3,235 research outputs found
Matchingâcentrality decomposition and the forecasting of new links in networks
Networks play a prominent role in the study of complex systems of interacting entities in biology, sociology, and economics. Despite this diversity, we demonstrate here that a statistical model decomposing networks into matching and centrality components provides a comprehensive and unifying quantification of their architecture. The matching term quantifies the assortative structure in which node makes links with which other node, whereas the centrality term quantifies the number of links that nodes make. We show, for a diverse set of networks, that this decomposition can provide a tight fit to observed networks. Then we provide three applications. First, we show that the model allows very accurate prediction of missing links in partially known networks. Second, when node characteristics are known, we show how the matchingâcentrality decomposition can be related to this external information. Consequently, it offers us a simple and versatile tool to explore how node characteristics explain network architecture. Finally, we demonstrate the efficiency and flexibility of the model to forecast the links that a novel node would create if it were to join an existing network
The feasibility of equilibria in large ecosystems: A primary but neglected concept in the complexity-stability debate
The consensus that complexity begets stability in ecosystems was challenged in the seventies, a result recently extended to ecologically-inspired networks. The approaches assume the existence of a feasible equilibrium, i.e. with positive abundances. However, this key assumption has not been tested. We provide analytical results complemented by simulations which show that equilibrium feasibility vanishes in species rich systems. This result leaves us in the uncomfortable situation in which the existence of a feasible equilibrium assumed in local stability criteria is far from granted. We extend our analyses by changing interaction structure and intensity, and find that feasibility and stability is warranted irrespective of species richness with weak interactions. Interestingly, we find that the dynamical behaviour of ecologically inspired architectures is very different and richer than that of unstructured systems. Our results suggest that a general understanding of ecosystem dynamics requires focusing on the interplay between interaction strength and network architecture
Bericht ĂŒber die in Berlin, Amsterdam, Rochdale, Manchester, Croydon, Leamington und Abingdon eingefĂŒhrten Systeme der StĂ€dtereinigung / unter Mitw. von R. Blasius ... erstattet von L. Mitgau. Mit in den Text gedruckten Holzschnitten und einem Plane von Abingdon
The anti-Pseudomonas aeruginosa antibody Panobacumab is efficacious on acute pneumonia in neutropenic mice and has additive effects with meropenem
Pseudomonas aeruginosa ( P. aeruginosa ) infections are associated with considerable morbidity and mortality in immunocompromised patients due to antibiotic resistance. Therefore, we investigated the efficacy of the anti- P. aeruginosa serotype O11 lipopolysaccharide monoclonal antibody Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia. We observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts. This suggests beneficial effects of co-treatment even in immunocompromised individuals, suffering most of the morbidity and mortality of P. aeruginosa infections
Role of the Occluded Conformation in Bacterial Dihydrofolate Reductases
Dihydrofolate reductase (DHFR) from Escherichia
coli (EcDHFR) adopts two major conformations, closed
and occluded, and movement between these two conformations
is important for progression through the catalytic cycle.
DHFR from the cold-adapted organism Moritella profunda
(MpDHFR) on the other hand is unable to form the two
hydrogen bonds that stabilize the occluded conformation in
EcDHFR and so remains in a closed conformation during
catalysis. EcDHFR-S148P and MpDHFR-P150S were examined
to explore the influence of the occluded conformation on
catalysis by DHFR. Destabilization of the occluded conformation did not affect hydride transfer but altered the affinity for the
oxidized form of nicotinamide adenine dinucleotide phosphate (NADP+) and changed the rate-determining step of the catalytic
cycle for EcDHFR-S148P. Even in the absence of an occluded conformation, MpDHFR follows a kinetic pathway similar to that
of EcDHFR with product release being the rate-limiting step in the steady state at pH 7, suggesting that MpDHFR uses a
different strategy to modify its affinity for NADP+. DHFRs from many organisms lack a hydrogen bond donor in the appropriate
position and hence most likely do not form an occluded conformation. The link between conformational cycling between closed
and occluded forms and progression through the catalytic cycle is specific to EcDHFR and not a general characteristic of
prokaryotic DHFR catalysis
Loss of Hyperconjugative Effects Drives Hydride Transfer during Dihydrofolate Reductase Catalysis
Hydride transfer is widespread in nature and has an essential role in applied research. However, the mechanisms of how this transformation occurs in living organisms remain a matter of vigorous debate. Here, we examined dihydrofolate reductase (DHFR), an enzyme that catalyzes hydride from C4âČ of NADPH to C6 of 7,8-dihydrofolate (H2F). Despite many investigations of the mechanism of this reaction, the contribution of polarization of the Ï-bond of H2F in driving hydride transfer remains unclear. H2F was stereospecifically labeled with deuterium ÎČ to the reacting center, and ÎČ-deuterium kinetic isotope effects were measured. Our experimental results combined with analysis derived from QM/MM simulations reveal that hydride transfer is triggered by polarization at the C6 of H2F. The Ï CÎČâH bonds contribute to the buildup of the cationic character during the chemical transformation, and hyperconjugation influences the formation of the transition state. Our findings provide key insights into the hydride transfer mechanism of the DHFR-catalyzed reaction, which is a target for antiproliferative drugs and a paradigmatic model in mechanistic enzymology
Isotope Substitution of Promiscuous Alcohol Dehydrogenase Reveals the Origin of Substrate Preference in the Transition State
The origin of substrate preference in promiscuous enzymes was investigated by enzyme isotope labelling of the alcohol dehydrogenase from Geobacillus stearothermophilus (BsADH). At physiological temperature, protein dynamic coupling to the reaction coordinate was insignificant. However, the extent of dynamic coupling was highly substrate-dependent at lower temperatures. For benzyl alcohol, an enzyme isotope effect larger than unity was observed, whereas the enzyme isotope effect was close to unity for isopropanol. Frequency motion analysis on the transition states revealed that residues surrounding the active site undergo substantial displacement during catalysis for sterically bulky alcohols. BsADH prefers smaller substrates, which cause less protein friction along the reaction coordinate and reduced frequencies of dynamic recrossing. This hypothesis allows a prediction of the trend of enzyme isotope effects for a wide variety of substrates
Including community composition in biodiversityâproductivity models
Studies on biodiversity and ecosystem functioning (BEF) have elicited debate over the interpretation of the positive relationship between species richness and plant productivity. Manipulating richness cannot be achieved without affecting composition; it is thus essential to consider the latter in statistical models.We firstly review existing approaches that use species richness as an explanatory variable and propose modifications to improve their performance. We use an original data set to illustrate the analyses. The classical method where composition is coded as a factor with a level for each different species mixture can be improved by defining the levels using clustering. Methods based on ordinations reduce the dimensionality of plant composition and use the new coordinates as fixed effects; they provide a much better fit to our observations.Secondly, we develop a new method where composition is included as a similarity matrix affecting the residual varianceâcovariance. Similarity in composition between plots is treated in the same way as shared evolutionary history between species in phylogenetic regression. We find that it outperforms the other models.We discuss the different approaches and suggest that our method is particularly suited for observational studies or for manipulative studies where plant diversity is not kept constant by weeding. By treating species composition in an intuitive and sensible way, it offers a valuable and powerful complement to existing models
The relative contributions of species richness and species composition to ecosystem functioning
How species diversity influences ecosystem functioning has been the subject of many experiments and remains a key question for ecology and conservation biology. However, the fact that diversity cannot be manipulated without affecting species composition makes this quest methodologically challenging. Here, we evaluate the relative importance of diversity and of composition on biomass production, by using partial Mantel tests for one variable while controlling for the other. We analyse two datasets, from the Jena (2002â2008) and the Grandcour (2008â2009) Experiments. In both experiments, plots were sown with different numbers of species to unravel mechanisms underlying the relationship between biodiversity and ecosystem functioning (BEF). Contrary to Jena, plots were neither mowed nor weeded in Grandcour, allowing external species to establish. Based on the diversityâecosystem functioning and competition theories, we tested two predictions: 1) the contribution of composition should increase with time; 2) the contribution of composition should be more important in non-weeded than in controlled systems. We found support for the second hypothesis, but not for the first. On the contrary, the contribution of species richness became markedly more important few years after the start of the Jena Experiment. This result can be interpreted as suggesting that species complementarity, rather than intraspecific competition, is the driving force in this system. Finally, we explored to what extent the estimated relative importance of both factors varied when measured on different spatial scales of the experiment (in this case, increasing the number of plots included in the analyses). We found a strong effect of scale, suggesting that comparisons between studies, and more generally the extrapolation of results from experiments to natural situations, should be made with caution
Cryo-kinetics reveal dynamic effects on the chemistry of human dihydrofolate reductase
Effects of isotopic substitution on the rate constants of human dihydrofolate reductase (HsDHFR), an important target for anti-cancer drugs, have not previously been characterized due to its complex fast kinetics. Here, we report the results of cryo-measurements of the kinetics of the HsDHFR catalyzed reaction and the effects of protein motion on catalysis. Isotopic enzyme labeling revealed an enzyme KIE (kHLE /kHHE ) close to unity above 0â°C; however, the enzyme KIE was increased to 1.72±0.15 at -20â°C, indicating that the coupling of protein motions to the chemical step is minimized under optimal conditions but enhanced at non-physiological temperatures. The presented cryogenic approach provides an opportunity to probe the kinetics of mammalian DHFRs, thereby laying the foundation for characterizing their transition state structure
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