Climate change and the fate of cereal aphids in Southern Britain

Climate change will drive dramatic changes in the abundance and distribution of species. Assessing the impacts of climate change on our agricultural systems is essential for mitigation planning. Here, I combine projections from the UK Hadley Centre's HadRM03 climate change model for Southern Britain with a general mechanistic model of the interaction between climate, temperate grass physiology and cereal aphid population dynamics. Aphids are one of the largest and most important groups of crop pests and disease vectors worldwide but particularly in temperate regions. The model predicts an increasingly dramatic decline in cereal aphid abundance from the 1961 to 1990 baseline with increasing CO₂ emissions: low emissions=?5%, medium low=?12%, medium high=?61%, and high=?92%. Of the six climate variables used in the model, changes in temperature and rainfall were the most important across all emissions scenarios and, counter‐intuitively, the direct impact of elevated CO₂ actually declines as emissions increase. The results suggest that the pest status of cereal aphids in Southern Britain will significantly decline by the end of this century.     

What lies beneath? Population dynamics conceal pace‐of‐life and sex ratio variation,with implications for resilience to environmental change

Life‐history and pace‐of‐life syndrome theory predict that populations are comprised of individuals exhibiting different reproductive schedules and associated behavioural and physiological traits, optimized to prevailing social and environmental factors. Changing weather and social conditions provide in situ cues altering this life‐history optimality; nevertheless, few studies have considered how tactical, sex‐specific plasticity over an individual's lifespan varies in wild populations and influences population resilience. We examined the drivers of individual life‐history schedules using 31 years of trapping data and 28 years of pedigree for the European badger (Meles meles L.), a long‐lived, iteroparous, polygynandrous mammal that exhibits heterochrony in the timing of endocrinological puberty in male cubs. Our top model for the effects of environmental (social and weather) conditions during a badger's first year on pace‐of‐life explained <10% of variance in the ratio of fertility to age at first reproduction (F/α) and lifetime reproductive success. Conversely, sex ratio (SR) and sex‐specific density explained 52.8% (males) and 91.0% (females) of variance in adult F/α ratios relative to the long‐term population median F/α. Weather primarily affected the sexes at different life‐history stages, with energy constraints limiting the onset of male reproduction but playing a large role in female strategic energy allocation, particularly in relation to ongoing mean temperature increases. Furthermore, the effects of social factors on age of first reproduction and year‐to‐year reproductive success covaried differently with sex, likely due to sex‐specific responses to potential mate availability. For females, low same‐sex densities favoured early primiparity; for males, instead, up to 10% of yearlings successfully mated at high same‐sex densities. We observed substantial SR dynamism relating to differential mortality of life‐history strategists within the population, and propose that shifting ratios of ‘fast’ and ‘slow’ life‐history strategists contribute substantially to population dynamics and resilience to changing conditions.     

Topology of NBCe1 Protein Transmembrane Segment 1 and Structural Effect of Proximal Renal Tubular Acidosis (pRTA) S427L Mutation

In the kidney proximal tubule, NBCe1-A plays a critical role in absorbing HCO₃⁻ from cell to blood. NBCe1-A transmembrane segment 1 (TM1) is involved in forming part of the ion permeation pathway, and a missense mutation S427L in TM1 impairs ion transport, causing proximal renal tubular acidosis. In the present study, we examined the topology of NBCe1-A-TM1 in detail and its structural perturbation induced by S427L. We analyzed the N-terminal cytoplasmic region (Cys-389–Gln-424) of NBCe1-A-TM1 using the substituted cysteine scanning accessibility method combined with extensive chemical stripping, in situ chemical probing, and functional transport assays. NBCe1-A-TM1 was previously modeled on the anion exchanger 1 TM1 (AE1-TM1); however, our data demonstrated that the topology of AE1-TM1 differs significantly from NBCe1-A-TM1. Our findings revealed that NBCe1-A-TM1 is unusually long, consisting of 31 membrane-embedded amino acids (Phe-412 to Thr-442). The linker region (Arg-394–Pro-411) between the N terminus of TM1 and the cytoplasmic domain is minimally exposed to aqueous and is potentially folded in a helical structure that intimately interacts with the NBCe1-A cytoplasmic domain. In contrast, AE1-TM1 contains 25 amino acids connected to an aqueous-exposed cytoplasmic region. Based on our new NBCe1-A-TM1 model, Ser-427 resides in the middle of TM1. Leucine substitution at Ser-427 blocks the normal aqueous access to Thr-442, Ala-435, and Lys-404, implying a significant alteration of NBCe1-TM1 orientation. Our study provides novel structural insights into the pathogenic mechanism of S427L in mediating proximal renal tubular acidosis.     

Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF–FVIIa inhibitors

Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF–FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.