Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses. Our finding that the pathogen-plus-susceptibility gene interaction is dependent on dose has important implications both for understanding how Mtb infections in humans lead to a spectrum of outcomes and for the potential use of autophagy modulators in clinical medicine.

MMVFL: A Simple Vertical Federated Learning Framework for Multi-Class Multi-Participant Scenarios.

Federated learning (FL) is a privacy-preserving collective machine learning paradigm. Vertical federated learning (VFL) deals with the case where participants share the same sample ID space but have different feature spaces, while label information is owned by one participant. Early studies of VFL supported two participants and focused on binary-class logistic regression problems, while recent studies have put more attention on specific aspects such as communication efficiency and data security. In this paper, we propose the multi-participant multi-class vertical federated learning (MMVFL) framework for multi-class VFL problems involving multiple parties. By extending the idea of multi-view learning (MVL), MMVFL enables label sharing from its owner to other VFL participants in a privacy-preserving manner. To demonstrate the effectiveness of MMVFL, a feature selection scheme is incorporated into MMVFL to compare its performance against supervised feature selection and MVL-based approaches. The proposed framework is capable of quantifying feature importance and measuring participant contributions. It is also simple and easy to combine with other communication and security techniques. The experiment results on feature selection for classification tasks on real-world datasets show that MMVFL can effectively share label information among multiple VFL participants and match the multi-class classification performance of existing approaches.

Changes in expression levels of erythrocyte and immune-related genes are associated with high altitude polycythemia.

BACKGROUND: As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood. METHODS: 37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis. RESULTS: The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent. CONCLUSION: This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.

Corticosteroids Treatment of Patients with Coronavirus Disease 2019: A Propensity Score Matching Study.

The role of corticosteroids in the treatment of Coronavirus disease 2019 (COVID-19) is controversial. In the present study, we evaluated the effects of adjuvant corticosteroids treatment on the outcome of patients with COVID-19 (n=966), using Propensity Score Matching to adjust for potential differences between the corticosteroids group (n=289) and the non-corticosteroids group (n=677). Analysis of data without adjusting differences in baseline characteristics indicated that the proportion of mechanical ventilation and the mortality was higher in the corticosteroids treatment group in total or severe/critical patients. The duration of viral shedding was longer in the non-corticosteroids treatment group in total or general/mild patients. After adjusting the difference between the corticosteroids and non-corticosteroids treatment group, the analysis revealed that the use of corticosteroids had no effect on the duration of viral shedding, in-hospital mortality or 28-day mortality.

Novel risk scoring system for predicting acute respiratory distress syndrome among hospitalized patients with coronavirus disease 2019 in Wuhan, China.

BACKGROUND: The mortality rate from acute respiratory distress syndrome (ARDS) is high among hospitalized patients with coronavirus disease 2019 (COVID-19). Hence, risk evaluation tools are required to immediately identify high-risk patients upon admission for early intervention. METHODS: A cohort of 220 consecutive patients with COVID-19 were included in this study. To analyze the risk factors of ARDS, data obtained from approximately 70% of the participants were randomly selected and used as training dataset to establish a logistic regression model. Meanwhile, data obtained from the remaining 30% of the participants were used as test dataset to validate the effect of the model. RESULTS: Lactate dehydrogenase, blood urea nitrogen, D-dimer, procalcitonin, and ferritin levels were included in the risk score system and were assigned a score of 25, 15, 34, 20, and 24, respectively. The cutoff value for the total score was > 35, with a sensitivity of 100.00% and specificity of 81.20%. The area under the receiver operating characteristic curve and the Hosmer-Lemeshow test were 0.967 (95% confidence interval [CI]: 0.925-0.989) and 0.437(P Value = 0.437). The model had excellent discrimination and calibration during internal validation. CONCLUSIONS: The novel risk score may be a valuable risk evaluation tool for screening patients with COVID-19 who are at high risk of ARDS.

NLRP3 inflammasome plays an important role in caspase-1 activation and IL-1ß secretion in macrophages infected with Pasteurella multocida.

Pasteurella multocida is a Gram-negative bacterium that is responsible for a variety of diseases in birds and mammals, including humans. We have previously reported that the P. multocida serotype A strain PmCQ2 causes severe lung pneumonia in bovines. Transcriptomic analysis showed that many genes related to the immune response were significantly upregulated in the lungs of mice infected with P. multocida compared with uninfected mice. However, the mechanism by which P. multocida induces host inflammatory cytokine secretion is poorly understood. In this study, the mechanism of caspase-1 activation and subsequent IL-1ß secretion in macrophages infected with P. multocida was elucidated. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome was shown to be involved in inducing this cellular response. Compared with wild-type macrophages, Nlrp3-/- macrophages exhibited a clear decrease in caspase-1 activation and IL-1ß secretion in response to P. multocida infection. Furthermore, spleen tyrosine kinase (Syk) was indicated to be involved in IL-1ß secretion, possibly by regulating the NLRP3 inflammasome. Our results provide new insight into the host proinflammatory immune response against P. multocida and the critical involvement of the NLRP3 inflammasome in this activity.

NLRP3/ASC/Caspase-1 axis and serine protease activity are involved in neutrophil IL-1ß processing during Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a pathogenic bacterium that can cause severe invasive diseases, such as pneumonia, otitis media and meningitis. The pro-inflammatory cytokine, IL-1ß, has been reported to play important role in host defense against S. pneumoniae. The mechanism of IL-1ß maturation and secretion in macrophages has been well studied. However, the precise mechanism of IL-1ß processing within neutrophils upon S. pneumoniae infection remains unclear. In this study, mouse peritoneal neutrophils from C57BL/6 WT and inflammasome components knockout mice were infected by S. pneumoniae in vitro. The results showed that NLRP3 inflammasome is critically involved in neutrophil IL-1ß secretion, while the AIM2 and NLRC4 inflammasomes were dispensable. Moreover, the upstream kinase, JNK, modulates ASC oligomerization and consequent caspase-1 activation and IL-1ß secretion. Additionally, neutrophil serine proteases also participate in IL-1ß secretion by mediating ASC oligomerization and caspase-1 activation. Taken together, these findings indicated that both the NLRP3 inflammasome-related pathway and neutrophil serine protease mediate IL-1ß processing upon S. pneumoniae infection.

Syk and JNK signaling pathways are involved in inflammasome activation in macrophages infected with Streptococcus pneumoniae.

Streptococcus pneumoniae is a pathogen of significant clinical importance worldwide that can cause severe invasive diseases, such as pneumonia, otitis media and meningitis. Inflammsomes has been reported to participate in host defense against S. pneumoniae infection. S. pneumoniae could induce the assembly of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/absent in melanoma 2 (AIM2) inflammasome, which mediates the activation of caspase-1 and the subsequent maturation of Interleukin-1ß (IL-1ß). However, the precise signals that activate inflammasomes during pneumococcal infection remain to be fully elucidated. In the present study, primary mouse macrophages were selected as a cell model, and the effects of kinases on inflammasome activity induced by S. pneumoniae infection were examined by ELISA and western blotting after pretreatment with a kinase inhibitor. Here, we show that Syk and JNK signaling are required for S. pneumoniae-induced activation of the inflammasome. Inhibitors of Syk and JNK almost abolished the oligomerization of apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC) and subsequent caspase-1 activation and IL-1ß secretion. Moreover, pneumolysin (PLY) participated in this process and was critical for Syk/JNK activation. These results suggested that the Syk/JNK signaling pathway may play a vital role in the inflammasome activation and modulate host immune responses against S. pneumoniae.

[Preparation and chiral recognition ability of chiral stationary phase based on immobilized polyacrylamide derivative].

High performance liquid chromatography (HPLC) has been widely considered as the most effective way for the separation and preparation of optically pure enantiomers. In the resolution by HPLC, the separation ability of a column strongly depends on the properties of a chiral stationary phase (CSP). Among many CSPs, the immobilized CSPs, which are becoming one of the most important kinds of CSPs, have the advantages of good solvent durability and enormous method flexibility. In this work, a novel optically active acrylamide derivative (S)-APACP was synthesized by two-step reactions, and its chemical structure was characterized by 1H NMR. The polyacrylamide derivatives were immobilized on silica gel by three-step reactions to prepare immobilized CSPs, and the immobilization amount of the polymers was tested by thermogravimetric analysis. The chiral recognition ability of the immobilized CSPs was evaluated by HPLC, and the effects of Lewis acid and mobile phase on the chiral recognition ability were investigated. The results showed that APACP polymer was successfully immobilized on silica gel to prepare immobilized-type CSP with better solvent durability, and the amount of immobilized polymer was 10. 2% to 11. 8%. The immobilized-type CSP showed good chiral recognition ability for several enantiomers.

Stimulus Specificity of Brain-Computer Interfaces Based on Code Modulation Visual Evoked Potentials.

A brain-computer interface (BCI) based on code modulated visual evoked potentials (c-VEP) is among the fastest BCIs that have ever been reported, but it has not yet been given a thorough study. In this study, a pseudorandom binary M sequence and its time lag sequences are utilized for modulation of different stimuli and template matching is adopted as the method for target recognition. Five experiments were devised to investigate the effect of stimulus specificity on target recognition and we made an effort to find the optimal stimulus parameters for size, color and proximity of the stimuli, length of modulation sequence and its lag between two adjacent stimuli. By changing the values of these parameters and measuring classification accuracy of the c-VEP BCI, an optimal value of each parameter can be attained. Experimental results of ten subjects showed that stimulus size of visual angle 3.8°, white, spatial proximity of visual angle 4.8° center to center apart, modulation sequence of length 63 bits and the lag of 4 bits between adjacent stimuli yield individually superior performance. These findings provide a basis for determining stimulus presentation of a high-performance c-VEP based BCI system.