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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.

An early step of evaluating a nanomaterial’s potential for biological applications is investigating its interactions with cells and biological fluids. These experiments generate complex data, which...

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.

Ancient shoreline–shelf depositional systems are influenced by an unusually wide array of geological, biological and hydrodynamic processes, with sediment transport and deposition primarily determined by the interaction of river, wave (including storm) and tidal processes, and changes in relative sea level. Understanding the impact of these processes on shoreline–shelf morphodynamics and stratigraphic preservation remains challenging. Numerical modelling integrated with traditional facies analysis provides an increasingly viable approach, with the potential to quantify, and thereby improve understanding of, the impact of these complex coastal sedimentary processes. An integrated approach is presented here that focuses on palaeotidal modelling to investigate the controls on ancient tides and their influence on sedimentary deposition and preservation – one of the three cornerstones of the ternary process classification scheme of shoreline-shelf systems. Numerical tidal modelling methodology is reviewed and illustrated in three palaeotidal model case studies of different scales and focus. The results are synthesised in the context of shoreline–shelf processes, including a critique and modification of the process-based classification scheme. The emphasis on tidal processes reflects their global importance throughout Earth’s history. Ancient palaeotidal models are able to highlight and quantify the following four controls on tidal processes: (1) the physiography (shape and depth) of oceans (1000s km scale) determines the degree of tidal resonance; (2) the physiography of ocean connections to partly enclosed water bodies (100–1000s km scale) determines the regional-scale flux of tidal energy (inflow versus outflow); (3) the physiography of continental shelves influences shelf tidal resonance potential; and (4) tides in relatively local-scale embayments (typically 1–10s km scale) are influenced by the balance of tidal amplification due to funnelling, shoaling and resonance effects versus frictional damping. In deep time, palaeogeographic and palaeobathymetric uncertainty can be accounted for in palaeotidal models by performing sensitivity analyses to different scenarios, across this range of spatial scales. These tidal process controls are incorporated into an updated predictive decision tree for determining shoreline–shelf process regime in terms of the relative interaction of wave, fluvial and tidal processes. The predictive decision tree considers the effects of basin physiography, shelf width and shoreline morphology on wave, fluvial and tidal processes separately. Uncertainty and ambiguity in applying the widely used three-tier process classification scheme are reduced by using the decision tree in conjunction with a proposed two-tier classification of process regime that is limited to primary and secondary processes. This two-tier classification scheme is illustrated in the three case studies, showing how integration of numerical modelling with facies analysis of the preserved stratigraphic record improves confidence in prediction of tide-influenced shoreline-shelf process regimes. Wider application of this approach will further improve process-based classifications and predictions of modern and ancient shoreline–shelf systems.

During ontogeny, macrophages develop from CD115+precursors, including erythro-myeloid progenitors (EMP). EMP arise in the embryonic yolk sac, the primary site of early haematopoiesis. In adults, CD115+bone marrow-derived monocytes represent essential macrophage precursors. Herein, we identify a CD115-macrophage precursor within the adult bone marrow that is unrelated to the classical monocyte lineage but rather shares transcriptomic and functional characteristics of embryonic EMP. These EMPROR (forErythroMyeloidPrecursor) cells are capable of efficiently generating macrophages in disease settings. During early development, EMPROR cells were largely absent from the yolk sac but were instead found at the embryonic-maternal interface in the uterine wall. Unexpectedly, the latter site contains robust haematopoietic activity and harbours defined embryonic haematopoietic progenitor cells, including classical CD115+EMP. Our data suggest the existence of an alternative pathway of macrophage generation in the adult. Further, we uncover a hitherto unknown site of earliest blood cell development.

Polymer nanocapsules, with a hollow structure, are increasingly finding widespread use as drug delivery carriers; however, quantitatively evaluating the bio-nano interactions of nanocapsules remains challenging. Herein, poly(ethylene glycol) (PEG)-based metal-phenolic network (MPN) nanocapsules of three sizes (50, 100, and 150 nm) are engineered via supramolecular template-assisted assembly and the effect of the nanocapsule size on bio-nano interactions is investigated using in vitro cell experiments, ex vivo whole blood assays, and in vivo rat models. To track the nanocapsules by mass cytometry, a preformed gold nanoparticle (14 nm) is encapsulated into each PEG-MPN nanocapsule. The results reveal that decreasing the size of the PEG-MPN nanocapsules from 150 to 50 nm leads to reduced association (up to 70%) with phagocytic blood cells in human blood and prolongs in vivo systemic exposure in rat models. The findings provide insights into MPN-based nanocapsules and represent a platform for studying bio-nano interactions.

Tissue-resident memory T cells (TRM) provide immune defence against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRMactivation and how the immune pressure exerted by TRMaffects developing tumours in humans. We performed deep profiling of lung cancers arising in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRMimmunosurveillance in ES lung. Only tumours arising in ES patients underwent clonal immune escape, even when evaluating cancers with similar tumour mutational burden to NS patients, suggesting that the timing of immune pressure exerted by TRMis a critical factor in the evolution of tumour immune evasion. Tumours grown in T cell quiescent NS lungs displayed little evidence of immune evasion and had fewer neoantigens with low diversity, paradoxically making them amenable to treatment with agonist of the costimulatory molecule, ICOS. These data demonstrate local environmental insults enhance TRMimmunosurveillance of human tissue, shape the evolution of tumour immunogenicity and that this interplay informs effective immunotherapeutic modalities.

High‐dimensional cytometry represents an exciting new era of immunology research, enabling the discovery of new cells and prediction of patient responses to therapy. A plethora of analysis and visualization tools and programs are now available for both new and experienced users; however, the transition from low‐ to high‐dimensional cytometry requires a change in the way users think about experimental design and data analysis. Data from high‐dimensional cytometry experiments are often underutilized, because of both the size of the data and the number of possible combinations of markers, as well as to a lack of understanding of the processes required to generate meaningful data. In this article, we explain the concepts behind designing high‐dimensional cytometry experiments and provide considerations for new and experienced users to design and carry out high‐dimensional experiments to maximize quality data collection., High‐dimensional cytometry represents an exciting new era of immunology research; however, the transition from low‐ to high‐dimensional cytometry requires a change in the way users think about experimental design and data analysis. We explain the concepts behind designing high‐dimensional cytometry experiments and provide considerations for new and experienced users to design and carry out high‐dimensional experiments. ​

Objectives: The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)-infected mice show only minor clinical signs. Methods: A 2-photon intravital microscopy (2P-IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM. Results: Early in the disease course, antigen-specific CD8+ T cells came in contact and arrested on the endothelium of post-capillary venules. CD8+ T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post-capillary venules. Closer examination revealed that CD8+ T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post-capillary venules. 'Activity hotspots' in large post-capillary venules were characterised by T-cell localisation, activated morphology and clustering of PVM, increased abutting of post-capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8+ T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short-term interactions with the inner vessel wall at hotspots. Conclusion: Our study suggests an active interaction between PVM and CD8+ T cells occurs across the blood-brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology.

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.

Objectives The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)‐infected mice show only minor clinical signs. Methods A 2‐photon intravital microscopy (2P‐IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM. Results Early in the disease course, antigen‐specific CD8+ T cells came in contact and arrested on the endothelium of post‐capillary venules. CD8+ T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post‐capillary venules. Closer examination revealed that CD8+ T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post‐capillary venules. ‘Activity hotspots’ in large post‐capillary venules were characterised by T‐cell localisation, activated morphology and clustering of PVM, increased abutting of post‐capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8+ T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short‐term interactions with the inner vessel wall at hotspots. Conclusion Our study suggests an active interaction between PVM and CD8+ T cells occurs across the blood–brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology., Our study suggests that perivascular macrophages and CD8+ T cells interact across the blood–brain barrier (BBB) in the early stages of experimental cerebral malaria, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology.

When nanoparticles interact with human blood, a multitude of plasma components adsorb onto the surface of the nanoparticles, forming a biomolecular corona. Corona composition is known to be influenced by the chemical composition of nanoparticles. In contrast, the possible effects of variations in the human blood proteome between healthy individuals on the formation of the corona and its subsequent interactions with immune cells in blood are unknown. Herein, we prepared and examined a matrix of 11 particles (including organic and inorganic particles of three sizes and five surface chemistries) and plasma samples from 23 healthy donors to form donor-specific biomolecular coronas (personalized coronas) and investigated the impact of the personalized coronas on particle interactions with immune cells in human blood. Among the particles examined, poly(ethylene glycol) (PEG)-coated mesoporous silica (MS) particles, irrespective of particle size (800, 450, or 100 nm in diameter), displayed the widest range (up to 60-fold difference) of donor-dependent variance in immune cell association. In contrast, PEG particles (after MS core removal) of 860, 518, or 133 nm in diameter displayed consistent stealth behavior (negligible cell association), irrespective of plasma donor. For comparison, clinically relevant PEGylated doxorubicin-encapsulated liposomes (Doxil) (74 nm in diameter) showed significant variance in association with monocytes and B cells across all plasma donors studied. An in-depth proteomic analysis of each biomolecular corona studied was performed, and the results were compared against the nanoparticle-blood cell association results, with individual variance in the proteome driving differential association with specific immune cell types. We identified key immunoglobulin and complement proteins that explicitly enriched or depleted within the corona and which strongly correlated with the cell association pattern observed across the 23 donors. This study demonstrates how plasma variance in healthy individuals significantly influences the blood immune cell interactions of nanoparticles.

Ancient shoreline–shelf depositional systems are influenced by an unusually wide array of geological, biological and hydrodynamic processes, with sediment transport and deposition primarily determined by the interaction of river, wave (including storm) and tidal processes, and changes in relative sea level. Understanding the impact of these processes on shoreline–shelf morphodynamics and stratigraphic preservation remains challenging. Numerical modelling integrated with traditional facies analysis provides an increasingly viable approach, with the potential to quantify, and thereby improve understanding of, the impact of these complex coastal sedimentary processes. An integrated approach is presented here that focuses on palaeotidal modelling to investigate the controls on ancient tides and their influence on sedimentary deposition and preservation – one of the three cornerstones of the ternary process classification scheme of shoreline-shelf systems. Numerical tidal modelling methodology is reviewed and illustrated in three palaeotidal model case studies of different scales and focus. The results are synthesised in the context of shoreline–shelf processes, including a critique and modification of the process-based classification scheme.The emphasis on tidal processes reflects their global importance throughout Earth’s history. Ancient palaeotidal models are able to highlight and quantify the following four controls on tidal processes: (1) the physiography (shape and depth) of oceans (1000s km scale) determines the degree of tidal resonance; (2) the physiography of ocean connections to partly enclosed water bodies (100–1000s km scale) determines the regional-scale flux of tidal energy (inflow versus outflow); (3) the physiography of continental shelves influences shelf tidal resonance potential; and (4) tides in relatively local-scale embayments (typically 1–10s km scale) are influenced by the balance of tidal amplification due to funnelling, shoaling and resonance effects versus frictional damping. In deep time, palaeogeographic and palaeobathymetric uncertainty can be accounted for in palaeotidal models by performing sensitivity analyses to different scenarios, across this range of spatial scales.These tidal process controls are incorporated into an updated predictive decision tree for determining shoreline–shelf process regime in terms of the relative interaction of wave, fluvial and tidal processes. The predictive decision tree considers the effects of basin physiography, shelf width and shoreline morphology on wave, fluvial and tidal processes separately. Uncertainty and ambiguity in applying the widely used three-tier process classification scheme are reduced by using the decision tree in conjunction with a proposed two-tier classification of process regime that is limited to primary and secondary processes. This two-tier classification scheme is illustrated in the three case studies, showing how integration of numerical modelling with facies analysis of the preserved stratigraphic record improves confidence in prediction of tide-influenced shoreline-shelf process regimes. Wider application of this approach will further improve process-based classifications and predictions of modern and ancient shoreline–shelf systems.

This chapter traces the evolution of Wagner’s engagement with Schopenhauer’s philosophy from the 1850s through 1883. It considers Wagner’s three Schopenhauerian operas in relation to the composer’s contemporary writings, suggesting that both music and prose were vehicles through which he sought to extend and correct what he perceived as shortcomings in Schopenhauer’s work. In Tristan und Isolde and related correspondence, Wagner identified a pathway to redemption from suffering born of Schopenhauerian will, attainable through the experience of erotic love. In Die Meistersinger von Nürnberg and the essay “Beethoven,” Wagner elaborated Schopenhauer’s theory of dreams to account for the origins of artistic creativity. In Parsifal and a series of essays appended to “Religion and Art,” Wagner extended Schopenhauer’s notion of compassion to include all living beings, identifying vegetarianism as one of its principal tenets and the Eucharist as its cardinal expression in ritual.

Particle‐based pulmonary delivery has great potential for delivering inhalable therapeutics for local or systemic applications. The design of particles with enhanced aerodynamic properties can improve lung distribution and deposition, and hence the efficacy of encapsulated inhaled drugs. This study describes the nanoengineering and nebulization of metal–phenolic capsules as pulmonary carriers of small molecule drugs and macromolecular drugs in lung cell lines, a human lung model, and mice. Tuning the aerodynamic diameter by increasing the capsule shell thickness (from ≈100 to 200 nm in increments of ≈50 nm) through repeated film deposition on a sacrificial template allows precise control of capsule deposition in a human lung model, corresponding to a shift from the alveolar region to the bronchi as aerodynamic diameter increases. The capsules are biocompatible and biodegradable, as assessed following intratracheal administration in mice, showing >85% of the capsules in the lung after 20 h, but 90% of capsules remaining nonassociated with cells. The amenability to nebulization, capacity for loading, tunable aerodynamic properties, high biocompatibility, and biodegradability make these capsules attractive for controlled pulmonary delivery., The aerodynamic diameters of metal–phenolic capsules are nanoengineered by increasing their shell thickness, which facilitates tailored capsule deposition in a mechanical lung model. The engineered capsules are promising for pulmonary delivery owing to their robustness for nebulization, biocompatibility, biodegradability, and their capacity for cargo loading and surface functionalization.

This essay explores Fichte’s influence on German Romantic literary theory and composition in the work of Novalis and Friedrich Schlegel. The key moment in Fichte that gets taken up by Novalis and Schlegel is the idea that the subject must posit itself. For Novalis, such self-positing is always a matter of self-representation, and thus an aesthetic act. Schlegel adds to this by showing that such self-positing is never certain of success, that one can never truly possess oneself fully. Each author begins from a Fichtean position in order to show not its limitations, but its primacy for aesthetic creation.

This chapter was inadvertently published with the acknowledgement section leaving out the following sentence: "This work received funding from South Australian Government PRIF program Project "International Cluster on Nanosafety" of Nicolas H. Voelcker and Enzo Lombi." This correction has been updated in the chapter.

Serpinb9 (Sb9, also called Spi6) is an intracellular inhibitor of granzyme B (grB) that protects cytotoxic lymphocytes from grB-mediated death. In addition, Sb9 is also expressed in accessory immune cells, including dendritic cells (DCs), although its role is debated. Recently, we have demonstrated that Sb9 plays a grB-independent role in cross-presentation of antigens by CD8+ DCs. Here, using a mouse line expressing green fluorescent protein knocked in under the control of the Sb9 promoter, we demonstrate that Sb9 expression is highest in those tissue-resident and migratory DC subsets capable of cross-presentation. Further, we show that CD8+ DCs can be divided into two subsets based on Sb9 expression, and that only the subset expressing higher levels of Sb9 is capable of cross-presentation. These findings add support for role for Sb9 cross-presentation, and indicate that high Sb9 expression is a novel marker of cross-presentation capable DCs.

The kynurenine pathway of tryptophan metabolism has been implicated in brain function, immunoregulation, anti-microbial mechanisms and pregnancy. Some of these actions are due to depletion of tryptophan and others to the formation of biologically active metabolites. This review focuses on the roles of the kynurenine pathway in host responses during two parasitic diseases of major health and economic importance, malaria and toxoplasmosis, with an emphasis on their impacts on CNS function. This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.