESULTS: In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer. CONCLUSIONS: Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.

The impact of sport-specific physical fitness change patterns on lower limb non-contact injury risk in youth female basketball players: a pilot study based on field testing and machine learning.

Background: In recent years, identifying players with injury risk through physical fitness assessment has become a hot topic in sports science research. Although practitioners have conducted many studies on the relationship between physical fitness and the likelihood of injury, the relationship between the two remains indeterminate. Consequently, this study utilized machine learning to preliminary investigate the relationship between individual physical fitness tests and injury risk, aiming to identify whether patterns of physical fitness change have an impact on injury risk. Methods: This study conducted a retrospective analysis by extracting the records of 17 young female basketball players from the sport-specific physical fitness monitoring and injury registration database in Fujian Province. Sports-specific physical fitness tests included physical performance, physiological, biochemical, and subjective perceived responses. The data for each player was standardized individually using Z-scores. Synthetic minority over-sampling techniques and edited nearest neighbor algorithms were used to sample the training set to address the negative impact of class imbalance on model performance. Feature extraction was performed on the dataset using linear discriminant analysis, and the prediction model was constructed using the cost-sensitive neural network. Results: The 10 replicate 5-fold stratified cross-validation showed that the lower limb non-contact injury prediction model based on the cost-sensitive neural network had achieved good discrimination and calibration (average Precision: 0.6360; average Recall: 0.8700; average F2-Score: 0.7980; average AUC: 0.8590; average Brier-score: 0.1020), which could be well applied in training practice. According to the attribution analysis, agility and speed were important physical attributes that affect youth female basketball players' non-contact lower limb injury risk. Specifically, there was enhance in the performance of the 1-min double under, accompanied by an increase in urinary ketone and urinary blood levels following the agility test. The 3/4 basketball court sprint performance improved, while urinary protein and RPE levels decreased after the speed test. Conclusion: The sport-specific physical fitness change pattern can impact the lower limb non-contact injury risk of young female basketball players in Fujian Province, specifically in terms of agility and speed. These findings will provide valuable insights for planning athletes' physical training programs, managing fatigue, and preventing injuries.

A novel approach for sports injury risk prediction: based on time-series image encoding and deep learning.

The rapid development of big data technology and artificial intelligence has provided a new perspective on sports injury prevention. Although data-driven algorithms have achieved some valuable results in the field of sports injury risk assessment, the lack of sufficient generalization of models and the inability to automate feature extraction have made it challenging to deploy research results in the real world. Therefore, this study attempts to build an injury risk prediction model using a combination of time-series image encoding and deep learning algorithms to address this issue better. This study used the time-series image encoding approach for feature construction to represent relationships between values at different moments, including Gramian Angular Summation Field (GASF), Gramian Angular Difference Field (GADF), Markov Transition Field (MTF), and Recurrence Plot (RP). Deep Convolutional Auto-Encoder (DCAE) learned the image-encoded data for representation to obtain features with good discrimination, and the classifier was performed using Deep Neural Network (DNN). The results from five repeated experiments show that the GASF-DCAE-DNN model is overall better in the training (AUC: 0.985 ± 0.001, Gmean: 0.930 ± 0.007, Sensitivity: 0.997 ± 0.003, Specificity: 0.868 ± 0.013) and test sets (AUC: 0.891 ± 0.026, Gmean: 0.830 ± 0.027, Sensitivity: 0.816 ± 0.039, Specificity: 0.845 ± 0.022), with good discriminative power, robustness, and generalization ability. Compared with the best model reported in the literature, the AUC, Gmean, Sensitivity, and Specificity of the GASF-DCAE-DNN model were higher by 23.9%, 27.5%, 39.7%, and 16.2%, respectively, which confirmed the validity and practicability of the model in injury risk prediction. In addition, differences in injury risk patterns between the training and test sets were identified through shapley additivity interpretation. It was also found that the training volume was an essential factor that affected injury risk prediction. The model proposed in this study provides a powerful injury risk prediction tool for future sports injury prevention practice.

Automatic Multichannel Electrocardiogram Record Classification Using XGBoost Fusion Model.

There is an increasing demand for automatic classification of standard 12-lead electrocardiogram signals in the medical field. Considering that different channels and temporal segments of a feature map extracted from the 12-lead electrocardiogram record contribute differently to cardiac arrhythmia detection, and to the classification performance, we propose a 12-lead electrocardiogram signal automatic classification model based on model fusion (CBi-DF-XGBoost) to focus on representative features along both the spatial and temporal axes. The algorithm extracts local features through a convolutional neural network and then extracts temporal features through bi-directional long short-term memory. Finally, eXtreme Gradient Boosting (XGBoost) is used to fuse the 12-lead models and domain-specific features to obtain the classification results. The 5-fold cross-validation results show that in classifying nine categories of electrocardiogram signals, the macro-average accuracy of the fusion model is 0.968, the macro-average recall rate is 0.814, the macro-average precision is 0.857, the macro-average F1 score is 0.825, and the micro-average area under the curve is 0.919. Similar experiments with some common network structures and other advanced electrocardiogram classification algorithms show that the proposed model performs favourably against other counterparts in F1 score. We also conducted ablation studies to verify the effect of the complementary information from the 12 leads and the auxiliary information of domain-specific features on the classification performance of the model. We demonstrated the feasibility and effectiveness of the XGBoost-based fusion model to classify 12-lead electrocardiogram records into nine common heart rhythms. These findings may have clinical importance for the early diagnosis of arrhythmia and incite further research. In addition, the proposed multichannel feature fusion algorithm can be applied to other similar physiological signal analyses and processing.

Increased CD4+ T cell count is associated with lower anal human papillomavirus prevalence among HIV-positive male cohort in Taizhou, China: a cross-sectional study.

OBJECTIVES: This study aims to investigate the association between CD4+ T cell count and combined antiretroviral therapy (cART) with the prevalence of anal human papillomavirus (HPV) infection among HIV-positive male cohort in China. METHODS: A survey was conducted in men from a HIV cohort in Taizhou, China between 2016 and 2019. A face-to-face questionnaire interview was administered, and an anal-canal swab was collected for HPV genotyping. RESULTS: A total of 766 HIV-positive men were recruited. The HPV prevalence was lower among those with increased CD4+ T cell count than those with decreased or unchanged (46.5 vs. 56.6%, p = 0.033) from baseline. In multivariable models, having the current CD4+ T cell count of 350-499 cells/µL (aOR 0.28, 95% CI 0.13-0.64), and of ≥ 500 cells/µL (aOR 0.26, 95% CI 0.11-0.60) were associated with lower prevalence of any type HPV infection compared with those with < 200 cells/µL. Having taken NVP + 3TC + AZT was inversely associated with any high-risk (HR)-HPV (aOR 0.47, 95% CI 0.25-0.90) and any low-risk (LR)-HPV infection (aOR 0.40, 95% CI 0.18-0.88), compared with those taking EFV + 3TC + TDF. CONCLUSIONS: Increased CD4+ T cell count at follow-up was significantly associated with lower prevalence of anal HPV infection. Inverse associations between NVP + 3TC + AZT and HR-HPV or LR-HPV infecton were observed.

Merbromin is a mixed-type inhibitor of 3-chyomotrypsin like protease of SARS-CoV-2.

3-chyomotrypsin like protease (3CLpro) has been considered as a promising target for developing anti-SARS-CoV-2 drugs. Herein, about 6000 compounds were analyzed by high-throughput screening using enzyme activity model, and Merbromin, an antibacterial agent, was identified as a potent inhibitor of 3CLpro. Merbromin strongly inhibited the proteolytic activity of 3CLpro but not the other three proteases Proteinase K, Trypsin and Papain. Michaelis-Menten kinetic analysis showed that Merbromin was a mixed-type inhibitor of 3CLpro, due to its ability of increasing the KM and decreasing the Kcat of 3CLpro. The binding assays and molecular docking suggested that 3CLpro possessed two binding sites for Merbromin. Consistently, Merbromin showed a weak binding to the other three proteases. Together, these findings demonstrated that Merbromin is a selective inhibitor of 3CLpro and provided a scaffold to design effective inhibitors of SARS-CoV-2.

Threat-relevant stimuli cannot be better detected by preschoolers in an inattentional blindness task.

Detecting the unexpected threat-relevant stimuli plays a vital role in preschoolers' daily life safety, but a few studies have investigated how preschoolers process this kind of stimuli. We applied a classical inattentional blindness task (designed by Mack and Rock Inattentional blindness. MIT Press, 1998) to explore whether threat-relevant stimuli could be better detected in an inattentional condition and whether the age and the fluid intelligence could predict the incidence of the detection. With the involvement of two hundred and thirty-nine preschoolers (aged from 4 to 6 years), we found that it was not more likely for preschoolers to detect the threat-relevant stimuli (Knife and Snake) compared with the non-threat-relevant stimuli (Spoon and Snail). The age difference of detection only occurred in the divided attentional condition, but not in the inattentional condition. Moreover, the group of 5-year-old preschoolers with higher fluid intelligence scores was more likely to detect the unexpected stimuli, but the prediction was not powerful. These findings demonstrate that the threat-superiority effect on IB does not occur on preschoolers and the individual difference of preschoolers' IB is unstable. This study enriches the cognition of young children's attentional bias to threat-relevant stimuli, and has certain significance to understand the essence of children's attentional process.

Diagnostic and Categorization Criteria for Palpitations Below the Heart in Traditional Chinese Medicine: A Delphi Consensus Study.

OBJECTIVES: To explore and establish the diagnosis, syndrome classification and syndrome differentiation criteria of palpitations below the heart in traditional Chinese medicine (TCM) in order to lay a foundation for the clinical diagnosis, treatment and research of palpitations below the heart. METHODS: In the early stage of this study, we searched the literature related to palpitations below the heart in TCM in domestic and foreign databases, analyzed the results and developed an expert consultation questionnaire. Using the Delphi method, a survey was conducted by 19 expert TCM practitioners. The survey results were statistically analyzed, aggregated and categorized to create the next round of questionnaires, and the process was repeated was repeated for a total of 4 rounds of expert opinions and until a consensus was achieved. Finally, the questionnaire items were classified into the main diagnosis (primary disease) and secondary diagnosis (secondary disease) for each syndrome. RESULTS: This study was completed ahead of schedule after 2 rounds of expert questionnaire surveys. A total of 19 exceptional TCM experts from all over China reached a consensus on 1 diagnostic standard and 4 syndrome types. The main diagnoses of palpitations below the heart included "conscious sub cardiac epigastric beating," "throbbing at the lower part of the heart" and "palpitation rhythm consistent with the pulse and obvious pulsation in the heart area," while the secondary diagnosis was "palpitation obvious after nervous tension, fatigue, drinking water or changing body position." Based on the balance of TCM Yin (negative, dark, feminine) and Yang (positive, bright, masculine) energy, TCM syndrome differentiation (Bian Zheng - the comprehensive analysis of clinical information obtained from the 4 main diagnostic TCM procedures: observation, listening, questioning, and pulse analysis, that is used to guide the choice of treatment by acupuncture and/or TCM) of palpitations below the heart are differentiated as heart yang deficiency syndrome, middle yang deficiency syndrome, kidney yang deficiency syndrome and phlegm drink syndrome, and the main and secondary syndromes of each are established. In the consultation process, the expert opinions were highly correlated, questionnaire reliability was strong and the results were credible. CONCLUSIONS: The criteria proposed in this study do not claim to be the best or the most accurate, but they do provide some guidelines for practitioners, a basis for clinical differentiation and treatment with TCM and a basis for further randomized controlled trials in the future. Further research is needed in order to reach a consensus regarding TCM treatment of palpitations below the heart.

Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability.

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.

Gut microbiota in children with juvenile idiopathic arthritis: characteristics, biomarker identification, and usefulness in clinical prediction.

BACKGROUND: Recent studies have suggested that the gut microbiota is altered in children with juvenile idiopathic arthritis (JIA). However, age, sex, and body mass index (BMI) were not matched in the previous studies, and the results are inconsistent. We conducted an age-, sex-, and BMI-matched cross-sectional study to characterize the gut microbiota in children with JIA, and evaluate its potential in clinical prediction. METHODS: A total of 40 patients with JIA and 42 healthy controls, ranging from 1 to 16 years, were enrolled in this study. Fecal samples were collected for 16S rDNA sequencing. The data were analyzed using QIIME software and R packages. Specifically, the random forest model was used to identify biomarkers, and the receiver operating characteristic curve and the decision curve analysis were used to evaluate model performance. RESULTS: A total of 39 fecal samples from patients with JIA, and 42 fecal samples from healthy controls were sequenced successfully. The Chao 1 and Shannon-Wiener index in the JIA group were significantly lower than those in the control group, and the Bray-Curtis dissimilarity also differed significantly between the two groups. The relative abundance of 4 genera, Anaerostipes, Dialister, Lachnospira, and Roseburia, decreased significantly in the JIA group compared to those in the control group. The 4 genera included microbes that produce short-chain fatty acids (SCFAs) and were negatively correlated with some rheumatic indices. Moreover, 12 genera were identified as potential biomarkers by using the nested cross-validation function of the random forest. A random forest model constructed using these genera was able to differentiate the patients with JIA from the healthy controls, and the area under the receiver operating characteristic curve was 0.7975. The decision curve analysis indicated that the model had usefulness in clinical practice. CONCLUSIONS: The gut microbiota in patients with JIA is altered and characterized by a decreased abundance of 4 SCFA-producing genera. The decreases in the 4 genera correlated with more serious clinical indices. Twelve genera could be used as biomarkers and predictors in clinical practice. TRIAL REGISTRATION: The study is registered online at the Chinese Clinical Trial Registry on 11 May 2018 (registration number: ChiCTR1800016110).

Low expression of miR-99b promotes progression of clear cell renal cell carcinoma by up-regulating IGF1R/Akt/mTOR signaling.

OBJECTIVE: Dysfunctions of microRNAs have been implicated in the progression of clear cell renal cell carcinoma (ccRCC). Here, we investigated the roles of miR-99b and miR-99b* in ccRCC development. METHODS: The expression levels of miR-99b and miR-99b* in tumor and tumor-adjacent tissues from ccRCC patients were quantified by quantitative Real-Time PCR (qRT-PCR). MicroRNA mimics and inhibitors were employed to evaluate the functions of miR-99b and miR-99b*. The effects of miR-99b on the proliferation and migration of ccRCC cells were analyzed by MTT and wound-healing assays, respectively. The effect of miR-99b on the expression of its target gene IGF1R and mTOR was determined by western blotting and qRT-PCR. RESULTS: The abundances of miR-99b and miR-99b* were lower in ccRCC tissues than in the tumor-adjacent tissues from patients. Similarly, the expression of these two microRNAs was higher in the normal kidney HK-2 cells than in the ccRCC cell lines. Moreover, miR-99b and miR-99b* inhibited the proliferation and migration of ccRCC cells. MiR-99b was found to down-regulate IGF1R and mTOR expression, likely through targeting their mRNAs to induce degradation. Consistently, the mRNA levels of IGF1R and mTOR were higher in ccRCC tissues than in the tumor-adjacent tissues, and Akt, a downstream factor of IGF1R, was highly activated correspondingly in ccRCC tissues. CONCLUSION: The low expression of miR-99b and miR-99b* contributes to ccRCC development and miR-99b acts as an onco-suppressor by suppressing IGF1R and mTOR expression to down-regulate IGF1R/AKT/mTOR signaling.

Association Study Between Methylation in the Promoter Regions of cGAS, MAVS, and TRAF3 Genes and the Risk of Cervical Precancerous Lesions and Cervical Cancer in a Southern Chinese Population.

A case-control study was used to explore the association between the methylation status in the promoter regions of the cGAS, MAVS, and TRAF3 genes and the diseases of cervical precancerous lesions (CPL) and cervical cancer (CC) in a Southern Chinese population, and to further explore their interaction effects with high-risk human papillomavirus (hrHPV) infection and environmental factors in these diseases. The study protocol was approved by the ethics committee of The First Affiliated Hospital of Jinan University, and this study was performed in 97 healthy controls, 75 patients with CPL and 33 patients with CC, while each participant has read and signed the informed consent forms before enrolment. The promoter methylation status genes were detected from the bisulfite-treated DNA by the bisulfite sequencing PCR (BSP) technique, which was carried out using MethPrimer. The cGAS, MAVS, and TRAF3 promoter methylation levels in CPL (CPL cGAS = 35.40%, CPL MAVS = 24.26%, and CPL TRAF3 = 96.76%) were significantly higher than those in the control (Control cGAS = 31.87%, Control MAVS = 21.16%, and Control TRAF3 = 96.26%, PcGAS < 0.001, PMAVS < 0.001, and PTRAF3 = 0.001); however, there was no significant differences between the CC and control. In the logistic regression model with adjusted covariates, compared with the individuals whose cGAS methylation levels were less than or equal to 31.87%, the women with the levels more than 31.87% increased the risk of CPL by 2.49 times (ORa = 2.49, 95% CI = 1.31-4.75, P a = 0.006). The women with MAVS methylation levels above 21.16% were 1.97 times more likely to have CPL than the those with the levels less than 21.16% (ORa = 1.97, 95% CI = 1.06-3.69, P a = 0.033). A synergistic interaction was found between hrHPV and gene promoter methylation levels of cGAS and MAVS in CPL; however, no potential interaction was observed in CC. The promoter methylation levels in cGAS, MAVS, and TRAF3 genes are higher in CPL than in control, indicating that hypermethylation might be an early event in the progression of cervical intraepithelial neoplasia (CIN). The interaction between the promoter methylation levels in cGAS and MAVS genes and hrHPV infection might play a role in the development of CPL.

The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING.

Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Stinggt/gt mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Stinggt/gt mice was significantly impaired. Stinggt/gt mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently, GRA15-/-T. gondii was more virulent and caused higher mortality of WT mice but not Stinggt/gt mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.

A randomized controlled trial of a mobile application-assisted nurse-led model used to improve treatment outcomes in children with asthma.

AIM: To evaluate the effectiveness of a mobile application-assisted nurse-led management model in childhood asthma. BACKGROUND: Studies have shown that a nurse-led asthma management model can improve asthma outcomes. However, the role of a mobile application-assisted nurse-led model in paediatric asthma management has not been studied well. DESIGN: A multi-centre randomized clinical trial. METHODS: The trial was conducted between March 2017-March 2018. A total of 152 children (6 to 11.9 years old) were enrolled, with 77 children in the experimental group and 75 in the control group. All children received nurse-led asthma management and other routine treatment measures, including inhaled corticosteroids. Meanwhile, a mobile application was used to manage asthma only for children in the experimental group. Primary outcome was frequency of asthma exacerbations. All outcomes were evaluated twice a month for 12 months. RESULTS: Compared with the pre-enrollment period, frequency of asthma exacerbations decreased in the post-enrollment period in the two groups, with a greater decrease in the experimental group. Compared with children in the control group, children in the experimental group had better secondary outcomes, such as improved adherence, higher Childhood Asthma Control Test scores, decreased respiratory tract infections, days of antibiotic use, days of school absence, parental work loss, and medical expenses. CONCLUSION: A mobile application-assisted nurse-led management model decreased asthma exacerbations and improved secondary outcomes in children with asthma. Further research is needed to verify its validity in larger population samples. IMPACT: Children with asthma benefited from a nurse-led asthma management model when combined with mobile application. This trial suggested that computer and Internet technologies should be incorporated into nurse-led asthma strategy in paediatric asthma management. TRIAL REGISTRATION: The current trial was registered online with the Chinese Clinical Trial Registry (registration number: ChiCTR1800016726).

Oncogenic potential of truncated RXRα during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling.

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.

Toxoplasma gondii Cathepsin C1 inhibits NF-κB signalling through the positive regulation of the HIF-1α/EPO axis.

Toxoplasma gondii has evolved many successful strategies for immune evasion. However, the parasite-derived effectors involved in modulating NF-κB signalling pathway are largely unknown. T. gondii Cathepsin C1 (CPC1) is widely conserved among T. gondii strains and is important for T. gondii intracellular growth and proliferation. Our study showed that CPC1 protein could abrogate NF-κB activation after screening dense granule proteins. CPC1 suppressed NF-κB activation at or downstream of p65 and decreased the production of IL-1, IL-8, IL-6, IL-12, and TNF-α. Western blot analysis revealed that CPC1 inhibited phospho-p65 and CPC1 proteins primarily settled in cytoplasm. RNA sequencing analysis revealed that overexpression of CPC1 significantly upregulated erythropoietin (EPO), which can be induced by the hypoxia-inducible factor -1α (HIF-1α) during hypoxia. Furthermore, dual-luciferase reporter assays confirmed that CPC1 upregulated HIF-1α. Finally, both the knockdown of EPO and restriction of HIF-1α partially eliminated the suppression impact of CPC1 on the NF-κB signalling pathway. Our study identified a previously unrecognized role of CPC1 in the negative regulation of NF-κB activation through positive regulation of the HIF-1α/EPO axis. For the first time, CPC1 was shown to play an important role in immune evasion during T. gondii infection.