Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections. (ClinicalTrials.gov number, NCT00034645 [ClinicalTrials.gov].).
VIPERdb (http://viperdb.scripps.edu) is a relational database and a web portal for icosahedral virus capsid structures. Our aim is to provide a comprehensive resource specific to the needs of the virology community, with an emphasis on the description and comparison of derived data from structural and computational analyses of the virus capsids. In the current release, VIPERdb2, we implemented a useful and novel method to represent capsid protein residues in the icosahedral asymmetric unit (IAU) using azimuthal polar orthographic projections, otherwise known as Φ–Ψ (Phi–Psi) diagrams. In conjunction with a new Application Programming Interface (API), these diagrams can be used as a dynamic interface to the database to map residues (categorized as surface, interface and core residues) and identify family wide conserved residues including hotspots at the interfaces. Additionally, we enhanced the interactivity with the database by interfacing with web-based tools. In particular, the applications Jmol and STRAP were implemented to visualize and interact with the virus molecular structures and provide sequence–structure alignment capabilities. Together with extended curation practices that maintain data uniformity, a relational database implementation based on a schema for macromolecular structures and the APIs provided will greatly enhance the ability to do structural bioinformatics analysis of virus capsids.
HslUV is a "prokaryotic proteasome" composed of the HslV protease and the HslU ATPase, a chaperone of the Clp/Hsp100 family. The 3.4 A crystal structure of an HslUV complex is presented here. Two hexameric ATP binding rings of HslU bind intimately to opposite sides of the HslV protease; the HslU "intermediate domains" extend outward from the complex. The solution structure of HslUV, derived from small angle X-ray scattering data under conditions where the complex is assembled and active, agrees with this crystallographic structure. When the complex forms, the carboxy-terminal helices of HslU distend and bind between subunits of HslV, and the apical helices of HslV shift substantially, transmitting a conformational change to the active site region of the protease.
Self-assembly of viral proteins into icosahedral capsids is an interesting yet poorly understood phenomenon of which elucidation may aid the exploration of beneficial applications of capsids in materials science and medicine. Using molecular dynamics simulations of coarse-grained models for capsid proteins, we show that the competition between the formation of full capsids and nonidealized structures is strongly dependent upon the protein concentration and temperature, occurring kinetically as a cascade of elementary reactions in which free monomers are added to the growing oligomers on a downhill free-energy landscape. However, the insertion of the final subunits is the rate-limiting, energetically unfavorable step in viral capsid assembly. A phase diagram has been constructed to show the regions where capsids or nonidealized structures are stable at each concentration and temperature. We anticipate that our findings will provide guidance in identifying suitable conditions required for in vitro viral capsid assembly experiments.
Although transplant practices have changed over the last decades there is no information on trends in incidence and outcome of cGVHD over time. This study utilized the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe the time trends for cGVHD incidence, non-relapse mortality, and the risk factors for cGVHD. The 12-year period was divided into three intervals: 1995-1999, 2000-2003, 2004-2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndrome. In the multivariate analysis, the incidence of cGVHD was shown to be increased in more recent years (odds ratio= 1.19, p<0.0001) and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, non-relapse mortality has decreased over time, but at 5-years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.
Rational development of adenovirus vectors for therapeutic gene transfer is hampered by the lack of accurate structural information. Here we report the X-ray structure at 3.5 Å resolution of the 150 megadalton adenovirus capsid containing nearly 1 million amino acids. We describe interactions between the major capsid protein (hexon) and several accessory molecules that stabilize the capsid. The virus structure also reveals an altered association between the penton base and the trimeric fiber protein, perhaps reflecting an early event in cell entry. The high-resolution structure provides a significant advance towards understanding the assembly and cell entry mechanisms of a large dsDNA virus and provides new opportunities for improving adenovirus-mediated gene transfer.Human adenoviruses (HAdV) are non-enveloped dsDNA viruses that are associated with acute infections (1-3). While these infections are generally self-limiting, the re-emergence of certain HAdV types has also been linked to potentially fatal respiratory infections in both civilian and military populations (4). Severe disseminated diseases also occur in patients receiving bone marrow-derived stem cells (5,6). In addition to their disease associations, replication-defective or conditionally replicating HAdVs continue to be evaluated in ~25% of approved Phase I-III clinical trials for vaccine and therapeutic gene transfer (7,8). However, the lack of accurate details of the virus structure limits the re-engineering of HAdV vectors and prevents a better understanding of the virus life cycle. High resolution HAdV structure determination presents a challenge because of the large size (910 Å ave. dia., 150 MDa) and complexity (pseudo-T=25) of the virus. The crystal structures of the major HAdV capsid proteins; the fiber (9), penton base (PB) (10) and hexon (11) have been solved. The hexon and penton base crystal structures were subsequently used to derive pseudo-atomic models of the HAdV capsid at moderately high resolution (7-10 Å) (12-14) by cryoelectron microscopy (cryoEM). CryoEM structural analyses provided considerable insight into HAdV organization; however, they did not furnish detailed information on the interactions between the major and accessory (cement) proteins (IIIa,VI,VIII, and IX).We report here the crystal structure of a recombinant HAdV-5 vector, designated Ad35F, that is equipped with a short and flexible fiber protein derived from . Details of the crystallization (16), diffraction data statistics (Table S1) and structure determination of Ad35F at near atomic resolution (3.5 Å) are described in the Methods (17).The architecture of the HAdV capsid is shown in Fig. 1a, b. The hexon is the most abundant protein in the capsid with 720 subunits arranged as 240 trimers on a pseudo-T=25 icosahedral * "This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any ma...
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