375 research outputs found
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
Model Fitting of a Two-Factor Arbitrage-Free Model for the Term Structure of Interest Rates using Markov Chain Monte Carlo: Part 2: Applications with UK Data
Model Fitting of a Two-Factor Arbitrage-Free Model For the Term Structure of Interest Rates using Markov Chain Monte Carlo: Part 1: Theory and Methodology
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
Insurance pricing for breast cancer under different multiple state models
In this paper we consider pricing of insurance contracts for breast cancer
risk based on three multiple state models. Using population data in England and
data from the medical literature, we calibrate a collection of semi-Markov and
Markov models. Considering an industry-based Markov model as a baseline model,
we demonstrate the strengths of a more detailed model while showing the
importance of accounting for duration dependence in transition rates. We
quantify age-specific cancer incidence and cancer survival by stage along with
type-specific mortality rates based on the semi-Markov model which accounts for
unobserved breast cancer cases and progression through breast cancer stages.
Using the developed models, we obtain actuarial net premiums for a specialised
critical illness and life insurance product. Our analysis shows that the
semi-Markov model leads to results aligned with empirical evidence. Our
findings point out the importance of accounting for the time spent with
diagnosed or undiagnosed pre-metastatic breast cancer in actuarial
applications
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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
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