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Membrane remodeling is a common theme in a wide variety of cellular processes. Here we investigated membrane remodeling N-BAR protein endophilin B1, a critical player in diverse intracellular trafficking events, including mitochondrial and Golgi fission, autophagy and apoptosis. We find that endophilin B1 assembles into helical scaffolds on model membranes, and that both membrane binding and assembly are driven by interactions between N-terminal helix H0 and the lipid bilayer. Furthermore, we find that endophilin B1 membrane remodeling is auto-inhibited and identify direct SH3 domain–H0 interactions as the underlying mechanism. Our results indicate that lipid composition plays a role in dictating endophilin B1 binding and remodeling activity. Taken together, this study provides novel insight into a poorly understood member of the N-BAR protein family and highlights molecular mechanisms that may be general for the regulation of membrane remodeling. Our work suggests that interplay between membrane lipids and membrane interacting proteins facilitates spatial and temporal coordination of membrane remodeling.

Background Preliminary evidence of safety and efficacy of an extracorporeal cellular therapy (ELAD®) has been demonstrated in subjects with acute forms of liver failure. This study compared ELAD with standard of care in Chinese subjects with acute-on-chronic liver failure (ACLF), predominantly secondary to chronic viral hepatitis. Subjects and methods Subjects meeting eligibility criteria were randomized to either the ELAD group or the control group. All subjects received plasma exchange and venovenous hemofiltration and either ELAD treatment for 3–5 days, unless terminated early, along with standard of care or standard of care alone (control) and were then followed up for 12 weeks. Results Forty-nine subjects (ELAD subjects, 32; controls, 17) were randomized under this protocol. Kaplan–Meier analysis of transplant-free survival (TFS) revealed a significant difference in favor of ELAD vs control (P=0.049, Wilcoxon signed-rank test). There was a significant difference in TFS on day 28 in ELAD vs control (P=0.022). In a multiple regression model, the relationship between group assignment and outcome was significant (P=0.031) when changes in food intake and Model for End-Stage Liver Disease (MELD) scores at screening were included as additional independent variables. The duration of ELAD treatment alone was a significant predictor of TFS (P=0.043). Median time to a 5-point increase in MELD, transplant, or death was longer than 72 days with ELAD vs 26 days for control (P=0.036). Total bilirubin level decreased by 25% during ELAD treatment vs 37% increase in the control group (P

Zhongping Duan,1,* Shaojie Xin,2,* Jing Zhang,1 Shaoli You,2 Yu Chen,1 Hongling Liu,2 Sujun Zheng,1 Zheng Li,3 Robert Ashley,3 Michael Millis4 1Artificial Liver Center, Beijing You’an Hospital of Capital Medical University, Beijing, China; 2Department of Infectious Disease, Division III, 302 Military Hospital of China, Beijing, China; 3Research and Development, Vital Therapies, Inc, San Diego, CA, USA; 4Department of Surgery, University of Chicago, Chicago, IL, USA *These authors contributed equally to this work Background: Preliminary evidence of safety and efficacy of an extracorporeal cellular therapy (ELAD®) has been demonstrated in subjects with acute forms of liver failure. This study compared ELAD with standard of care in Chinese subjects with acute-on-chronic liver failure (ACLF), predominantly secondary to chronic viral hepatitis.Subjects and methods: Subjects meeting eligibility criteria were randomized to either the ELAD group or the control group. All subjects received plasma exchange and venovenous hemofiltration and either ELAD treatment for 3–5 days, unless terminated early, along with standard of care or standard of care alone (control) and were then followed up for 12 weeks.Results: Forty-nine subjects (ELAD subjects, 32; controls, 17) were randomized under this protocol. Kaplan–Meier analysis of transplant-free survival (TFS) revealed a significant difference in favor of ELAD vs control (P=0.049, Wilcoxon signed-rank test). There was a significant difference in TFS on day 28 in ELAD vs control (P=0.022). In a multiple regression model, the relationship between group assignment and outcome was significant (P=0.031) when changes in food intake and Model for End-Stage Liver Disease (MELD) scores at screening were included as additional independent variables. The duration of ELAD treatment alone was a significant predictor of TFS (P=0.043). Median time to a 5-point increase in MELD, transplant, or death was longer than 72 days with ELAD vs 26 days for control (P=0.036). Total bilirubin level decreased by 25% during ELAD treatment vs 37% increase in the control group (P

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.