Design of crystal-like aperiodic solids with selective disorder--phonon coupling

Functional materials design normally focuses on structurally-ordered systems because disorder is considered detrimental to many important physical properties. Here we challenge this paradigm by showing that particular types of strongly-correlated disorder can give rise to useful characteristics that are inaccessible to ordered states. A judicious combination of low-symmetry building unit and high-symmetry topological template leads to aperiodic "procrystalline" solids that harbour this type of topological disorder. We identify key classes of procrystalline states together with their characteristic diffraction behaviour, and establish a variety of mappings onto known and target materials. Crucially, the strongly-correlated disorder we consider is associated with specific sets of modulation periodicities distributed throughout the Brillouin zone. Lattice dynamical calculations reveal selective disorder-phonon coupling to lattice vibrations characterised by these same periodicities. The principal effect on the phonon spectrum is to bring about dispersion in energy rather than wave-vector, as in the poorly-understood "waterfall" effect observed in relaxor ferroelectrics. This property of procrystalline solids suggests a mechanism by which strongly-correlated topological disorder might allow new and useful functionalities, including independently-optimised thermal and electronic transport behaviour as required for high-performance thermoelectrics.Comment: 4 figure

Design and synthesis of small molecule probes for metabolic processes

Synthesis of a photoactivated uncoupler I was completed and subsequently used by collaborators to demonstrate mitochondria uptake. The synthesis of a ratiometric, targetable calcium sensor was completed up to intermediate II (9 steps), alongside a thiohydantoin heterocycle III synthesised in 5 steps. A co-worker has subsequently completed the probe synthesis based on this route, with the resulting probe showing good binding and optical responses in testing. Numerous routes to 5,6-disubstituted phenanthridinium salts were investigated towards the synthesis of a mitochondrially targeted superoxide probe and hydroxylated standards. In the course of this work a novel cyclisation was developed based on intramolecular SNAr giving access to 9-benzyloxyphenanthridinium salt V. Rapid and high-yielding access to 5,6-disubstituted phenanthridinium salts IX was then achieved through forming benzophenones VIII via Suzuki coupling and converting these to imines with the alkylamine. The nitrogen atom of the imine then undergoes cyclisation onto the aryl fluoride in an intramolecular SNAr upon heating. This transformation was shown to have good steric and electronic tolerance in the synthesis of 13 phenanthridinium analogues with 6 structural diversification points. Subsequent DFT calculations by a colleague showed this reaction proceeds in a concerted fashion and as such represents a considerable mechanistic novelty. Efforts towards a new probe for mitochondrial superoxide led to the synthesis of 3-tertbutyl-dihydrophenanthridine X, which does not intercalate into DNA upon oxidation. This concept was refined and lead to the development of neopentyl ethidium XI and the targeted analogue MitoBNH XII and its deuterated analogue XIII

The effect of the COVID-19 health disruptions on breast cancer mortality for older women: A semi-Markov modelling approach

We propose a methodology to quantify the impact on breast cancer mortality of diagnostic delays caused by public health measures introduced as a response to the COVID-19 pandemic. These measures affected cancer pathways by halting cancer screening, delaying diagnostic tests, and reducing the numbers of patients starting treatment. We introduce a semi-Markov model, to quantify the impact of the pandemic based on publicly available population data for women age 65{89 years in England and relevant medical literature. We quantify age-specific excess deaths, for a period up to 5 years, along with years of life expectancy lost and change in cancer mortality by cancer stage. Our analysis suggests a 3-6% increase in breast cancer deaths, corresponding to more than 40 extra deaths, per 100,000 women, after age 65 years old over 5 years, and a 4-6% increase in registrations of advanced (Stage 4) breast cancer. Our modelling approach exhibits consistent results in sensitivity analyses, providing a model that can account for changes in breast cancer diagnostic and treatment services

Translation of Diverse Aramid- And 1,3-Dicarbonyl-peptides by Wild Type Ribosomes in Vitro

Here, we report that wild type Escherichia coli ribosomes accept and elongate precharged initiator tRNAs acylated with multiple benzoic acids, including aramid precursors, as well as malonyl (1,3-dicarbonyl) substrates to generate a diverse set of aramid-peptide and polyketide-peptide hybrid molecules. This work expands the scope of ribozyme- and ribosome-catalyzed chemical transformations, provides a starting point for in vivo translation engineering efforts, and offers an alternative strategy for the biosynthesis of polyketide-peptide natural products

MitoNeoD:a mitochondria-targeted superoxide probe

Mitochondrial superoxide (O2⋅−) underlies much oxidative damage and redox signaling. Fluorescent probes can detect O2⋅−, but are of limited applicability in vivo, while in cells their usefulness is constrained by side reactions and DNA intercalation. To overcome these limitations, we developed a dual-purpose mitochondrial O2⋅− probe, MitoNeoD, which can assess O2⋅− changes in vivo by mass spectrometry and in vitro by fluorescence. MitoNeoD comprises a O2⋅−-sensitive reduced phenanthridinium moiety modified to prevent DNA intercalation, as well as a carbon-deuterium bond to enhance its selectivity for O2⋅− over non-specific oxidation, and a triphenylphosphonium lipophilic cation moiety leading to the rapid accumulation within mitochondria. We demonstrated that MitoNeoD was a versatile and robust probe to assess changes in mitochondrial O2⋅− from isolated mitochondria to animal models, thus offering a way to examine the many roles of mitochondrial O2⋅−production in health and disease

Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo

There is increasing interest in the effect of energy metabolism on oxidative stress, but much ambiguity over the relationship between the rate of oxygen consumption and the generation of reactive oxygen species (ROS). Production of ROS (such as hydrogen peroxide, H2O2) in the mitochondria is primarily inferred indirectly from measurements in vitro, which may not reflect actual ROS production in living animals. Here, we measured in vivo H2O2 content using the recently developed MitoB probe that becomes concentrated in the mitochondria of living organisms, where it is converted by H2O2 into an alternative form termed MitoP; the ratio of MitoP/MitoB indicates the level of mitochondrial H2O2 in vivo. Using the brown trout Salmo trutta, we tested whether this measurement of in vivo H2O2 content over a 24 h-period was related to interindividual variation in standard metabolic rate (SMR). We showed that the H2O2 content varied up to 26-fold among fish of the same age and under identical environmental conditions and nutritional states. Interindividual variation in H2O2 content was unrelated to mitochondrial density but was significantly associated with SMR: fish with a higher mass-independent SMR had a lower level of H2O2. The mechanism underlying this observed relationship between SMR and in vivo H2O2 content requires further investigation, but may implicate mitochondrial uncoupling which can simultaneously increase SMR but reduce ROS production. To our knowledge, this is the first study in living organisms to show that individuals with higher oxygen consumption rates can actually have lower levels of H2O2