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Abstract Zero-shot stance detection is pivotal for autonomously discerning user stances on novel emerging topics. This task hinges on effective feature alignment transfer from known to unseen targets. To address this, we introduce a zero-shot stance detection framework utilizing multi-expert cooperative learning. This framework comprises two core components: a multi-expert feature extraction module and a gating mechanism for stance feature selection. Our approach involves a unique learning strategy tailored to decompose complex semantic features. This strategy harnesses the expertise of multiple specialists to unravel and learn diverse, intrinsic textual features, enhancing transferability. Furthermore, we employ a gating-based mechanism to selectively filter and fuse these intricate features, optimizing them for stance classification. Extensive experiments on standard benchmark datasets demonstrate that our model significantly surpasses existing baseline models in performance.

Abstract Macrophages play a pivotal role in the inflammatory response to the zoonotic pathogen E. coli, responsible for causing enteric infections. While considerable research has been conducted to comprehend the pathogenesis of this disease, scant attention devoted to host-derived H2S. Herein, we reported that E. coli infection enhanced the expression of CSE in macrophages, accompanied by a significantly increased inflammatory response. This process may be mediated by the involvement of excessive autophagy. Inhibition of AMPK or autophagy with pharmacological inhibitors could alleviate the inflammation. Additionally, cell model showed that the mRNA expression of classic inflammatory factors (Il-1β, Il-6), macrophage polarization markers (iNOS, Arg1) and ROS production was significantly down-regulated after employing CSE specific inhibitor PAG. And PAG is capable of inhibiting excessive autophagy through the LKB1-AMPK-ULK1 axis. Interestingly, exogenous H2S could suppress inflammation response. Our study emphasizes the importance of CSE in regulating the macrophage-mediated response to E. coli. Increased CSE in macrophages leads to excessive inflammation, which should be considered a new target for drug development to treat intestinal infection.

Abstract Previous research has demonstrated that ferredoxin 1 (FDX1) contributes to the accumulation of toxic lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and results in cuproptotic cell death. However, the role that FDX1 plays in human cancer prognosis and immunology is still not well understood. The original data was obtained from TCGA and GEO databases and integrated using R 4.1.0. The TIMER2.0, GEPIA, and BioGPS databases were used to explore FDX1 expression. The impact of FDX1 on prognosis was analyzed using the GEPIA and Kaplan–Meier Plotter databases. External validation will be performed using the PrognoScan database. FDX1 expression in different immune and molecular subtypes of human cancers was evaluated using the TISIDB database. The correlation between FDX1 expression and immune checkpoints (ICP), microsatellite instability (MSI), and tumor mutational burden (TMB) in human cancers was analyzed using R 4.1.0. The TIMER2.0 and GEPIA databases were used to study the relationship between FDX1 expression and tumor-infiltrating immune cells. With the c-BioPortal database, we investigated the genomic alterations of FDX1. Pathway analysis and assessment of the sensitivity potential of FDX1-related drugs were also performed. Using the UALCAN database, we analyzed the differential expression of FDX1 in KIRC (kidney renal clear cell carcinoma) with different clinical features. Coexpression networks of FDX1 were analyzed using LinkedOmics. In general, FDX1 was expressed differently in different types of cancer in humans. Expression of FDX1 was strongly correlated with patient prognosis, ICP, MSI, and TMB. FDX1 was also participated in immune regulation and the tumor microenvironment. Coexpression networks of FDX1 were primarily involved in oxidative phosphorylation regulation. Pathway analysis revealed that the expression of FDX1 was correlated to cancer-related and immune-related pathways. FDX1 has the potential to serve as a biomarker for pan-cancer prognosis and immunology, as well as a novel target for tumor therapy.

Knowledge graphs (KGs) have become a cornerstone for structuring vast amounts of information, enabling sophisticated AI applications across domains. The progression to temporal knowledge graphs (TKGs) introduces time as an essential dimension, allowing for a dynamic representation of entity relationships. Despite their potential, TKGs often suffer from incompleteness, necessitating the development of temporal knowledge graph completion (TKGC) techniques. These methods, particularly focusing on interpolation within the known timeframe, aim to infer missing temporal facts and enhance the predictive capabilities of TKGs. The prevalent reliance on Euclidean space modeling in TKGC methods presents challenges in capturing the complex, hierarchical, and time-varying nature of TKGs. To overcome these limitations, we introduced the attention-based geometry interaction embedding (ATGIE) method, a novel approach that leverages the strengths of multiple geometric spaces, i.e., Euclidean, hyperbolic, and hypersphere, to model the intricacies of TKGs more effectively. ATGIE employs an attention mechanism to dynamically weigh the contributions of different geometric spaces, allowing it to adaptively form reliable spatial structures based on interactive geometric information. This multi-space modeling not only captures the diverse relationships within TKGs but also facilitates a nuanced understanding of how entities and their relationships evolve over time. Through extensive experiments, we demonstrate ATGIE’s superiority in TKGC tasks, showcasing its improvement over existing methods, robustness to noise, and sensitivity to temporal dynamics. The results highlight ATGIE’s potential to advance the state-of-the-art in TKGC, offering a promising direction for research and application in the field.

Abstract Background Post-stroke depression (PSD) can be conceptualized as a complex network where PSD symptoms (PSDS) interact with each other. The neural mechanism of PSD and interactions among PSDS remain to be elucidated. This study aimed to investigate the neuroanatomical substrates of, as well as the interactions between, individual PSDS to better understand the pathogenesis of early-onset PSD. Methods A total of 861 first-ever stroke patients admitted within 7 days poststroke were consecutively recruited from three independent hospitals in China. Sociodemographic, clinical and neuroimaging data were collected upon admission. PSDS assessment with Hamilton Depression Rating Scale was performed at 2 weeks after stroke. Thirteen PSDS were included to develop a psychopathological network in which central symptoms (i.e. symptoms most strongly correlated with other PSDS) were identified. Voxel-based lesion-symptom mapping (VLSM) was performed to uncover the lesion locations associated with overall PSDS severity and severities of individual PSDS, in order to test the hypothesis that strategic lesion locations for central symptoms could significantly contribute to higher overall PSDS severity. Results Depressed mood, Psychiatric anxiety and Loss of interest in work and activities were identified as central PSDS at the early stage of stroke in our relatively stable PSDS network. Lesions in bilateral (especially the right) basal ganglia and capsular regions were found significantly associated with higher overall PSDS severity. Most of the above regions were also correlated with higher severities of 3 central PSDS. The other 10 PSDS could not be mapped to any certain brain region. Conclusions There are stable interactions among early-onset PSDS with Depressed mood, Psychiatric anxiety and Loss of interest as central symptoms. The strategic lesion locations for central symptoms may indirectly induce other PSDS via the symptom network, resulting in higher overall PSDS severity. Trial registration URL: http://www.chictr.org.cn/enIndex.aspx ; Unique identifier: ChiCTR-ROC-17013993.

Staphylococcus aureus can survive within phagocytes. Indeed, we confirm in this study that approximately 10% of population persists in macrophages during S. aureus infection, while the rest are eliminated due to bacteriolysis, which is of particular interest to us. Herein, we observe that the bacteriolysis is an early event accompanied by macrophage death during S. aureus infection. Furthermore, the cell death is significantly accelerated following increased intracellular bacteriolysis, indicating that intracellular bacteriolysis induces cell death. Subsequently, we establish that the cell death is not apoptosis or pyroptosis, but AIM2-mediated necroptosis, accompanied by AIM2 inflammasome activation. This finding challenges the classical model that the cell death that accompanies inflammasome activation is always pyroptosis. In addition, we observe that the apoptosis-associated genes are highly inhibited during S. aureus infection. Finally, we establish in vivo that increased bacteriolysis significantly enhances S. aureus pathogenicity by promoting its dissemination to kidney and leading to an inflammatory cytokine storm in AIM2-mediated manner. Collectively, our data demonstrate that bacteriolysis is detrimental when triggered in excess and its side effect is mediated by AIM2. Meanwhile, we propose a potential immune manipulation strategy by which S. aureus sacrifices the minority to trigger a limited necroptosis, thereby releasing signals from dead cells to inhibit apoptosis and other anti-inflammatory cascades of live cells, eventually surviving within host cells and establishing infection.

Abstract Background Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. The occurrence, development and prognosis of PSD have long been different between males and females. The main purpose of this study was to explore the influencing factors of PSD at 3 months in males and females, and construct random forest (RF) models to rank the influencing factors. Methods This is a prospective multicenter cohort study (Registration number: ChiCTR-ROC-17013993). Stroke patients hospitalized in the department of Neurology of three hospitals in Wuhan were enrolled from May 2018 to August 2019. Scale assessments were performed 24 hours after admission and 3 months after stroke onset. Binary logistic regression analysis was used for univariate and multivariate (stepwise backward method) analysis, when p was less than 0.05, the difference between groups was considered statistically significant. Lastly, the RF models were constructed according to the results of multivariate regression analysis. Results This study found that several baseline variables were associated with PSD at 3 months in males and females. RF model ranked them as stroke severity (OR [odds ratio] =1.17, p

Abstract Poststroke depression (PSD) is a common complication of stroke. Brain network disruptions caused by stroke are potential biological determinants of PSD but their conclusive roles are unavailable. Our study aimed to identify the strategic structural disconnection (SDC) pattern for PSD at three months poststroke and assess the predictive value of SDC information. Our prospective cohort of 697 first-ever acute ischemic stroke patients were recruited from three hospitals in central China. Sociodemographic, clinical, psychological and neuroimaging data were collected at baseline and depression status was assessed at three months poststroke. Voxel-based disconnection-symptom mapping found that SDCs involving bilateral temporal white matter and posterior corpus callosum, as well as white matter next to bilateral prefrontal cortex and posterior parietal cortex, were associated with PSD. This PSD-specific SDC pattern was used to derive SDC scores for all participants. SDC score was an independent predictor of PSD after adjusting for all imaging and clinical-sociodemographic-psychological covariates (odds ratio, 1.25; 95% confidence interval, 1.07, 1.48; P = 0.006). Split-half replication showed the stability and generalizability of above results. When added to the clinical-sociodemographic-psychological prediction model, SDC score significantly improved the model performance and ranked the highest in terms of predictor importance. In conclusion, a strategic SDC pattern involving multiple lobes bilaterally is identified for PSD at 3 months poststroke. The SDC score is an independent predictor of PSD and may improve the predictive performance of the clinical-sociodemographic-psychological prediction model, providing new evidence for the brain-behavior mechanism and biopsychosocial theory of PSD.

Abstract Foamy macrophages containing prominent cytoplasmic lipid droplets (LDs) are found in a variety of infectious diseases. However, their role in Streptococcus uberis-induced mastitis is unknown. Herein, we report that S. uberis infection enhances the fatty acid synthesis pathway in macrophages, resulting in a sharp increase in LD levels, accompanied by a significantly enhanced inflammatory response. This process is mediated by the involvement of fatty acid binding protein 4 (FABP4), a subtype of the fatty acid-binding protein family that plays critical roles in metabolism and inflammation. In addition, FABP4 siRNA inhibitor cell models showed that the deposition of LDs decreased, and the mRNA expression of Tnf, Il1b and Il6 was significantly downregulated after gene silencing. As a result, the bacterial load in macrophages increased. Taken together, these data demonstrate that macrophage LD formation is a host-driven component of the immune response to S. uberis. FABP4 contributes to promoting inflammation via LDs, which should be considered a new target for drug development to treat infections.

Abstract Background Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. Studies on the underlying mechanisms and biological markers of sex differences in PSD are of great significance, but there are still few such studies. Therefore, the main objective of this study was to investigate the association of biomarkers with PSD at 3 months after minor stroke in men and women. Methods This was a prospective multicenter cohort study that enrolled 530 patients with minor stroke (males, 415; females, 115). Demographic information and blood samples of patients were collected within 24 h of admission, and followed up at 3 months after stroke onset. PSD was defined as a depressive disorder due to another medical condition with depressive features, major depressive-like episode, or mixed-mood features according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V). Univariate analysis was performed using the chi-square test, Mann–Whitney U test, or t-test. Partial least-squares discriminant analysis (PLS-DA) was used to distinguish between patients with and without PSD. Factors with variable importance for projection (VIP) > 1.0 were classified as the most important factors in the model segregation. Results The PLS-DA model mainly included component 1 and component 2 for males and females. For males, the model could explain 13% and 16.9% of the variables, respectively, and 29.9% of the variables in total; the most meaningful predictors were exercise habit and fibrinogen level. For females, the model could explain 15.7% and 10.5% of the variables, respectively, and 26.2% of the variables in total; the most meaningful predictors in the model were brain-derived neurotrophic factor (BDNF), magnesium and free T3. Fibrinogen was positively correlated with the Hamilton Depression Scale-17 items (HAMD-17) score. BDNF, magnesium, and free T3 levels were negatively correlated with the HAMD-17 score. Conclusions This was a prospective cohort study. The most important markers found to be affecting PSD at 3 months were fibrinogen in males, and free T3, magnesium, and BDNF in females. Trial registration ChiCTR-ROC-17013993 .

BackgroundPost-stroke depression (PSD) has been proven to be associated with stroke severity. Thus, we hypothesized that the prevalence of PSD would be lower in patients with mild stroke. We aim to explore predictors of depression at 3 months after mild acute ischemic stroke (MAIS) onset and to develop a practical and convenient prediction model for the early identification of patients at high risk.MethodsA total of 519 patients with MAIS were consecutively recruited from three hospitals in Wuhan city, Hubei province. MAIS was defined as a National Institute of Health Stroke Scale (NIHSS) score of ≤5 at admission. Meeting the DSM-V diagnostic criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) score of >7 at their 3-month follow-up were considered the primary outcomes. A multivariable logistic regression model was used to determine the factors adjusted for potential confounders, and all independent predictors were brought into the construction of a nomogram to predict PSD.ResultsThe prevalence of PSD is up to 32% at 3 months after MAIS onset. After adjusting for potential confounders, indirect bilirubin (p = 0.029), physical activity (p = 0.001), smoking (p = 0.025), hospitalization days (p = 0.014), neuroticism (p < 0.001), and MMSE (p < 0.001) remained independently and significantly related with PSD. The concordance index (C-index) of the nomogram jointly constructed by the aforementioned six factors was 0.723 (95% CI: 0.678–0.768).ConclusionThe prevalence of PSD seems equally high even if the ischemic stroke is mild, which calls for great concern from clinicians. In addition, our study found that a higher level of indirect bilirubin can lower the risk of PSD. This finding may provide a potential new approach to PSD treatment. Furthermore, the nomogram including bilirubin is convenient and practical to predict PSD after MAIS onset.

The balance between oxidation and antioxidant is crucial for maintaining homeostasis. Once disrupted, it can lead to various pathological outcomes and diseases, such as depression. Oxidative stress can result in or aggravate a battery of pathological processes including mitochondrial dysfunction, neuroinflammation, autophagical disorder and ferroptosis, which have been found to be involved in the development of depression. Inhibition of oxidative stress and related pathological processes can help improve depression. In this regard, the nuclear factor erythroid 2-related factor 2 (Nrf2) in the antioxidant defense system may play a pivotal role. Nrf2 activation can not only regulate the expression of a series of antioxidant genes that reduce oxidative stress and its damages, but also directly regulate the genes related to the above pathological processes to combat the corresponding alterations. Therefore, targeting Nrf2 has great potential for the treatment of depression. Activation of Nrf2 has antidepressant effect, but the specific mechanism remains to be elucidated. This article reviews the key role of Nrf2 in depression, focusing on the possible mechanisms of Nrf2 regulating oxidative stress and related pathological processes in depression treatment. Meanwhile, we summarize some natural and synthetic compounds targeting Nrf2 in depression therapy. All the above may provide new insights into targeting Nrf2 for the treatment of depression and provide a broad basis for clinical transformation.

ABSTRACT Klebsiella pneumoniae is an opportunistic pathogen that causes serious infections in humans and animals. However, the availability of epidemiological information on clinical mastitis due to K. pneumoniae is limited. To acquire new information regarding K. pneumoniae mastitis, data were mined about K. pneumoniae strains on dairy cattle farms (farms A to H) in 7 Chinese provinces in 2021. Hypermucoviscous strains of K. pneumoniae were obtained by the string test. MICs of antimicrobial agents were determined via the broth microdilution method. Ten antimicrobial resistance genes and virulence genes were identified by PCR. The prevalence of K. pneumoniae was 35.91% (65/181), and 100% of the bacteria were sensitive to enrofloxacin. Nine antimicrobial resistance genes and virulence genes were identified and compared among farms. The hypermucoviscous phenotype was present in 94.44% of isolates from farm B, which may be a function of the rmpA virulence gene. Based on these data, the multidrug-resistant strains SD-14 and HB-21 were chosen and sequenced. Genotypes were assayed for K. pneumoniae isolates from different countries and different hosts using multilocus sequence typing (MLST). Ninety-four sequence types (STs) were found, and 6 STs present a risk for spreading in specific regions. Interestingly, ST43 was observed in bovine isolates for the first time. Our study partially reveals the current distribution characteristics of bovine K. pneumoniae in China and may provide a theoretical basis for the prevention and treatment of bovine K. pneumoniae mastitis. IMPORTANCE K. pneumonia is ubiquitous in nature and infects a wide range of hosts, including animals, and humans. It is one of the leading inducements of clinical mastitis (CM) in dairy cows, a prevalent and costly disease that is predominantly associated with bacterial infection. In general, CM caused by Gram-negative bacteria is more difficult to cure than that associated with Gram-positive pathogens, with an average cost per case of 211.03 U.S. dollars (USD) for Gram-negative bacterial infections compared with 133.73 USD for Gram-positive bacterial CM cases. After Escherichia coli, K. pneumoniae is the second most common Gram-negative cause of bovine CM, but it is the most detrimental in terms of decreased milk yield, discarded milk, treatment costs, death, and culling. In view of the economic implications of K. pneumoniae infection in dairy farming, research into population structure and antibiotic resistance is particularly important.

Abstract Background Fasting C-peptide (FCP) has been shown to play an important role in the pathophysiology of mood disorders including depression and schizophrenia, but it is unknown whether it also predicts post-stroke depression (PSD). This study examined the association between FCP and PSD at 6 months after acute ischemic-stroke onset among Chinese subjects. Methods A total of 656 stroke patients were consecutively recruited from three hospitals of Wuhan city, Hubei province. Clinical and laboratory data were collected on admission. PSD status was evaluated by DSM-V criteria and 17-item Hamilton Rating Scale for Depression (HAMD-17) at 6 months after acute ischemic stroke. The χ2-test, Mann-Whitney U-test, and t-test were used to check for statistical significance. Multivariate logistic regression model was used to explore independent predictor of PSD. Results In the univariate analysis, significant differences were found between the PSD and non-PSD groups in terms of FCP level (p = 0.009). After multivariate adjustments, FCP remained a significant independent predictor of PSD, with an adjusted odds ratio of 1.179 (95%CI: 1.040–1.337, p = 0.010). Conclusions Higher FCP levels on admission were found to be associated with PSD at 6 months after acute ischemic-stroke onset. For stroke patients, doctors should pay attention to the baseline FCP for screening high-risk PSD in clinical practice.

Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the most prevalent neurodegenerative disease worldwide. The primary pathological hallmarks of AD are the deposition of β-amyloid plaques and neurofibrillary tangles. Autophagy, a pathway of clearing damaged organelles, macromolecular aggregates, and long-lived proteins via lysosomal degradation, has emerged as critical for proteostasis in the central nervous system (CNS). Studies have demonstrated that defective autophagy is strongly implicated in AD pathogenesis. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, enhances the expression of related genes that control autophagosome formation, lysosome function, and autophagic flux. The study of TFEB has greatly increased over the last decade, and the dysfunction of TFEB has been reported to be strongly associated with the pathogenesis of many neurodegenerative disorders, including AD. Here, we delineate the basic understanding of TFEB dysregulation involved in AD pathogenesis, highlighting the existing work that has been conducted on TFEB-mediated autophagy in neurons and other nonneuronal cells in the CNS. Additionally, we summarize the small molecule compounds that target TFEB-regulated autophagy involved in AD therapy. Our review may yield new insights into therapeutic approaches by targeting TFEB and provide a broadly applicable basis for the clinical treatment of AD.

Neutrophil extracellular traps (NETs) are produced by neutrophil activation and usually have both anti-infective and pro-damage effects. Streptococcus uberis (S. uberis), one of the common causative organisms of mastitis, can lead to the production of NETs. Taurine, a free amino acid abundant in the organism, has been shown to have immunomodulatory effects. In this study, we investigated the molecular mechanisms of S. uberis-induced NETs formation and the regulatory role of taurine. The results showed that NETs had a disruptive effect on mammary epithelial cells and barriers, but do not significantly inhibit the proliferation of S. uberis. S. uberis induced NADPH oxidase-dependent NETs. TLR2-mediated activation of the MAPK signaling pathway was involved in this process. Taurine could inhibit the activation of MAPK signaling pathway and NADPH oxidase by modulating the activity of TAK1, thereby inhibiting the production of ROS and NETs. The effects of taurine on NADPH oxidase and NETs in S. uberis infection were also demonstrated in vivo. These results suggest that taurine can protect mammary epithelial cells and barriers from damage by reducing S. uberis-induced NETs. These data provide new insights and strategies for the prevention and control of mastitis.

Abstract Background Exploring etiological clues to adolescent depression, especially in female adolescents, might be helpful to improve the social environment of female adolescents. The aim at this study is to explore psycho-social factors of female adolescents with high depressive symptomatology and gender differences in depressive symptoms among Chinese adolescents. Method We examined 4100 adolescents from Wuhan city and Jianli county via a cross-sectional study. Depressive symptomatology was screened through the Chinese version of Center for Epidemiology Studies Depression Scale. Multivariate logistic regression was performed to explore the factors related to high depressive symptomatology in female and male adolescents, respectively. Results The prevalence of high depressive symptomatology in female and male were 38.9 and 30.2% respectively. The psycho-social factors of high depressive symptomatology in female adolescents were age (Adjusted odds ratio [aOR] = 1.201, 95% confidence interval [CI], 1.076 ~ 1.341), single parent family (aOR = 2.004, 95%CI, 1.448 ~ 2.772) and fathers’ education level (compared to primary school and below, [Junior middle school, aOR = 0.641, 95%CI, 0.439 ~ 0.934; Senior middle school, aOR = 0.603, 95%CI, 0.410 ~ 0.888; College degree and above, aOR = 0.639, 95%CI, 0.437 ~ 0.936]). Conclusion Fathers’ education level was associated with high depressive symptomatology in female adolescents. Female adolescents whose father with primary school education or below deserves more attention. Further epidemiologic researches need to be conducted to explore the different risk factors between female and male adolescents in China.

Abstract Background For large hemispheric infarction (LHI), malignant cerebral edema (MCE) is a life-threatening complication with a mortality rate approaching 80%. Establishing a convenient prediction model of MCE after LHI is vital for the rapid identification of high-risk patients as well as for a better understanding of the potential mechanism underlying MCE. Methods One hundred forty-two consecutive patients with LHI within 24 h of onset between January 1, 2016 and August 31, 2019 were retrospectively reviewed. MCE was defined as patient death or received decompressive hemicraniectomy (DHC) with obvious mass effect (≥ 5 mm midline shift or Basal cistern effacement). Binary logistic regression was performed to identify independent predictors of MCE. Independent prognostic factors were incorporated to build a dynamic nomogram for MCE prediction. Results After adjusting for confounders, four independent factors were identified, including previously known atrial fibrillation (KAF), midline shift (MLS), National Institutes of Health Stroke Scale (NIHSS) and anterior cerebral artery (ACA) territory involvement. To facilitate the nomogram use for clinicians, we used the “Dynnom” package to build a dynamic MANA (acronym for MLS, ACA territory involvement, NIHSS and KAF) nomogram on web ( http://www.MANA-nom.com ) to calculate the exact probability of developing MCE. The MANA nomogram’s C-statistic was up to 0.887 ± 0.041 and the AUC-ROC value in this cohort was 0.887 (95%CI, 0.828 ~ 0.934). Conclusions Independent MCE predictors included KAF, MLS, NIHSS, and ACA territory involvement. The dynamic MANA nomogram is a convenient, practical and effective clinical decision-making tool for predicting MCE after LHI in Chinese patients.

Abstract Background The prognosis of patients with advanced schistosomiasis is poor. Pre-existing prognosis studies did not differentiate the causes of the deaths. The objectives were to evaluate the 2-year overall survival (OS) and advanced schistosomiasis-specific survival (ASS) in patients with advanced schistosomiasis after discharge through competing risk analysis and to build predictive nomograms. Methods Data was extracted from a previously constructed database from Hubei province. Patients were enrolled from September 2014 to January 2015, with follow up to January 2017. OS and ASS were primary outcome measures. Nomograms for estimating 2-year OS and ASS rates after discharge were established based on univariate and multivariate Cox regression model and Fine and Gray’s model. Their predictive performances were evaluated using C-index and validated in both internal and external validation cohorts. Results The training cohort included 1487 patients with advanced schistosomiasis. Two-year mortality rate of the training cohort was 8.27% (123/1487). Competing events accounted for 26.83% (33/123). Older age, splemomegaly clinical classification, abnormal serum DBil, AST, ALP and positive HBsAg were significantly associated with 2-year OS. Older age, splemomegaly clinical classification, abnormal serum AST, ALP and positive HBsAg were significantly associated with 2-year ASS. The established nomograms were well calibrated, and had good discriminative ability, with a C-index of 0.813 (95% CI 0.803–0.823) for 2-year OS prediction and 0.834 (95% CI 0.824–0.844) for 2-year ASS prediction. Their predictive performances were well validated in both internal and external validation cohorts. Conclusion The effective predictors of 2-year OS and ASS were discovered through competing risk analysis. The nomograms could be used as convenient predictive tools in clinical practice to guide follow-up and aid accurate prognostic assessment.

Poststroke depression (PSD), affecting about one-third of stroke survivors, exerts significant impact on patients’ functional outcome and mortality. Great efforts have been made since the 1970s to unravel the neuroanatomical substrate and the brain-behavior mechanism of PSD. Thanks to advances in neuroimaging and computational neuroscience in the past two decades, new techniques for uncovering the neural basis of symptoms or behavioral deficits caused by focal brain damage have been emerging. From the time of lesion analysis to the era of brain networks, our knowledge and understanding of the neural substrates for PSD are increasing. Pooled evidence from traditional lesion analysis, univariate or multivariate lesion-symptom mapping, regional structural and functional analyses, direct or indirect connectome analysis, and neuromodulation clinical trials for PSD, to some extent, echoes the frontal-limbic theory of depression. The neural substrates of PSD may be used for risk stratification and personalized therapeutic target identification in the future. In this review, we provide an update on the recent advances about the neural basis of PSD with the clinical implications and trends of methodology as the main features of interest.

Abstract Background China has experienced rapid socioeconomic, and health transitions over the last four decades, and urban–rural disparities are becoming increasingly apparent. Research on depression among rural and urban students can provide evidence on the relationship between sociodemographic characteristics and adolescent depression. Methods We examined the association between sociodemographic characteristics and adolescent depression among 3605 students from Wuhan city and Jianli county that was recruited from the local junior middle school via a cross-sectional study. Univariate and multivariate logistic regression models were used to explore the sociodemographic characteristics of adolescent depression in urban and rural areas, respectively. Nomograms were constructed to calculate individual depression risk of junior middle school students. Results 32.47% of rural students and 35.11% of urban students display depressive symptoms. The protective factors of depression in urban students are exercise habit, younger, key class, better academic achievement and males, while Left-behind children (LBC), poor academic achievement and females had higher depression risk in rural area. Two nomograms were constructed to screen the adolescent depression in urban and rural junior middle school students, respectively. The clinical tools were well calibrated. Conclusion The field-based research examined sociodemographic characteristics potentially associated with adolescent depression and offered an effective and convenient tool of individualized depression risk evaluation for junior middle school students. Future longitudinal epidemiologic research on adolescent depression may help to further validate the discovery of present study, which will support developing policies and practices to minimize the factors of adolescent depression.

Abstract Background Large hemispheric infarction (LHI) is a severe form of stroke with high mortality and disability rates. The purpose of this study was to explore predictive indicators of the in-hospital mortality of LHI patients treated conservatively without decompressive hemicraniectomy. Method We performed a retrospective study of 187 consecutive patients with LHI between January 1, 2016 to May 31, 2019. The receiver operating curves were preformed to evaluate predictive performance of demographics factors, biomarkers and radiologic characteristics. Significant prognostic factors were combined to build a nomogram to predict the risk of in-hospital death of individual patients. Result One hundred fifty-eight patients with LHI were finally enrolled, 58 of which died. Through multivariate logistic regression analysis, we identified that independent prognostic factors for in-hospital death were age (adjusted odds ratio [aOR] = 1.066; 95% confidence interval [CI], 1.025–1.108; P = 0.001), midline shift (MLS, aOR = 1.330, 95% CI, 1.177–1.503; P

Abstract The function of Autoinducer-2 (AI-2) which acts as the signal molecule of LuxS-mediated quorum sensing, is regulated through the lsr operon (which includes eight genes: lsrK, lsrR, lsrA, lsrC, lsrD, lsrB, lsrF, and lsrG). However, the functions of the lsr operon remain unclear in avian pathogenic Escherichia coli (APEC), which causes severe respiratory and systemic diseases in poultry. In this study, the presence of the lsr operon in 60 APEC clinical strains (serotypes O1, O2, and O78) was investigated and found to be correlated with serotype and has the highest detection rate in O78. The AI-2 binding capacity of recombinant protein LsrB of APEC (APEC-LsrB) was verified and was found to bind to AI-2 in vitro. In addition, the lsr operon was mutated in an APEC strain (APEC94Δlsr(Cm)) and the mutant was found to be defective in motility and AI-2 uptake. Furthermore, deletion of the lsr operon attenuated the virulence of APEC, with the LD50 of APEC94Δlsr(Cm) decreasing 294-fold compared with wild-type strain APEC94. The bacterial load in the blood, liver, spleen, and kidneys of ducks infected with APEC94Δlsr(Cm) decreased significantly (p

To date, no risk prediction tools have been developed to identify high mortality risk of patients with advanced schistosomiasis within 2 years after discharge. We aim to derive and validate a risk prediction model to be applied in clinical practice. The risk prediction model was derived from 1487 patients from Jingzhou and externally validated by 723 patients of Huangshi, two prefecture-level cities in Hubei province, China (from September 2014 to January 2015, with follow-up to January 2017). The baseline variables were collected. The mean age [SD] was 62.89 [10.38] years for the derivation cohort and 62.95 [12.22] years for the external validation cohort. The females accounted for 36.3% and 43.7% of the derivation and validation cohorts, respectively. 8.27% patients (123/1487) in the derivation cohort and 7.75% patients (56/723) in the external validation cohort died within 2 years after discharge. We constructed 4 models based on the 7 selected variables: age, clinical classification, serum direct bilirubin (DBil), aspartate aminotransferase (AST), alkaline phosphatase (ALP), hepatitis B surface antigen (HBsAg), alpha fetoprotein (AFP) at admission. In the external validation cohort, the multivariate model including 7 variables had a C statistic of 0.717 (95% CI, 0.646–0.788) and improved integrated discrimination improvement (IDI) value and net reclassification improvement (NRI) value compared to the other reduced models.Therefore, a multivariate model was developed to predict the 2-year mortality risk for patients with advanced schistosomiasis after discharge. It could also help guide follow-up, aid prognostic assessment and inform resource allocation. Keywords: Advanced Schistosomiasis, Mortality risk, Prediction model, Integrated discrimination improvement, Net reclassification improvement

Background: The coronavirus disease-2019 (COVID-19) outbreak and a 3-month lockdown of Wuhan may have had a long-term impact on the mental health of frontline healthcare workers (HWs). However, there is still a lack of comparative studies on the mental health of front-line HWs in the initial phase of the lockdown and 1 month after the lifting of the lockdown.Methods: We recruited 1717 HWs during the initial phase of the lockdown and 2214 HWs 1 month after the lifting of the lockdown, and their baseline characteristics and psychiatric health in these two phases were compared. Furthermore, Pearson's Chi-square test and multivariate logistic regression analysis were used to determine the possible risk factors associated with depressive symptoms in the front-line HWs.Results: Compared with the initial phase of the lockdown, the proportion of HWs with anxiety symptoms and stress decreased, while the proportion of HWs with depressive symptoms increased a month after the lifting of the lockdown. Male sex, exercise habit, comorbidities, and having family members or relatives with suspected or confirmed COVID-19 infection were significantly related to the increased incidence of depressive symptoms during the initial phase of the lockdown. Comorbidities, negative effect of media coverage, working >4 days a week, lower annual household income, and deteriorating relationships with family members were associated with depressive symptoms a month after the lifting of the lockdown.Conclusion: The increased proportion of HWs with depressive symptoms 1 month after the lifting of the lockdown suggested that mental health of front-line HWs should be a top-priority issue, not only during, but also after the pandemic.

Streptococcus uberis (S. uberis) is an important pathogen causing mastitis, which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. Mouse is a common animal model for studying bovine mastitis. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis-induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of mammary glands and mammary epithelial cells (the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK–mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis.

Streptococcus uberis infection can cause serious inflammation and damage to mammary epithelial cells and tissues that can be significantly alleviated by taurine. Autophagy plays an important role in regulating immunity and clearing invasive pathogens and may be regulated by taurine. However, the relationships between taurine, autophagy, and S. uberis infection remain unclear. Herein, we demonstrate that taurine augments PTEN activity and inhibits Akt/mTOR signaling, which decreases phosphorylation of ULK1 and ATG13 by mTOR and activates autophagy. Activating autophagy accelerates the degradation of intracellular S. uberis, reduces intracellular bacterial load, inhibits over-activation of the NF-κB pathway, and alleviates the inflammation and damage caused by S. uberis infection. This study increases our understanding of the mechanism through which taurine regulates autophagy and is the first to demonstrate the role of autophagy in S. uberis infected MAC-T cells. Our study also provides a theoretical basis for employing nutritional elements (taurine) to regulate innate immunity and control S. uberis infection. It also provides theoretical support for the development of prophylactic strategies for this important pathogen.

Background: Post-stroke depression (PSD) is one of the most common complications after stroke, which seriously affects patients' recovery outcome. Although vascular depression has been extensively studied, the relationship between cerebral artery stenosis and PSD has not been clarified so far.Methods: Two hundred ninety-eight patients with ischemic stroke (72 women, 226 men) with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) were included in this study. Cerebral artery stenosis ≥50% was used as the cut-off value. The DSM-V diagnostic criteria of PSD was met and the 17-item Hamilton Rating Scale for Depression (HAMD-17) score over 7 at discharge and 3 months after stroke onset was regarded as the primary outcome. The χ2-test, Mann-Whitney U-test, and t-test were used to check for statistical significance.Results: At discharge, Barthel index (p < 0.001), left middle cerebral artery stenosis (p = 0.019), drinking history (p = 0.048), basilar artery stenosis (p = 0.037) were significantly associated with PSD. At 3 months after ischemic stroke onset, Barthel index (p = 0.011), left middle cerebral artery stenosis (p = 0.012), female gender (p = 0.001) were significantly associated with PSD.Conclusions: The findings demonstrated that left middle cerebral artery and basilar artery stenosis are associated with PSD. It was suggested that cerebral artery stenosis was a risk factor of PSD and should be recognized and intervened early.Registration Number: ChiCTR-ROC-17013993.

Stroke has been a leading cause of mortality in China. Stroke-associated infections (SAI) are common complications, occurring in 5–65% of stroke patients. Faced with SAI, clinicians often are placed in a considerable dilemma. On the one hand, preventive overuse of antibiotics will lead to the emergence of drug-resistant bacteria. On the other hand, treatment delay of the infection will likely result in a poor outcome. Therefore, it is necessary to determine the early predictors of post-stroke infection to screen patients with high infection risk for early clinical intervention, thereby promoting and improving survival rates. We assessed 257 patients with acute ischemic stroke from a consecutive retrospective cohort. Data of these patients were obtained from three hospitals (TongJi Hospital and its two branches) between August 2018 and June 2019. Of these patients, 59 (23.0%) developed SAI. SAI was defined according to the modified Centers for Disease Control and Prevention criteria. There were 38 patients (64.4%) who developed pneumonia, 11 with urinary tract infections (18.6%), and 10 with other infections (16.9%). We found that a higher neutrophil-to-lymphocyte ratio (adjusted odds ratio [aOR] = 1.16; 95% confidence interval [CI], 1.01–1.33; P = 0.034), National Institutes of Health Stroke Scale score (aOR = 1.18; CI, 1.09–1.27; p < 0.001), and dysphagia (aOR = 2.95; CI, 1.40–6.22; P = 0.004) were risk factors for SAI. Of note, hypertriglyceridemia (aOR = 0.35; CI, 0.13–0.90; P = 0.029) was a protective factor, lowering the risk of SAI. To this end, a reliable nomogram was constructed for the prediction of SAI in our study (mean C-index value ± standard deviation = 0.821 ± 0.03). It has the potential to be widely used and may help identify patients at high risk for SAI and make timely clinical decisions. Given our study was based on relatively small dataset, the results should be interpreted with care and external validation in independent datasets is very necessary.

Background: The outbreak of COVID-19 has laid unprecedented threats and challenges to health workers (HWs) in Wuhan, China. We aimed to assess the sociodemographic characteristics and hospital support measures associated with the immediate psychological impact on HWs at Tongji Hospital in Wuhan during COVID-19 outbreak. Methods: We conducted a single-center, cross-sectional survey of HWs via online questionnaires between February 8th and 10th, 2020. We evaluated stress, depression and anxiety by IES-R, PHQ-9, and GAD-7, respectively. We also designed a questionnaire to assess the perceptions of threat of COVID-19, and the satisfactions of the hospital's support measures. Multivariate logistic regressions were used to identify associated variables of acute stress, depression, and anxiety. Findings: We received 5062 completed questionnaires (response rate, 77.1%). 29.8%, 13.5% and 24.1% HWs reported stress, depression and anxiety symptoms. Women (odds ratio [OR], 1.31; 95% CI, 0.47–0.97; p = 0.032), years of working >10 years (OR, 2.02; 95% CI, 1.47–2.79; p

BackgroundSerum uric acid (SUA) has been shown to play an important role in the pathophysiology of mood disorders including 3- and 6-month post-stroke depression (PSD). This study aimed to investigate whether SUA levels on admission were associated with PSD at discharge.MethodsA total of 498 stroke patients were consecutively recruited from Tongji Hospital. Clinical and laboratory test data were collected on admission. They were categorized into equal tertiles according to the distribution of SUA and the number of patients. PSD status was evaluated by DSM-V criteria and 17-item Hamilton Rating Scale for Depression at discharge.ResultsThe optimal cut-off points of SUA were: (T1) 80.00~300.80 µmo1/L, (T2) 300.81~391.67 µmo1/L, (T3) 391.68~710.0 µmo1/L. A total of 232 patients (46.59%) were diagnosed as PSD at discharge. Significant differences were found between the PSD and non-PSD groups in SUA tertiles of patients (P = 0.00). After adjustment for conventional confounding factors, the odds ratios of PSD were 5.777 (95% CI = 3.463~9.637, P = 0.00) for the lowest tertile and 4.153 (95% CI = 2.492~6.921, P = 0.00) for the middle tertile of SUA, as compared with the highest tertile. In restricted cubic spline regression, continuous SUA showed linear relation with PSD risk at discharge after 300 µmol/L.ConclusionsLower SUA levels on admission were found to be associated with PSD at discharge and the threshold effect was also revealed. For stroke patients, doctors should pay attention to the baseline SUA for screening high-risk PSD at discharge in clinical practice.

Abstract Background Vaccination is the principal strategy for prevention and control of diseases, and adjuvant use is an effective strategy to enhance vaccine efficacy. Traditional mineral oil-based adjuvants have been reported with post-immunization reactions. Developing new adjuvant formulations with improved potency and safety will be of great value. Results In the study reported herein, a novel oil-in-water (O/W) Emulsion Adjuvant containing Squalane (termed EAS) was developed, characterized and investigated for swine influenza virus immunization. The data show that EAS is a homogeneous nanoemulsion with small particle size (~ 105 nm), low viscosity (2.04 ± 0.24 cP at 20 °C), excellent stability (at least 24 months at 4 °C) and low toxicity. EAS-adjuvanted H3N2 swine influenza vaccine was administrated in mice subcutaneously to assess the adjuvant potency of EAS. The results demonstrated that in mice EAS-adjuvanted vaccine induced significantly higher titers of hemagglutination inhibition (HI) and IgG antibodies than water-in-oil (W/O) vaccines or antigen alone, respectively, at day 42 post vaccination (dpv) (P

Taurine may alleviate the inflammatory injury induced by Streptococcus uberis (S. uberis) infection by regulating intracellular Ca2+ levels. However, the underlying mechanisms remain unclear. Infection leads to subversion of phosphoinositides (PIs) which are closely related to Ca2+ signaling. In order to investigate whether taurine regulates inflammation by means of PIs/ Ca2+ systems, competitive inhibitors of taurine (β-alanine) siTauT, siPAT1, siPLC, siCaN, siPKC, and inhibitors of PLC (U73122), PKC (RO31-8220), and CaN (FK 506) were used. The results indicate that taurine transfers the extracellular nutrient signal for intercellular innate immunity to phosphoinositides without a need to enter the cytoplasm while regulating intracellular Ca2+ levels during inflammation. Both the Ca2+-PKCα-NF-κB, and Ca2+-CaM-CaN-NFAT signaling pathways of S. uberis infection and the regulatory roles of taurine follow activation of PIs/Ca2+ systems. These data increase our understanding on the mechanisms of multifunctional nutrient, taurine attenuated inflammatory responses caused by S. uberis infection, and provide theoretical support for the prevention of this disease.

Mastitis caused by Streptococcus uberis (S. uberis) is a common and difficult-to-cure clinical disease in dairy cows. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated signaling pathways in mastitis caused by S. uberis was investigated using mouse models and mammary epithelial cells (MECs). We used S. uberis to infect mammary glands of wild type, TLR2−/− and TLR4−/− mice and quantified the adaptor molecules in TLR signaling pathways, proinflammatory cytokines, tissue damage, and bacterial count. When compared with TLR4 deficiency, TLR2 deficiency induced more severe pathological changes through myeloid differentiation primary response 88 (MyD88)-mediated signaling pathways during S. uberis infection. In MECs, TLR2 detected S. uberis infection and induced mitochondrial reactive oxygen species (mROS) to assist host in controlling the secretion of inflammatory factors and the elimination of intracellular S. uberis. Our results demonstrated that TLR2-mediated mROS has a significant effect on S. uberis-induced host defense responses in mammary glands as well as in MECs.

Neutrophil extracellular traps (NETs) are produced by neutrophil activation and usually have both anti-infective and pro-damage effects. Streptococcus uberis (S. uberis), one of the common causative organisms of mastitis, can lead to the production of NETs. Taurine, a free amino acid abundant in the organism, has been shown to have immunomodulatory effects. In this study, we investigated the molecular mechanisms of S. uberis-induced NETs formation and the regulatory role of taurine. The results showed that NETs had a disruptive effect on mammary epithelial cells and barriers, but do not significantly inhibit the proliferation of S. uberis. S. uberis induced NADPH oxidasedependent NETs. TLR2-mediated activation of the MAPK signaling pathway was involved in this process. Taurine could inhibit the activation of MAPK signaling pathway and NADPH oxidase by modulating the activity of TAK1, thereby inhibiting the production of ROS and NETs. The effects of taurine on NADPH oxidase and NETs in S. uberis infection were also demonstrated in vivo. These results suggest that taurine can protect mammary epithelial cells and barriers from damage by reducing S. uberis-induced NETs. These data provide new insights and strategies for the prevention and control of mastitis. [ABSTRACT FROM AUTHOR]