Structure-Guided Recombination Creates an Artificial Family of Cytochromes P450

Creating artificial protein families affords new opportunities to explore the determinants of structure and biological function free from many of the constraints of natural selection. We have created an artificial family comprising ~3,000 P450 heme proteins that correctly fold and incorporate a heme cofactor by recombining three cytochromes P450 at seven crossover locations chosen to minimize structural disruption. Members of this protein family differ from any known sequence at an average of 72 and by as many as 109 amino acids. Most (>73%) of the properly folded chimeric P450 heme proteins are catalytically active peroxygenases; some are more thermostable than the parent proteins. A multiple sequence alignment of 955 chimeras, including both folded and not, is a valuable resource for sequence-structure-function studies. Logistic regression analysis of the multiple sequence alignment identifies key structural contributions to cytochrome P450 heme incorporation and peroxygenase activity and suggests possible structural differences between parents CYP102A1 and CYP102A2

COMPUTER-GENERATED CARS YOU HAVE TO LOVE: HOW IMAGE MORPHING AND WARPING HELP DESIGNERS TO OPTIMIZE THEIR DESIGN SKETCHES

Although product design is considered as a core determinant of a product\u27s market success, systematic approaches that allow managers to increase a product\u27s visual attractiveness are not available. The present research addresses this gap by adapting an approach that was originally developed in research on human facial attractiveness to a product design context. In particular, we propose that image morphing and warping techniques can be used to identify and manipulate those design features that drive a product\u27s perceived attractiveness. Moreover, we also develop a computer-assisted interface that allows consumers to individually determine their optimal car design. Three studies with real consumers focusing on the automotive market confirm the viability and the usefulness of our approach. From a managerial perspective, the approach may increase the effectiveness of design efforts and may help in integrating consumers\u27 preferences in an early stage of the product design process

Auf den Rangplatz kommt es an - Wirkung der Rangfolge von Produkten auf das Entscheidungsverhalten

Zusammenfassung: Häufig präsentieren Anbieter ihren Nachfragern die zur Auswahl stehenden Produkte in Listen. Beispiele hierfür bilden Online-Shops (z.B. für Nahrungsmittel, Elektroartikel oder Kleider), die ihre Erzeugnisse zumeist unter Berücksichtigung der vom Kunden gewünschten Auswahlkriterien in einer Rangfolge darbieten. Auch Auktionsportale, Suchmaschinen sowie Wohnungs-, Partner- oder Pkw-Börsen zeigen die für den Kunden als relevant erachteten Erzeugnisse bzw. Treffer in einer Liste. Aus theoretischen Ansätzen, die vor allem aus der deskriptiven Entscheidungstheorie stammen, lässt sich die Vermutung ableiten, dass der Rangplatz eines Produkts in einer Liste einen Effekt auf die Präferenz des Kunden für dieses Gut ausübt. Im Rahmen einer empirischen Studie im Markt für gebrauchte Fahrzeuge kann dieser Zusammenhang bestätigt werden. Bestimmte Rangplätze sind unabhängig von der Beschaffenheit der an diesen Stellen präsentierten Erzeugnisse bei den Individuen beliebter als andere. Für Hersteller und Händler (etwa Online-Shops) liefert die Studie Hinweise über den Zusammenhang zwischen der Art und Weise der Gestaltung von Listen (z.B. geordnet nach einem Kriterium oder randomisiert) und der Neigung von Individuen, sich für das erste, das mittlere etc. Produkt zu entscheiden. Wissenschaftler erlangen ein tieferes Verständnis über individuelles Verhalten bei der Wahl eines Produkts aus einer Liste und der dieses Verhalten determinierenden Faktore

Selfish Network Creation with Non-Uniform Edge Cost

Network creation games investigate complex networks from a game-theoretic point of view. Based on the original model by Fabrikant et al. [PODC'03] many variants have been introduced. However, almost all versions have the drawback that edges are treated uniformly, i.e. every edge has the same cost and that this common parameter heavily influences the outcomes and the analysis of these games. We propose and analyze simple and natural parameter-free network creation games with non-uniform edge cost. Our models are inspired by social networks where the cost of forming a link is proportional to the popularity of the targeted node. Besides results on the complexity of computing a best response and on various properties of the sequential versions, we show that the most general version of our model has constant Price of Anarchy. To the best of our knowledge, this is the first proof of a constant Price of Anarchy for any network creation game.Comment: To appear at SAGT'1

Diversification of Catalytic Function in a Synthetic Family of Chimeric Cytochrome P450s

We report initial characterization of a synthetic family of more than 3000 cytochrome P450s made by SCHEMA recombination of 3 bacterial CYP102s. A total of 16 heme domains and their holoenzyme fusions with each of the 3 parental reductase domains were tested for activity on 11 different substrates. The results show that the chimeric enzymes have acquired significant functional diversity, including the ability to accept substrates not accepted by the parent enzymes. K-means clustering analysis of the activity data allowed the enzymes to be classified into five distinct groups based on substrate specificity. The substrates can also be grouped such that one can be a “surrogate” for others in the group. Fusion of a functional chimeric heme domain with a parental reductase domain always reconstituted a functional holoenzyme, indicating that key interdomain interactions are conserved upon reductase swapping

Cross-sectional survey of off-label and unlicensed prescribing for inpatients at a paediatric teaching hospital in Western Australia

Objectives: To evaluate the prevalence of off-label and unlicensed prescribing in inpatients at a major paediatric teaching hospital in Western Australia and to identify which drugs are commonly prescribed off-label or unlicensed, including factors influencing such prescribing. Methods: A retrospective cross-sectional study was conducted in June, 2013. Patient and prescribing data were collected from 190 inpatient medication chart records which had been randomly selected from all admissions during the second week of February 2013. Drugs were catego-rised as licensed, off-label or unlicensed, according to their approved Australian registration product information (PI). All drugs were classified according to the Anatomical Therapeutic Chemical (ATC) code. Results There were 120 male and 70 female inpatients. The average age was 6.0 years (± 4.7). The study included 1160 prescribed drugs suitable for analysis. The number of drugs prescribed per patient ranged from 1 to 25 with an average of 6.1 (± 4.3). More than half (54%) were prescribed off-label. Oxycodone, clonidine, parecoxib and midazolam were always prescribed off-label. The most common off-label drugs were ondansetron (18.5%), fentanyl (12.9%), oxycodone (8.8%) and paracetamol (6.1%). Many ATC classifications included high off-label proportions especially the genitourinary system and sex hormones, respiratory system drugs, systemic hormonal preparations and alimentary tract and metabolism drugs. Conclusions: This study highlights that prescribing of paediatric drugs needs to be better supported by existing and new evidence. Incentives should be established to foster the conduct of evidence-based studies in the paediatric population. The current level of off-label prescribing raises issues of unexpected toxicity and adverse drug effects in children that are in some cases severely ill

Correlation of the Cd-to-Te ratio on CdTe surfaces with the surface structure

We report here that reconstruction on (100), (1lIlA, and (1l1lB CdTe surfaces is either C(2X2), (2X2), and (l X I) or (2X I), (l X I), and (l X I) when they are Cd or Te stabilized, respectively. There is a mixed region between Cd and Te stabilization in which the reflected high-energy electron-diffraction (RHEED) patterns contain characteristics of both Cd- and Te-stabilized surfaces. We have also found that the Cd-to-Te ratio of the x-ray photoelectron intensities of their 3d$_{3/ 2}$ core levels is about 20% larger for a Cd-stabilized (1lIlA, (1lIlB, or (100) CdTe surface than for a Te-stabilized one. According to a simple model calculation, which was normalized by means of the photoelectron intensity ratio of a Cd-stabilized (lll)A and aTe-stabilized (1l1lB CdTe surface, the experimental data for CdTe surfaces can be explained by a linear dependence of the photoelectron-intensity ratio on the fraction of Cd in the uppermost monatomic layer. This surface composition can be correlated with the surface structure, i.e., the corresponding RHEED patterns. This correlation can in turn be employed to determine Te and Cd evaporation rates. The Te reevaporation rate is increasingly slower for the Te-stabilized (Ill) A, (l1l)B, and (100) surfaces, while the opposite is true for Cd from Cd-stabilized (Ill) A and (Ill)B surfaces. In addition, Te is much more easily evaporated from all the investigated surfaces than is Cd, if the substrate is kept at normal molecular-beam-epitaxy growth temperatures ranging from 2oo·C to 300 ·C

The Pervasive Effect of Aesthetics on Choice: Evidence From a Field Study

Do people think logically and carefully before buying an expensive item, or are more superficial forces such as product appearance at work? To investigate this question, six months of car sales were predicted using objective measures of a design's typicality and complexity. The data revealed that cars conforming closely to a morph of designs of all cars outsell cars conforming less closely to the morph, but only when the design is visually complex. These design factors explain 42% of the sales variance and are independent of retail price, brand associations, technological specifications, and advertising. Subjective measures controlling for brand recognition further confirm the considerable impact of design factors on real purchases involving large financial commitments

Enantioselective α-Hydroxylation of 2-Arylacetic Acid Derivatives and Buspirone Catalyzed by Engineered Cytochrome P450 BM-3

Here we report that an engineered microbial cytochrome P450 BM-3 (CYP102A subfamily) efficiently catalyzes the α-hydroxylation of phenylacetic acid esters. This P450 BM-3 variant also produces the authentic human metabolite of buspirone, R-6-hydroxybuspirone, with 99.5% ee