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Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.

We delved into the upward negative precursors that occur at the wire tip of the rocket during ascent as well as the initial negative leaders, by analyzing comprehensive data of rocket-triggered positive lightning. Our high vertical resolution current detection identified a significant number of weak current pulses in addition to the typical precursors with peak currents of tens of amperes. These weak pulses could occur as isolated events or could be prior the typical-intensity precursors with a lead time of approximately 20 μs. The typical-intensity precursors created visible discharge channels that can be identified using optical means. The development of those clustered precursors featured step-wise channel extensions that were consistent with the initial sustained upward leaders, with an average 2-D speed of around 105 m/s. The temporal and spatial relationship of adjacent precursor-producing channels was analyzed. After the extinction of the previous precursor channel, a new one formed at the apex of the previous channel as the triggering wire tip arrived there. The study confirmed that the precursors were actually un-sustained leader development, which produced initial leader channel segment at the triggering wire tip but eventually extinguished due to the insufficient conditions. The sustained upward negative leader development signified the successful triggering of the lightning. The leader propagated in distinct step-wise manner with average 2-D velocity of 1.85×105 m/s. For a total of 132 steps captured by the highspeed video camera, the step lengths ranged from 0.8 m to 8.7 m, with an average of 3.9 m. During the initial stage of the upward negative stepped leader, there was a notable impulse feature in both the current and electromagnetic field. The equivalent linear charge density of a single step was 118.5 µC/m. The branching of the leader channel typically occurred in connection with the stepping process in two ways. The first involved creating multiple connections between clustering space stems/space leaders and the leader head within a single step. This resulted in a multi-peak current waveform with a peak interval of roughly 2-3 µs (up to 6-7 µs). The second involved reactivating previously extinguished space stems/space leaders and connecting them to the lateral surface of the channel.

In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL, P 0.0001), primary biliary cholangitis (7.32 ng/mL, P 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL, P 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.

The epigenetic factor bromodomain and extra-terminal domain (BET) proteins have multiple functions in regulating cell proliferation, differentiation and inflammation via binding to acetylated lysines on histones. JQ1 and I-BET726, new inhibitors of BET proteins, have potential therapeutic benefit for autoimmune diseases (AD). In this study, we explored the effects of JQ1 and I-BET726 on innate and adaptive immunity in experimental autoimmune encephalomyelitis (EAE) model to investigate the mechanism and therapeutic benefit for AD. The effects of JQ1 and I-BET726 on LPS-induced inflammation were investigated in innate and adaptive immune cells of dendritic cells (DCs), macrophages, and DC-dependent T cells. Different pro-inflammatory cytokines were assessed via real-time PCR, flow cytometry, and Elispot. Moreover, the effects of JQ1 and I-BET726 on EAE animals were further investigated, including the effects on alleviating clinical symptoms and inhibiting inflammation and demyelination in spinal cords via real-time PCR and immunohistochemical staining. JQ1 and I-BET726 efficiently inhibited LPS-increased TNF-α and IL-6 expression in bone marrow-derived DC and macrophage of Raw264.7 cells. They also suppressed adaptive immunity by down-regulating CD80/CD86 and IL-12/GM-CSF expressions, and inhibiting DC-dependent T cell priming. Moreover, they effectively inhibited TNF-α and IL-6 involved inflammatory changes in the spinal cords of EAE model, including inflammatory cell infiltration and demyelination. Most importantly, JQ1 and I-BET726 efficiently attenuated the clinical deterioration of EAE mice. Our results indicate that JQ1 and I-BET726 possess therapeutic benefits for autoimmune diseases by adjusting innate and adaptive immune response, indicating that BET bromodomain might be potential molecular targets for autoimmune disease therapy.

Background and aims The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. Approach and results We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-β on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-β and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. Conclusions Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.

Pyruvate dehydrogenase (PDC)-E2 specific CD8Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103Intrahepatic CD103CD103Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8

Methicillin-resistant Staphylococcus aureus has emerged as a significant contributor to morbidity and mortality associated with influenza infection. In this study, we show in a mouse model that preceding influenza infection promotes S. aureus resistance to killing by antibiotics. This resistance coincides with influenza-induced accumulation of inflammatory monocytes in the lung. CCR type 2 (CCR2) is responsible for pulmonary monocyte recruitment after influenza infection. We found that antibiotic-treated Ccr2-deficient (Ccr2−/−) mice exhibit significantly improved bacterial control and survival from influenza and methicillin-resistant S. aureus coinfection, despite a delay in viral clearance. Mechanistically, our results from in vivo studies indicate that influenza-induced monocytes serve as reservoirs for intracellular S. aureus survival, thereby promoting bacterial resistance to antibiotic treatment. Blocking CCR2 with a small molecular inhibitor (PF-04178903), in conjunction with antibiotic treatment, enhanced lung bacterial clearance and significantly improved animal survival. Collectively, our study demonstrates that inflammatory monocytes constitute an important and hitherto underappreciated mechanism of the conflicting immune requirements for viral and bacterial clearance by hosts, which subsequently leads to exacerbated outcomes of influenza and S. aureus coinfection.

The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic.We report herein that CD69Our data suggest that CD8

ObjectiveMultiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC.DesignWe performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling.ResultsCompared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host–microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion ofBlautiaand elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease ofEubacteriumand microbiota-derived metabolites, including secondary bile acids, implicated novel host–microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes.ConclusionsOur data reveal that IgG4-SC and PSC possess divergent host–microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.

Background: As there is a growing concern about the cerebral embolism events secondary to non-valvular atrial fibrillation (NVAF), novel oral anticoagulant (NOAC) has been more and more widely used as an anticoagulation treatment for the prevention of stroke. However, in the face of life-threatening bleeding or emergency surgery/treatment, NOAC-related antagonists such as idarucizumab need to be urgently used to reverse the NOAC. Using recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis for acute ischemic stroke requires a time window of 4.5 h. This case reports rt-PA intravenous thrombolysis after reversal of dabigatran anticoagulation with idarucizumab in patients with acute ischemic stroke.Case Presentation: We report the case of 62-year-old Chinese female with NVAF treated with dabigatran 110 mg twice daily, and missed a dose on the eve of the stroke. The patient presented with acute ischemic stroke causing the angle of mouth deviated to right side and left limb weakness in the early morning of the next day. However, the last dosing time of dabigatran was between 24 and 48 h, the patients were given rt-PA intravenous thrombolysis after reversal of dabigatran anticoagulation with idarucizumab, while any potential relative contraindication had been excluded by means of laboratory test and CT scan in the hospitalization services. National Institute of Health stroke scale (NIHSS) score was reduced from 4 to 1, and the patient was discharged after 2 weeks.Conclusion: Our case report adds to the evidence that idarucizumab administration is safe and effective in the setting of patients with atrial fibrillation treated with dabigatran who develop acute ischemic stroke requiring rt-PA intravenous thrombolysis.

Norvancomycin (NVCM) is used in treating patients with infections caused by drug-resistant gram-positive bacteria. The NVCM plasma concentration varies greatly among individuals. To avoid the adverse drug reactions and prevent the presence of drug-resistant bacteria, the routine monitoring of NVCM in blood plasma was strongly recommended. However, there were few methods for plasma NVCM analysis. To the best of our knowledge, this is the first validated ultra performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) method for plasma NVCM analysis. The ion transition for NVCM was m/z 718.5 > 144.1. The flow rate was 0.4 mL/min with a run time of 3.5 min. The calibration range of the UPLC–MS/MS method was 1–100 mg/L. The intra-day and inter-day inaccuracy and imprecision were −7.39%–10.27% and less than 11.55%. The internal standard (IS) normalized recovery and matrix factor were 68.24%–78.24% and 94.53% to 115.80%, respectively. The coefficient variations of IS normalized recovery and matrix factor were less than 11.24% and 9.14%. Age, body weight, and creatinine clearance affect NVCM plasma concentrations in 20 patients. Further studies are warranted to confirm the results.

This study aimed to evaluate the clinical characteristics, pregnancy outcomes and prognostic factors for pregnancy of female with chromosomal abnormalities (CAs) after artificial insemination with donor's sperm (AID) treatment. A retrospective case–control study was analyzed by using the data of 29 female patients with CA and 116 controlled patients with normal karyotype (1:4 ratio) who underwent AID cycles at Guangdong Family Planning Special Hospital from January 2011 to December 2017. In all cases, reproductive histories were collected, and the cytogenetic analysis was performed by Trypsin-Giemsa banding and karyotyping. The embryos were fertilized via intracervical or intrauterine insemination. Clinical characteristic variables were compared. The prevalence of CA was found to be 0.29% in the whole AID population. The live birth rates of CA group and controlled group were 41.4% and 31.0% (P = .29) respectively. Compared to normal karyotype group, patients with CA showed higher rate of primary infertility (93.1% vs 75.9%, P = .049); Multivariate analysis demonstrated that ovarian stimulation (odds ratio, 3.055; 95% confidence interval, 1.421–6.568; P = .004) was associated with adverse pregnancy outcomes in female patients with AID treatment. For the infertility CA patients who were phenotypically normal, AID was a suitable choice, whereas ovarian stimulation results in an improvement in the pregnancy rate.

Ring1 and YY1 binding protein (RYBP), a member of the polycomb group proteins, has been implicated in transcription repression and tumor cell-specific apoptosis. Previously, RYBP has been reported as a putative tumor suppressor in cancer tissues by regulating mouse double minute 2 homolog-p53 signaling. However, the exact role and underlying mechanisms of RYBP in cancer remain to be fully elucidated. The present study investigated the expression profile of RYBP in hepatocellular carcinoma (HCC) and examined the association between the expression of RYBP and metastasis of HCC. It was found that RYBP was downregulated in HCC tissues, compared with matched adjacent non-tumor tissues, as detected by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. In addition, Kaplan-Meier survival analysis showed that the negative expression of RYBP was associated with decreased overall survival rates in patients with HCC. It was also found that RYBP was associated with zinc finger E-box binding homeobox 1 and zinc finger E-box binding homeobox 2, which were overexpressed in HCC and correlated with epithelial-mesenchymal transition. The results of the present study suggested the importance of RYBP in HCC and its possible mechanism in the metastasis of HCC.

Although the application of multiple chemotherapy brought revolutionary changes to improve overall survival of osteosarcoma patients, the existence of multidrug resistance (MDR) has become a great challenge for successful osteosarcoma treatment in recent decades. Substantial studies have revealed various underlying mechanisms of MDR in cancers. As for osteosarcoma, evidence has highlighted that microRNAs (miRNAs) can mediate in the processes of DNA damage response, apoptosis avoidance, autophagy induction, activation of cancer stem cells, and signal transduction. Besides, these drug resistance‐related miRNAs showed much promise for serving as candidates for predictive biomarkers of poor outcomes and shorter survival time, and therapeutic targets to reverse drug resistance and overcome treatment refractoriness. This review aims to demonstrate the potential molecular mechanisms of miRNAs‐regulated drug resistance in osteosarcoma, and provide insight in translating basic evidence into therapeutic strategies.

Tectonic and environmental patterns and evolution of the present North Tibetan Plateau (NTP) prior to the India collision with Asia is significant to understand the formation of the Tibetan Plateau and its influence on the environment. In this study, we integrated and analyzed the tectonostratigraphy and the special sedimentary layers whose climatic implications are clear in the NTP. Additionally, we stressed the tectonic and environmental events and their evolutions from the Mesozoic to the Early Cenozoic. Our results show that four tectonic phases, which sequentially took place during the Triassic, Jurassic, Cretaceous and Paleogene, played an important role on the formation of the North Tibet. The climate was basically dry and hot from the Triassic to the Eocene and became dry and cool since the Oligocene in this region. The climatic evolution was characterized by a transition from a wet and hot phase during the Triassic – Middle Jurassic, to a dry and hot phase during the Late Jurassic – Eocene. Both phases encompassed 5 wet and hot periods followed by 5 dry and hot climate events, respectively. In addition, we found that the tectonic deformation and the climatic conditions were spatially and temporally different. In detail, in the regions north of the Paleo-Tian Shan and Paleo-Qilian Mts. the tectonic deformation and climatic condition were stronger and wetter than in regions south of the Paleo-Tian Shan and Paleo-Qilian Mts. during the Late Triassic – Jurassic. Whereas in the Cretaceous, the tectonic movement was intensive in the west but steady in the east, and climate was dry in the south but wet in the north of NTP. The formation of the tectonic and climatic patterns in NTP were the consequence of either global climate change or regional tectonics, including the Paleo-Asian Ocean closure and the Qiangtang block, Lhasa block and India plate collision subsequently to Asia. Furthermore, the regional tectonic events occurred before any global climate change and drove the climatic change in the NTP.

Vancomycin (VCM) is clinically used in treating patients with postoperative intracranial infections. The cerebrospinal fluid (CSF) concentration of VCM varies greatly among patients. To guide the dosage regimens, monitoring of VCM in CSF is needed. However a method for analysis of VCM in human CSF is lacking. An ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for analysis of VCM in human CSF, and the agreement of UPLC-MS/MS and chemiluminescence immunoassay (CLIA) in the analysis of CSF VCM was evaluated. The ion transitions were m/z 725.5 144.1 for VCM and m/z 455.2 308.2 for methotrexate (internal standard). The agreement between UPLC-MS/MS and CLIA was evaluated by Bland-Altman plot in 179 samples. The calibration range of the UPLC-MS/MS method was 1-400 mg/L. The inaccuracy and imprecision were -0.69-10.80% and4.95%. The internal standard normalized recovery and matrix factor were 86.14-99.31 and 85.84-92.07%, respectively. The measurements of CLIA and UPLC-MS/MS were strongly correlated (r 0.98). The 95% limit of agreement of the ratio of CLIA to UPLC-MS/MS was 61.66-107.40%. Further studies are warranted to confirm the results.