9 research outputs found
A new era for understanding amyloid structures and disease
The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention
Should the dilated ascending aorta be repaired at the time of bicuspid aortic valve replacement?
OBJECTIVES Bicuspid aortic valve (BAV) is the most common congenital valvular abnormality and frequently presents with accelerated calcific aortic valve disease, requiring aortic valve replacement (AVR) and thoracic aortic aneurysm and dissection. Supporting evidence for Association Guidelines of aortic dimensions for aortic resection is sparse. We sought to determine whether concurrent repair of dilated or aneurysmal aortic disease during AVR in patients with BAV substantially improves morbidity and mortality outcomes. METHODS Mortality and reoperation outcomes of 1301 adults with BAV and dilated aorta undergoing AVR-only surgery were compared to patients undergoing AVR with aortic resection (AVR-AR) using Cox proportional hazards modelling and patient matching. RESULTS Clinically important differences in patient characteristics, aortic valve function and aortic dimensions were identified between cohorts. Event rates were low, with rates of reoperation and death within 1 year of only 1.8% and 5.4%, respectively, and no aortic dissection observed during follow-up. There were no significant differences in reoperation or mortality outcomes between the AVR-only and AVR-AR cohorts. Age, aortic dimension or a combination thereof was not associated with better or worse outcomes after each AVR-AR compared with AVR. CONCLUSIONS We conclude AVR-only and AVR-AR surgery have low morbidity and mortality and have utility over a wide range of age and aortic sizes. Our results do not provide support for the 45-mm aortic dimension recommended in the current guidelines for aortic resection while performing AVR or any other specific dimension
Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V
Predicting Functions of Disordered Proteins with MoRFpred
Intrinsically disordered proteins and regions are involved in a wide range of cellular functions, and they often facilitate protein-protein interactions. Molecular recognition features (MoRFs) are segments of intrinsically disordered regions that bind to partner proteins, where binding is concomitant with a transition to a structured conformation. MoRFs facilitate translation, transport, signaling, and regulatory processes and are found across all domains of life. A popular computational tool, MoRFpred, accurately predicts MoRFs in protein sequences. MoRFpred is implemented as a user-friendly web server that is freely available at http://biomine.cs.vcu.edu/servers/MoRFpred/. We describe this predictor, explain how to run the web server, and show how to interpret the results it generates. We also demonstrate the utility of this web server based on two case studies, focusing on the relevance of evolutionary conservation of MoRF regions