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Background & Aims: There is an unmet clinical need for non‐invasive tests to diagnose non‐alcoholic fatty liver disease (NAFLD) and individual fibrosis stages. We aimed to test whether urine protein panels could be used to identify NAFLD, NAFLD with fibrosis (stage F ≥ 1) and NAFLD with significant fibrosis (stage F ≥ 2). Methods: We collected urine samples from 100 patients with biopsy‐confirmed NAFLD and 40 healthy volunteers, and proteomics and bioinformatics analyses were performed in this derivation cohort. Diagnostic models were developed for detecting NAFLD (UPNAFLD model), NAFLD with fibrosis (UPfibrosis model), or NAFLD with significant fibrosis (UPsignificant fibrosis model). Subsequently, the derivation cohort was divided into training and testing sets to evaluate the efficacy of these diagnostic models. Finally, in a separate independent validation cohort of 100 patients with biopsy‐confirmed NAFLD and 45 healthy controls, urinary enzyme‐linked immunosorbent assay analyses were undertaken to validate the accuracy of these new diagnostic models. Results: The UPfibrosis model and the UPsignificant fibrosis model showed an AUROC of.863 (95% CI:.725–1.000) and 0.858 (95% CI:.712–1.000) in the training set; and.837 (95% CI:.711–.963) and.916 (95% CI:.825–1.000) in the testing set respectively. The UPNAFLD model showed an excellent diagnostic performance and the area under the receiver operator characteristic curve (AUROC) exceeded.90 in the derivation cohort. In the independent validation cohort, the AUROC for all three of the above diagnostic models exceeded.80. Conclusions: Our newly developed models constructed from urine protein biomarkers have good accuracy for non‐invasively diagnosing liver fibrosis in NAFLD. [ABSTRACT FROM AUTHOR]

In this article, molecular dynamics simulation is used to primarily explore the lattice matching problem of solute atoms in different configurations after entering the Fe lattice at 0 K temperature. It reveals that by changing the initial configurations, metal solute atoms (Cr, Cu, Ti, Al) are more stable in the <110> configuration while C atom tends to stay in the octahedral gap of the BCC lattice. In addition, the matching mechanisms of different solute atoms in BCC Fe lattice in different configurations are elaborated in detail. The relaxation of metal solute atoms in different configurations eventually forms different stable structures while C atoms only exist in the nearest‐neighbor octahedral gap of the BCC Fe lattice in each configuration. [ABSTRACT FROM AUTHOR]

Semaphorin 7A (SEMA7A) is a membrane‐bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC‐MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance‐associated protein‐2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression. SYNOPSIS: A new type of progressive familial intrahepatic cholestasis (PFIC) was caused by the homozygous R148W mutation in SEMA7A. Preliminary mechanistic studies revealed that the mutation reduced hepatic expression of canalicular membrane bile acid (BA) efflux transporters Bsep and Mrp2, resulting in intrahepatic cholestasis. A female child patient presented with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology.A SEMA7AR148W homozygous mutation was identified in the child patient.The Sema7aR145W (human R148W) homozygous mice displayed elevated levels of serum ALT, AST, and TBA, as well as hepatocyte hydropic degeneration and intrahepatic accumulation of conjugated BAs.The Sema7aR145W homozygous mutation reduced the expression of canalicular membrane Bsep and Mrp2 in mouse livers and sandwich‐cultured primary hepatocytes.Administration with ursodeoxycholic acid (UDCA) and a dietary supplement glutathione (GSH) were effective for this new type of PFIC. [ABSTRACT FROM AUTHOR]

We report here, for the first time, that interleukin 32 (IL32) expression is elevated in the liver of patients with obstructive cholestasis, and its upregulation ameliorates cholestatic liver injury by repressing bile acid (BA) synthesis and the inflammatory response. Cholestasis is characterized by excessive accumulation of intrahepatic BA that causes liver injury and inflammation.1,2 IL32, a predominantly intracellular proinflammatory mediator, is involved in infectious diseases and cancers,3-7 but at present, its role in cholestasis remains unknown. To reveal how IL32 represses BA synthesis in cholestasis, we assessed the expression of major genes involved in the biosynthesis and transportation of BA. Together, these data indicate that hepatic IL32 can ameliorate cholestatic liver injury by repressing BA synthesis and liver inflammation. [Extracted from the article]