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.

Read the paper here.

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.

Read the paper here.

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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Dr John James' lab have used a cellular reconstitution of preTCR function to investigate the trafficking dynamics of this developmentally important immune receptor, work which has just been published in the Journal of Cell Biology.

Expression of the pre-T cell receptor (preTCR) is an important checkpoint during the development of T cells, an essential cell type of our adaptive immune system. The preTCR complex is only transiently expressed and rapidly internalized in developing T cells and is thought to signal in a ligand-independent manner. However, identifying a mechanistic basis for these unique features of the preTCR compared with the final TCR complex has been confounded by the concomitant signaling that is normally present. Thus, we have reconstituted preTCR expression in non-immune cells to uncouple receptor trafficking dynamics from its associated signaling. We find that all the defining features of the preTCR are intrinsic properties of the receptor itself, driven by exposure of an extracellular hydrophobic region, and are not the consequence of receptor activation. Finally, we show that transitory preTCR cell surface expression can sustain tonic signaling in the absence of ligand binding, suggesting how the preTCR can nonetheless drive αβTCR lineage commitment.

Read the paper here.

Advanced cell-based therapies are often delivered to the patient frozen. Hence, any technology which increases the number of recovered, viable, cells post-thaw may improve clinical outcomes or allow more treatments per donation. The GibsonGroup have previously shown strategies to protect cells during freezing. In this latest work, in collaboration with Cytiva, the team show that incubating a model t-cell line with proline before cryopreservation leads to increased post-thaw cell yields. All proline is removed before cryopreservation so the actual freezing and thawing processes are unchanged. It was shown that proline limits cell proliferation, which might be contributing to its mode of action similar to ‘metabolic pre-conditioning’ which has been shown before.

Read the paper here.

Glycans (sugars) dictate cell-cell communication, are sites for pathogen invasion and are a key part of our immune systems. Current synthetic platforms to display glycans to investigate their biology almost always are imperfect, with heterogeneity in terms of number of glycans and the synthesis is not reproducible batch to batch. The Gibson and Ward (chemistry) groups have collaborated on a Leverhulme-Trust funded project to create ‘programmable’ glyco-clusters - before entering the lab, this method enables a research to know exactly how many glycans and their 3-D location are present on a material, and gives zero heterogeneity. This is achieved using metal co-ordination cages - 3D structures formed by spontaneous self-assembly. The team used these with model glycan-binding proteins to identify key interactions which would not be possible with traditional materials. The team are now using this to interrogate a range of targets including toxins, for diagnostics.

Read the paper here.