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Evidence for a HURP/EB free mixed-nucleotide zone in kinetochore-microtubules

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.

Fri 12 Aug 2022, 15:27 | Tags: BMS BMS_newpub

Controlling signalling pathways with light

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.
Read the paper hereLink opens in a new window.

Fri 12 Aug 2022, 15:21 | Tags: BMS BMS_newpub

Understanding polysulphoxides as macromolecular cryoprotectants

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.
Read the paper hereLink opens in a new window.

Fri 12 Aug 2022, 15:19 | Tags: BMS BMS_newpub

The influence of extrachromosomal elements in the anthrax "cross-over" strain Bacillus cereus G9241

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.

Read the paper here.

Wed 03 Aug 2022, 14:55 | Tags: BMS BMS_newpub

From cereus to anthrax and back again: The role of the PlcR regulator in the “cross-over” strain Bacillus cereus G9241

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.

Read the paper here.

Wed 03 Aug 2022, 14:52 | Tags: BMS BMS_newpub

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

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.

Mon 01 Aug 2022, 10:45 | Tags: news BMS BMS_newpub

All hail the mighty MitoPits!

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.

Fri 29 Jul 2022, 15:12 | Tags: BMS BMS_newpub

Using amino acids to control ice growth

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.

Read the paper here.

Mon 20 Jun 2022, 15:09 | Tags: BMS BMS_newpub

Characterisation of the Ubiquitin-ESCRT pathway in Asgard archaea sheds new light on origins of membrane trafficking in eukaryotes

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.
Read the paper hereLink opens in a new window.

Wed 18 May 2022, 09:02 | Tags: BMS BMS_newpub

Cancer origin identified through cell ‘surgery’

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.

Thu 05 May 2022, 09:05 | Tags: news BMS BMS_newpub

Development is more than just growth: Understanding the mechanics of organ shrinkage during embryo formation

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.

Fri 29 Apr 2022, 15:19 | Tags: BMS BMS_newpub

Life is the (mito)pits

The formation of a clathrin-coated vesicle is a major membrane remodeling process that is crucial for membrane traffic in cells. Besides clathrin, these vesicles contain at least 100 different proteins although it is unclear how many are essential for the formation of the vesicle. Here, we show that intracellular clathrin-coated formation can be induced in living cells using minimal machinery and that it can be achieved on various membranes, including the mitochondrial outer membrane. Chemical heterodimerization was used to inducibly attach a clathrin-binding fragment "hook" to an "anchor" protein targeted to a specific membrane. Endogenous clathrin assembled to form coated pits on the mitochondria, termed MitoPits, within seconds of induction. MitoPits are double-membraned invaginations that form preferentially on high curvature regions of the mitochondrion. Upon induction, all stages of CCV formation - initiation, invagination, and even fission - were faithfully reconstituted. We found no evidence for the functional involvement of accessory proteins in this process. In addition, fission of MitoPit-derived vesicles was independent of known scission factors including dynamins and dynamin-related protein 1 (Drp1), suggesting that the clathrin cage generates sufficient force to bud intracellular vesicles. Our results suggest that, following its recruitment, clathrin alone is sufficient for intracellular clathrin-coated vesicle formation.

Read more hereLink opens in a new window.

Fri 25 Mar 2022, 14:47 | Tags: BMS

Understanding how to stop ice growth with amino acids

The GibsonGroup, working with the Sosso Group in chemistry have demonstrated that simple amino acids can slow the recrystallisation of ice. Ice recrystallisation inhibition (IRI) is normally associated with ice binding proteins, but the team show that amino acids can also achieve this. Using a combination of experiments and modelling the importance of the structure of the amino acid is explored, and the relative role of ice binding investigated.

Read the paper here.

Wed 09 Mar 2022, 08:54 | Tags: BMS

Detecting SARS-COV-2 Using Plasmonic Nanoparticles

The GibsonGroup, working with colleagues at UHCW, have demonstrated the detection of SARS-COV-2 virus using liquid samples. The team, in 2020, discovered that SARS-COV-2 spike protein could bind sialic acids (specialised sugars) and developed this for lateral-flow detection. In this present work, the team show a solution-phase assay which can be conducted in multiwell plates and is hence suitable for automation. The key design of this was rod-shaped gold nanoparticles, with a synthetic polymer tether connecting the sugars.

Read the paper here

Tue 22 Feb 2022, 14:17 | Tags: BMS

€150,000 grant to investigate big improvements to medicines using tiny particles

A project to improve the efficiency of our medicines using tiny particles at the University of Warwick has received funding to take it a step closer towards commercialisation.

Thu 17 Feb 2022, 10:18 | Tags: news BMS

Getting the embryo into position

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.

Read the paper here.

Thu 03 Feb 2022, 15:50 | Tags: BMS BMS_newpub

Cell-Type-Specific Circadian Bioluminescence Rhythms in Dbp Reporter Mice

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.

Read the paper here.

Mon 17 Jan 2022, 08:00 | Tags: BMS BMS_newpub

Lighting Up Tumour Treatments

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.

Fri 14 Jan 2022, 15:30 | Tags: BMS BMS_newpub

GibsonGroup COVID-19 work featured in Medical School Council Report

The Medical Schools Council has released its report into how university research contributed during the COVID-19 pandemic. Work undertaken by the GibsonGroup is featured in this report.

Wed 15 Dec 2021, 16:15 | Tags: news BMS

Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase

Chromosome mis-segregation during mitosis leads to aneuploidy, which is a hallmark of cancer and linked to cancer genome evolution. Errors can manifest as ‘‘lagging chromosomes’’ in anaphase, although their mechanistic origins and likelihood of correction are incompletely understood. Here, we combine lattice light-sheet microscopy, endogenous protein labeling, and computational analysis to define the life history of >104 kinetochores. By defining the ‘‘laziness’’ of kinetochores in anaphase, we reveal that chromosomes are at a considerable risk of mis-segregation. We show that the majority of lazy kinetochores are corrected rapidly in anaphase by Aurora B; if uncorrected, they result in a higher rate of micronuclei formation. Quantitative analyses of the kinetochore life histories reveal a dynamic signature of metaphase kinetochore oscillations that forecasts their anaphase fate. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with an additional layer of anaphase error correction required for stable karyotype propagation. Read the paper here

Fri 03 Dec 2021, 14:51 | Tags: BMS

Cryopreservation of Phage

The GibsonGroup, working with the Sagona group in SLS and Cytivia (who host Prof Gibson as a Royal Society Industry fellow) have investigated how polymers can be used to cryopreserve bacteriophages. Methods to freeze cells have attracted huge interest of late, for application in cell based therapies and biotechnology. However, virus storage is less explored. The team showed that a simple commodity polymer could (surprisingly) protect phage and offers a new approach for banking, or even storing cocktails of phages for future use in therapy or diagnostics.

Read the paper here

Wed 01 Dec 2021, 09:04 | Tags: BMS

An Entirely Glycan-Based Lateral flow device

The GibsonGroup and their Industrial partners Iceni Diagnostics have been collaborating on new tools for Lateral Flow Diagnostics(LFDs). In particular, on replacing antibodies as the recognition units with glycans (sugars). Here the team show the first example of a complete LFD which uses glycans as both the mobile and stationary phase, providing complete proof-of-concept that a lateral flow diagnostic can be achieved without antibodies. This is demonstrated for the sensitive detection of lectins and could be applied to a range of biological targets, spanning toxins, viruses and more.

Read the paper here

Thu 18 Nov 2021, 08:09 | Tags: BMS

Removing the need for proteins in lateral flow diagnostics

The GibsonGroup with their industry partner Iceni Diagnostics have demonstrated a new approach to make ’test lines’ in lateral flow diagnostics. Current methods to make a test line involve immobilising antibodies, or using high molecular weight proteins with chemical modifications to display binding ligands. In this work, the team showed that a synthetic polymer can be used instead, which could dramatically simply the process of making a new test line, and using ’small molecule ligands’ as the targets, shown here with a glycan and biotin.

Read the paper here

Thu 18 Nov 2021, 08:07 | Tags: BMS

Long COVID risk - a signal to address sex hormones and women’s health

The COVID-19 pandemic has brought health inequalities into sharp focus on an international scale. Vulnerability to and mortality from acute COVID-19 infection is higher in men, whereas, Long COVID disproportionately affects women. Why?

Read the paper here

Tue 02 Nov 2021, 15:06 | Tags: BMS

Evolutionary transcriptomics implicates new genes and pathways in human pregnancy and adverse pregnancy outcomes

Dr Joanne Muter and Professor Jan Brosens collaborated with researchers in Chicago and Buffalo, USA, in a study that used comparative transcriptomics to reconstruct the evolutionary history of gene expression in the pregnant endometrium. The study identified hundreds of genes that were gained or lost in the womb lining of primate and human lineages. Genes that evolved to be expressed at the maternal-fetal interface in the human lineage were enriched for immune functions and diseases, such as preterm birth and pre-eclampsia. Read the paper here

Fri 15 Oct 2021, 16:48 | Tags: BMS

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