European springtime temperature synchronises ibex horn growth across the eastern Swiss Alps

Direct effects of climate change on animal physiology, and indirect impacts from disruption of seasonal synchrony and breakdown of trophic interactions are particularly severe in Arctic and Alpine ecosystems. Unravelling biotic from abiotic drivers, however, remains challenging because high‐resolution animal population data are often limited in space and time. Here, we show that variation in annual horn growth (an indirect proxy for individual performance) of 8043 male Alpine ibex (Capra ibex) over the past four decades is well synchronised among eight disjunct colonies in the eastern Swiss Alps. Elevated March to May temperatures, causing premature melting of Alpine snowcover, earlier plant phenology and subsequent improvement of ibex food resources, fuelled annual horn growth. These results reveal dependency of local trophic interactions on large‐scale climate dynamics, and provide evidence that declining herbivore performance is not a universal response to global warming even for high‐altitude populations that are also harvested.     

High frequency of polyandry in a lek mating system

The adaptive significance of polyandry by female birds in theabsence of direct benefits remains unclear. We determined thefrequencies of polyandrous mating and multiple paternity inthe ruff, a lekking shorebird with a genetic dimorphism inmale mating behavior. More than half of female ruffs mate with, and have clutches fertilized by, more than one male. Individualfemales mate with males of both behavioral morphs more oftenthan expected. Polyandrous mating was more likely followingcopulation interference, but interference was uncommon. Themultiple paternity rate of ruffs is the highest known for avian lekking species and for shorebirds. The general hypothesis thatpair-bond constraints are the major selective factor favoringmultiple mating in birds does not predict our findings. Activegenetic diversification, which has been widely dismissed asa functional explanation for polyandrous mating in birds, mayapply with respect to the behavioral polymorphism in ruffs becauseof a Mendelian genetic basis for male behavioral morph determinationand aspects of male—male cooperation and female choice.However, rates of multiple paternity in other species of lekkingbirds are higher than generally realized, and the potentialbenefits of diversification in general deserve further consideration.     

Mechanistic insights into the inhibition of prostate specific antigen by beta-lactam class compounds

Prostate Specific Antigen (PSA) is a biomarker used in the diagnosis of prostate cancer and to monitor therapeutic response. However, its precise role in prostate carcinogenesis and metastasis remains largely unknown. A number of studies arguing in the favor of an active role of PSA in prostate cancer development and progression have implicated this serine protease in the release and activation of growth factors such as insulin-like growth factor 1 (IGF1) through cleavage of insulin like growth factor binding protein 3 and Transforming Growth Factor beta (TGF-beta) through cleavage of Latent TGF-beta. In contrast, other studies suggest that PSA activity might hinder tumor development and progression. In light of these contradictory findings, efficient inhibitors of PSA are needed for exploring its biological role in tumor development and metastasis. Towards the goal of developing potent inhibitors of PSA, we have explored the molecular mechanism of a series of beta-lactam based compounds on binding to PSA using activity assays, matrix assisted laser desorption ionization with a time-of-flight mass spectrometry, and GOLD docking methodology. The mass spectrometry experiments and the activity assays confirmed the time-dependent and covalent nature of beta-lactam binding. To gain insights on the reaction intermediates at the molecular level, we docked beta-lactam inhibitors to a homology modeled PSA using the GOLD docking program in noncovalent and covalent binding modes. The docking studies elucidated the molecular details of the early noncovalent Michaelis complex, the acyl-enzyme covalent complex, and the nature of conformational reorganization required for the long term stability of the covalent complex. Additionally, the molecular basis for the effect of stereochemistry of the lactam ring on the inhibitory potency was elucidated through docking of beta-lactam enantiomers. As a validation of our docking methodology, two novel enantiomers were synthesized and evaluated for their inhibitory potency using fluorogenic substrate based activity assays. Additionally, cis enantiomers of eight beta-lactam compounds reported in a previous study were docked and their GOLD scores and binding modes were analyzed in order to assess the general applicability of our docking results. The close agreement of our docking results with the experimental data validates the mechanistic insights revealed through the docking studies and paves the way for the design and development of potent and specific inhibitors of PSA.     

High evolutionary constraints limited adaptive responses to past climate changes in toad skulls

Interactions among traits that build a complex structure may be represented as genetic covariation and correlation. Genetic correlations may act as constraints, deflecting the evolutionary response from the direction of natural selection. We investigated the relative importance of drift, selection, and constraints in driving skull divergence in a group of related toad species. The distributional range of these species encompasses very distinct habitats with important climatic differences and the species are primarily distinguished by differences in their skulls. Some parts of the toad skull, such as the snout, may have functional relevance in reproductive ecology, detecting water cues. Thus, we hypothesized that the species skull divergence was driven by natural selection associated with climatic variation. However, given that all species present high correlations among skull traits, our second prediction was of high constraints deflecting the response to selection. We first extracted the main morphological direction that is expected to be subjected to selection by using within- and between-species covariance matrices. We then used evolutionary regressions to investigate whether divergence along this direction is explained by climatic variation between species. We also used quantitative genetics models to test for a role of random drift versus natural selection in skull divergence and to reconstruct selection gradients along species phylogeny. Climatic variables explained high proportions of between-species variation in the most selected axis. However, most evolutionary responses were not in the direction of selection, but aligned with the direction of allometric size, the dimension of highest phenotypic variance in the ancestral population. We conclude that toad species have responded to selection related to climate in their skulls, yet high evolutionary constraints dominated species divergence and may limit species responses to future climate change.     

Rhodanine derivatives as novel inhibitors of PDE4

The discovery, synthesis and in vitro activity of a novel series of rhodanine based phosphodiesterase-4 (PDE4) inhibitors is described. Structure-activity relationship studies directed toward improving potency led to the development of submicromolar inhibitors 2n and 3i (IC(50)=0.89 & 0.74 microM). The replacement of rhodanine with structurally related heterocycles was also investigated and led to the synthesis of pseudothiohydantoin 7 (IC(50)=0.31 microM).     

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

1. Download : Download high-res image (226KB)
2. Download : Download full-size image