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Objective: Bile acids (BAs) are important molecules in the progression of nonalcoholic fatty liver disease. This study aimed to investigate BA profile alterations in Chinese nonalcoholic steatohepatitis (NASH) patients.Methods: BA profiles in serum and liver tissues were determined by ultraperformance liquid chromatography coupled to tandem mass spectrometry in patients from two different clinical centers.Results: A total of 134 participants were enrolled in this study to serve as the training (n = 87) and validation (n = 47) cohorts. The ratio of circulating conjugated chenodeoxycholic acids to muricholic acids (P = 0.001) was elevated from healthy controls to non-NASH individuals to NASH individuals in a stepwise manner in the training cohort and was positively associated with the histological severity of NASH: steatosis (R2  = 0.12), lobular inflammation (R2  = 0.12), ballooning (R2  = 0.11), and fibrosis stage (R2  = 0.18). The ratio was elevated in the validation cohort of NASH patients (P < 0.001), and it was able to predict NASH (area under the receiver operating characteristic curve: 75%) and significant fibrosis (area under the receiver operating characteristic curve: 71%) in these two cohorts. Moreover, this elevated ratio and impaired farnesoid X receptor signaling were found in the NASH liver.Conclusions: Altered BA profile in NASH is closely associated with the severity of liver lesions, and it has the potential for predicting NASH development. [ABSTRACT FROM AUTHOR]

As the evolutionary ancestor of Cas9 nuclease, IscB proteins serve as compact RNA-guided DNA endonucleases and nickases, making them strong candidates for base editing. Nevertheless, the narrow targeting scope limits the application of IscB systems; thus, it is necessary to find more IscBs that recognize different target-adjacent motifs (TAMs). Here, we identified 10 of 19 uncharacterized IscB proteins from uncultured microbes with activity in mammalian cells. Through protein and ωRNA engineering, we further enhanced the activity of IscB ortholog IscB.m16 and expanded its TAM scope from MRNRAA to NNNGNA, resulting in a variant named IscB.m16*. By fusing the deaminase domains with IscB.m16* nickase, we generated IscB.m16*-derived base editors that exhibited robust base-editing efficiency in mammalian cells and effectively restored Duchenne muscular dystrophy proteins in diseased mice through single adeno-associated virus delivery. Thus, this study establishes a set of compact base-editing tools for basic research and therapeutic applications., (© 2024. The Author(s).)

Targeted delivery of anti-cancer drugs is a highly desirable strategy to improve therapeutic outcome because of the combination of enhanced efficacy and reduced toxicity. In this study, the anti-cancer drug doxorubicin (DOX) was accommodated in the cores of polymeric micelles self-assembled from amphiphilic block copolymers of poly(ethylene glycol)(PEGs) and poly(D,L-lactide) (PDLLA) with a targeting ligand (folate) attached to the distal ends of the PEG (Folate-PEG-PDLLA). In vitro tumor cell targeting efficacy was evaluated upon observing cellular uptake of these micelles by human hepatic carcinoma cells (Bel 7402 cells) overexpressing surface receptors for folate. In control release tests, DOX behavior of controlled release in folate receptor-mediated micellar folate-PEG-PDLLA-DOX-micelles was obvious, with pH sensitivity. Bel 7402 cells showed micelles to have low toxicity and suggested potential therapeustic application as a multifunctional platform for tumor management.

Objective: This work was done to compare the validity of various imaging methods, e.g. ultrasonography (US), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), and, especially, magnetic resonance cholangiopancreatography (MRCP) for extrahepatic bile duct carcinoma., Methods: Sixty-five such patients who were operated and confirmed by pathology were used. Sixty patients had been examined by US; 52 by CT; 20 by ERCP; 9 by PTC and 20 by MRCP. The results of these imaging methods were compared with those of operative and pathological findings., Results: The diagnostic accuracy rates of site location were US 81.7%, CT 84.6%, ERCP 75.0%, PTC 88.9% and MRCP 100%, respectively. The quality diagnostic accuracy rates were US 73.3%, CT 82.7%, ERCP 75.0%, PTC 88.9% and MRCP 95.0%, respectively., Conclusion: MRCP is superior to US, CT, ERCP and PTC not only in demonstrating the position but also the nature of extrahepatic bile duct carcinoma.