Structures of the Hepaci-, Pegi-, and Pestiviruses envelope proteins suggest a novel membrane fusion mechanism.

Enveloped viruses encode specialised glycoproteins that mediate fusion of viral and host membranes. Discovery and understanding of the molecular mechanisms of fusion have been achieved through structural analyses of glycoproteins from many different viruses, and yet the fusion mechanisms of some viral genera remain unknown. We have employed systematic genome annotation and AlphaFold modelling to predict the structures of the E1E2 glycoproteins from 60 viral species in the Hepacivirus, Pegivirus, and Pestivirus genera. While the predicted structure of E2 varied widely, E1 exhibited a very consistent fold across genera, despite little or no similarity at the sequence level. Critically, the structure of E1 is unlike any other known viral glycoprotein. This suggests that the Hepaci-, Pegi-, and Pestiviruses may possess a common and novel membrane fusion mechanism. Comparison of E1E2 models from various species reveals recurrent features that are likely to be mechanistically important and sheds light on the evolution of membrane fusion in these viral genera. These findings provide new fundamental understanding of viral membrane fusion and are relevant to structure-guided vaccinology.

Degenerative Mitral Valve Repair Simplified: An Evolution to Universal Artificial Cordal Repair.

BACKGROUND: Resectional and artificial cordal repair techniques are effective strategies for degenerative mitral valve (MV) repair. However, resectional repair requires a tailored approach using various techniques, whereas cordal repair offers a simpler, easily reproducible repair. The approach described in this study approach has evolved from resectional to cordal over time, and outcomes are compared between the eras. METHODS: Clinical and echocardiographic outcomes of all patients undergoing MV repair for degenerative mitral regurgitation (MR) from January 2004 to September 2017 were reviewed. Patients were stratified by era: from January 2004 to June 2011 (era 1; n = 405), resectional techniques were used in 62% and artificial cordal techniques were used in 38%. From July 2011 to September 2017 (era 2; n = 438), artificial cordal repair was used in 98% of patients. The primary outcome was repair failure, defined as greater than moderate MR or MV reoperation. RESULTS: Of 847 patients with degenerative MR, successful repair was achieved in 843 patients (99.5% repair rate). Leaflet prolapse was posterior in 66%, anterior in 8%, and bileaflet in 26%. Cardiopulmonary bypass time and cross-clamp times were shorter in era 2 (CPB: 109 [IQR, 92-128] minutes vs 97 [IQR, 76-121] minutes; P < .001; cross-clamp: 88 [IQR, 73-106] minutes vs. 79 [IQR, 61-99] minutes; P < .001). Predismissal echocardiography demonstrated no MR or trace MR in 95%, mild MR in 4.7%, and moderate MR in 0.3% of patients. Operative mortality was similar in the eras (0.5% vs 0.5%; P > .999). The rates of 5-year freedom from repair failure (95.1% vs 95.5%; P = .707), stroke (96.8% vs 95.3%; P = .538), and endocarditis (99.3% vs 99.7%; P = .604) were similar between the eras. CONCLUSIONS: Artificial cordal repair for all patients with degenerative MR simplifies MV repair and yields equivalent, excellent outcomes compared with a tailored resectional approach.

Diffuse large B-cell lymphoma recurrence presenting as multiple, progressive cranial neuropathies.

A 58-year-old man with a history of rheumatoid arthritis and stage IV diffuse large B-cell lymphoma, in complete remission with no evidence of residual disease on positron emission tomography/CT after completing six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy, presented with acute onset of dysphagia to solids and liquids. On further evaluation, his dysphagia was attributed to a vagus nerve palsy, and later during his admission, he developed rapidly progressing left facial and vestibulocochlear nerve palsies. Imaging studies displayed pathological enhancement of bilateral seventh and eighth cranial nerves, concerning for leptomeningeal recurrence of lymphoma. Cerebrospinal fluid analysis and flow cytometry were confirmatory, revealing markedly atypical monotypic CD19 positive B cells.

Laparoscopic Subxiphoid Hernia Repair with Intracorporeal Suturing of Mesh to the Diaphragm as a Means to Decrease Recurrence.

BACKGROUND: Subxiphoid hernias are a rare complication of median sternotomy with an incidence of 1%-4.2%. Repair of subxiphoid hernias is technically demanding with recurrence rates of 42% and 30% following open and laparoscopic repairs, respectively. We present a novel approach to the laparoscopic repair of subxiphoid hernias with improved overlap and fixation. MATERIALS AND METHODS: A novel technique for repairing subxiphoid hernias is described. The falciform ligament is dissected superiorly toward the diaphragm to allow proper subfascial positioning of the mesh with adequate overlap. Multiple nonabsorbable intracorporeal sutures are used to anchor the mesh to the diaphragm above the costal margins. Transfascial nonabsorbable sutures and tacks are used to fix the mesh to the anterior abdominal wall below the costal margin. RESULTS: We have used this method in 4 patients with a mean age of 60.5 years and a female to male ratio of 4:0. The average hernia defect size was 20.5 cm(2), and the average duration of operation was 93 minutes. There were no reported postoperative complications or evidence of recurrence at the 1-year follow-up. CONCLUSIONS: Laparoscopic repair of subxiphoid hernias can be safely accomplished with mesh sutured to the diaphragm for improved overlap and fixation with the goal of reducing recurrence rates.

Network-based criterion for the success of cooperation in an evolutionary prisoner's dilemma.

We consider an evolutionary prisoner's dilemma on a random network. We introduce a simple quantitative network-based parameter and show that it effectively predicts the success of cooperation in simulations on the network. The criterion is shown to be accurate on a variety of networks with degree distributions ranging from regular to Poisson to scale free. The parameter allows for comparisons of random networks regardless of their underlying topology. Finally, we draw analogies between the criterion for the success of cooperation introduced here and existing criteria in other contexts.

Cooperation in an evolutionary prisoner's dilemma on networks with degree-degree correlations.

We study the effects of degree-degree correlations on the success of cooperation in an evolutionary prisoner's dilemma played on a random network. When degree-degree correlations are not present, the standardized variance of the network's degree distribution has been shown to be an accurate analytical measure of network heterogeneity that can be used to predict the success of cooperation. In this paper, we use a local-mechanism interpretation of standardized variance to give a generalization to graphs with degree-degree correlations. Two distinct mechanisms are shown to influence cooperation levels on these types of networks. The first is an intrinsic measurement of base-line heterogeneity coming from the network's degree distribution. The second is the increase in heterogeneity coming from the degree-degree correlations present in the network. A strong linear relationship is found between these two parameters and the average cooperation level in an evolutionary prisoner's dilemma on a network.

Evolution of cooperation through the heterogeneity of random networks.

We use the standardized variance (nu_{st}) of the degree distribution of a random network as an analytic measure of its heterogeneity. We show that nu_{st} accurately predicts, quantitatively, the success of cooperators in an evolutionary prisoner's dilemma. Moreover, we show how the generating functional expression for nu_{st} suggests an intrinsic interpretation for the heterogeneity of the network that helps explain local mechanisms through which cooperators thrive in heterogeneous populations. Finally, we give a simple relationship between nu_{st} , the cooperation level, and the epidemic threshold of a random network that reveals an appealing connection between epidemic disease models and the evolutionary prisoner's dilemma.