From principal component to direct coupling analysis of coevolution in proteins: Low-eigenvalue modes are needed for structure prediction

Various approaches have explored the covariation of residues in multiple-sequence alignments of homologous proteins to extract functional and structural information. Among those are principal component analysis (PCA), which identifies the most correlated groups of residues, and direct coupling analysis (DCA), a global inference method based on the maximum entropy principle, which aims at predicting residue-residue contacts. In this paper, inspired by the statistical physics of disordered systems, we introduce the Hopfield-Potts model to naturally interpolate between these two approaches. The Hopfield-Potts model allows us to identify relevant 'patterns' of residues from the knowledge of the eigenmodes and eigenvalues of the residue-residue correlation matrix. We show how the computation of such statistical patterns makes it possible to accurately predict residue-residue contacts with a much smaller number of parameters than DCA. This dimensional reduction allows us to avoid overfitting and to extract contact information from multiple-sequence alignments of reduced size. In addition, we show that low-eigenvalue correlation modes, discarded by PCA, are important to recover structural information: the corresponding patterns are highly localized, that is, they are concentrated in few sites, which we find to be in close contact in the three-dimensional protein fold.Comment: Supporting information can be downloaded from: http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.100317

Photoswitchable catalysis by a nanozyme mediated by a lightsensitive cofactor

The activity of a gold nanoparticle-based catalyst can be reversibly up- and down-regulated by light. Light is used to switch a small molecule between cis- and trans-isomers, which inhibits the catalytic activity of the nanoparticles to different extent. The system is functional in aqueous buffer, which paves the way for integrating the system in biological networks

Inverse Statistical Physics of Protein Sequences: A Key Issues Review

In the course of evolution, proteins undergo important changes in their amino acid sequences, while their three-dimensional folded structure and their biological function remain remarkably conserved. Thanks to modern sequencing techniques, sequence data accumulate at unprecedented pace. This provides large sets of so-called homologous, i.e.~evolutionarily related protein sequences, to which methods of inverse statistical physics can be applied. Using sequence data as the basis for the inference of Boltzmann distributions from samples of microscopic configurations or observables, it is possible to extract information about evolutionary constraints and thus protein function and structure. Here we give an overview over some biologically important questions, and how statistical-mechanics inspired modeling approaches can help to answer them. Finally, we discuss some open questions, which we expect to be addressed over the next years.Comment: 18 pages, 7 figure

Beltanelliformis brunsae Menner in Keller et al., 1974: an undoubted Ediacaran fossil from Neoproterozoic of Dobrogea (Romania)

International audienceEdiacaran fossils are now largely known in different parts of the world. However, some countries are poorly documented on these remains of a still enigmatic life. Thus, rare fossils from the Neoproterozoic Histria Formation of central Dobrogea (Romania) have been reported. Two specimens with discoid imprints are described here in detail and assigned to the typical Ediacaran species Beltanelliformis brunsae Menner in Keller et al., 1974. This paleontological development confirms both the large geographical distribution of this species and the Ediacaran age of the Histria Formation. KEY WORDS Flat discoid imprints, Ediacaran biota, Precambrian, Dobrogea, Romania. RÉSUMÉLes fossiles édiacariens sont maintenant largement connus à travers le monde. Cepednant, certaines régions restent peu documentées sur ces restes, témoignages d’une vie qui apparaît encore aujourd’hui assez énigmatique. Ainsi, seuls de rares fossiles provenant de la Formation Histria du Néoprotérozoïque de Dobrogea centrale (Roumanie) avaient été signalés. Deux échantillons portant des impressions discoïdes sont ici décrits en détail et attribués à l’espèce typiquement édiacarienne Beltanelliformis brunsae Menner in Keller et al., 1974. Cette identification permet de confirmer la large répartition de cette espèce et l’âge édiacarien de la Formation Histria

Free-Riding in Pharmaceutical Price Regulation: Theory and Evidence

We present a model of the strategic interaction among authorities regulating pharmaceutical prices in different countries and the R&D investment decisions of pharmaceutical firms. Regulators’ decisions affect consumer surplus directly, via prices, and indirectly via firms’ profits and R&D investment policies, which in turn affect patient health. The positive externality of a price increase in one country provides an incentive for other countries to free-ride, and we show how country-level characteristics affect optimal pricing decisions and equilibria. Our theoretical predictions are tested using price data for a set of 70 cancer drugs in 25 OECD countries. We find evidence of behaviour that is consistent with the free-riding hypothesis and which, in line with the theoretical predictions, differs according to country-level characteristics. Countries with comparatively large market shares tend to react to increases in other countries’ prices by lowering their own prices; in countries with comparatively small market shares, regulators’ decisions are consistent with the objective of introducing the product at as low a price as possible. We discuss the policy implications of our results for incentivising global pharmaceutical R&D and the recent proposal to move towards a joint pharmaceutical procurement process at the European level

On the Structure of the Lower Troposphere in the Summertime Stratocumulus Regime of the Northeast Pacific

Data collected in situ as part of the second field study of the Dynamics and Chemistry of Marine Stratocumulus field program are used to evaluate the state of the atmosphere in the region of field operations near 30°N, 120°W during July 2001, as well as its representation by a variety of routinely available data. The routine data include both the 40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40) and NCEP–NCAR reanalyses, forecasts from their respective forecast systems (the Integrated and Global Forecast Systems), the 30-km archive from the International Satellite Cloud Climatology Project (ISCCP), the Quick Scatterometer surface winds, and remotely sensed fields derived from radiances measured by the Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI), the Advanced Microwave Sounding Unit, and the Advanced Very High Resolution Radiometer. The analysis shows that outside of the boundary layer the state of the lower troposphere is reasonably represented by the reanalysis and forecast products, with the caveat of a slight warm bias at 850 hPa in the NCEP–NCAR products. Within the planetary boundary layer (PBL) the agreement is not as good: both the boundary layer depth and cloud amount are underpredicted, and the boundary layer temperature correlates poorly with the available data, which may be related to a poor representation of SSTs in this region of persistent cloud cover. ERA-40 also suffers from persistently weak zonal winds within the PBL. Among the satellite records the ISCCP data are found to be especially valuable, evincing skill in both predicting boundary layer depth (from cloud-top temperatures and TMI surface temperatures) and cloud liquid water paths (from cloud optical depths). An analysis of interannual variability (among Julys) based on ERA-40 and the 1983–2001 ISCCP record suggests that thermodynamic quantities show similar interannual and synoptic variability, principally concentrated just above the PBL, while dynamic quantities vary much more on synoptic time scales. Furthermore, the analysis suggests that the correlation between stratocumulus cloud amount and lower-tropospheric stability exhibits considerable spatial structure and is less pronounced than previously thought

Nine-amino-acid transactivation domain: Establishment and prediction utilities

AbstractHere we describe the establishment and prediction utilities for a novel nine-amino-acid transactivation domain, 9aa TAD, that is common to the transactivation domains of a large number of yeast and animal transcription factors. We show that the 9aa TAD motif is required for the function of the transactivation domain of Gal4 and the related transcription factors Oaf1 and Pip2. The 9aa TAD possesses an autonomous transactivation activity in yeast and mammalian cells. Using sequence alignment and experimental data we derived a pattern that can be used for 9aa TAD prediction. The pattern allows the identification of 9aa TAD in other Gal4 family members or unrelated yeast, animal, and viral transcription factors. Thus, the 9aa TAD represents the smallest known denominator for a broad range of transcription factors. The wide occurrence of the 9aa TAD suggests that this domain mediates conserved interactions with general transcriptional cofactors. A computational search for the 9aa TAD is available online from National EMBnet-Node Austria at http://www.at.embnet.org/toolbox/9aatad/