In this study, we investigate the differences between the pathogenic activities of P. asymbiotica isolates from different geographic locations. Pathogenicity was analysed using infection assays with both cultured cell lines (THP-1, CHO, and HEK cells) and primary immune cells, and peripheral blood mononuclear cells (PBMCs) isolated from human blood.

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Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6, and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis.
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Professor Justin Molloy has a new paper in the journal "Scientific Reports" in collaboration with Gregory I. Mashanov of the Francis Crick institute, London.
The paper describes a multiscale computer model that simulates the dynamics of individual molecules within the complex architecture of a living cell.

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In this work, we explored how molecules (e.g., morphogens) move within biologically realistic domains. Our Singapore-based collaborators (Wohland lab) generated subcellular resolution maps of the developing zebrafish hindbrain using electron microscopy. Yi Ting Loo, a MathSys PhD student in the Saunders lab, built a simulation environment to explore how molecules would move within these maps. We accounted for tortuosity, dead-ends and receptor binding. Our results reveal how measurement techniques such as FCS and FRAP can lead to very different estimations of dynamic parameters (e.g., the diffusivity). Hopefully, this work provides a framework for properly accounting for biologically complex environments in estimating dynamics in living organisms.
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We demonstrate the cryopreservation of vero-cells in assay ready format using macromolecular cryoprotectants and induce ice nucleation.

Photo reversible deactivation radical polymerization and, in particular, photoiniferter-reversible addition–fragmentation chain transfer (PI-RAFT) polymerization have become popular approaches to polymer synthesis in recent years. There is, however, a lack of fundamental investigations concerning the mechanism and kinetics of such reactions.

Sumiyoshi et al. is a collaboration addressing a question Robert Cross and Jun Yajima first asked themselves almost 20 years ago – would monomeric kinesin molecular motors tethered via surface loops still drive microtubule gliding? It turns out yes! Scanning a dsDNA tether across all exposed loops reveals a core mechanical cycle of the kinesin-1 motor domain that underlies, and is amplified by, linker docking.

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Scientists have developed a new approach to store and distribute crucial protein therapeutics without the need for fridges or freezers.

The breakthrough, published in the journal Nature, could significantly improve accessibility of essential protein-based drugs in developing countries where cold storage infrastructure may be lacking, helping efforts to diagnose and treat more people with serious health conditions.

The researchers, from the Universities of Manchester, Glasgow and Warwick, have designed a hydrogel – a material mostly made of water – that stabilises proteins, protecting its properties and functionality at temperatures as high as 50°C.

nervous system of the gastrointestinal tract, causing problems with peristalsis. Using an experimental model, Khan et al show that if the infection is successfully treated early enough then the damage can be reversed via a repair mechanism involving regeneration of nerve cells in the colon.
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Much of our knowledge about how T. cruzi causes Chagas disease comes from studies of infections in mice, but the data do not capture the full range of clinical outcomes seen in humans. In this paper, we developed a hamster model of T. cruzi infection with two striking features – almost exclusive restriction of chronic infection to a skin tissue niche and a progressive gait dysfunction resembling cerebral palsy.
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The Chagas disease drug discovery pipeline has been focused on a few model T. cruzi strains, but this does not reflect the parasite’s genetic diversity present across the millions of infected people. Here we present an expanded panel of strains engineered to express dual bioluminescent-fluorescent fusion reporter genes that can be used to ensure candidate compounds have in vivo activity across the species before being advanced into clinical testing.
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In this paper we use a combination of cryo-electron microscopy (CryoEM) and total internal reflection fluorescence microscopy (TIRFM) to investigate structural plasticity of the multi-subunit protein kinase called CaMKII. CaMKII plays a critical role in synaptic transmission by neuronal cells and the fact we observe intrinsic variation in stoichiometry and pleomorphology of the complex is important because subunit number is thought to play a critical role in alteration of dendritic spine anatomy, which underlies the structural basis of learning.
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In this paper we describe the structure of the interaction between TACC3 and ch-TOG. A single helix from ch-TOG, normally bound to two hairpins, pops out and binds to the coiled-coil of TACC3. We then isolated Affimers (non-antibody binders) that inhibit this interaction in vitro. Moving into cells, we could express the Affimers to inhibit the ch-TOG–TACC3 interaction and found a new function for these two proteins in stabilizing the pericentriolar material.
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Laura Downie has invented a new way of labelling ER-Membrane Contact Sites in live cells on-demand. It uses the Lamin B Receptor so we called it “LaBeRling”. Unlike other methods, LaBeRling doesn’t distort existing contacts. It can label many different contacts between ER and other organelles (plasma membrane, mitochondria, lysosomes, endosomes, lipid droplets). Here, Laura uses LaBeRling to look at ER-Golgi contact sites in mitosis for the first time.
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Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Obesity exacerbates the reproductive complications of PCOS; however, the management of obesity in women with PCOS remains a large unmet clinical need. Observational studies have indicated that bariatric surgery could improve the rates of ovulatory cycles and prospects of fertility; however, the efficacy of surgery on ovulation rates has not yet been compared with behavioural modifications and medical therapy in a randomised trial. The aim of this study was to compare the safety and efficacy of bariatric surgery versus medical care on ovulation rates in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea.
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In a collaboration between Soochow (China), Institut Pasteur (Shanghai), CDC (China), Liverpool, Georgia (US), and Warwick we investigated the host-specificity of S. enterica based on 362,931 publically accessible genomes in EnteroBase (a database of sequenced enteric bacteria genomes hosted and developed at Warwick). We detected the presence of nine populations that are enriched in pigs and observed frequent intercontinental transmission of genetically almost identical strains in these pig-enriched populations, which cannot be explained solely by natural causes. Therefore, we focused on one population enriched in pigs, serovar Choleraesuis, reconstructing the historical fluctuations in this population, accumulation of antimicrobial-resistant genes, and international transmissions. We revealed a 2-stage expansion in the population of this serovar, the first associated with the development of intensive pig farming in the early 20th century and the second due to the increased frequency of antimicrobial resistance after the 1960s. Additionally, we found that Europe and the USA contributed the most to international transmissions of this serovar.
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Morphogen gradients provide essential positional information to gene networks through their spatially heterogeneous distribution, yet how they form is still hotly contested, with multiple models proposed for different systems. Here, we focus on the transcription factor Bicoid (Bcd), a morphogen that forms an exponential gradient across the anterior-posterior (AP) axis of the early Drosophila embryo. Using fluorescence correlation spectroscopy we find there are spatial differences in Bcd diffusivity along the AP axis, with Bcd diffusing more rapidly in the posterior. We establish that such spatially varying differences in Bcd dynamics are sufficient to explain how Bcd can have a steep exponential gradient in the anterior half of the embryo and yet still have an observable fraction of Bcd near the posterior pole. In the nucleus, we demonstrate that Bcd dynamics are impacted by binding to DNA. Addition of the Bcd homeodomain to eGFP::NLS qualitatively replicates the Bcd concentration profile, suggesting this domain regulates Bcd dynamics. Our results reveal how a long-range gradient can form while retaining a steep profile through much of its range. Read the paper here.

More and more evidence suggest that circadian clock disruption or misalignment is a feature of many diverse chronic diseases including metabolic syndrome, depression but also a number of cancers. For the latter, recent mechanistic studies in cancer models have established an understanding of how the circadian clock influences onset, progression and therapeutic outcomes. Moreover, it has been proposed that tumours might have disrupted circadian oscillators. In patients, however, this is more difficult to establish as usually only single samples, e.g., tumour biopsies, are available. Therefore, novel tools to measure the functional state of the molecular circadian clock are needed.

Here, we introduce TimeTeller, a machine learning tool that analyses the clock as a system and aims to estimate circadian clock function from a single sample’s transcriptome by modelling the multi-dimensional state of the clock. We demonstrate TimeTeller’s utility for analysing experimental in vitro and in vivo, as well as healthy human and patient samples from various platforms (microarray, RNA-Seq and NanoString) and highlight TimeTeller’s potential relevance for advancing circadian medicine. The project is an inter-disciplinary collaboration including significant work by Warwick’s MRCDTP students Laura Usselmann and Vadim Vasilyev and is setting the stage for further applications of TimeTeller in experimental models and human breast tumours.
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This work is based on the discovery of diurnal variations impacting cancer therapy. Especially, use of chronomodulated treatment with 5-fluorouracil (5-FU) has gained significance. Studies indicate high inter-individual variability in diurnal variations in dihydropyrimidine dehydrogenase (DPD) activity – a key enzyme for 5-FU metabolism. However, the influence of individual chronotypes on chronomodulated therapy was unclear but is needed to optimize precision dosing of chronomodulated 5‑FU. Lead by the Thorsten Lehr's PKPD group at the University of Saarland, this collaborative paper is taking a treasure trove of patient 5-FU PK data amalgamated with DPD enzyme activity data from health people to establish a novel PKPD model of 5-FU that captures the extent of diurnal variations in DPD activity and can help investigate individualized chronomodulated 5-FU therapy through testing alternative personalized dosing strategies. Read the paper here.

Work by recent WMS PhD graduate Agnieszka Nagorska and PDRA Andreas Zaucker shows that translational control of an enzyme, FurinA, is important for normal positioning of the heart, and for cardiac valve function. FurinA cleaves the growth factor signal and morphogen, Nodal. Mutant zebrafish embryos with mis-regulated furina show premature and increased levels of FurinA, ectopic Nodal signalling, and defects in heart positioning and valve development. This is similar to human patients with mitral valve regurgitation. The findings pave the way for potential diagnostic tests for patients with heart valve dysfunctions. The work was supported by grants from the Leverhulme Trust, UKRI-BBSRC, MLSRF, and doctoral studentships from Warwick Medical School, MRC DTP, and Warwick-ARAP.
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Gram negative bacterial pathogens use so called Type VI secretion systems (T6SSs) to deliver virulence effectors into target cells (either animal cells or other bacteria). Besides structural and effector proteins, many other proteins, such as adaptors, co-effectors and accessory proteins, are involved in this process. MIX domains can assist in the delivery of T6SS effectors when encoded as a stand-alone gene or fused at the N-terminal of the effector. However, whether there are other conserved domains exhibiting similar encoding forms to MIX in T6SS remains obscure.

In this work, we scanned publicly available bacterial genomes and established a database which include 130,825 T6SS vgrG loci from 45,041 bacterial genomes. Based on this, we revealed six domain families encoded within vgrG loci, which are either fused at the C-terminus of VgrG/N-terminus of T6SS toxin or encoded by an independent gene. Among them, DUF2345 was further validated and shown to be indispensable for the T6SS effector delivery and LysM was confirmed to assist the interaction between VgrG and the corresponding effector. Together, our results implied that these widely distributed domain families with similar genetic configurations may be required for the T6SS effector recruitment process.

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The dramatic global impact of the coronavirus pandemic has increased consideration on epidemiological progressions of pandemics. Measures implemented to reduce viral transmission have been largely historical, comparable in nature with the 1918 and 2009 influenza pandemics, demonstrating the importance of clinicians’ awareness on historical pandemics.

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Liver hepatocytes are the front-line cells for screening new compounds for toxicity. However, hepatocytes are stored frozen in vials, not in monolayers meaning they need substantial processing to be ‘usable’ especially for high throughput screening. To solve this the Gibson and Dallman groups have collaborated, so show that immortalised and primary hepatocytes can be cryopreserved whilst attached to 96 well microplates. These can then be taken from the freezer, and simple thawed and are ready to use in under 24 hours. Post-thaw the cells show equal performance to fresh. This was achieved by careful consideration of the molecular mechanism damage during freezing, with the team using patent-pending controlled ice nucleation technology, rather than a traditional re-formulation of cryoprotectants approach. This work was in collaboration with Cryologyx, a University of Warwick Spin out, which has commercialised aspects of this technology.  
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Trafficking of proteins, lipids, and other molecules between cellular compartments is carried out by vesicular carriers. Material destined for transfer is packaged into a small trafficking vesicle at the donor compartment; the vesicle must then travel to its destination, before fusing with the target compartment to deliver the material.

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