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Misfolding and aggregation of alpha-synuclein (αS) within dopaminergic neurons is a key factor in the development and progression of a group of age-related neurodegenerative diseases, termed synucleinopathies, that include Parkinson's disease (PD). We previously derived a peptide inhibitor from a 209,952-member intracellular library screen by employing the preNAC region (45-54) as a design template. At least six single-point mutations firmly linked to early-onset Parkinson's disease (E46K, H50Q, G51D, A53T/E/V) are located within this region, strongly implicating a pathogenic role within αS that leads to increased cytotoxicity. A library-derived ten residue peptide, 4554W, was consequently shown to block αS aggregation at the point of primary nucleation via lipid induction, inhibiting its conversion into downstream cytotoxic species. Here we couple truncation with a full alanine scan analysis, to establish the effect upon the αS aggregation pathway relative to 4554W. This revealed the precise residues responsible for eliciting inhibitory interaction and function, as well as those potentially amenable to modification or functionalisation. We find that modification N6A combined with N-terminal truncation results in a peptide of significantly increased efficacy. Importantly, our data demonstrate that the peptide does not directly disrupt αS lipid-binding, a desirable trait since antagonists of αS aggregation and toxicity should not impede association with small synaptic neurotransmitter vesicles, and thus not disrupt dopaminergic vesicle fusion and recycling. This work paves the way toward the major aim of deriving a highly potent peptide antagonist of αS pathogenicity without impacting on native αS function., Competing Interests: Declaration of Competing Interest JMM is an advisor to Sapience Therapeutics. There are no other financial or commercial conflicts to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aggregation of α-Synuclein (αS) is widely regarded as a key factor in neuronal cell death, leading to a wide range of synucleinopathies, including Parkinson's Disease. Development of therapeutics has therefore focused on inhibiting aggregation of αS into toxic forms. One such inhibitor, based on the preNAC region αS 45-54 (4554W), was identified using an intracellular peptide library screen, and subsequently shown to both inhibit formation of αS aggregates while simultaneously lowering toxicity. Subsequent efforts have sought to determine the mode of 4554W action. In particular, and consistent with the fact that both target and peptide are co-produced during library screening, we find that the peptide inhibits primary nucleation of αS, but does not modulate downstream elongation or secondary nucleation events. These findings hold significant promise towards mechanistic understanding and development of molecules that can module the first steps in αS aggregation towards novel treatments for Parkinson's disease and related synucleinopathies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JMM is an advisor to Sapience Therapeutics. There are no other financial or commercial conflicts to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sheep naturally acquire a degree of resistant immunity to parasitic worm infection through repeated exposure. However, the immune response and clinical outcome vary greatly between animals. Genetic polymorphisms in genes integral to differential T helper cell polarization may contribute to variation in host response and disease outcome. A total of twelve single nucleotide polymorphisms (SNPs) were sequenced in IL23R, RORC2 and TBX21 from genomic DNA of Scottish Blackface lambs. Of the twelve SNPs, six were non-synonymous (missense), four were within the 3' UTRs and two were intronic. The association between nine of these SNPs and the traits of body weight, faecal egg count (FEC) and relative T. circumcincta L3-specific IgA antibody levels was assessed in a population of domestic Scottish Blackface ewe lambs and a population of free-living Soay ewe lambs both naturally infected with a mixture of nematodes. There were no significant associations identified between any of the SNPs and phenotypes recorded in either of the populations after adjustment for multiple testing (Bonferroni corrected P value≤0.002). In the Blackface lambs, there was a nominally significant association (P=0.007) between IL23R p.V324M and weight at 20 weeks. This association may be worthy of further investigation in a larger sample of sheep., (Copyright © 2017. Published by Elsevier B.V.)

Molecular methods based on ITS2 sequence analysis were used to identify strongylid parasites and describe their diversity in a management intervention and anthelmintic drug treatment-free sheep flock. Fourteen different nematode parasite species were identified in the flock and the results showed a greater level of nematode species diversity than is normally reported in managed farmed flocks, with the presence of parasites such as Bunostomum trigonocephalum, Ostertagia leptospicularis, Spiculopteragia houdemeri and Trichostrongylus retortaeformis that are considered to be absent or rare in sheep kept in comparable localities. The implied prevalences of Haemonchus contortus in lambs, and of Trichostrongylus axei in lambs, ewes and rams, were higher than those in farmed sheep kept in similar regions, while those of Teladorsagia circumcincta and Trichostrongylus vitrinus were lower. Comparison of the patterns of nematode parasite infection between the summer and autumn sampling periods showed differences from the scenarios that are commonplace in comparable managed flocks; with T. vitrinus burdens of the lambs being higher in the summer than in the winter, and Oesophagostomum venulosum being the predominant nematode species in the adult sheep during the summer, while more-or-less absent from these groups during the winter. Rams played an important role in the epidemiology of certain parasitic nematode species. The relatively non-pathogenic O. venulosum was the only parasitic nematode species to predominate in any group during the study. This preliminary characterisation of the nematode parasite burdens of sheep extensively grazed on diverse unimproved pastures will aid in the understanding of the parasitological consequences of intensive grazing management and of the manner in which modern agriculture upsets the equilibrium between parasites and their hosts. These factors must be accounted for when defining the concept of sustainable parasite control and informing sustainability with reference to commercially efficient sheep farming., (Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.)

Critical to the inhibitory action of the oncogene product, MDM2, on the tumour suppressor, p53, is association of the N-terminal domain of MDM2 (MDM2N) with the transactivation domain of p53. The structure of MDM2N was previously solved with a p53-derived peptide, or small-molecule ligands, occupying its binding cleft, but no structure of the non-liganded MDM2N (i.e. the apo-form) has been reported. Here, we describe the solution structure and dynamics of apo-MDM2N and thus reveal the nature of the conformational changes in MDM2N that accompany binding of p53. The new structure suggests that p53 effects displacement of an N-terminal segment of apo-MDM2N that occludes access to the shallow end of the p53-binding cleft. MDM2N must also undergo an expansion upon binding, achieved through a rearrangement of its two pseudosymetrically related sub-domains resulting in outward displacements of the secondary structural elements that comprise the walls and floor of the p53-binding cleft. MDM2N becomes more rigid and stable upon binding p53. Conformational plasticity of the binding cleft of apo-MDM2N could allow the parent protein to bind specifically to several different partners, although, to date, all the known liganded structures of MDM2N are highly similar to one another. The results indicate that the more open conformation of the binding cleft of MDM2N observed in structures of complexes with small molecules and peptides is a more suitable one for ligand discovery and optimisation.