Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.

Abstract. We examine the onset of classical topological order in a nearest-neighbor kagome ice model. Using Monte Carlo simulations, we characterize the topological sectors of the groundstate using a non-local cut measure which circumscribes the toroidal geometry of the simulation cell. We demonstrate that simulations which employ global loop updates that are allowed to wind around the periodic boundaries cause the topological sector to fluctuate, while restricted local loop updates freeze the simulation into one topological sector. The freezing into one topological sector can also be observed in the susceptibility of the real magnetic spin vectors projected onto the kagome plane. The ability of the susceptibility to distinguish between fluctuating and non-fluctuating topological sectors should motivate its use as a local probe of topological order in a variety of related model and experimental systems.

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Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are life-threatening illnesses requiring intensive care admission and potentially liver transplantation. Artificial extracorporeal liver support (ECLS) systems remove water-soluble and albumin-bound toxins to maintain normal serum chemistry, prevent further hepatic/organ system damage, and create an environment for potential hepatic regeneration/recovery (ALF) or bridge to liver transplantation (ALF and ACLF). Use of artificial ECLS has been studied in both ALF and ACLF. Artificial ECLS systems have been found to be safe and have demonstrated the following benefits: improvement of biochemistries, hemodynamic status, and hepatic encephalopathy. Despite this, only one prospective randomized controlled trial examining the use of high-volume plasma exchange has demonstrated improvement in transplant-free survival. Bioartificial (cell-based) ECLS systems build on the technology of artificial systems, incorporating living hepatocytes in a bioactive platform to further mimic endogenous hepatic detoxification and synthetic functions. Currently, no bioartificial system has been found to confer a mortality benefit; however, these platforms offer the greatest potential for future development.