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Vancomycin, a branched tricyclic glycosylated peptide antibiotic, is a last-line defence against serious infections caused by staphylococci, enterococci and other Gram-positive bacteria. Orally-administered vancomycin is the drug of choice to treat pseudomembranous enterocolitis in the gastrointestinal tract. However, the risk of vancomycin-resistant enterococcal infection or colonization is significantly associated with oral vancomycin. Using the powerful matrix-free assay of co-sedimentation analytical ultracentrifugation, reinforced by dynamic light scattering and environmental scanning electron microscopy, and with porcine mucin as the model mucin system, this is the first study to demonstrate strong interactions between vancomycin and gastric and intestinal mucins, resulting in very large aggregates and depletion of macromolecular mucin and occurring at concentrations relevant to oral dosing. In the case of another mucin which has a much lower degree of glycosylation (~60%) – bovine submaxillary mucin - a weaker but still demonstrable interaction is observed. Our demonstration - for the first time - of complexation/depletion interactions for model mucin systems with vancomycin provides the basis for further study on the implications of complexation on glycopeptide transit in humans, antibiotic bioavailability for target inhibition, in situ generation of resistance and future development strategies for absorption of the antibiotic across the mucus barrier., The authors are grateful for a grant from the Independent Diabetes Trust (G.G.A. and S.E.H.) and the Engineering and Physical Sciences Research Council, grant number EP/L015633/1 (I.F., S.E.H., G.G.A., V.D.).

12 páginas, 5 figuras., We combine model results with feld data for a system of wolves (Canis lupus) that prey on wild boar (Sus scrofa), a wildlife reservoir of tuberculosis, to examine how predation may contribute to disease control in multi-host systems. Results show that predation can lead to a marked reduction in the prevalence of infection without leading to a reduction in host population density since mortality due to predation can be compensated by a reduction in disease induced mortality. A key fnding therefore is that a population that harbours a virulent infection can be regulated at a similar density by disease at high prevalence or by predation at low prevalence. Predators may therefore provide a key ecosystem service which should be recognised when considering human-carnivore conficts and the conservation and re-establishment of carnivore populations., This is a contribution to MINECO Plan Nacional grant WILD DRIVER ref. CGL2017-89866 and EU-FEDER. Eleanor Tanner was supported by The Maxwell Institute Graduate School in Analysis and its Applications, a Centre for Doctoral Training funded by the UK Engineering and Physical Sciences Research Council (grant EP/L016508/01), the Scottish Funding Council, Heriot-Watt University and the University of Edinburgh. Pelayo Acevedo was supported by the Ministerio de Economia y Competitividad (MINECO) and the University of Castilla-La Mancha through a "Ramon y Cajal" contract (RYC-2012-11970). This research was also supported by Ministerio para la Transicion Ecologica, through Fundacion Biodiversidad.

MAPK/ERK kinase (MEK) 1/2 are central signaling proteins that serve as specificity determinants of the MAPK/ERK cascade. More than twenty activating mutations have been reported for MEK1/2, and many of them are known to cause diseases such as cancers, arteriovenous malformation and RASopathies. Changes in their intrinsic activity do not seem to correlate with the severity of the diseases. Here we studied four MEK1/2 mutations using biochemical and molecular dynamic methods. Although the studied mutants elevated the activating phosphorylation of MEK they had no effect on the stimulated ERK1/2 phosphorylation. Studying the regulatory mechanism that may explain this lack of effect, we found that one type of mutation affects MEK stability and two types of mutations demonstrate a reduced sensitivity to PP2A. Together, our results indicate that some MEK mutations exert their function not only by their elevated intrinsic activity, but also by modulation of regulatory elements such as protein stability or dephosphorylation, This study was supported by grants from ISF to RS. RS is an incumbent of the Yale S. Lewine and Ella Miller Lewine professorial chair for cancer research. CP acknowledges Severo Ochoa grant (SEV-2015-0493) for fnancial support. FLG acknowledges EPSRC [grant no EP/P022138/1; EP/P011306/1; EP/M013898/1] for fnancial support. HecBioSim [EPSRC grant no EP/P022138/1], Archer, JADE, the Hartree Centre, the Barcelona Supercomputing Center and PRACE are acknowledged for computer time. JF-R acknowledges Spanish MICINN grant [number BIO2016-79930-R] for fnancial support.

The origin and shape of metabolic scaling has been controversial since Kleiber found that basal metabolic rate of animals seemed to vary as a power law of their body mass with exponent 3/4, instead of 2/3, as a surface-to-volume argument predicts. The universality of exponent 3/4 -claimed in terms of the fractal properties of the nutrient network- has recently been challenged according to empirical evidence that observed a wealth of robust exponents deviating from 3/4. Here we present a conceptually simple thermodynamic framework, where the dependence of metabolic rate with body mass emerges from a trade-off between the energy dissipated as heat and the energy efficiently used by the organism to maintain its metabolism. This balance tunes the shape of an additive model from which different effective scalings can be recovered as particular cases, thereby reconciling previously inconsistent empirical evidence in mammals, birds, insects and even plants under a unified framework. This model is biologically motivated, fits remarkably well the data, and also explains additional features such as the relation between energy lost as heat and mass, the role and influence of different climatic environments or the difference found between endotherms and ectotherms., This work has been funded by projects AYA2013-48623-C2-2, FIS2013-41057-P, CGL2013-46862-C2-1-P and SAF2015-65878-R from the Spanish Ministerio de Economia y Competitividad and PrometeoII/2014/086, PrometeoII/2014/060 and PrometeoII/2014/065 from the Generalitat Valenciana (Spain). BL acknowledges funding from a Salvador de Madariaga fellowship, and L.L. acknowledges funding from EPSRC Early Career fellowship EP/P01660X/1.

Despite the presence of increasing pressure towards globalisation, the coexistence of different cultures is a distinctive feature of human societies. However, how multiculturality can emerge in a population of individuals inclined to imitation, and how it remains stable under cultural drift, i.e. the spontaneous mutation of traits in the population, still needs to be understood. To solve such a problem, we propose here a microscopic model of culture dissemination which takes into account that, in real social systems, the interactions are organised in various layers corresponding to different interests or topics. We show that the addition of multiplexity in the modeling of our society generates qualitatively novel dynamical behavior, producing a new stable regime of cultural diversity. This finding suggests that the layered organisation of social influence typical of modern societies is the key ingredient to explain why and how multiculturality emerges and thrives in our world., The authors acknowledge the support of the EU Project LASAGNE, Contract no. 318132 (STREP). V.L. also acknowledges support from EPSRC projects EP/N013492/1. M.S.M. also acknowledges financial support from FEDER (EU) and MINECO (Spain) under Grant ESOTECOS FIS2015-63628-C2-R.