Comparative agonist/antagonist responses in mutant human C5a receptors define the ligand binding site

The C terminus is responsible for all of the agonist activity of C5a at human C5a receptors (C5aRs). In this report we have mapped the ligand binding site on the C5aR using a series of agonist and antagonist peptide mimics of the C terminus of C5a as well as receptors mutated at putative interaction sites (Ile(116), Arg(175,) Arg(206), Glu(199), Asp(282), and Val(286)). Agonist peptide 1 (Phe-Lys-Pro-d-cyclohexylalanine-cyclohexylalanine-d-Arg) can be converted to an antagonist by substituting the bulkier Trp for cyclohexylalanine at position 5 (peptide 2). Conversely, mutation of C5aR transmembrane residue Ile(116) to the smaller Ala (I116A) makes the receptor respond to peptide 2 as an agonist (Gerber, B. O., Meng, E. C., Dotsch, V., Baranski, T. J., and Bourne, H. R. (2001) J. Biol. Chem. 276, 3394-3400). However, a potent cyclic hexapeptide antagonist, Phe-cyclo-[Orn-Pro-d-cyclohexylalanine-Trp-Arg] (peptide 3), derived from peptide 2 and which binds to the same receptor site, remains a full antagonist at I116AC5aR. This suggests that although the residue at position 5 might bind near to Ile(116), the latter is not essential for either activation or antagonism. Arg(206) and Arg(175) both appear to interact with the C-terminal carboxylate of C5a agonist peptides, suggesting a dynamic binding mechanism that may be a part of a receptor activation switch. Asp(282) has been previously shown to interact with the side chain of the C-terminal Arg residue, and Glu(199) may also interact with this side chain in both C5a and peptide mimics. Using these interactions to orient NMR-derived ligand structures in the binding site of C5aR, a new model of the interaction between peptide antagonists and the C5aR is presented.     

Middle Pleistocene Steppe Lion Remains from Grotte de la Carrière (Têt Valley,Eastern Pyrenees)

Journal of Mammalian Evolution - Late Pleistocene cave lions are one of the most iconic species of Northern Hemisphere Quaternary taphocoenoses. Despite their often-scarce record in cave...     

Contrasting patterns of Andean diversification among three diverse clades of Neotropical clearwing butterflies

The Neotropical region is the most biodiverse on Earth, in a large part due to the highly diverse tropical Andean biota. The Andes are a potentially important driver of diversification within the mountains and for neighboring regions. We compared the role of the Andes in diversification among three subtribes of Ithomiini butterflies endemic to the Neotropics, Dircennina, Oleriina, and Godyridina. The diversification patterns of Godyridina have been studied previously. Here, we generate the first time‐calibrated phylogeny for the largest ithomiine subtribe, Dircennina, and we reanalyze a published phylogeny of Oleriina to test different biogeographic scenarios involving the Andes within an identical framework. We found common diversification patterns across the three subtribes, as well as major differences. In Dircennina and Oleriina, our results reveal a congruent pattern of diversification related to the Andes with an Andean origin, which contrasts with the Amazonian origin and multiple Andean colonizations of Godyridina. In each of the three subtribes, a clade diversified in the Northern Andes at a faster rate. Diversification within Amazonia occurred in Oleriina and Godyridina, while virtually no speciation occurred in Dircennina in this region. Dircennina was therefore characterized by higher diversification rates within the Andes compared to non‐Andean regions, while in Oleriina and Godyridina, we found no difference between these regions. Our results and discussion highlight the importance of comparative approaches in biogeographic studies.     

Addressing antimicrobial resistance by improving access and quality of care—A review of the literature from East Africa

Universal access to healthcare, including quality medicines, is a fundamental human right but is still out of reach for many in low- and middle-income countries (LMICs). An existing framework capturing variability of access to healthcare in low-resource settings includes the 5 dimensions: availability, accessibility, affordability, adequacy, and acceptability. This framework encompasses key components, including health infrastructure and means to access it as well as service organisation, costs, and factors that influence users’ satisfaction. However, in reality, the effectiveness of accessed healthcare is measured by the likelihood of a positive outcome. We therefore propose an expansion of this framework to include an additional dimension, “aspects of quality,” incorporating quality, which critically influences the ability of the accessed services to generate optimal health outcomes. Within this framework, we explore literature from East Africa likely relevant to a range of LMIC contexts, mainly focusing on the provision of widely used antimicrobials such as antimalarials and antibiotics. We argue that major inadequacies exist across all 6 dimensions of access and quality of drugs and their provision. While the global focus is on curbing excessive antimicrobial use to tackle the antimicrobial resistance (AMR) crisis, major constraints around access shape patients’ health-seeking decisions leading to potentially problematic practices that might exacerbate the AMR problem. We advocate for a holistic approach to tackling these inadequacies, encompassing all dimensions of access and quality of healthcare in order to improve health outcomes while simultaneously counteracting the AMR crisis.     

Blinded and unblinded sample size reestimation procedures for stepped‐wedge cluster randomized trials

The ability to accurately estimate the sample size required by a stepped‐wedge (SW) cluster randomized trial (CRT) routinely depends upon the specification of several nuisance parameters. If these parameters are misspecified, the trial could be overpowered, leading to increased cost, or underpowered, enhancing the likelihood of a false negative. We address this issue here for cross‐sectional SW‐CRTs, analyzed with a particular linear‐mixed model, by proposing methods for blinded and unblinded sample size reestimation (SSRE). First, blinded estimators for the variance parameters of a SW‐CRT analyzed using the Hussey and Hughes model are derived. Following this, procedures for blinded and unblinded SSRE after any time period in a SW‐CRT are detailed. The performance of these procedures is then examined and contrasted using two example trial design scenarios. We find that if the two key variance parameters were underspecified by 50%, the SSRE procedures were able to increase power over the conventional SW‐CRT design by up to 41%, resulting in an empirical power above the desired level. Thus, though there are practical issues to consider, the performance of the procedures means researchers should consider incorporating SSRE in to future SW‐CRTs.     

Intraspecific competition of endophyte infected vs uninfected plants of two woodland grass species

Grass endophytes (Clavicipitaceae, Ascomycota) are generally considered to be mutualists which increase the host's fitness. Infected plants are often more persistent and competitive than uninfected plants, influencing population dynamics and plant community diversity. However, most of this empirical evidence is based on studies focusing on agronomically important grass species such as tall fescue or perennial ryegrass and their implications for livestock and man-made habitats. Recent studies indicate that endophyte-plant associations may be more variable, ranging from parasitic to mutualistic. In the present study, we investigated the influence of endophyte infection on two wild woodland grasses, which are naturally infected with distinct fungal endophytes: Brachypodium sylvaticum with Epichloë sylvatica and Bromus benekenii with Epichloë bromicola . An intraspecific competition experiment was conducted over two growing seasons in the greenhouse and in an experimental garden. At first harvest (after 12 weeks growing), endophyte infection had a significant negative effect on above ground dry matter yield (DMY) of B. sylvaticum , but a significant positive effect on DMY of Br. benekenii under competition. The same differential effects on DMY and on total seed number were also observed at final harvest (after 62 weeks growing). Results from Br. benekenii were consistent with our hypothesis of increased competitive abilities of infected plants in nature which could explain the high infection rate observed in natural populations. In contrast, this explanation does not hold true for B. sylvaticum , and other factors such as increased herbivore and pathogen resistance together with frequent horizontal transmission may be responsible for the very high incidence of this association in nature. Our results confirm previous predictions that beneficial effects of endophyte infection in wild grasses can vary for different grass species, even in comparable habitats.     

COMPARISONS OF THE VOCALIZATIONS AND SOCIAL BEHAVIOUR OF SOUTHERN AFRICAN PYCNONOTUS BULBULS

Lloyd, P., Hulley, P.E. & Craig, A.J.F.K. 1996. Comparisons of the vocalizations and social behaviour of southern African Pycnonotus bulbuls. Ostrich 67: 118–125.

Vocalizations and associated behaviour of three Pycnonotus species are described, based on field observations and tape recordings from which sonagrams were produced. These species, which are locally sym-patric and hybridize, have similar vocalizations and displays; differences are most apparent in their contact calls and songs. Quantitative analysis of the songs showed that P. barbatus and P. capensis are easily distinguished, whereas the song characteristics of P. nigricans overlap those of both the other species. Playback experiments with territorial male P. barbatus in an area of allopatry showed similar responses to songs of conspecifics and of P. nigricans, but almost no response to the song of P. capensis.     

Geochemistry and Microbial Populations in Sediments of the Northern Baffin Bay,Arctic

The Northern Baffin Bay between Greenland and Canada is a remote Arctic area restricted in primary production by seasonal ice cover, with presumably low sedimentation rates, carbon content and microbial activities in its sediments. Our aim was to study the so far unknown subseafloor geochemistry and microbial populations driving seafloor ecosystems. Shelf sediments had the highest organic carbon content, numbers of Bacteria and Archaea, and microcosms inoculated from Shelf sediments showed highest sulfate reduction and methane production rates. Sediments in the central deep area and on the southern slope contained less organic carbon and overall lower microbial numbers. Similar 16S rRNA gene copy numbers of Archaea and Bacteria were found for the majority of the sites investigated. Sulfate in pore water correlated with dsrA copy numbers of sulfate-reducing prokaryotes and differed between sites. No methane was found as free gas in the sediments, and mcrA copy numbers of methanogenic Archaea were low. Methanogenic and sulfate-reducing cultures were enriched on a variety of substrates including hydrocarbons. In summary, the Greenlandic shelf sediments contain vital microbial communities adapted to their specific environmental conditions.     

Late‐glacial recolonization and phylogeography of European red deer (Cervus elaphus L.)

The Pleistocene was an epoch of extreme climatic and environmental changes. How individual species responded to the repeated cycles of warm and cold stages is a major topic of debate. For the European fauna and flora, an expansion–contraction model has been suggested, whereby temperate species were restricted to southern refugia during glacial times and expanded northwards during interglacials, including the present interglacial (Holocene). Here, we test this model on the red deer (Cervus elaphus) a large and highly mobile herbivore, using both modern and ancient mitochondrial DNA from the entire European range of the species over the last c. 40 000 years. Our results indicate that this species was sensitive to the effects of climate change. Prior to the Last Glacial Maximum (LGM) haplogroups restricted today to South‐East Europe and Western Asia reached as far west as the UK. During the LGM, red deer was mainly restricted to southern refugia, in Iberia, the Balkans and possibly in Italy and South‐Western Asia. At the end of the LGM, red deer expanded from the Iberian refugium, to Central and Northern Europe, including the UK, Belgium, Scandinavia, Germany, Poland and Belarus. Ancient DNA data cannot rule out refugial survival of red deer in North‐West Europe through the LGM. Had such deer survived, though, they were replaced by deer migrating from Iberia at the end of the glacial. The Balkans served as a separate LGM refugium and were probably connected to Western Asia with genetic exchange between the two areas.