Search

Background The ACURATE neo™ is a novel, second-generation self-expanding supra-annular transcatheter heart valve (THV). The objective of this multi-centre registry is to assess the safety, clinical utility, and impact of 'learning-curve-experience' (LCE) on transcatheter aortic valve replacement outcomes in the United Kingdom (UK) and Ireland. Methods We prospectively collected data from seven ACURATE neo™ THV implanting centres (n = 484) between February 2016 and November 2020. We compared mortality rates and outcomes in the LCE group (n = 120) compared to next successive 120 cases. Results The mean age of the cohort was 81.9(SD: 6.1) years and the majority were in the moderate risk category (EuroSCORE-II):3.3(SD: 3). The 97.5% of cases were performed under local anesthetic. The valve was successfully deployed in 98.8% of cases. The survival rate at 30 days was 97.9%. The incidence of stroke was 2.5%. Life threatening bleeding occurred in 0.6% of cases and vascular access complications occurred in 21 (4.3%) patients. Implantation-related conduction abnormalities occurred in 8.3% but only 5.6% required a PPM. The successful valve deployment occurred in 96% of the patients in the LCE group compared to 100% in the other group (p = 0.04; OR-2[CI 1.7-2.3]). The mortality rates at 30 days (1.7% vs. 1.7%) and 1 year (1.9% vs. 2.7%) were comparable between the two groups. Conclusions This study represents the largest published UK and Ireland real-world experience of the ACURATE neo™ valve. The procedural success rates and safety outcomes were excellent and endorse its utility in clinical practice. The LCE appears to have an impact on the successful valve deployment but without translating into short-term or long-term outcomes.

Plants contain rapidly evolving specialized metabolic enzymes to support the synthesis of a myriad of functionally diverse natural products. In the case of coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered in Arabidopsis that catalyzes coumarin formation fromo-hydroxylatedtrans-hydroxycinnamoyl-CoA substrates. COSY is the first and only BAHD enzyme known to date that catalyzes an intramolecular acyl transfer reaction. Here we combine structural, biochemical, and computational approaches to investigate the mechanistic basis for the unique coumarin synthase activity of COSY. Comparative analyses of crystal structures ofArabidopsis thalianaCOSY relative to other BAHD proteins reveal that COSY possesses an unconventional active-site configuration adapted to its specialized activity. Through deuterium exchange experiments, we discover a unique proton exchange mechanism at the α-carbon of theo-hydroxylatedtrans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Mutagenesis studies and quantum mechanical cluster modeling further support that this mechanism is key to COSY’s ability to lower the activation energy of thetrans-to-cisisomerization of the hydroxycinnamoyl-CoA substrates, a critical rate-limiting step leading to coumarin production. This study unveils the emergence of an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on the potential evolutionary origin of COSY and its recruitment to the evolutionarily new coumarin biosynthetic pathway in eudicots.

The biomolecular corona that forms on particles upon contact with blood plays a key role in the fate and utility of nanomedicines. Recent studies have shown that precoating nanoparticles with serum proteins can improve the biocompatibility and stealth properties of nanoparticles. However, it is not fully clear how precoating influences biomolecular corona formation and downstream biological responses. Herein, we systematically examine three precoating strategies by coating bovine serum albumin (single protein), fetal bovine serum (FBS, mixed proteins without immunoglobulins), or bovine serum (mixed proteins) on three nanoparticle systems, namely supramolecular template nanoparticles, metal-phenolic network (MPN)-coated template (core-shell) nanoparticles, and MPN nanocapsules (obtained after template removal). The effect of protein precoating on biomolecular corona compositions and particle-immune cell interactions in human blood was characterized. In the absence of a pre-coating, the MPN nanocapsules displayed lower leukocyte association, which correlated to the lower amount (by 2-3 fold) of adsorbed proteins and substantially fewer immunoglobulins (more than 100 times) in the biomolecular corona relative to the template and core-shell nanoparticles. Among the three coating strategies, FBS precoating demonstrated the most significant reduction in leukocyte association (up to 97% of all three nanoparticles). A correlation analysis highlights that immunoglobulins and apolipoproteins may regulate leukocyte recognition. This study demonstrates the impact of different precoating strategies on nanoparticle-immune cell association and the role of immunoglobulins in bio-nano interactions.

High-dimensional mass cytometry provides unparalleled insight into the cellular composition of the immune system. Here, we describe a mass-cytometry-based protocol to examine memory CD4

A detailed analysis of steady coating flow of a thin film of a viscous fluid on the outside of a uniformly rotating horizontal circular cylinder in the absence of surface-tension effects but in the presence of a non-uniform pressure distribution due to an irrotational airflow with circulation shows that the presence of the airflow can result in qualitatively different behaviour of the fluid film from that in classical coating flow. Full-film solutions corresponding to a continuous film of fluid covering the entire cylinder are possible only when the flux and mass of fluid do not exceed critical values, which are determined in terms of the non-dimensional parameters $F$ and $K$ representing the speed of the far-field airflow and the circulation of the airflow, respectively. The qualitative changes in the behaviour of the film thickness as $F$ and $K$ are varied are described. In particular, the film thickness can have as many as four stationary points and, in general, has neither top-to-bottom nor right-to-left symmetry. In addition, when the circulation of the airflow is in the same direction as the rotation of the cylinder the maximum mass of fluid that can be supported on the cylinder is always less than that in classical coating flow, whereas when the circulation is in the opposite direction the maximum mass of fluid can be greater than that in classical coating flow.

Unsteady two-dimensional coating flow of a thin film of a viscous fluid on the outside of a uniformly rotating horizontal circular cylinder in the presence of a steady two-dimensional irrotational airflow with circulation is considered. The analysis of this problem by Newell and Viljoen [Phys. Fluids 31(3), 034106 (2019)], who sought to generalize the work of Hinch and Kelmanson [Proc. R. Soc. London, Ser. A 459(2033), 1193–1213 (2003)] to include the effect of the airflow, is revisited. In contrast with the claim of Newell and Viljoen that the flow is conditionally unstable (in the sense that the solution for the film thickness grows without bound for certain values of the physical parameters), it is shown that, in fact, the film remains unconditionally stable in the presence of the airflow.