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Background Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methods Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood–brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. Results Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood–brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. Conclusions Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

In this paper, we mainly show some bounds and inequalities for the $ p $-generalized trigonometric functions defined by Richter.

For traditional agricultural product traceability system, there are some problems, such as information asymmetry and serious centralized storage. To solve the problems, a set of an agricultural product traceability information analysis system based on blockchain is designed. The overall framework of the agricultural product information traceability system is built, and the traceability model and process are designed in detail from the data layer, consensus layer, and contract layer. Collaborative verification function modules are added in the data layer to ensure the authenticity of data on the blockchain. The integral penalty mechanism is introduced to improve the practical Byzantine fault tolerance algorithm (PBFT), which ensures the security of the block network and the validity of data. Smart contracts are adopted to ensure that changes in agricultural information are actually recorded on blockchain. The results show that the designed blockchain-based agricultural product information traceability system solves the problem of difficult sharing and traceability of agricultural product information, which realizes the traceability of agricultural product production information, processing information, transportation information, and transaction query information, and has certain theoretical and practical value for the information traceability of agricultural products and other products.

Background Primary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. Results We constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). The ORMDL3+ cholangiocytes have prominently higher metabolism activity score than ORMDL3− cholangiocytes (P = 1.38 × 10–15). Compared with ORMDL3− cholangiocytes, there were 77 significantly differentially expressed genes among ORMDL3+ cholangiocytes (FDR ORMDL3+ cholangiocytes exhibited relatively high communications with macrophage and monocyte. Compared with ORMDL3− cholangiocytes, the VEGF signaling pathway is specific for ORMDL3+ cholangiocytes to interact with other cell populations. Conclusions To the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3+ cholangiocytes with higher metabolism activity play important immune-modulatory roles in the etiology of PBC. Graphical Abstract

ImportancePrimary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear.ObjectiveTo identify genetics-modulated functional liver cell subsets involved in the pathogenesis of PBC.Design, Setting, and ParticipantsIn this present study, 13,239 European participants were collected from IEU open GWAS project on PBC. There were 1,124,241 qualified SNPs used for GWAS analysis. Expression quantitative trait loci (eQTL) data across 49 tissues were downloaded from the GTEx database. Two single cell RNA sequencing (scRNA-seq) profiles and two bulk-based RNA transcriptomes were downloaded from the GEO database. Data collection and analyses were performed from August 2020 to June 2021.Main outcomes and measuresWe constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations.ResultsBased on our multi-omics integrative analysis, we found that 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. Gene-property analysis revealed that four immune cell types, including Cst3+ dendritic cell, Chil3+ macrophage, Trbc2+ T cell, and Gzma+ T cell, were significantly enriched by PBC-risk genes. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). Compared with ORMDL3+ cholangiocytes, there were 71 significantly highly-expressed genes among ORMDL3- cholangiocytes (FDR < 0.05), such as inflammatory cytokine genes CXCL8, CCL3, IFI16, and IRF1. These highly-expressed genes were significantly enriched in numerous biological pathways and functional terms associated with autoimmune diseases (FDR < 0.05).Conclusions and relevanceTo the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3- cholangiocytes play important immune-modulatory roles in the etiology of PBC.Key pointsQuestionAre genetics factors influenced liver cell subpopulations and its immune microenvironment for PBC?FindingsIn this comprehensive genomics study based on multi-omics data, genetic determinants were significantly enriched in cholangiocytes and immune cells including subsets of macrophage, dendritic cells, and T cells. ORMDL3- cholangiocytes have crucial immune-modulatory roles in developing PBC.MeaningFindings suggest that integration of single cell sequencing data with GWAS summary statistics contribute to pinpoint PBC-relevant cell types and risk genes.

Purpose of the study: Multiple sclerosis is a CD4+ T cell mediated autoimmune disease characterized by inflammatory demyelination in the central nervous system. Acetylcholine (ACh) has been reporte...

This paper is concerned with a nonlinearly modified Kawahara equation with periodic boundary conditions $$ u_{t}+u_{xxx}-u_{5x}+\alpha u^{2}u_{x}=0. $$ Based on an abstract infinite-dimensional KAM theorem for unbounded perturbation vector fields and partial Birkhoff normal form, we prove the existence of n-dimensional invariant tori for the equation.

The solutions to the Riemann problem for the isentropic relativistic Euler system for the extended Chaplygin gas are constructed for all kinds of situations by using the method of phase plane analysis. The asymptotic limits of solutions to the Riemann problem for the relativistic extended Chaplygin Euler system are investigated in detail when the pressure given by the equation of state of extended Chaplygin gas becomes that of the pressureless gas. During the process of vanishing pressure, the phenomenon of concentration can be identified and analyzed when the two-shock Riemann solution tends to a delta shock wave solution as well as the phenomenon of cavitation also being captured and observed when the two-rarefaction-wave Riemann solution tends to a two-contact-discontinuity solution with a vacuum state between them.

The exact solutions of the Riemann problem for a symmetric system of Keyfitz–Kranzer type are obtained in fully explicit forms. Furthermore, the global solutions of the double Riemann problems are also constructed explicitly when the initial data are taken to be three piecewise constant states. During the process of constructing the global solutions, all occurring wave interactions have been dealt with in detail by using the method of characteristics. In addition, it is shown that the Riemann solutions are stable with respect to the specific small perturbations of the Riemann initial data.

Exercise therapy including endurance training and resistance training is a promising non-pharmacological therapy in patients with multiple sclerosis (MS). Recent studies have revealed that exercise exerts beneficial impacts on gut microbiota. However, the role of gut microbiota in the immune benefits of strength exercise (SE; one of resistance training) in central nervous system (CNS) autoimmunity is barely known. Here, we observed that 60-min SE ameliorated disease severity and neuropathology in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. SE increased the abundance and diversity of the gut microbiota, and decreased Firmicutes/Bacteroidetes ratio (F/B ratio) and intestinal mucosal permeability, and enrichment of several short-chain fatty acid (SCFA)-producing bacteria. Furthermore, SE reduced Th17 responses and increased Treg responses in the small intestine lymphoid tissues. Compared to the control group, microbiota-depleted mice receiving SE microbiome fecal transplants had lower disease severity and neuropathology scores. These results uncovered a protective role of SE in neuroimmunomodulation effects partly via changes to the gut microbiome.

The significance of the microbiota-gut-brain axis has been increasingly recognized as a major modulator of autoimmunity. Here, we aim to characterize the gut microbiota of a large cohort of treatment-naïve anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis patients relative to that of healthy controls (HCs). Relative to HCs, anti-NMDAR encephalitis patients had a decreased microbiome alpha-diversity index, marked disturbances of gut microbial composition and intestinal permeability damage. Disturbed microbiota in anti-NMDAR encephalitis patients might be linked with different clinical characteristics. Imputed KEGG analysis revealed perturbations of functional modules in the gut microbiomes of anti-NMDAR encephalitis. Compared to HCs, microbiota-depleted mice receiving fecal microbiota transplantation (FMT) from anti-NMDAR encephalitis patients had hypersensitivity and cognitive impairment. Furthermore, anti-NMDAR encephalitis FMT mice showed altered T cells in the spleen and small intestine lamina propria with an increased Th17 cells. Overall, this study first suggests that the anti-NMDAR encephalitis microbiome itself can influence neurologic, Th17 response and behavioral function. The gut microbiota is a potential therapeutic target for anti-NMDAR encephalitis.

Anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis is a rare autoimmune encephalitis (AE). We investigated the clinical features and gut microbial alterations of anti-LGI1 encephalitis. Fifteen patients newly diagnosed with anti-LGI1 encephalitis were recruited in the study prior to the administration of immunotherapy. The control group contains 25 well-matched healthy controls (HCs). All participants were Han Chinese from South China. Their clinical data and fecal samples were collected. The diversity and composition of gut microbiota were analyzed by 16S ribosomal RNA (16S rRNA) gene sequencing. The results showed that anti-LGI1 encephalitis was characterized by cognitive impairment, faciobrachial dystonic seizures, hyponatremia, and psychiatric symptoms. Abnormal EEG and brain MRI were presented in 9 and 10 patients, respectively. Compared to HCs, the anti-LGI1 encephalitis patients exhibited a decreased microbial diversity and an altered overall composition of gut microbiome. At the phylum level, anti-LGI1 encephalitis patients exhibited a higher abundance of Proteobacteria and a lower abundance of Firmicutes. The alterations in the phylum level were associated with autoimmune and inflammatory disorders. At the genus level, there was an increase in Sphingomonas, Anaerofustis, Succinvibrio, Clostridium, and SMB53 (genera related to movement disorders, psychiatric diseases, and with proinflammatory effects). However, the Faecalibacterium, Roseburia, Lachnospira, Ruminococcus, and Blautia [genera with ability to produce short-chain fatty acids (SCFAs)] were obviously reduced in the patient group. Our results suggest that anti-LGI1 encephalitis is characterized by special clinical features and is accompanied by alterations in specific gut microbiota. For the limited sample size and non-applicability to other populations, further studies are warranted to explore the relationships between gut microbiota and anti-LGI1 encephalitis.

This study aimed to investigate the association between parity and bone mineral density in postmenopausal Chinese women, as well as the interference of physical activity and sedentary time on this association. A total of 1,712 participants were enrolled in this study. Participants were separated into three groups according to the number of parities: group 1, 1-2; group 2, 3-4; group 3, ≥5. Physical activity level was assessed according to the International Physical Activity Questionnaire. Calcaneus bone mineral density (BMD) and bone quality were assessed by qualitative ultrasound. As a result, logistic regression showed that compared to that in group 1, the risk of fracture in group 3 was increased significantly (p < 0.001). A greater number of parities was associated with a lower BMD, broadband ultrasonic attenuation (BUA), quantitative ultrasound index (QUI), speed of sound (SOS), and T-score among the three groups after adjustment for age (All p for trend < 0.05). The number of parities was an independent factor negatively correlated with BMD, BUA, QUI, SOS and T-score (All p < 0.05). BMD, BUA, QUI, SOS, and T-score were significantly increased in the physically a participants independent of parity (all p < 0.05), and decreased in the sedentary participants independent of parity (p < 0.05, except BUA). A great number of parities was negatively associated with bone health. Physical activity was positively correlated and sedentary time was negatively correlated with bone health independent of parity.

Adaptogens are stress-response modifiers which have been considered to exert important influences on cytokines activities and immune response. Here, we investigated the effects of Rhodiola rosea (R. rosea), a natural adaptogen on the experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We found that R. rosea alleviated the severity of EAE as evaluated by clinical and histopathology scores. R. rosea decreased IL-6, sIL-6R, IFN-γ and IL-17A in both serum and splenocytes supernatants while increased IL-4 in splenocytes supernatants of EAE mice. R. rosea also modulated the T cell response by inhibiting Th1 and Th17 cells, restoring Treg cells, combining with regulated Th17/Th1, Th17/Th2 and Th17/Treg ratios in the spleen, inguinal lymph nodes, brain and spinal cord of EAE mice. Furthermore, R. rosea regulated the expression of JAK1, JAK2, STAT3 and RORγt in the spinal cord of EAE mice. Together, our findings suggested the adaptogenic effects of R. rosea on EAE, which may help to deepen the understanding of potential therapeutic values of traditional Chinese medicines for autoimmune diseases of CNS.

Multiple sclerosis (MS) is a disease with complex etiology and pathophysiology. Approved drugs for MS treatment are only partly effective, and some of them show obvious side effects and resistance. In this review, we will discuss the philosophy and advantages of traditional Chinese medicine (TCM) as a complementary and alternative therapy for MS treatment. The purpose of this review is to provide novel insights and directions for MS management. TCM is an empirical medical system which has established its own unique method of diagnosis and therapy for over thousands of years. The concept of holism and yin-yang balance are its core theories. From TCM perspective, syndrome differentiation, deficiency tonification, stasis removal, and detoxication are the four main principles of MS treatment. Clinical trials have shown that TCM is effective to alleviate symptoms, prevent recurrence, and delay disease progression in MS patients. Experimental evidences also have confirmed the effect of TCM in experimental autoimmune encephalomyelitis (EAE), which is in the multitarget and multicomponent pattern. TCM maximize therapeutic efficacy by facilitating synergistic actions, exhibiting various biological activities including anti-inflammatory, anti-oxidative, immune-regulatory, and neuro-protective effects in MS and EAE. Treatment with TCM alone or combined with western medicine can greatly improve the body’s resistance and reduce side effects of the treatment. Integrating TCM with Western medicine have great promise for inspiring new ideas and therapies for prevention and treatment of MS. The appropriate combination can improve efficacy, reduce toxicity, and make the best benefits in MS patients.

We construct the solutions to the Riemann problem for the isentropic extended Chaplygin gas dynamic system for all kinds of situations by the phase plane analysis. We investigate the asymptotic limits of solutions to this problem in detail when the pressure given by the state equation of the system becomes the one of pressureless gas. During the process of vanishing pressure, the two-shock Riemann solution tends to a delta shock solution, whereas the two-rarefaction-wave Riemann solution tends to a two-contact-discontinuity solution with a vacuum state.

The authors obtain some Wilker and Cusa type inequalities for generalized trigonometric and hyperbolic functions and generalize some known inequalities.

Android system uses a permission mechanism to allow users and developers to regulate access to private information and system resources required by Android applications (apps). Permissions can be behaviors and characteristics of an app, and widely used by Android malware detection. This paper designs a novel method to extract contrasting permission patterns for comparing the differences between Android benign apps and malware based on permissions, and use these differences to detect Android malware. Unlike existing works, this work first analyzes required and used permission. Then use support-based permission candidate method to mining unique required or used permission patterns, and use these patterns to detect Android malware. In experiment, this approach uses permission patterns from Android malware to detect a mixed Android app dataset. The results show that the proposed method can achieve 94% accuracy, 5% false positive, and 1% false negative.

Background: The significance of the microbiota-gut-brain axis has been increasingly recognized as a major modulator of autoimmunity. However, little is known about the effects of the gut microbiome on immune function and behaviors in autoimmune encephalitis. In this study, we aim to take advantage of a large cohort of treatment naive anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis to rigorously characterise gut dysbiosis and investigated the roles of immune function and behaviors. Methods : We first conducted a cross-sectional study of 40 MSA treatment-naive patients and 54 matched healthy controls (HCs). Then fecal microbiota transplantation (FMT) from anti-NMDAR encephalitis patients to microbiota-depleted mice was performed to investigate the immune function and behaviors. Findings : Relative to HCs, anti-NMDAR encephalitis patients had a decreased microbiome alpha-diversity index, marked disturbances of gut microbial composition and intestinal permeability damage. Disturbed microbiota in anti-NMDAR encephalitis patients might be linked with different clinical characteristics. Imputed KEGG analysis revealed perturbations of functional modules in the gut microbiomes of anti-NMDAR encephalitis. Compared to HCs, microbiota-depleted mice receiving FMT from anti-NMDAR encephalitis patients had hypersensitivity and cognitive impairment. Furthermore, anti-NMDAR encephalitis FMT mice showed altered T cells in the spleen and inguinal lymph node with an increased Th17 cells. Interpretation: Our study presents a comprehensive gut microbiota landscape in anti-NMDAR encephalitis. It suggests that the anti-NMDAR encephalitis microbiome itself can influence neurologic, immune and behavioral function. The gut microbiota is a potential therapeutic target for anti-NMDAR encephalitis. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No. 81971141), the Israel Science Foundation and the National Natural Science Foundation of China joint programme (No. 813111290), the Natural Science Foundation of Guangdong Province (No. 2019A1515010201) and Tianhe District Technology Project (2018YT019). Declaration of Interests: All authors declare that there are no conflicts of interest. Ethics Approval Statement: This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval ID: [2018]02-363-01). The subjects or the guardians of patients with severe cognitive impairment provided written informed consent for research and publication. Animal protocols were performed using C57BL/6J wild-type (WT) female mice in accordance with guidelines for animal care, according to the National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the Bioethics Committee of South China Agricultural University (approval ID: 2019-D063).

In this paper, we prove complete monotonicity of some functions involving k-polygamma functions. As an application of the main result, we also give new upper and lower bounds of the k-digamma function.

Gut microbiota has been proposed as an important environmental factor which can intervene and modulate central nervous system autoimmunity. Here, we altered the composition of gut flora with Clostridium butyricum and norfloxacin in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We found that appropriate C. butyricum (5.0 × 106 CFU/mL intragastrically daily, staring at weaning period of age) and norfloxacin (5 mg/kg intragastrically daily, 1 week prior to EAE induction) treatment could both ameliorate EAE although there are obvious differences in gut microbiota composition between these two interventions. C. butyricum increased while norfloxacin decreased the abundance and diversity of the gut microbiota in EAE mice, and both of the treatments decreased firmicutes/bacteroidetes ratio. In the genus level, C. butyricum treatment increased the abundance of Prevotella while Akkermansia and Allobaculum increased in norfloxacin treatment. Moreover, both interventions reduced Desulfovibroneceae and Ruminococcus species. Although there was discrepancy in the gut microbiota composition with the two interventions, C. butyricum and norfloxacin treatment both reduced Th17 response and increased Treg response in the gastrointestinal tract and extra-gastrointestinal organ systems in EAE mice. And the reduced activity of p38 mitogen-activated kinase and c-Jun N-terminal kinase signaling in spinal cord could be observed in the two interventions. The results suggested that manipulation of gut microbiota interventions should take factors such as timing, duration, and dosage into consideration. The discrepancy in the gut microbiota composition and the similar protective T cells response of C. butyricum and norfloxacin implies that achieving intestinal microecology balance by promoting and/or inhibiting the gut microbiota contribute to the well-being of immune response in EAE mice.