Knockout of receptor for advanced glycation end‐products attenuates age‐related renal lesions

Pro‐aging effects of endogenous advanced glycation end‐products (AGEs) have been reported, and there is increasing interest in the pro‐inflammatory and ‐fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill‐defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CML) suggests the kidneys may be particularly affected. We studied the impact of RAGE invalidation and a CML‐enriched diet on renal aging. Two‐month‐old male, wild‐type (WT) and RAGE^?/? C57Bl/6 mice were fed a control or a CML‐enriched diet (200 μg CML/g_food) for 18 months. Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE^?/? mice, with a predominantly tubular localization. The CML‐rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE^?/? mice were significantly protected against nephrosclerosis lesions (hyalinosis, tubular atrophy, fibrosis and glomerular sclerosis) and renal senile apolipoprotein A‐II (ApoA‐II) amyloidosis (p < 0.001). A positive linear correlation between sclerosis score and ApoA‐II amyloidosis score (r = 0.92) was observed. Compared with old WT mice, old RAGE^?/? mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE^?/? mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE^?/? mice, suggesting RAGE is an important receptor in so‐called inflamm‐aging.     

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel,CNS penetrant tricyclic M4 PAMs

This letter describes progress towards an M₄ PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M₄ PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.     

Selection for genetics‐based architecture traits in a native cottonwood negatively affects invasive tamarisk in a restoration field trial

Climate change and competition from invasive species remain two important challenges in restoration. We examined the hypothesis that non‐native tamarisk (Tamarix spp.) reestablishment after aboveground removal is affected by genetics‐based architecture of native Fremont cottonwood (Populus fremontii) used in restoration. As cottonwood architecture (height, canopy width, number of stems, and trunk diameter) is, in part, determined by genetics, we predicted that trees from different provenances would exhibit different architecture, and mean annual maximum temperature transfer distance from the provenances would interact with the architecture to affect tamarisk. In a common garden in Chevelon, AZ, U.S.A. (elevation 1,496 m), with cottonwoods from provenances spanning its elevation distribution, we measured the performance of both cottonwoods and tamarisk. Several key findings emerged. On average, cottonwoods from higher elevations were (1) two times taller and wider, covered approximately 3.5 times more basal area, and were less shrubby in appearance, by exhibiting four times fewer number of stems than cottonwoods from lower elevations; (2) had 50% fewer tamarisk growing underneath, which were two times shorter and covered 6.5 times less basal area than tamarisk growing underneath cottonwoods of smaller stature; and (3) the number of cottonwood stems did not affect tamarisk growth, possibly because the negative relationship between cottonwood stems and basal area. In combination, these findings argue that cottonwood architecture is affected by local conditions that interact with genetics‐based architecture. These interactions can negatively affect the growth of reinvading tamarisk and enhance restoration success. Our study emphasizes the importance of incorporating genetic and environmental interactions of plants used in restoration.     

The distribution of the orange‐striped green anemone,Diadumene lineata,in relation to environmental factors along coastal British Columbia,Canada

The cosmopolitan nonindigenous sea anemone, Diadumene lineata, has been recorded from the Pacific coast of Canada since 1859. Despite its long historical presence in the region, the factors influencing the distribution of this species in British Columbia, Canada, are poorly understood, as are the factors that may restrict its local abundance. We conducted large‐scale surveys of D. lineata during the winter and summer of 2016, coupled with higher frequency surveys at one focal site. Furthermore, we used laboratory and field experiments to determine the potential importance of a large‐scale driver, salinity, and a small‐scale driver, microhabitat within boulders, in setting distributional limits at various spatial scales. Our results confirm that D. lineata is widely distributed within the Salish Sea. This broad distribution may be facilitated by post‐introduction dispersal; we observed anemones attached to floating substrata, and a few mature specimens contained eggs, suggesting that reproduction is perhaps not limited to asexual fission. We found that D. lineata was abundant throughout the year, although absent from the lowest salinity sites. This corresponded with our laboratory experiments, in which survival of individuals of D. lineata declined at salinities below 10 psu, and no survivors were observed at or below 2 psu. Manipulative experiments in the field demonstrated that survival was high under rocks where D. lineata is commonly found, but was reduced on the tops of rocks, highlighting the importance of microhabitat refugia in buffering temperature and reducing desiccation. A better understanding of the factors that limit the broad‐scale and local distribution of this anemone are an important step in determining potential ecological impacts of this organism and how distributions may shift into the future.     

Assessing factors associated with changes in the numbers of birds visiting gardens in winter: Are predators partly to blame?

The factors governing the recent declines observed in many songbirds have received much research interest, in particular whether increases of avian predators have had a negative effect on any of their prey species. In addition, further discussion has centered on whether or not the choice of model formulation has an effect on model inference. The study goal was to evaluate changes in the number of 10 songbird species in relation to a suite of environmental covariates, testing for any evidence in support of a predator effect using multiple model formulations to check for consistency in the results. We compare two different approaches to the analysis of long‐term garden bird monitoring data. The first approach models change in the prey species between 1970 and 2005 as a function of environmental covariates, including the abundance of an avian predator, while the second uses a change–change approach. Significant negative relationships were found between Eurasian Sparrowhawk Accipiter nisus and three of the 10 species analyzed, namely house Sparrow Passer domesticus, starling Sturnus vulgaris, and blue tit Cyanistes caeruleus. The results were consistent under both modeling approaches. It is not clear if this is a direct negative impact on the overall populations of these species or a behavioral response of the prey species to avoid feeding stations frequented by Sparrowhawks (which may in turn have population consequences, by reducing available resources). The species showing evidence of negative effects of Sparrowhawks were three of the four species most at risk to Sparrowhawk predation according to their prevalence in the predator's diet. The associations could be causal in nature, although in practical terms the reduction in the rate of change in numbers visiting gardens accredited to Sparrowhawks is relatively small, and so unlikely to be the main driver of observed population declines.     

Assessment of a large number of empirical plant species niche models by elicitation of knowledge from two national experts

Quantitative models play an increasing role in exploring the impact of global change on biodiversity. To win credibility and trust, they need validating. We show how expert knowledge can be used to assess a large number of empirical species niche models constructed for the British vascular plant and bryophyte flora. Key outcomes were (a) scored assessments of each modeled species and niche axis combination, (b) guidance on models needing further development, (c) exploration of the trade‐off between presenting more complex model summaries, which could lead to more thorough validation, versus the longer time these take to evaluate, (d) quantification of the internal consistency of expert opinion based on comparison of assessment scores made on a random subset of models evaluated by both experts. Overall, the experts assessed 39% of species and niche axis combinations to be “poor” and 61% to show a degree of reliability split between “moderate” (30%), “good” (25%), and “excellent” (6%). The two experts agreed in only 43% of cases, reaching greater consensus about poorer models and disagreeing most about models rated as better by either expert. This low agreement rate suggests that a greater number of experts is required to produce reliable assessments and to more fully understand the reasons underlying lack of consensus. While area under curve (AUC) statistics showed generally very good ability of the models to predict random hold‐out samples of the data, there was no correspondence between these and the scores given by the experts and no apparent correlation between AUC and species prevalence. Crowd‐sourcing further assessments by allowing web‐based access to model fits is an obvious next step. To this end, we developed an online application for inspecting and evaluating the fit of each niche surface to its training data.     

Gene-based sequence diversity analysis of field pea (Pisum)

Sequence diversity of 39 dispersed gene loci was analyzed in 48 diverse individuals representative of the genus Pisum. The different genes show large variation in diversity parameters, suggesting widely differing levels of selection and a high overall diversity level for the species. The data set yields a genetic diversity tree whose deep branches, involving wild samples, are preserved in a tree derived from a polymorphic retrotransposon insertions in an identical sample set. Thus, gene regions and intergenic "junk DNA" share a consistent picture for the genomic diversity of Pisum, despite low linkage disequilibrium in wild and landrace germplasm, which might be expected to allow independent evolution of these very different DNA classes. Additional lines of evidence indicate that recombination has shuffled gene haplotypes efficiently within Pisum, despite its high level of inbreeding and widespread geographic distribution. Trees derived from individual gene loci show marked differences from each other, and genetic distance values between sample pairs show high standard deviations. Sequence mosaic analysis of aligned sequences identifies nine loci showing evidence for intragenic recombination. Lastly, phylogenetic network analysis confirms the non-treelike structure of Pisum diversity and indicates the major germplasm classes involved. Overall, these data emphasize the artificiality of simple tree structures for representing genomic sequence variation within Pisum and emphasize the need for fine structure haplotype analysis to accurately define the genetic structure of the species.     

Intellectual property, genetically modified crops and bioethics

The implementation of a new technology is almost always surrounded by a debate on the moral and social implications that may arise. The debate with regard to genetically modified (GM) crops has been one of the longest and most controversial. However, one area of the debate that receives less attention is the role that intellectual property can play. The introduction of an effective and yet appropriate intellectual property system addressing society's particular needs can eliminate some of these issues. This paper looks at whether the situation in Europe is meeting our current needs and also addresses the role intellectual property can play in the debate over the introduction of GM crops in developing countries.     

Induced prion protein controls immune-activated retroviruses in the mouse spleen

The prion protein (PrP) is crucially involved in transmissible spongiform encephalopathies (TSE), but neither its exact role in disease nor its physiological function are known. Here we show for mice, using histological, immunochemical and PCR-based methods, that stimulation of innate resistance was followed by appearance of numerous endogenous retroviruses and ensuing PrP up-regulation in germinal centers of the spleen. Subsequently, the activated retroviruses disappeared in a PrP-dependent manner. Our results reveal the regular involvement of endogenous retroviruses in murine immune responses and provide evidence for an essential function of PrP in the control of the retroviral activity. The interaction between PrP and ubiquitous endogenous retroviruses may allow new interpretations of TSE pathophysiology and explain the evolutionary conservation of PrP.