Insights into varicella-zoster virus assembly from the B-and C-capsid at near-atomic resolution structures

Varicella-zoster is a highly communicable virus that can be transmitted through the airborne route.About one quarter of people are infected with this virus.Previous studies have described the structure of A-capsid and a blurred reconstruction of the C-capsid with icosahedral symmetry.In this study,we have determined the more precise detailed structures of the varicella-zoster virus(VZV)B-and C-capsid in icosahedral symmetry using a combination of block-based reconstruction and symmetry relaxation strategies.In addition,we are reporting structural details of the portal vertex reconstructions in five-fold symmetry and portal reconstructions in twelve-fold symmetry.The structures unveil the basis for the high thermal stability of the VZV capsid.The conformational flexibility of structural elements of the capsid plays a role in the assembly of the capsid and drives processes critical for the viral life cycle.The results of the study open up new avenues for the development of drugs against a highly prevalent and contagious pathogen.

High-affinity mutant Interleukin-13 targeted CAR T cells enhance delivery of clickable biodegradable fluorescent nanoparticles to glioblastoma

Glioblastoma(GBM),the deadliest form of brain cancer,presents long-standing problems due to its localization.Chimeric antigen receptor(CAR)T cell immunotherapy has emerged as a powerful strategy to treat cancer.IL-13-receptor-α2(IL13Rα2),present in over 75%of GBMs,has been recognized as an attractive candidate for antiglioblastoma therapy.Here,we propose a novel multidisciplinary approach to target brain tumors using a combination of fluorescent,therapeutic nanoparticles and CAR T cells modified with a targeted-quadruplemutant of IL13(TQM-13)shown to have high binding affinity to IL13Rα2-expressing glioblastoma cells with low off-target toxicity.Azide-alkyne cycloaddition conjugation of nanoparticles to the surface of T cells allowed a facile,selective,and high-yielding clicking of the nanoparticles.Nanoparticles clicked onto T cells were retained for at least 8 days showing that the linkage is stable and promising a suitable time window for in vivo delivery.T cells clicked with doxorubicin-loaded nanoparticles showed a higher cytotoxic effect in vitro compared to bare T cells.In vitro and in vivo T cells expressing TQM-13 served as delivery shuttles for nanoparticles and significantly increased the number of nanoparticles reaching brain tumors compared to nanoparticles alone.This work represents a new platform to allow the delivery of therapeutic nanoparticles and T cells to solid tumors.

Fabricating 3-dimensional human brown adipose microtissues for transplantation studies

Transplanting cell cultured brown adipocytes(BAs)represents a promising approach to prevent and treat obesity(OB)and its associated metabolic disorders,including type 2 diabetes mellitus(T2DM).However,transplanted BAs have a very low survival rate in vivo.The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells.There is a critical need for novel methods that can avoid cell death during cell preparation,transplantation,and in vivo.Here,we reported that preparing BAs as injectable microtissues could overcome the problem.We found that 3D culture promoted BA differentiation and UCP-1 expression,and the optimal initial cell aggregate size was 100μm.The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved.Fabricated microtissues could survive in vivo for long term.They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet(HFD)-induced OB and T2DM mice.Transplanted microtissues impacted multiple organs,secreted protein factors,and influenced the secretion of endogenous adipokines.To our best knowledge,this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice.The proposal of transplanting fabricated BA microtissues,the microtissue fabrication method,and the demonstration of efficacy in T2DM mice are all new.Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability,storage,purity,safety,dosage,survival,and efficacy.