A Common Variant in CLDN14 is Associated with Primary Biliary Cirrhosis and Bone Mineral Density.

Primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD). These observations led us to investigate the genetic variants shared between PBC and BMD. We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8392), with replication of significant findings in a Chinese cohort (685 cases, 1152 controls). Our analysis identified a novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; one SNP rs170183 demonstrated consistent evidence of association in diverse ethnic populations (Pcombined = 2.43 × 10(-5)). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with a decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). In conclusion, our study identified a novel PBC susceptibility variant that has been shown to be strongly associated with BMD, highlighting the potential of pleiotropy to improve gene discovery

Architecture of Heptagonal Metallo-macrocycles via Embedding Metal Nodes Into Its Rigid Backbone

Metal-organic macrocycles have received increasing attention not only due to their versatile applications such as molecular recognition, compounds encapsulation, anti-bacteria and others, but also for their important role in the study of structure-property relationship at nano scale. However, most of the constructions utilize benzene ring as the backbone, which restricts the ligand arm angle in the range of 60, 120 and 180 degrees. Thus, the topologies of most metallo-macrocycles are limited as triangles and hexagons, and explorations of using other backbones with large angles and the construction of metallo-macrocycles with more than six edges are very rare. In this study, we present a novel strategy for self-assembly two giant heptagonal metallo-macrocycles with an inner diameter of 5 nm, by embedding metal nodes into the ligand backbone and regulating the ligand arm angle. By complexing with metal ions, the angle between two arms at the 4,4” position of the central terpyridine (tpy) was extended, resulting in ring expansion of the metallo-macrocycle. This approach enabled the construction of giant and more complex metallo- macrocycles that could not be achieved with traditional benzene ring backbones. The characterization of complex molecules often requires the use of multiple techniques, such as multi-dimensional and multinuclear NMR and multidimensional mass spectrometry analysis. Here, we also utilized transmission electron microscopy (TEM) and ultra-high vacuum (∼E-10 torr) low-temperature (∼77 K) scanning tunneling microscopy (UHV-LT-STM) to characterize complex supramolecules. The resulting metallo-macrocycles formed hierarchical self-assembled nanotube structures at larger densities, which is observed by TEM, while UHV-LT-STM was used for direct visualization of individual complex supramolecules deposited on an Au(111) substrate. Our findings indicate that UHV-LT-STM is an effective methodology for characterizing supramolecules at a single molecule level, providing more details of the molecular structure that is difficult to resolve by the resolution of TEM.https://digitalcommons.odu.edu/gradposters2023_sciences/1005/thumbnail.jp

Core-sheath nanofibers as drug delivery system for thermoresponsive controlled release

In this work, a smart drug delivery system of core–sheath nanofiber is reported. The core-sheath nanofibers were prepared with thermoresponsive poly-(N-isopropylacrylamide) (PNIPAAm) (as core) and hydrophobic ethylcellulose (EC) (as sheath) by coaxial electrospinning. Analogous medicated fibers were prepared by loading with a model drug ketoprofen (KET). The fibers were cylindrical without phase separation and have visible core-sheath structure as shown by scanning and transmission electron microscopy. X-ray diffraction patterns demonstrated the drug with the amorphous physical form was present in the fiber matrix. Fourier transform infrared spectroscopy analysis was conducted, finding that there were significant intermolecular interactions between KET and the polymers. Water contact angle measurements proved that the core-sheath fibers from hydrophobic transformed into hydrophobic when the temperature reached the lower critical solution temperature. In vitro drug-release study of nanofibers with KET displayed that the coaxial nanofibers were able to synergistically combine the characteristics of the two polymers producing a temperature-sensitive drug delivery system with sustained release properties. In addition, they were established to be non-toxic and suitable for cell growth. These findings show that the core–sheath nanofiber is a potential candidate for controlling drug delivery system

Alterations to the Lung Microbiome in Idiopathic Pulmonary Fibrosis Patients

Lung microbiome ecosystem homeostasis in idiopathic pulmonary fibrosis (IPF) remains uncharacterized. The aims of this study were to identify unique microbial signatures of the lung microbiome and analyze microbial gene function in IPF patients. DNA isolated from BALF samples was obtained for high-throughput gene sequencing. Microbial metagenomic data were used for principal component analysis (PCA) and analyzed at different taxonomic levels. Shotgun metagenomic data were annotated using the KEGG database and were analyzed for functional and metabolic pathways. In this study, 17 IPF patients and 38 healthy subjects (smokers and non-smokers) were recruited. For the PCA, the first and the second principal component explained 16.3 and 13.4% of the overall variability, respectively. The β diversity of microbiome was reduced in the IPF group. Signature of IPF's microbes was enriched of Streptococcus, Pseudobutyrivibrio, and Anaerorhabdus. The translocation of lung microbiome was shown that 32.84% of them were from oral. After analysis of gene function, ABC transporter systems, biofilm formation, and two-component regulatory system were enriched in IPF patients' microbiome. Here we shown the microbiology characteristics in IPF patients. The microbiome may participate in altering internal conditions and involving in generating antibiotic resistance in IPF patients

Efficacy and safety of mycophenolate mofetil and tacrolimus as second-line therapy for patients with autoimmune hepatitis

Background: Predniso(lo)ne, alone or in combination with azathioprine, is the standard of care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. Patients and methods: We performed a retrospective study of data (from 19 centres in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 months). Patients were categorized according to their response to SOC. Patients in group 1 (n=108) had a complete response to the SOC, but were switched to second line therapy due to side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n=93) had not responded to SOC. Results: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P=.639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P=.682). Significantly more group 2 patients given tacrolimus compared to MMF had a complete response (56.5 % vs. 34%, P=.029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P=.472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. Conclusions: Long-term therapy with MMF or tacrolimus was generally well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous non-responder patients compared to MMF

Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization

Mucosal-associated invariant T (MAIT) cells, a novel population of innate-like lymphocytes, have been involved in various inflammatory and autoimmune diseases. However, their role in the development of nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated the alterations of phenotype and immunological function of MAIT cells in NAFLD. Analysis of PBMCs in 60 patients with NAFLD and 48 healthy controls (HC) revealed that circulating MAIT cell frequency decreased in NAFLD, especially in the patients with higher serum levels of γ-glutamyl transferase or total triglyceride. Functional alterations of circulating MAIT cells were also detected in NAFLD patients, such as the increased production of IL-4 whereas the decreased production of IFN-γ and TNF-α. Furthermore, elevated expression of CXCR6 was observed in circulating MAIT cells of patients. Meanwhile, we found an increased number of MAIT cells in the livers of NAFLD, and the number was even greater in patients with higher NAFLD activity score. Moreover, activated MAIT cells induced monocytes/macrophages differentiation into M2 phenotype in vitro. Additionally, MAIT cells were enriched and displayed Th2 type cytokines profile in livers of wild type mice fed with methionine and choline deficient diet (MCD). Notably, mice deficient of MAIT cells exhibited more severe hepatic steatosis and inflammation upon MCD, accompanied with more CD11c+ proinflammatory macrophages (M1) and less CD206+ anti-inflammatory macrophages (M2) in livers. Our results indicate that MAIT cells protect against inflammation in NAFLD through producing regulatory cytokines and inducing anti-inflammatory macrophage polarization, which may provide novel therapeutic strategies for NAFLD

Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression

T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis

Primary biliary cholangitis: opportunities and challenges

Primary biliary cholangitis (PBC) is an autoimmune liver disease mainly involving the interlobular bile ducts and can progress to liver cirrhosis and liver failure. Early diagnosis and management can significantly improve the prognosis of such patients and their quality of life. This article focuses on the achievements of PBC research and related difficult issues in China, with reference to the clinical practice guidelines for PBC by European Association for the Study of the Liver in 2017 and experience in clinical practice