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"Webb, Andrew"
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Food Britannia
Andrew Webb travels the country to bring together a treasury of regional and heroic local producers. He investigates the history of saffron farming in the UK, tastes the first whisky to be produced in Wales for 100 years, and tracks down the New Forest's foremost expert on wild mushrooms. And along the way, he uncovers some historical surprises--for example, that the method for making clotted cream, that stalwart of the cream tea, was probably introduced from the Middle East; and that fish and chips may have started life as a Jewish-Portuguese dish. The result is a rich and kaleidoscopic survey of a remarkably vibrant food scene, steeped in history but full of fresh ideas for the future.--From publisher description.
Book
Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential
Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.
Journal Article
The genesis machine : our quest to rewrite life in the age of synthetic biology
\"Synthetic biology is the promising and controversial technology platform that combines biology and artificial intelligence, opening up the potential to program biological systems much as we program computers. Synthetic biology enables us not just to read and edit DNA - the technique of CRISPR - but also write it. Rather than life being \"a beautiful game of chance\", synthetic biology creates the potential to control our genetic destiny, to say \"no\" to bad genes and build a veritable genetic app store for downloading and adding new capabilities into any cell, microbe, plant, or animal. Amy Webb and Andrew Hessel's riveting stories include: the work of scientists to develop plants that can be grown in sprawling indoor farms capable of feeding millions with a fraction of the usual resources required; a synthetic, self-regulating insulin that doesn't require injections or a pump; life-altering regenerative, personalized medicine; and novel, durable solutions to climate change. There is also whimsy, such as the dream of some geneticists to \"unextinct\" the wooly mammoth. By examining both the science and the ethical, moral, and religious issues surrounding synthetic biology, Webb and Hessel provide the background for preventing its misuse by some to re-engineer their bodies and that of their children, further increasing the disturbing division and polarization of societies into the haves (the enhanced) and the have nots. They provide the background for making wise decisions about issues such as: whether to program novel viruses to fight diseases, what genetic privacy will look like, who will \"own\" living organisms, how companies should earn revenue from engineered cells, and how to contain a synthetic organism in a lab. Whether we approve or disapprove of synthetic biology, it is coming. Now, we need to understand its promise and peril. Webb and Hessel help us understand the science as well as the political and societal issues involved\"-- Provided by publisher.
BOOK
A de novo MS1 feature detector for the Bruker timsTOF Pro
Identification of peptides by analysis of data acquired by the two established methods for bottom-up proteomics, DDA and DIA, relies heavily on the fragment spectra. In DDA, peptide features detected in mass spectrometry data are identified by matching their fragment spectra with a peptide database. In DIA, a peptide’s fragment spectra are targeted for extraction and matched with observed spectra. Although fragment ion matching is a central aspect in most peptide identification strategies, the precursor ion in the MS1 data reveals important characteristics as well, including charge state, intensity, monoisotopic m/z, and apex in retention time. Most importantly, the precursor’s mass is essential in determining the potential chemical modification state of the underlying peptide sequence. In the timsTOF, with its additional dimension of collisional cross-section, the data representing the precursor ion also reveals the peptide’s peak in ion mobility. However, the availability of tools to survey precursor ions with a wide range of abundance in timsTOF data across the full mass range is very limited. Here we present a de novo feature detector called three-dimensional intensity descent (3DID). 3DID can detect and extract peptide features down to a configurable intensity level, and finds many more features than several existing tools. 3DID is written in Python and is freely available with an open-source MIT license to facilitate experimentation and further improvement (DOI 10.5281/zenodo.6513126 ). The dataset used for validation of the algorithm is publicly available (ProteomeXchange identifier PXD030706).
Journal Article
Flexible and compact hybrid metasurfaces for enhanced ultra high field in vivo magnetic resonance imaging
Developments in metamaterials and related structures such as metasurfaces have opened up new possibilities in designing materials and devices with unique properties. Here we report a new hybrid metasurface structure, comprising a two-dimensional metamaterial surface and a very high permittivity dielectric substrate, that has been designed to enhance the local performance of an ultra-high field MRI scanner. This new flexible and compact resonant structure is the first metasurface which can be integrated with multi-element close-fitting receive coil arrays that are used for all clinical MRI scans. We demonstrate the utility of the metasurface acquiring
in-vivo
human brain images and proton MR spectra with enhanced local sensitivity on a commercial 7 Tesla system.
Journal Article
Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis
Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.
RIPK3-mediated phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase is thought to be the trigger for MLKL activation during necroptotic signaling. Here the authors provide evidence that the transition of human MLKL from a monomeric state to a tetramer is essential for necroptosis signalling.
Journal Article
The permanent magnet hypothesis: an intuitive approach to designing non-circular magnet arrays with high field homogeneity
Does the Halbach magnetization rotation rule that is used for designing circular magnet arrays for achieving the best homogeneity hold also for an elliptical or other non-circular cross-section? In this article, it is shown that a new numerically optimized magnetization rotation rule can provide more than three orders of magnitude improvement in field homogeneity as compared to a Halbach configuration for elliptical systems. Further it is demonstrated that such optimized magnetization rules can be easily derived in an intuitive way by studying virtual permanent magnets of a similar cross-section as the desired magnet array. This is coined as a permanent magnet hypothesis. Finally, it is shown that the applicability of this technique is not limited to circular or elliptical systems but can be applied to any arbitrarily shaped cross-section.
Journal Article
Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death
Significance The four-helix bundle (4HB) domain of Mixed Lineage Kinase Domain-Like (MLKL) bears two clusters of residues that are required for cell death by necroptosis. Mutations within a cluster centered on the α4 helix of the 4HB domain of MLKL prevented its membrane translocation, oligomerization, and ability to induce necroptosis. This cluster is composed principally of acidic residues and therefore challenges the idea that the 4HB domain engages negatively charged phospholipid membranes via a conventional positively charged interaction surface. The importance of membrane translocation to MLKL-mediated death is supported by our identification of a small molecule that binds the MLKL pseudokinase domain and retards membrane translocation to inhibit necroptotic signaling.
Necroptosis is considered to be complementary to the classical caspase-dependent programmed cell death pathway, apoptosis. The pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) is an essential effector protein in the necroptotic cell death pathway downstream of the protein kinase Receptor Interacting Protein Kinase-3 (RIPK3). How MLKL causes cell death is unclear, however RIPK3–mediated phosphorylation of the activation loop in MLKL trips a molecular switch to induce necroptotic cell death. Here, we show that the MLKL pseudokinase domain acts as a latch to restrain the N-terminal four-helix bundle (4HB) domain and that unleashing this domain results in formation of a high-molecular-weight, membrane-localized complex and cell death. Using alanine-scanning mutagenesis, we identified two clusters of residues on opposing faces of the 4HB domain that were required for the 4HB domain to kill cells. The integrity of one cluster was essential for membrane localization, whereas MLKL mutations in the other cluster did not prevent membrane translocation but prevented killing; this demonstrates that membrane localization is necessary, but insufficient, to induce cell death. Finally, we identified a small molecule that binds the nucleotide binding site within the MLKL pseudokinase domain and retards MLKL translocation to membranes, thereby preventing necroptosis. This inhibitor provides a novel tool to investigate necroptosis and demonstrates the feasibility of using small molecules to target the nucleotide binding site of pseudokinases to modulate signal transduction.
Journal Article
The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation
Interleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1β activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1β is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1β cleavage by caspase-1. IL-1β K133 is modified by ubiquitin and forms a salt bridge with IL-1β D129. Loss of IL-1β K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1β. Accordingly,
Il1b
K133R/K133R
mice have increased levels of precursor IL-1β upon inflammasome priming and increased production of bioactive IL-1β, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1β activity and safeguard against damaging inflammation.
Hyperactivation of inflammasome-induced IL-1β can cause immunopathology and is a feature of autoinflammatory diseases. Here, the authors show how ubiquitination of IL-1β limits its activity by targeting it for proteasomal degradation and preventing its cleavage by caspase-1.
Journal Article