The conservation and evolutionary modularity of metabolism

A novel evolutionary analysis of metabolic networks across 26 taxa reveals a highly-conserved but flexible core of metabolic enzymes

Developing a method to determine the flux of material arriving and leaving a crystal at equilibrium

It is often said that a crystal in a saturated solution neither grows nor dissolves, however, this is an equilibrium so there must be some flux between the crystal and the solution. The question is how could this be measured. The aim of this work was to develop a method to make this measurement, as a prelude to investigating the effect of ultrasound on the rate of molecular exchange between the surface layer of a growing crystal and the surrounding slightly supersaturated solution

Development of a new CEDAR for kaon identification at the NA62 experiment at CERN

The NA62 experiment at CERN utilises a differential Cherenkov counter with achromatic ring focus (CEDAR) for tagging kaons within an unseparated monochromatic beam of charged hadrons. The CEDAR-H detector was developed to minimise the amount of material in the path of the beam by using hydrogen gas as the radiator medium. The detector was shown to satisfy the kaon tagging requirements in a test-beam before installation and commissioning at the experiment. The CEDAR-H performance was measured using NA62 data collected in 2023

Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays

Target recognition by the ubiquitin system is mediated by E3 ubiquitin ligases. Nedd4 family members are E3 ligases comprised of a C2 domain, 2–4 WW domains that bind PY motifs (L/PPxY) and a ubiquitin ligase HECT domain. The nine Nedd4 family proteins in mammals include two close relatives: Nedd4 (Nedd4-1) and Nedd4L (Nedd4-2), but their global substrate recognition or differences in substrate specificity are unknown. We performed in vitro ubiquitylation and binding assays of human Nedd4-1 and Nedd4-2, and rat-Nedd4-1, using protein microarrays spotted with ∼8200 human proteins. Top hits (substrates) for the ubiquitylation and binding assays mostly contain PY motifs. Although several substrates were recognized by both Nedd4-1 and Nedd4-2, others were specific to only one, with several Tyr kinases preferred by Nedd4-1 and some ion channels by Nedd4-2; this was subsequently validated in vivo. Accordingly, Nedd4-1 knockdown or knockout in cells led to sustained signalling via some of its substrate Tyr kinases (e.g. FGFR), suggesting Nedd4-1 suppresses their signalling. These results demonstrate the feasibility of identifying substrates and deciphering substrate specificity of mammalian E3 ligases

2dFLenS and KiDS: determining source redshift distributions with cross-correlations

We develop a statistical estimator to infer the redshift probability distribution of a photometric sample of galaxies from its angular cross-correlation in redshift bins with an overlapping spectroscopic sample. This estimator is a minimum-variance weighted quadratic function of the data: a quadratic estimator. This extends and modifies the methodology presented by McQuinn & White. The derived source redshift distribution is degenerate with the source galaxy bias, which must be constrained via additional assumptions. We apply this estimator to constrain source galaxy redshift distributions in the Kilo-Degree imaging survey through cross-correlation with the spectroscopic 2-degree Field Lensing Survey, presenting results first as a binned step-wise distribution in the range z < 0.8, and then building a continuous distribution using a Gaussian process model. We demonstrate the robustness of our methodology using mock catalogues constructed from N-body simulations, and comparisons with other techniques for inferring the redshift distribution

Submission of Microarray Data to Public Repositories

The Microarray Gene Expression Data Society believe that the time is right for journals to require that microarray data be deposited in public repositories, as a condition for publicatio

In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling

<p>Abstract</p> <p>Background</p> <p>Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was <it>Dicoma anomala </it>subsp. <it>gerrardii</it>, based on its ethnomedicinal profile.</p> <p>Methods</p> <p>Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of <it>Dicoma anomala </it>subsp. <it>gerrardii</it>. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested <it>in vitro </it>on <it>Plasmodium falciparum </it>cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications <it>in vitro </it>using the pLDH assay. The effects of the pure compound on the <it>P. falciparum </it>transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis.</p> <p>Results</p> <p>The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an <it>in vitro </it>IC₅₀of 1.865 μM against a chloroquine-sensitive strain (D10) of <it>P. falciparum</it>. Synthetic analogues of the compound confirmed an absolute requirement that the α-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes and molecular functions that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. These results strengthen the notion that the isolated compound and the artemisinins have differentiated modes of action.</p> <p>Conclusions</p> <p>The novel mode of action of dehydrobrachylaenolide, detected during these studies, will play an ongoing role in advancing anti-plasmodial drug discovery efforts.</p