Tohidul Islam et al, including Emily Hill & Mark J Wall

Patients with Alzheimer’s disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking. Our findings inform about the status of early-stage tau aggregation, reveal aggregation-relevant phosphorylation epitopes in tau and offer a diagnostic biomarker and targeted therapeutic opportunities for AD.

Nature Medicine. February 2025 

Press Release

Sarbjit Nijjar, Deborah Brotherton, Jack Butler, Valentin-Mihai Dospinescu, Harry G Gannon, Victoria Linthwaite, Martin Cann, Alexander Cameron, Nicholas Dale 

CO₂ directly modifies the gating of connexin26 (Cx26) gap junction channels and hemichannels. This gating depends upon Lys125, and the proposed mechanism involves carbamylation of Lys125 to allow formation of a salt bridge with Arg104 on the neighbouring subunit. We demonstrate via carbamate trapping and tandem mass spectrometry that five Lys residues within the cytoplasmic loop, including Lys125, are indeed carbamylated by CO₂ . Our findings directly demonstrate carbamylation in connexins, provide further insight into the differential action of CO₂ on Cx26 hemichannels and gap junction channels, and increase support for the role of the N-terminus in gating the Cx26 channel. KEY POINTS: Direct evidence of carbamylation of multiple lysine residues in the cytoplasmic loop of Cx26. Concentration-dependent carbamylation at lysines 108, 122 and 125. Only carbamylation of lysine 125 is essential for hemichannel opening to CO₂. Carbamylation of lysine 108 along with lysine 125 is essential for CO₂-dependent gap junction channel closure.

Journal of Physiology. February 2025

Julia A. Fairbairn, Rachel V. Kerr, Nika-Kare A. Pierre-White, Anthony Jacovides, Becca W. A. Baileeves, Phillip J. Stansfeld, Gerhard Bringmann, Andrew T. Merritt and Timothy D. H. Bugg

Escherichia coli translocase MraY is the target for bacteriolytic protein E from bacteriophage fX174, interacting at a site close to Phe-288 on helix 9, on the extracellular face of the protein. A peptide motif Arg-Trp-x-x-Trp from protein E was used to design a set of triazinedione peptidomimetics, which inhibit particulate MraY (6d IC50 48 µM), and show antimicrobial activity against Gram-negative and Gram-positive antibiotic-resistant clinical strains (7j MIC Acinetobacter baumannii 16 µg/mL, Staphyloccoccus aureus MRSA 2-4 µg/mL). Docking against a predicted structure for E. coli MraY revealed two possible binding sites close to helix 9, the binding site for protein E. Antimicrobial activity of analogue 6j was found to be synergistic with bacitracin in Micrococcus flavus, consistent with a link between this inhibition site and undecaprenyl phosphate uptake. Alkaloid michellamine B, also predicted to bind in the cleft adjacent to helix 9, was also found to be synergistic with bacitracin. These data provide experimental evidence that the unusual hydrophobic cleft adjacent to helix 9 in MraY is involved in uptake of undecaprenyl phosphate, in addition to recently identified transporters UptA and PopT, and that this process can be targetted by small molecules as a novel antibacterial mechanism.

RSC Medicinal Chemistry. January 2025

Baudin, Nastasia, Garrod, Mark, Bramke, Irene, Mckillican, Carol, Schafer, Hendrik, Hand, Laurence, Cione, Ana, Bending, Gary D, Marshall, Samantha

Brazilian soils have distinctive characteristics to European and North American soils which are typically used to investigate pesticide fate. This study aimed to compare soil–water partition coefficient (K_d), reversibility of adsorption and degradation half-life (DT₅₀) of 5 pesticides covering a wide range of physico-chemical properties in contrasting Brazilian soils and a temperate (UK) alfisol soil, and to study their relationship with soil OM, clay and expandable clay content, CEC and pH. The results showed that pesticide behaviour in Brazilian soils was not systematically different from those in European and North American soils. The 3PA was shown to be a reliable and simple method for assessing pesticide desorption in soil and could be adapted to assess pesticide bioavailability. The use of the 3PA allowed a more thorough explanation of the observed differences in degradation behaviour between the compounds.

Environmental Monitoring and Assessment. January 2025

Prakash R., Waseem A., Siddiqui A.J., Naim M., Khan M.A., Robertson A.A.B., Boltze J., Raza S.S.

after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke.

Biomedicine and Pharmacotherapy. January 2025

Helekal, David, Koskela, Jere and Didelot, Xavier

Here we consider the problem of detecting the presence of multiple mergers in the context of dating a phylogeny, that is determining the date of each of the nodes. We use the Lambda-coalescent theory as a modelling framework and show how Bayesian inference can be efficiently performed using a Billera-Holmes- Vogtmann space embedding and a customised Markov Chain Monte Carlo sampling scheme. We applied this new analysis methodology to a large number of simulated datasets to show that it is possible to infer if and when multiple merger events occurred, and that the phylogenetic dating is improved as a result of taking this information into account. We also analysed real datasets of Vibrio cholerae and Mycobacterium tuberculosis to demonstrate the relevance of our approach to real pathogen evolutionary epidemiology. We have implemented our new methodology in a R package which is freely available at https://github.com/dhelekal/MMCTime.

Systematic Biology. January 2025