Lipid-enveloped viruses replicate and bud from the host cell where they acquire their lipid coat. Ebola virus, which buds from the plasma membrane of the host cell, causes viral hemorrhagic fever and has a high fatality rate. To date, little has been known about how budding and egress of Ebola virus are mediated at the plasma membrane. We have found that the lipid phosphatidylserine (PS) regulates the assembly of Ebola virus matrix protein VP40. VP40 binds PS-containing membranes with nanomolar affinity, and binding of PS regulates VP40 localization and oligomerization on the plasma membrane inner leaflet. Further, alteration of PS levels in mammalian cells inhibits assembly and egress of VP40. Notably, interactions of VP40 with the plasma membrane induced exposure of PS on the outer leaflet of the plasma membrane at sites of egress, whereas PS is typically found only on the inner leaflet. Taking the data together, we present a model accounting for the role of plasma membrane PS in assembly of Ebola virus-like particles. IMPORTANCEThe lipid-enveloped Ebola virus causes severe infection with a high mortality rate and currently lacks FDA-approved therapeutics or vaccines. Ebola virus harbors just seven genes in its genome, and there is a critical requirement for acquisition of its lipid envelope from the plasma membrane of the human cell that it infects during the replication process. There is, however, a dearth of information available on the required contents of this envelope for egress and subsequent attachment and entry. Here we demonstrate that plasma membrane phosphatidylserine is critical for Ebola virus budding from the host cell plasma membrane. This report, to our knowledge, is the first to highlight the role of lipids in human cell membranes in the Ebola virus replication cycle and draws a clear link between selective binding and transport of a lipid across the membrane of the human cell and use of that lipid for subsequent viral entry. Lipid-enveloped viruses harbor a lipid membrane bilayer derived from their host cell during the budding process. This envelope provides the virus stability, protection of its genetic contents, and a reservoir for its transmembrane glycoprotein, which mediates entry into cells (1, 2). The viral lipid envelope may be a viable target for drug development, as particular alterations in the lipid coat or receptor-lipid interaction can inhibit viral entry (3-6). The lipid-dependent budding and egress of some lipid-enveloped viruses have been investigated. For example, it is well established that HIV-1 binds and utilizes 1,2-dioleoyl-sn-glycero-3-phospho-(1=-myo-inositol-4=,5=-bisphosphate) [PI(4,5)P 2 ] enriched in the plasma membrane (PM) inner leaflet for assembly and egress from the cell (7,8). Enteroviruses and flaviviruses use a phosphatidylinositol-4-phosphate [PI(4)P]-enriched organelle to replicate (9), and enteroviruses are packaged into phosphatidylserine (PS)-enriched vesicles, thereby enhancing the efficiency of viral transmission (10). The budding and egres...

Black patients have higher mortality and are less likely to receive liver transplantation for hepatocellular carcinoma (HCC) than white patients. Reasons for these disparities have not been fully elucidated. Comorbid disease, liver disease severity, cirrhosis etiologies, and tumor characteristics were compared between black and white patients with HCC seen at the Indiana University Academic Medical Center from January 2000 to June 2014. Logistic regression was used to investigate the primary outcome, which was liver transplantation. Log‐rank testing was used to compare survival between the two groups. Subgroup analysis explored reasons for failure to undergo liver transplantation in patients within Milan criteria. The cohort included 1,032 (86%) white and 164 (14%) black patients. Black and white patients had similar Model for End‐Stage Liver Disease (MELD) and Child‐Pugh scores (CPSs). There was a trend toward larger tumor size (5.3 cm versus 4.7 cm; P = 0.05) in black patients; however, Barcelona Clinic Liver Cancer (BCLC) staging and Milan criteria were similar. Black patients were less likely to undergo liver transplantation than white patients; this was a disparity that was not attenuated (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.21‐0.90) on multivariable analysis. Substance abuse was more frequently cited as the reason black patients within Milan criteria failed to undergo transplantation compared to white patients. Survival was similar between the two groups. Conclusion: Racial differences in patient and tumor characteristics were small and did not explain the disparity in liver transplantation. Higher rates of substance abuse in black patients within Milan criteria who failed to undergo transplantation suggest social factors contribute to this disparity in this cohort.

Background: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood. Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design. Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case. Results: Out of 1,250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men, and 100% Caucasian. 10% of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, P=0.049), with longer AIH duration (median 16 years vs. 5 years, P=0.004). Prolonged AIH duration (OR 1.68, p=0.006) and older age (OR 1.15, p=0.049) were risk factors for HCC. Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern United States with a decreasing trend over 14.5 years. 10% of AIH-HCC patients occurs without cirrhosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC.

Reduced miR-26a expression is a common phenomenon in HCC arising in North American patients with different underlying liver diseases and may increase recurrence and mortality after surgery.

Paired helical filaments (PHFs) constitute the majority of filaments in neurofibrillary tangles (NFTs), an Alzheimer's disease (AD) characteristic. PHFs consists of two filaments helically twisted around one another in a regular pattern. The effects of possible PHF-inducing candidates, namely aluminium and glutamate, were observed at the ultrastructural level in this investigation. Rat cerebral explants were exposed to aluminium, citric acid and glutamate singly or combined from 7-12 days in vitro (DIV), while control explants remained in basal medium. On 12 DIV, explants were processed for EM. Three-four EM explants were serially sectioned per condition. Ten 60 nm sections from five systematically sampled areas per explant were collected. One section was randomly chosen per sampled area and all neurons within it observed at 81,200x to record the presence of accumulations of curved filaments (CFs), straight filaments (SFs) or PHFs. Using stereological methods, absolute numbers and the percentage incidence of CFs and SFs were calculated. A significant increase in the frequency of neurons containing CF aggregations in aluminium explants compared to glutamate explants was found. There were no significant differences between conditions for neurons containing SF accumulations. Possible PHFs were observed in one aluminium/glutamate-treated explant. These results suggest that aluminium alone can cause significant formation of accumulations of C- or S-shaped CFs, some of which are double-stranded and twisted around one another regularly. However, structures that were possibly PHF-like were only observed in one aluminium-treated explant, thus making it premature to draw an association between aluminium and the induction of AD-like pathology.

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Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related death in the United States. Colonoscopy and fecal immunochemistry testing are the primary recommended CRC screening modalities. The purpose of this study is to improve rates of CRC screening in Veterans and County hospital patients referred to gastroenterology fellow's clinics. A total of 717 patients between the ages of 49 and 75 (mean 62.0 ± 6.5) were seen. Prior CRC screening was not done in 109 (15.2%) due to not being offered (73.4%) or declining (26.6%) screening. Patients who received prior CRC screening compared to no prior screening were older (mean age 62.3 ± 6.4 vs 60.3 ± 6.8, p=0.003), white race (88.6% vs 78.3%, p=0.027), and more likely to be Veterans patients (90.8% vs 77.5%, p<0.001). After systematically discussing options for screening with 78 of the 109 unscreened patients, 56 of them (71.8%) underwent screening with either colonoscopy (32) or FIT (24). Patients seen by fellows in their last year of training agreed to undergo screening more often than those seen by other fellows (100% vs 66.2%, p=0.033). Systematic discussions about both colonoscopy and FIT can improve overall rates of CRC screening.