Sleep and circadian rhythm disruption (SCRD), as encountered during shift work, increases the risk of respiratory viral infection including SARS-CoV-2. However, the mechanism(s) underpinning higher rates of respiratory viral infection following SCRD remain poorly characterised. To address this, we investigated the effects of acute sleep deprivation on the mouse lung transcriptome. Here we show that sleep deprivation profoundly alters the transcriptional landscape of the lung, causing the suppression of both innate and adaptive immune systems, disrupting the circadian clock, and activating genes implicated in SARS-CoV-2 replication, thereby generating a lung environment that promotes viral infection and associated disease pathogenesis. Our study provides a mechanistic explanation of how SCRD increases the risk of respiratory viral infections including SARS-CoV-2 and highlights therapeutic avenues for the prevention and treatment of COVID-19.
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Nuria Ferrandiz and colleagues in the Royle lab published a paper in J Cell Biol this summer on mitotic chromosome "ensheathing" by endomembranes. This paper was selected by the JCB as one of the 10 best papers of 2022. JCB have put together a supplement containing summaries of all ten papers with photos of the authors.
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The GibsonGroup have a large interest in mimicking the function of ice binding proteins (IBPs) using polymers, which have huge biotechnological, biomedical and industrial potential. The team have previously made progress in mimicking ‘antifreeze’ proteins, but the search for a polymer which can nucleate ice has been elusive. Ice nucleating proteins (INPs) are very large, and truncated versions are far less active, and the native proteins are immobilised in membranes making their study challenging. In this latest work, the team report (what they believe) is the first polymeric ice nucleator. To achieve this they took an ice binding polymer and used synthetic polymer chemistry to make a ‘brush shaped’ polymer to introduce rigidity and very high molecular weight (100’s of kDAs). This new tool is the first synthetically accessible ‘organic’ probe for ice nucleation.
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Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study

New study from the Bowman Lab published in eLife defines a novel nuclear translocation pathway involving the specific import receptor Importin-5 and the histone chaperone NASP that specialise in ferrying monomeric histones to the nucleus.

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Nanoparticles have found widespread use in diagnostics and have been suggested for e.g. drug delivery. Chemists can now fine tune the nanoparticle surface to e.g target cell types. However, what a cell 'sees' is not what is made by the chemists, but rather a complex mixture of proteins which ‘foul’ the surface, recruited from the blood, termed the protein corona. There has been extensive research into the proteins which make up the corona, but the glycans on these proteins have received less attention. This is a major problem, as > 50 % of our proteome is glycosylated, and hence investigating a nanoparticle’s protein corona, without considering the glycans, does not give an accurate picture.

In our latest work, we investigate the impact of the glycoprotein corona on how polymer-coated nanoparticles bind lectins. We show that serum proteins bring significant sialic acids to the particle surface. The impact of this, is that the particles can bind additional lectins (which were not intended) as well as those which are intended. Finally, we show that 'blocking' the surface does reduce the amount of protein, but sufficient glycans remain to cause off-target binding. These results will help guide the next generation of nanoparticle sensing and delivery agents.
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The use of nanoparticles as drug delivery vehicles is well established. Numerous studies have investigated the impact of size, shape, charge, and surface functionality of nanoparticles on mammalian cellular uptake. Rigidity, however, has been studied to a far lesser extent, and its effects are still unclear. Here, in a collaboration between the Chemistry and BMS, this is systematically explored.

Three different polymeric core rigidities were tested: hard, medium and soft using two 50 and 100 nm diameter particles. Cellular uptake studies indicated that 100nm softer particles are taken up faster and 3-fold more into mammalian cells compared to harder nanoparticles, probably via major differences in the cellular uptake pathways. However, 50 nm derivatives did not show any appreciable differences in uptake efficiency suggesting that rigidity as a parameter for nanomaterials in the biological regime might be size dependent.

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In a recent study published in Cell Reports, teams from University College London and Warwick Medical School describe how protein fusion of two epigenetic modulators, JAZF1 and SUZ12, causes oncogenesis in human endometrial stromal cells by disrupting the composition of the polycomb repressive complex 2 (PRC2), resulting in aberrant histone modification, gene expression and cell differentiation (decidualization). The results reveal how dysregulation of PRC2 drives the emergence of low-grade endometrial stromal sarcomas in the womb, which provide opportunities to improve the treatment of this disease.

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All cells must accurately separate their chromosomes during mitosis to avoid errors that are associated with cancer development, reproductive failure and even ageing. This feat is accomplished by the mitotic spindle – this microtubule-based machine has a bipolar geometry and contains hundreds of protein components. A subset of microtubules form bundles that make contact with kinetochores on the chromosome (these are called K-fibres). The growth and shrinkage of these microtubules, through addition and loss of tubulin, is coupled to the hydrolysis of GTP: this powers chromosome movement. Previous work identified a protein called HURP (hepatoma up-regulated protein) that forms distinctive stripes on each half spindle (see schematic). Here, through collaboration with University of Geneva, we identified a new region within the mitotic spindle, termed “HURP-gap”. This HURP free region of the K-fibre is located between the stripe and the kinetochore.

Discovery: How do organs reach a specific size during development? The Hippo/YAP pathway has been identified as a critical regulator of organ size control. It also plays an important role in homeostasis and cancer progression, in part due to its mechanosensitive response. Here, the Saunders lab have developed an optogenetic version of YAP (optoYAP) that enables its localisation to the nucleus to be tightly controlled in both space and time. This enables targeted perturbation of the pathway, with potential applications to wound healing and regeneration.
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The GibsonGroup are developing macromolecular (polymer) cryoprotectants to enable next-generation cell based therapies, and to simplify cell-based assays. A key feature identified in the teams most potent materials is a mixture of cationic/anionic charges on the side chain, but the exact mechanism of action is under investigation. In this latest work the team explored sulphoxide (‘DMSO like’) side chains, which are actually highly polarised with S+-O- character. The team also explore N-oxide polymers which have similar charged character. Using a range of phyical and biochemical assays the team investigated if these motifs could aid in cryopreservation.
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We have now published back to back two papers on the so called anthrax “cross over strain Bacillus cereus G9241. The first paper (From cereus to anthrax and back again: The role of the PlcR regulator in the “cross-over” strain Bacillus cereus G9241) has already been highlighted. This current paper is titled, “The influence of extrachromosomal elements in the anthrax “cross-over” strain Bacillus cereus G9241.”

The work investigates the contribution of anthrax-like plasmids and a lysogenic phagemid to the pathogenic potential of the normally relatively harmless Bacillus cereus. We investigated the role of temperature and carriage of the pBCXO1 plasmid (which is homologous to the pXO1 anthrax toxin plasmid) in regulation of chromosomal genes, heavily affecting metabolism. In addition we have shown that sporulation of G9241 is very rapid at 37’C, which is characteristic of B. anthracis but unlike the ancestral B. cereus strains. Finally we isolated phagemid virions which are produced at 37’C and visualised them with electron microscopy.

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In our recent paper “From cereus to anthrax and back again: The role of the PlcR regulator in the “cross-over” strain Bacillus cereus G9241” we have investigated how a normally low risk Bacillus cereus strain has evolved to mimic Bacillus anthracis, the causative agent of the highly feared lethal anthrax infection. The B. cereus G9241 strain is one of several relatively recent isolates that are termed “anthrax cross over strains” that intriguingly seem to preferentially infect metal workers in the USA (welders / millers). These strains are of particular concern as, unlike B. anthracis proper, they can switch between a form that can survive and replicate in the environment using invertebrate hosts and the more lethal mammalian infective anthrax like form. B. anthracis must pass from mammalian host to mammalian host as a spore form thus somewhat limiting its spread. This is due to a loss of function mutation in a key regulator protein named PlcR, which in all other B. cereus sensu lato group strains allows for survival outside of a mammalian host. Our work has identified the specific mechanism by which G9241 can switch on and off the PlcR regulation endowing it with a “Dr. Jekyll or Mr. Hyde” like life cycle. This work was a culmination of a Marie Curie fellow, 3 PhD students and one postdoc and was supported by MoD Porton Down DSTL funding and advice, for which we are very grateful.

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One of the key questions relating to the COVID-19 pandemic is how prior immunity to related endemic coronaviruses affects the SARS-CoV-2 immune response. In this study, we provide evidence of immunological imprinting in individuals with fatal outcomes from COVID-19, suggesting an antibody profile consistent with an original antigenic sin type-response. Read the paper hereLink opens in a new window.

Cansu Küey’s PhD work was published this week in eLife. Together with Méghane, Gabrielle and Miguel, she showed that clathrin-coated pits can be made to form on intracellular membranes. This phenomenon allowed us to redefine two key concepts in clathrin-coated vesicle formation. First, a scission molecule is not needed to pinch off vesicles inside the cell. Second, that most of the other proteins found in regular clathrin coats are not essential for vesicle formation.

The GibsonGroup, in collaboration with the Sosso Group (chemistry) are investigating how small molecules can inhibit ice recrystallisation - a property more commonly associated with macromolecules, such as ice binding proteins or some polymers. The challenge of the macromolecules is that sequential modification is challenging, and hence structure-property relationships are often missing. Here the team show that phenyl alanine can inhibit ice recrystallisation and that modulation of the hydrophobic face impacts the magnitude of the activity. This work shows that ’small molecule’ approaches can be taken to probe the complex ice/water interface, with the long term goal of finding new molecules to control ice growth.

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This work answers the mystery surrounding when in evolution did a key class of membrane remodelling factors arise. The collaborative team comprising Balasubramanian (Warwick), Baum (Cambridge), Lowe (Cambridge), Robinson (Lancaster), and Ettema (Wageningen, Netherlands) worked on proteins encoded by Heimdall archaea, thought to be most related to eukaryotes. They found that, contrary to existing dogma, a complex eukaryote-like ESCRT family of membrane remodelling factors were present in archaea and are therefore not eukaryotic inventions. Warwick post-doctoral fellow and first author Hatano “reconstituted” key steps of the process using purified components helping arrive at the conclusions.
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Research from the University of Warwick sheds new light on a key cause of cancer formation during cell division (or mitosis), and points towards potential solutions for preventing it from occurring.

When we think about embryo growth, we often focus on tissue growth. However, this is not always the case: for example, the nervous system actually shrinks during parts of development. How do tissues condense in size while maintaining mechanical integrity? In recent work from the Saunders lab, with Spanish collaborators Enrique Martin-Blanco and Jose Munoz, they show that the Drosophila nervous system condenses through alternating waves of contraction from the anterior and posterior ends of the embryo. Further, they use the power of Drosophila genetics to reveal that the glial cells provide an essential mechanical support, effectively acting like a compression sock during condensation. This work opens up new avenues to study the mechanobiology of tissues that shrink – such tissues display behaviour very much distinct from growing tissues. Read the paper here.

During development, many organisms initially undergo multiple rounds of nuclei division before cellularisation occurs. Such systems are known as syncytia. Other processes such as muscle formation – which have multiple nuclei in a single cell – are similar.

In syncytia, nuclei distribute in a regular pattern. Yet, how does this occur? Answering this question is important for understanding how life developments and muscles form. In recent work from the Saunders lab, in collaboration with the Telley lab at the Gulbenkian Institute in Portugal, they used quantitative measurements to unravel how the nuclei regularly position in the fruit fly syncytium. They took advantage of explants – whereby material is removed from the egg and imaged – to reveal that are repulsive interactions between microtubules (rod like structures) in the syncytia. They used modelling and experimental tests to show that these repulsive interactions drive the ordering of the nuclei.

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In collaboration with groups at UMass Med School, Smith College and Morehouse University, we have developed a reporter mouse generated by modification of a widely expressed and highly rhythmic gene encoding D-site albumin promoter binding protein (Dbp). In this line of mice, firefly luciferase is expressed from the Dbp locus in a Cre recombinase-dependent manner, allowing assessment of bioluminescence rhythms in specific cellular populations. Our studies reveal cell-type-specific characteristics of rhythms among neuronal populations and liver cells. Our model allowed assessment of the rate of recovery from circadian misalignment once animals were provided with food ad libitum. These studies confirm the previously demonstrated circadian misalignment following environmental perturbations and reveal the utility of this model for minimally invasive, longitudinal monitoring of rhythmicity from specific mouse tissues.

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The Perrier Lab have just published a new study in Angewandte Chemie which shows how polymeric nanotubes can be designed to switch their fluorescence on as they deliver a commercial anticancer drug (doxorubicin), thereby permitting the in-situ visualization of drug release. By this method, we can both treat a cancer tumour and show where the tumour is located. These theranostic systems (from therapeutic and diagnostic) form a new approach to drug delivery.

Read the paper here.