Biomarker clustering of colorectal cancer data to complement clinical classification

In this paper, we describe a dataset relating to cellular and physical conditions of patients who are operated upon to remove colorectal tumours. This data provides a unique insight into immunological status at the point of tumour removal, tumour classification and postoperative survival. Attempts are made to cluster this dataset and important subsets of it in an effort to characterize the data and validate existing standards for tumour classification. It is apparent from optimal clustering that existing tumour classification is largely unrelated to immunological factors within a patient and that there may be scope for re-evaluating treatment options and survival estimates based on a combination of tumour physiology and patient histochemistry

Effect of sink layer thickness on damping in CoMnGe (5 nm) / Ag (6 nm) / NiFe (x nm) spin valves

Poster presented at Magnetism 4 – 5 April 2016, Sheffield.In spin valve structures the damping of a ferromagnetic layer driven at resonance can be modified by the transfer of spin angular momentum into a ‘sink’ ferromagnetic layer. This effect, known as spin pumping, is interface dominated and expected to increase with increasing sink layer thickness up to a saturation absorption depth, previously reported to be 1.2 nm regardless of the sink layer’s composition [1]. Using vector network analyser ferromagnetic resonance (VNA-FMR), we have studied the variation in damping as a function of sink layer thickness in a series of CoMnGe (5 nm) / Ag (6 nm) / NiFe (x nm) spin valves. These measurements show only small variations in the CoMnGe Gilbert damping parameter for x ≤ 1.8 nm, although damping is observed to increase at x = 0.3 and 0.6 nm. Element-resolved x-ray detected ferromagnetic resonance (XFMR) [2] measurements confirm spin transfer torque due to spin pumping as the origin of the damping for x = 1.5 and 1.8 nm, with both thicknesses having the same effective spin mixing conductance, supporting the findings of Ghosh et al [1]. For thicker sink layers the source and sink FMR fields are seen to coincide, hampering the identification of spin pumping. [1] A Ghosh, et al. Physical Review Letters 109, 127202 (2012) [2] M Marcham, et al. Physical Review B 87, 180403 (2013)We thank the Advanced Light Source for access to beamlines 4.0.2 and 6.3.1 (ALS-06433, ALS-07116). The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.We thank Diamond Light Source for access to beamlines I06 and I10 (SI8782, SI11585, SI13063) that contributed to the results presented here.This work was supported by the Engineering and Physical Sciences Research Council [grant number EP/J018767/1]

From Byte to Bench to Bedside: Molecular Dynamics Simulations and Drug Discovery

Molecular dynamics (MD) simulations and computer-aided drug design (CADD) have advanced substantially over the past two decades, thanks to continuous computer hardware and software improvements. Given these advancements, MD simulations are poised to become even more powerful tools for investigating the dynamic interactions between potential small-molecule drugs and their target proteins, with significant implications for pharmacological research.Comment: 15 pages including references, 0 figure

Combining high-resolution cryo-electron microscopy and mutagenesis to develop cowpea mosaic virus for bionanotechnology

Particles of cowpea mosaic virus (CPMV) have enjoyed considerable success as nanoparticles. The development of a system for producing empty virus-like particles (eVLPs) of the virus, which are non-infectious and have the potential to be loaded with heterologous material, has increased the number of possible applications for CPMV-based particles. However, for this potential to be realised, it was essential to demonstrate that eVLPs were accurate surrogates for natural virus particles, and this information was provided by high-resolution cryo-EM studies of eVLPs. This demonstration has enabled the approaches developed for the production of modified particles developed with natural CPMV particles to be applied to eVLPs. Furthermore, a combination of cryo-EM and mutagenic studies allowed the development of particles which are permeable but which could still assemble efficiently. These particles were shown to be loadable with cobalt, indicating that they can, indeed, be used as nano-containers

A haplotype-resolved chromosome-level genome assembly of Urochloa decumbens cv. Basilisk resolves its allopolyploid ancestry and composition

Haplotyped-resolved phased assemblies aim to capture the full allelic diversity in heterozygous and polyploid species to enable accurate genetic analyses. However, building non-collapsed references still presents a challenge. Here, we used long-range interaction Hi-C reads (high-throughput chromatin conformation capture) and HiFi PacBio reads to assemble the genome of the apomictic cultivar Basilisks from Urochloa decumbens (2n = 4x = 36), an outcrossed tetraploid Paniceae grass widely cropped to feed livestock in the tropics. We identified and removed Hi-C reads between homologous unitigs to facilitate their scaffolding and employed methods for the manual curation of rearrangements and misassemblies. Our final phased assembly included the 4 haplotypes in 36 chromosomes. We found that 18 chromosomes originated from diploid Urochloa brizantha and the other 18 from either Urochloa ruziziensis or diploid U. decumbens. We also identified a chromosomal translocation between chromosomes 5 and 32, as well as evidence of pairing exclusively within subgenomes, except for a homoeologous exchange in chromosome 21. Our results demonstrate that haplotype-aware assemblies accurately capture the allelic diversity in heterozygous species, making them the preferred option over collapsed-haplotype assemblies

The rational design of affinity attenuated OmCI for the purification of Complement C5

Complement component C5 is the target of the monoclonal antibody Eculizumab, and the focus of a sustained drug discovery effort to prevent complement-induced inflammation in a range of autoimmune diseases. The immune evasion protein OmCI binds to, and potently inactivates, C5; this tight-binding interaction can be exploited to affinity-purify C5 protein from serum, offering a vastly simplified protocol compared to existing methods. However, breaking the high-affinity interaction requires conditions which risk denaturing or activating C5. We performed structure-guided in silico mutagenesis to identify prospective OmCI residues that contribute significantly to the binding affinity. We tested our predictions in vitro, using site directed mutagenesis, and characterised mutants using a range of biophysical techniques as well as functional assays. Our biophysical analyses suggest the C5-OmCI interaction is complex with potential for multiple binding modes.We present single mutations that lower the affinity of OmCI for C5 and combinations of mutations that significantly decrease, or entirely abrogate, formation of the complex. The affinity attenuated forms of OmCI are suitable for affinity purification and allow elution under mild conditions that are non-denaturing or activating to C5. We present the rational design, biophysical characterisation and experimental validation of affinity reduced forms of OmCI as tool reagents to enable the affinity purification of C5.</p

Digitising historical sea level records in the Thames Estuary, UK

London is one of the world’s most important coastal cities and is located around the Thames Estuary, United Kingdom (UK). Quantifying changes in sea levels in the Thames Estuary over the 20th century and early part of the 21st century is vital to inform future management of flood risk in London. However, there are currently relatively few long, digital records of sea level available in the Thames. Here we present a new extensive sea level dataset that we have digitised from historical hand-written tabulated ledgers of high and low water, from the Port of London Authority (PLA). We captured 463 years of data, from across 15 tide gauge sites, for the period 1911 to 1995. When these historical datasets are combined with digital records available from the PLA since 1995, the sea level time-series span the 111-year period from 1911 to 2021. This new dataset will be of great importance for ongoing monitoring of mean sea-level rise, and changes in tidal range and extreme sea levels in the Thames Estuary

Toward Improved Environmental Stability of Polymer:Fullerene and Polymer:Nonfullerene Organic Solar Cells: A Common Energetic Origin of Light- and Oxygen-Induced Degradation

With the emergence of nonfullerene electron acceptors resulting in further breakthroughs in the performance of organic solar cells, there is now an urgent need to understand their degradation mechanisms in order to improve their intrinsic stability through better material design. In this study, we present quantitative evidence for a common root cause of light-induced degradation of polymer:nonfullerene and polymer:fullerene organic solar cells in air, namely, a fast photo-oxidation process of the photoactive materials mediated by the formation of superoxide radical ions, whose yield is found to be strongly controlled by the lowest unoccupied molecular orbital (LUMO) levels of the electron acceptors used. Our results elucidate the general relevance of this degradation mechanism to both polymer:fullerene and polymer:nonfullerene blends and highlight the necessity of designing electron acceptor materials with sufficient electron affinities to overcome this challenge, thereby paving the way toward achieving long-term solar cell stability with minimal device encapsulation

In Vivo Evaluation of Pam2Cys‐Modified Cancer‐Testis Antigens as Potential Self‐Adjuvanting Cancer Vaccines

Peptide-based vaccines, formulated with an appropriate adjuvant, offer a versatile platform for targeted cancer immunotherapy. While adjuvants are usually coadministered for nucleic acid and protein vaccines, synthetic peptide antigens afford a more effective opportunity to covalently and regioselectively graft immunostimulatory motifs directly onto the antigen scaffold to yield self-adjuvanting vaccines. Herein, we explore the synthesis of two tissue-restricted cancer-testis antigens (CTAs); New York oesophageal cell carcinoma 1 (NY-ESO-1) and B melanoma antigen 4 (BAGE4), both carrying the toll-like receptor (TLR) agonist, Pam2Cys. These constructs were evaluated in vivo along with a lipid nanoparticle (LNP) preparation of the underexplored BAGE4 melanoma antigen

Roadmap on established and emerging photovoltaics for sustainable energy conversion

Photovoltaics (PVs) are a critical technology for curbing growing levels of anthropogenic greenhouse gas emissions, and meeting increases in future demand for low-carbon electricity. In order to fulfill ambitions for net-zero carbon dioxide equivalent (CO2eq) emissions worldwide, the global cumulative capacity of solar PVs must increase by an order of magnitude from 0.9 TWp in 2021 to 8.5 TWp by 2050 according to the International Renewable Energy Agency, which is considered to be a highly conservative estimate. In 2020, the Henry Royce Institute brought together the UK PV community to discuss the critical technological and infrastructure challenges that need to be overcome to address the vast challenges in accelerating PV deployment. Herein, we examine the key developments in the global community, especially the progress made in the field since this earlier roadmap, bringing together experts primarily from the UK across the breadth of the PVs community. The focus is both on the challenges in improving the efficiency, stability and levelized cost of electricity of current technologies for utility-scale PVs, as well as the fundamental questions in novel technologies that can have a significant impact on emerging markets, such as indoor PVs, space PVs, and agrivoltaics. We discuss challenges in advanced metrology and computational tools, as well as the growing synergies between PVs and solar fuels, and offer a perspective on the environmental sustainability of the PV industry. Through this roadmap, we emphasize promising pathways forward in both the short- and long-term, and for communities working on technologies across a range of maturity levels to learn from each other