15 research outputs found
A Comparative Analysis of High-Speed Rail Station Development into Destination and Multi-Use Facilities: The Case of San Jose Diridon
As a burgeoning literature on high-speed rail development indicates, good station-area planning is a very important prerequisite for the eventual successful operation of a high-speed rail station; it can also trigger opportunities for economic development in the station area and the station-city. At the same time, “on the ground” experiences from international examples of high-speed rail stations can provide valuable lessons for the California high-speed rail system in general, and the San Jose Diridon station in particular. This study identifies and draws lessons from European HSR stations that share similarities across several criteria with the San Jose area context. From an initial consideration of twenty European HSR stations, the researchers chose five stations for in depth case studies: Euralille and Lyon Part Dieu in France, Rotterdam Centraal and Utrecht Centraal in the Netherlands, and Torino Porta Susa in Italy. Additionally, the study drew information from relevant local actors and stakeholders to better tailor recommendations to the particular California context.Through the undertaking of different research tasks–literature review, case studies of European railway stations, survey of existing station plans and other planning documents for the Diridon station, station area analysis, and interviews with station area planners and designers–the study compiles timely recommendations for the successful planning of the Diridon station and other stations along the California high-speed rail corridor
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Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2.
Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these non-neutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies
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Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.
Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy