Latest Publications
Quantifying infectious disease epidemic risks: A practical approach for seasonal pathogens
Alexander R Kaye, Giorgio Guzzetta, Michael J Tildesley
For many infectious diseases, the risk of outbreaks varies seasonally. If a pathogen is usually absent from a host population, a key public health policy question is whether the pathogen’s arrival will initiate local transmission, which depends on the season in which arrival occurs. This question can be addressed by estimating the “probability of a major outbreak” (the probability that introduced cases will initiate sustained local transmission). We have devised an approach for inferring outbreak risks for seasonal pathogens (involving calculating the Threshold Epidemic Risk; TER). Estimation of the TER involves calculating the probability that introduced cases will initiate a local outbreak in which a threshold number of cumulative infections is exceeded before outbreak extinction. For simple seasonal epidemic models, such as the stochastic Susceptible-Infectious-Removed model, the TER can be calculated numerically (without model simulations). For more complex models, such as stochastic host-vector models, the TER can be estimated using model simulations.
Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease
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.
Multiple carbamylation events are required for differential modulation of Cx26 hemichannels and gap junctions by CO2
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.
Antimicrobial triazinedione inhibitors of the translocase MraY–protein E interaction site: synergistic effects with bacitracin imply a new mechanism of action
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.
A comparative study of ionic pesticide sorption and degradation in contrasting Brazilian soils and the development of a novel 3-Phase Assay to assess sorption reversibility
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 (Kd), 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.
MCC950 Mitigates SIRT3-NLRP3-driven Inflammation and Rescues Post-Stroke Neurogenesis
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.